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tomekkorbak

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[ "Anxiety and confidence in using a library by college freshmen and seniors.", "\nThe first study using a measure of library anxiety showed that 180 college freshmen have significantly higher scores than college seniors. ", "A second study found that among freshmen students, those with high scores on Library Anxiety reported less confidence in using the library than those with low scores, even though the students were equal on several indices of academic ability and performance." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Porous, cellular material can be generally described as having either closed cells, in which the cells or pores are not interconnected, or open cells, in which the cells or pores are interconnected and may extend to the surface of the material in which they are formed and display the structure and appearance of open pits. ", "The cellular fibers of the present invention predominantly contain the closed type of cells.", "\nIn the past, cell formation has been used in thermoplastic sheet materials using practices as described in U.S. Pat. ", "Nos. ", "2,531,665; 2,751,627; 4,473,665; and 5,158,986 the teachings of which are all incorporated by reference as if fully set forth herein. ", "However, the technology embodied in these patents which addresses cell formation in thermoplastic sheet materials and methods to reduce out-diffusion of an impregnating gas to increase nucleation is not believed to be adaptable to forming fibers.", "\nIn the past, cell formation has been achieved in fibers by dispersing blowing agents into the molten polymer prior to extrusion. ", "A wide variety of agents has been used including air, nitrogen, chlorinated fluorocarbons, and other gases, as well as volatile materials that are gaseous at molten polymer temperatures, such as methylene chloride and other halogenated hydrocarbons, materials that decompose to form gas products (such as azides), and materials that react to form gaseous products, such as acids and carbonates. ", "The blowing agent may be added to the precursor resin or dispersed into the molten polymer. ", "For example, U.S. Pat. ", "No. ", "4,164,603 and divisionally related U.S. Pat. ", "No.4,380,594 (both incorporated by reference herein) are directed to processes and fibers with variable cells formed using a silicon blowing agent. ", "U.S. Pat. ", "No. ", "4,728,472 (incorporated by reference) describes a process to produce fibers with closed cells that requires the introduction of a fluorocarbon blowing agent into a molten polymer. ", "While it is possible to achieve a percentage of closed cells using a blowing agent in a fiber extrusion process, experience indicates that the process yields a material with an undesirably high closed cell length to diameter ratio (greater than 500 and up to 2,000). ", "Moreover, such processes may produce undesired levels of open cells.", "\nIn actual practice there are two primary drawbacks to the process of simultaneously extruding and foaming fibers to generate a cellular structure. ", "First, such practices give rise to enhanced manufacturing difficulty due to the complexity of the process. ", "Second, such practices generally provide poor uniformity. ", "In particular, when extruding foamed fibers it is extremely difficult to extrude small uniform fibers without breaking the filaments. ", "The polymer filaments have lower tenacity making it difficult to draw them properly. ", "The lower tenacity also makes it more difficult to properly texture the yarn, so it loses body and texture that is needed in the final fabric. ", "Further, during yarn formation it is difficult to spin foamed fiber at the same rate and quality as non-foamed fiber. ", "In addition, many of the additives used to improve production rate, such as silicon oil or polydimethylsiloxane are undesirable in the final fabric. ", "Such additives can have such adverse effects as creating uneven dyeings, leaving deposits on the processing machinery, and increasing the flammability of the fabric. ", "It is also believed to be difficult to controllably vary the level of opacity at different zones along the length of the fiber when foaming and extrusion are carried out simultaneously. ", "The ability to provide such controlled variation may be desirable for some applications.", "\nAs regards the above-referenced problem of poor uniformity, it is not possible to control the shape, size and distribution of the cells during simultaneous foaming and extrusion. ", "In particular, the closed cells of fibers formed from simultaneous extrusion and foaming have undesirably high length to diameter (L/D) ratios. ", "More specifically, in such prior art fibers the cells nucleate coming out of the extrusion head and the L/D (length to diameter ratio) increases as the fiber is drawn down to the desired denier. ", "Although the cells have a large volume, the number of cells per unit length is consequently small. ", "Conversely, greater light scattering corresponding to enhanced opacity (which is desirable to enhance whiteness) is achieved by a larger number of cells per unit length and, therefore, a larger surface area." ]

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[ "Crowning glory: The art of Kentucky Derby hats\n\nBy Ashley Strickland, Special to CNN\n\nUpdated 1443 GMT (2143 HKT) May 4, 2012\n\nHats off to the races20 photos\n\nHats off to the races – You may not be able to spot every single hat at the Derby, but four milliners shared their custom designs with us. ", "Sally Faith Steinmann of Maggie Mae Designs created this hat in honor of Arson Squad, a retired race horse, who belongs to the Old Friends of Kentucky, a facility for retired thoroughbreds. ", "The hat was auctioned to raise money and awareness for the foundation. ", "Steinmann's love of horses inspires her designs.", "\n\nHide Caption\n\n1 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Steinmann's \"Michaela\" hat uses dupioni silk to create a wide brim hat, as well as a large rose curl, and one of her trademarks, several silk organza \"feathers.\" ", "She doesn't like to use real feathers.", "\n\nHide Caption\n\n2 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Vintage netting, featured on designs like Steinmann's \"Marguerite\" hat, is still a favorite among the Derby crowd, as is her use of pleated satin.", "\n\nHide Caption\n\n3 of 20\n\nHats off to the races20 photos\n\nHats off to the races – This \"Candy\" creation by Steinmann showcases the bright pinks and flowers that Derby-goers love, like the fabric peony that dominates this wide brim design.", "\n\nHide Caption\n\n4 of 20\n\nHats off to the races20 photos\n\nHats off to the races – The ruffled edges of Steinmann's \"Jamie\" hat have long been a tradition at the Derby, as well as the braiding and bows that adorn the top.", "\n\nHide Caption\n\n5 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Diane Siverson, of Lady Diane Hats, is proud of her \"Morning Star\" hat. ", "The design inspires her customers to order similar customized hats.", "\n\nHide Caption\n\n6 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Siverson's \"At the Races\" fascinator is one example of how milliners took the trend, popularized and worn largely at the 2011 Derby, and gave it new life.", "\n\nHide Caption\n\n7 of 20\n\nHats off to the races20 photos\n\nHats off to the races – A classic Derby design, Siverson's \"Triple Crown\" hat, is piled high with feathers and floral motifs. ", "Large hats full of feathers are a nostalgic reminder of past years.", "\n\nHide Caption\n\n8 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Siverson's special wire design within the brim of each of her hats allows for them to be easily reshaped once customers receive them. ", "This \"Gentle Breeze\" hat showcases her characteristic \"sexy swoop.\"", "\n\nHide Caption\n\n9 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Siverson's customers call her hats, like this \"Ocean Mist\" design, a \"party in a box\" because she uses balloons to stabilize the hats within their boxes when she ships them.", "\n\nHide Caption\n\n10 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Gena Conti, of Gena Conti Millinery, is proud that her \"Spectator Roses\" hat is housed in the Kentucky Derby Museum at Churchill Downs. ", "It won the museum award for \"Most Representative of the Kentucky Derby.\"", "\n\nHide Caption\n\n11 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Conti's \"Bed of Roses\" hat is made from sinamay, a plant-derived straw-like fabric that involves shaping and stabilizing over wooden blocks.", "\n\nHide Caption\n\n12 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Conti says she is a \"frustrated sculptor,\" so she likes to create angles and volume in her designs, like this \"Tracey Luinda\" hat.", "\n\nHide Caption\n\n13 of 20\n\nHats off to the races20 photos\n\nHats off to the races – One of Conti's best-selling designs is the \"Where's Robin?\" ", "fascinator. ", "She has styled it in different colors to match her varied clients.", "\n\nHide Caption\n\n14 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Animal prints are often a trend spotted at the Derby, where they are usually adorned with similar accents like these zebra stripe dyed feathers on Conti's \"Where the Wild Things Are\" hat.", "\n\nHide Caption\n\n15 of 20\n\nHats off to the races20 photos\n\nHats off to the races – The bigger, the better! ", "Jill Henning's wide brims are easy to spot, and she watches for them on Derby day.", "\n\nHide Caption\n\n16 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Accent feathers make a statement all their own, and they can be used to decorate fascinators or Henning's angled wide brims.", "\n\nHide Caption\n\n17 of 20\n\nHats off to the races20 photos\n\nHats off to the races – Every milliner is inspired by something else in their life, and for Henning, it's roses. ", "She grows more than 100 rose bushes in her backyard and garden.", "\n\nHide Caption\n\n18 of 20\n\nHats off to the races20 photos\n\nHats off to the races – The great thing about a wide brim? ", "No matter the weather at the Derby, if the sun is out, you're completely shaded by your own hat, like this bright wide brim from Henning.", "\n\nHide Caption\n\n19 of 20\n\nHats off to the races20 photos\n\nHats off to the races – The big, floppy Southern-style hat, with a round crown, is a perennial favorite for Derby-goers young and old.", "\n\nHide Caption\n\n20 of 20\n\nStory highlights\n\nOther attractions may draw spectators to the Kentucky Derby, but the hats reign supreme\n\nMilliners make custom bespoke hats, from fascinators to wide brims, for each customer\n\nThis business has become a passionate second career for each of them\n\nDuring the 138th annual \"Greatest Two Minutes in Sports,\" bets will be lost, hearts will break and mint juleps will be sipped, but for many spectators at the Kentucky Derby and elsewhere, \"It's all about the hats.\" ", "And it's a time for the artists who craft these hats to sit back, rest their exhausted hands and look for their creations among the crowds on TV.", "\n\nBut it's the moment when a woman carefully removes her crown from the clouds of hatbox tissue and places it at just the right angle, the brim dipping down alluringly over one eye and reaching up to the heavens at the other end, that she and her hat embody the same intriguing personality.", "\n\n\"My husband's mother went to the Derby when she was a teenager -- she's 98 years old -- and she remembers the sea of hats. ", "In our culture, we don't have all that many occasions like this. ", "There is nothing like it, from the infield to Millionaire's Row.\"", "\n\nBreeding Kentucky Derby studs\n\nJust Watched\n\nFemale jockey aims to win Derby\n\nAny woman wearing the right hat can feel like queen for a day at the Derby event of her choice. ", "Perhaps it is an escape from her daily life, or even daily persona, that lies behind the feminine mystery of Derby millinery.", "\n\nFrom towering fascinators to 25-inch-wide Southern sloping brim hats, all adorned with an array of feathers, bows or giant flowers, each topper has a story to tell about the classically chic or flamboyantly bold woman wearing \"her.\" ", "The hat is too special to be an \"it,\" Steinmann said.", "\n\nWhile so many great traditions associated with the Derby, like the hats, largely stay the same, there is one constant unknown: the weather. ", "If it rains, don't be surprised to witness a sea of bobbing plastic bags shielding these prize hats from the elements. ", "After all, the custom creations will become heirlooms, passed down for generations.", "\n\nIt is why these hats, and their wearers, cause spectators at the Derby to take pause, snap photos and vote for them in contests. ", "Some hats even wind up in the Kentucky Derby Museum at Churchill Downs. ", "The colorful headpieces are also on display at the Kentucky Oaks, the \"little sister of the Derby\" race on Friday, as well as races like the Belmont Stakes and Preakness, or parties, high teas, luncheons and charity events planned around race season.", "\n\nFor the women who craft and sell these soft sculptures, hat-making is an intimate art form relying on the intricately plaited bond of creativity and tradition. ", "For a true milliner, none of the hats is bought and spruced up -- these women are starting from scratch.", "\n\n\"I love making the bodies of the hat out of the silk dupioni, but then when it gets to trimming the hat, and I can actually take a strip of fabric and weave it, wind it and swirl it up with silk organza into a rose curl or a Marguerite, and I feel like a sculptor,\" Steinmann said.", "\n\nIn the same way a painter communicates with a custom palette, Steinmann and other designers speak fabric. ", "They work with ruffles, layers, buttons, swirls, crinkles, rosettes and \"feathers that dance in the sunlight\" to create dazzling combinations of texture and hue that define the singular woman who requests one.", "\n\n\"It's the one time you can feel that you are in the lap of luxury,\" Detroit milliner Gena Conti explained. \"", "It is an excuse. ", "And sometimes we need an excuse to step outside ourselves and do something that we really want to do all along.\"", "\n\nOne of Conti's clients is celebrating her 30th birthday on Derby day. ", "The woman had a choice: She could spend her money on great box seats for the Derby or buy outrageous hats. ", "She bought mediocre seats and called Conti, asking for two hats.", "\n\nJust how extreme is \"outrageous\"? ", "Bespoke Derby hats and fascinators can cost anywhere from $135 to thousands, depending on the labor, materials and design.", "\n\nSome milliners believe the average range to be between $300 and $500. ", "But accents like ostrich feathers can be expensive on their own; not to mention Parisian silk hand-pleated ribbon, which can cost Conti $800 a spool.", "\n\nMilliners are generally happy to work within a budget, but why are women willing to pay thousands for a hat that they may wear only a few times, or just once? ", "Even if they can wear the hat to another race or luncheon, it won't be seen at another Kentucky Derby.", "\n\n\"People won't do it,\" said Diane Siverson, owner and milliner of Lady Diane Hats in Idaho. \"", "I have a customer that buys one every year. ", "They wouldn't dream of wearing it again -- it just isn't done.\"", "\n\nBut the hat is a memory, an heirloom and a work of art that is uniquely hers, Steinmann said. ", "The Derby is a once-in-a-lifetime experience for some, because the expenses can add up quickly.", "\n\n\"People tell me 'I'll never get to do this again,' and I hear this time and time again, 'This is on my bucket list, and if I'm going to do it, I'm going to do it right,'\" Siverson said.", "\n\nWhile women preparing for the Derby or other events can look within their city for a milliner, many customers turn to searching online, which is how they find designers like Conti, Siverson, Steinmann and Jill Henning of Jill Henning Fineries, based in Toledo, Ohio.", "\n\n\"I never started this for money. ", "I started because I love to create,\" Henning said. \"", "The inspiration comes from everywhere.\"", "\n\nFor these women, millinery has become a second career, born out of a shared epiphany: \"I want to make hats!\"", "\n\nThey each took classes, apprenticed under other hat makers or worked off of a basic sewing knowledge and taught themselves millinery.", "\n\nConti and Siverson's inspiration stemmed from things they loved, like showcasing the flowers from their well-tended gardens. ", "Henning was a fan of hats and used to buy them, but after finding only disappointment in department store selections, she began to make her own.", "\n\nSteinmann's spark grew from a simple pattern for a felted hat that her mother gave her. ", "As a child, she made clothes for her stuffed animals, and later in life, she sewed her own clothes. ", "After trying the pattern, she began to sell hats locally at a gallery shop on Cape Cod. ", "Now, her site delivers to people all over the world.", "\n\nFrom Michigan to Idaho and Ohio to Cape Cod, they craft custom hats for women they may never meet in person.", "\n\nIt means e-mailing photographs and mailing swatches of outfits to match the hats, hours of chatting on the phone and even using software to \"try on\" a hat (a feature Siverson's website offers) or a virtual \"sitting room\" with everything from a \"millinery mugshot\" to photos of the hat in progress on Conti's site.", "\n\nSiverson and Steinmann chat with their customers, listening for the nuances in their voices. ", "The conversations reveal the kind of hat they want, from reserved to loud and crazy. ", "Because a bespoke hat is such a personal thing, they want the finished product to project the customer's personality.", "\n\nAfter investing anywhere from three weeks to an entire year into the making of a hat, a connection forms between the milliner, eager to hear her customer's response, and the wearer, who usually picks up the phone as soon as the box arrives, squealing.", "\n\n\"It is so amazing to pop it into the box after that kind of involved process,\" Steinmann said. \"", "I not only have a relationship by then with the customer, but the hat as well.\"", "\n\nLike the other milliners, the hats featured on Henning's site aren't \"sitting on the shelf\" and ready to ship. ", "Rather, the photos are inspiration for what customers might want to build. ", "And just about every client asks, \"Have you already sold a hat like this for the Derby?\"", "\n\nInspirations for the hats come from their customers, but Conti is especially influenced by the glamour of 1930s and 1940s millinery. ", "Because she is \"creating all the time,\" Conti can even find inspiration by looking at a bowl or a lamp. ", "For 19 years, she has been creating almost all her hats by hand: \"It makes the stitches less easy to see.\"", "\n\nHelping a woman find her perfect hat can be inspiring, as veteran Derby hat seller Lucille Jackson, owner of Hunter's Hatters in Lexington, Kentucky, knows well. ", "The 80-year-old has been in business since 1984, but her shop could close after the Derby because her older, loyal customer base has shrunk due to illness and old age.", "\n\nAlthough she orders 95% of the hats in her store, she customizes most of them to suit the individual personality of her customers, from one-timers to regulars. \"", "I would rather see a lady happy in a hat that completes her wardrobe than to do a lot of things, honey,\" Jackson said\n\nBut she remains optimistic that she'll stay in business, because Jackson offers the kind of personal, by-appointment service that isn't available in department stores today. ", "She sits down with her \"ladies\" and helps them determine their color, style and \"hattitude,\" something the milliners are well-versed in spotting.", "\n\n\"You've got to know how to wear it,\" Jackson said. \"", "You have to have an attitude for a hat, and that creates a hattitude. ", "If you don't have an attitude about the hat, it doesn't mean anything, like a stick pin -- it's just there. ", "A hat is a true accessory and so important, because it makes a woman look so beautiful and feminine.\"", "\n\nHave you ever been to the Kentucky Derby? ", "Did you wear an incredible eye-catching hat? ", "Please share your experience in the comments below!", "\n\nMichael Matz was a member of the U.S. showjumping team that won the silver medal at the 1996 Atlanta Olympics, and more recently a trainer of racehorses. ", "But he will always be remembered for just one: Barbaro." ]

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[ "Memory devices are typically provided as internal storage areas in a computer. ", "One type of memory used to store data in a computer is random access memory (RAM). ", "RAM is typically used as main memory in a computer environment. ", "Most RAM is volatile. ", "That is, RAM generally requires a steady flow of electricity to maintain its contents. ", "As soon as the power is turned off, all data stored in the RAM is lost.", "\nAnother type of memory is a non-volatile memory. ", "A non-volatile memory is a type of memory that retains stored data when power is turned off. ", "A flash memory is a type of non-volatile memory. ", "An important feature of a flash memory is that it can be erased in blocks instead of one byte at a time. ", "Each block of memory in a memory array of the flash memory comprises rows and columns of memory cells. ", "Many modern computers have their basic I/O system (BIOS) stored on flash memory chips.", "\nAs with other memory devices, defects can occur during the manufacture of a flash memory array having rows and columns of memory cells. ", "Typical defects can include bad memory cells, open circuits, shorts between a pair of rows and shorts between a row and column. ", "Shorts typically occur because of the large number of rows and columns of memory cells that have to be placed in close proximity to each other on an integrated circuit. ", "Defects can reduce the yield of the flash memory device. ", "A way to resolve this problem, without discarding the memory device, is to incorporate redundant elements in the memory that selectively replace defective elements. ", "For example, redundant rows are a common form of redundant elements used in flash memory to replace a defective primary row. ", "Redundant columns are another common form of redundant elements used in flash memory to replace a defective primary column.", "\nAfter a memory die has been manufactured, it is tested for defects. ", "Generally with volatile memory, redundancy circuitry is used to selectively route access requests directed to the defected elements to the redundant elements. ", "Redundancy circuitry can comprise electrical fuses that are selectively “blown” (i.e. open circuited) to disconnect the shorted rows. ", "The redundant rows are then activated to replace the shorted rows. ", "The electrical fuses are generally blown by one of two methods. ", "The first is known as the Ohm heating method. ", "This method involves driving a substantial current through a fuse to melt the fuse's conductive material. ", "The other method is known as the laser method. ", "The laser method uses a laser to cut a fuse's conductive material. ", "Anti-fuse circuitry can also be used. ", "Anti-fuses are normally open and short-circuited (closed) when programmed.", "\nSome memory devices, including some flash memory devices, utilize non-volatile registers to store addresses of primary elements that are designated to be replaced. ", "The addresses of the primary elements are stored in the registers by the manufacturer. ", "The registers are generally coupled to a redundant circuit. ", "The redundant circuit compares address requests to addresses stored in the registers. ", "If an address request matches an address stored in a register, the redundant circuit directs or maps the access request to the redundant row instead of the shorted row.", "\nGenerally, the use of redundant elements work well, however, problems can occur if the defect involves shorts between two rows or shorts between a row and a column in the primary array. ", "This is because, even though a redundant row or column is read to or written to instead of the shorted row or column, the short is still embedded in the primary memory array and the defect can effect other elements in the primary memory array. ", "One problem generally arises during pre-program and soft program cycles of an erase operation. ", "An erase operation is an algorithm that typically comprises a pre-programmed cycle, an erase cycle and a soft program cycle. ", "The pre-programmed cycle of an erase operation puts each memory cell in a programmed state by applying a program pulse to each row of memory cells. ", "The soft program cycle or heal cycle corrects any over-erased memory cells after the erase cycle has been completed by applying a soft program pulse to the over-erased memory cells.", "\nDisabling the redundancy circuit during the pre-program and soft program cycle when a row or column is addressed that is shorted to another row is one method of dealing with this problem. ", "This allows the pre-program and soft program cycle to be applied to the shorted rows and columns in the primary memory array. ", "By doing this, the effect of the shorts on other elements in the primary memory array is eliminated or at least minimized.", "\nHowever, a problem arises when dealing with a row-to-row short. ", "When a first row is addressed that is shorted to a second row and a pre-program pulse of a pre-program cycle is applied or a soft program pulse of a soft program cycle is applied, the second row also receives the respective pre-program pulse or soft program pulse. ", "This creates a conflict between a driver of the first shorted row and the driver of the second shorted row that could lead to a collapse of the voltage supply that is driving the rows. ", "If this were to happen, the memory cells in the first and second rows may not get properly programmed. ", "A method of dealing with this problem is by activating the first row and the second row and simultaneously applying the respective pre-program cycle or soft program cycle to the rows. ", "This in turn, creates another problem when the address is incremented after the respective pre-program cycle or soft program cycle has been completed because the next address will be the second shorted row. ", "A way to skip over the second row is needed or another pre-program cycle or soft program cycle will be applied to the first and second shorted rows. ", "This could potentially place too much charge on the memory cells of the rows.", "\nFor the reasons stated above, and for other reasons stated below which will become apparent to those skilled in the art upon reading and understanding the present specification, there is a need in the art for a flash memory that has the ability to reduce exposure of programming voltages to rows shorted together." ]

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[ "Introduction {#Sec1}\n============\n\nThe main physiological function of osteoclasts in vivo is the resorption of bone matrix, which precedes the formation of new bone; this skeletal remodeling cycle allows adaptation to physical loading conditions, which in turn maintains the integrity of the skeleton \\[[@CR1]\\]. ", "This cycle also exhibits a key function in skeletal repair, which is a fundamental process ranging from the healing of traumatic fractures to the healing of osteotomies performed during reconstructive surgery \\[[@CR2]\\]. ", "An imbalance in osteoclastic activity can lead to implant loosening or bone diseases. ", "Increased resorption can lead to postmenopausal osteoporosis, whereas dysfunction of osteoclasts leads to osteopetrosis \\[[@CR3]\\].", "\n\nResorbing osteoclasts develop by the fusion of mononuclear precursor cells of the monocyte--macrophage lineage in the presence of the osteogenetic cytokines macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL) \\[[@CR4]\\]. ", "In order to resorb bone, osteoclasts become polarized, which involves the organization of the F-actin cytoskeleton into a typical densely packed ring-like structure, thus sealing the area beneath and forming a closed compartment in which the bone matrix and mineral can be resorbed, resulting in the formation of resorption pits \\[[@CR5], [@CR6]\\]. ", "The sealing zone is composed of an F-actin ring, consisting of podosomes that mediate the attachment of the cells to the extracellular matrix and encircling a highly ruffled secretory membrane \\[[@CR6], [@CR7]\\]. ", "Luxenburg et al. ", "\\[[@CR8]\\] demonstrated that during the polarization process new actin is recruited to fibers that directly interconnect the podosome actin cores and undergo dramatic reorganization during osteoclast maturation. ", "During the resorption process, bone mineral, mainly hydroxyapatite, is dissolved by the secretion of acid that is brought about by fusion of acidic vesicles to the plasma membrane and insertion of proton pumps into the ruffled border membrane. ", "The organic matrix is degraded by proteolytic enzymes, e.g., matrix metalloproteinases and cathepsin K, that are released into the resorption lacunae with further digestion/transport of internalized protein fragments. ", "Nevertheless, this general task can be regulated by a variety of factors including the chemical and physical nature of the mineralized resorption substrate. ", "The process of osteoclastic activity leaves behind resorption traces in the form of pits or trails, which are generally used to describe osteoclastic resorption behavior. ", "Formation of a single resorption pit occurs when an osteoclast resorbs a discrete cavity beneath the cell \\[[@CR9]\\], but the formation of resorption trails is less well understood.", "\n\nThe formation of pits and trails is a general hallmark of osteoclastic activity, observed in pure cultures or in coculture with other cell types from a variety of tissue sources (bone marrow, bone, blood, or cell lines) and species (human, mouse, rat, rabbit). ", "Additionally, the same pits or trails are generated regardless of the offered mineral substrate (dentin, bone, artificial ceramic, or hydroxyapatite substrates). ", "For in vitro investigations, dentin is often used as a mineralized substrate, and data obtained from such experiments are often extrapolated to osteoclastic behavior on bone \\[[@CR10]--[@CR13]\\]; but there is little information regarding direct comparison between these two materials, bone and dentin.", "\n\nFor this reason, we generated human osteoclasts from cultured precursor cells isolated from human peripheral blood and analyzed and compared the resorption behavior of these osteoclasts on these two materials histomorphometrically. ", "Beyond that, we studied trail-forming osteoclasts during the resorption process with confocal laser scanning microscopy and provide a model of how resorption trails occur.", "\n\nMaterials and Methods {#Sec2}\n=====================\n\nAntibodies and Chemicals {#Sec3}\n------------------------\n\nPrimary antibodies included monoclonal anti-vinculin (clone hVIN-1; Sigma, St. Louis, MO), used in dilution 1:250; monoclonal anti-vitronectin receptor (CD51/CD61; AbD Serotech, Düsseldorf, Germany), used in dilution 1:1,000; and monoclonal anti-paxillin (BD Transduction Laboratories, Lexington, KY), used in dilution 1:250. ", "Secondary antibodies included Alexa Fluor 488 goat anti-rabbit IgG (Invitrogen, Life Technologies, Carlsbad, CA), used in dilution 1:250; phalloidin-TRITC (Sigma), used at a concentration of 4 × 10^−8^ M; and Western blocking reagent (Roche, Indianapolis, IN). ", "Dentin of elephant tusk (ivory) was kindly provided by German Customs in accordance with international laws.", "\n\nMineralized Tissue Substrates {#Sec4}\n-----------------------------\n\nAs a model system, we chose two different mineralized substrates, bone (bovine cortical bone) and dentin (elephant ivory), which are widely described in the literature. ", "The bone was stored at −20 °C until use. ", "Pieces with a thickness of approximately 300 μm were cut with a diamond saw. ", "Slices directly obtained from sawing were used as rough substrates and slices that had been polished with tissue loaded with diamond grains were used as smooth substrates. ", "Slices were cleaned by ultrasonication in distilled water and placed in 70 % ethanol for 5 min for sterilization before use.", "\n\nProfilometry {#Sec5}\n------------\n\nThe surface roughness of the bone and dentin slices was determined by profilometry at the Materials Center Leoben (Leoben, Austria) using a Nanofocus μsurf Confocal Microscope (Nanofocus, Oberhausen, Germany). ", "Values were obtained over a scan length of approximately 600--1,300 μm to gain *R*~a~ and *R*~q~. *R*~a~ is the arithmetic average of the absolute values of all points of the profile, also called \"average roughness value\"; *R*~q~ is the root mean square of the values of all points of the profile.", "Bone roughBone smoothDentin roughDentin smooth*R* ~a~ (μm)6.271.0515.143.75*R* ~q~ (μm)7.712.2718.515.21\n\nOsteoclast Cultures {#Sec6}\n-------------------\n\nOsteoclasts were generated from human peripheral blood mononuclear cells obtained from 16 healthy donors (aged 19--55 years) as previously described \\[[@CR14]\\]. ", "Experiments were approved by the Austrian Ethics Committee, and informed consent was obtained from all volunteers. ", "Briefly, peripheral blood mononuclear cells were isolated by centrifugation over a Lymphoprep gradient and then seeded into a Petri dish containing αMEM (Sigma) supplemented with 10 % fetal calf serum (FCS; Thermo Fisher, Geel, Belgium), 2 mM [l]{.smallcaps}-glutamine, 20 ng/mL M-CSF (R&D Systems, Wiesbaden-Nordenstadt, Germany), and 30 μg/mL gentamycin. ", "This resulted in a pure preosteoclastic cell culture with no contamination by other cell populations. ", "After approximately 10 days in culture (preculture), adherent cells were removed using trypsin and experiments were seeded into 48-well plates containing bone or dentin slices at a density of 7.2 × 10^4^ cells/cm² in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 30 μg/mL gentamycin, 20 ng/mL M-CSF, and 2 ng/mL RANKL (R&D Systems, Wiesbaden-Nordenstadt, Germany). ", "Culture medium was changed twice per week.", "\n\n\"Resorbing\" and \"Nonresorbing\" Osteoclast Cultures {#Sec7}\n--------------------------------------------------\n\nTo generate the two populations (1) \"resorbing osteoclasts\" and (2) \"nonresorbing osteoclasts,\" we isolated osteoclasts from human peripheral blood mononuclear cells from two different donors as described in \"Osteoclast Cultures.\" ", "The resorption activity of the osteoclasts from these two donors was known from previous experiments as a resorbing or nonresorbing population. ", "These cells were also introduced into a 10-day preculture period in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 20 ng/mL M-CSF, and 30 μg/mL gentamycin. ", "Afterward, cells were seeded into 48-well plates containing bone or dentin slices at a density of 7.2 × 10^4^ cells/cm² in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 30 μg/mL gentamycin, 20 ng/mL M-CSF, and 2 ng/mL RANKL. ", "These cultures are referred to here as \"resorbing\" and \"nonresorbing\" osteoclasts. ", "No additional substances were added to influence resorption activity in those two populations. ", "Culture medium was changed twice per week.", "\n\nCell Adhesion on Mineralized Substrates {#Sec8}\n---------------------------------------\n\nFor cell adhesion studies, after 10 days of preculture, cells were seeded onto bone or dentin slices (as described above) in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 30 μg/mL gentamycin, 20 ng/mL M-CSF, and 2 ng/mL RANKL and fixed 6 h after seeding in a solution of 4 % paraformaldehyde in PBS for 20 min. ", "After staining with 1 % crystal violet for 20 min at room temperature, cells were washed extensively with PBS and the number of cells adhered to the surfaces was determined under a reflected light microscope. ", "The number of cells was then normalized to the area of substrate and expressed as cells per square centimeter. ", "Statistical analysis was carried out using a *t* test (Prism 4.0; GraphPad Software, San Diego, CA).", "\n\nHistomorphometric Measurements/Assessment of Osteoclastic Resorption {#Sec9}\n--------------------------------------------------------------------\n\nAfter 10 days of preculture in the medium described above, cells were seeded onto bone and dentin slices at a density of 7.2 × 10^4^ cells/cm² in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 30 μg/mL gentamycin, 20 ng/mL M-CSF, and 2 ng/mL RANKL and kept in culture for 14 days. ", "After this culture time, substrates were put into water, sonicated for 10 min to remove cells, and air-dried. ", "Photographs were obtained by reflected light microscopy (objective 20×) of the entire substrate surface, and resorption trails were analyzed with standard image analysis software (ImageJ, [rsbweb.nih.gov/ij/](http://rsbweb.nih.gov/ij/)). ", "For quantitative analysis, pit areas were defined by an area of resorption surrounded by a margin of unresorbed material. ", "We counted the number of \"resorption events\" on the substrates and measured their area, length, and width to obtain the following parameters: resorbed area (percent), mean pit size (square micrometers), number of pits per square centimeter, and mean pit length and width (micrometers). ", "We did not distinguish between pits and trails in these analyses. ", "Statistical analysis was done by *t*-test (Prism 4.0), and data were represented as mean ± SEM.", "\n\nImmunofluorescence {#Sec10}\n------------------\n\nFor cell adhesion studies, after 10 days of preculture, cells were seeded onto bone or dentin substrates in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 30 μg/mL gentamycin, 20 ng/mL M-CSF, and 2 ng/mL RANKL. ", "After 8 h, cells were fixed in a solution of 4 % paraformaldehyde in PBS for 20 min, washed with PBS, and permeabilized in 0.1 % Triton X-100. ", "After blocking with 10 % Western blocking reagent (Roche) for 20 min at room temperature, cells were incubated with the primary antibody (anti-vinculin or anti-paxillin) diluted in 10 % Western blocking reagent for 1 h. After several washing steps with PBS, cells were incubated with an Alexa Fluor 488--labeled goat anti-mouse IgG antibody for 1 h. Afterward, the actin cytoskeleton of the cells was stained with TRITC-labeled phalloidin for 40 min and the mineralized substrate was stained with 10 μg/mL calcein for 30 min. ", "Substrates were mounted on glass slides and examined using a confocal laser scanning microscope (TCS SP5; Leica, Solms, Germany).", "\n\nFor determination of pit volume and depth, cells were removed from the substrate surface and the mineralized matrix of the substrate was stained with 10 μg/mL calcein for 30 min, followed by washing with PBS and air drying. *", "Z*-stacks of each resorption pit were obtained with a confocal laser scanning microscope (Leica TCS SP5), followed by image analysis and volume calculations. ", "Pit depth was determined by multiplication of the number of *z*-slices with step size. ", "Two independent experiments, obtained from two blood samples, were done from each donor.", "\n\nFor 3D analyses of resorbing osteoclasts, after 10 days of preculture, cells were seeded onto bone or dentin substrates in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 30 μg/mL gentamycin, 20 ng/mL M-CSF, and 2 ng/mL RANKL. ", "After 14 days, cells were fixed with 4 % paraformaldehyde in PBS for 20 min and washed with PBS. ", "After blocking with 10 % Western blocking reagent for 20 min at room temperature, cells were incubated with anti-VNR antibody in 5 % Western blocking reagent for 1 h, followed by incubation with an Alexa Fluor 633-labeled goat anti-mouse IgG antibody for 1 h. After washing with PBS, the actin cytoskeleton of the cells was stained with TRITC-labeled phalloidin for 40 min. ", "Then the sample was stained with 10 μg/mL calcein, washed with PBS, and examined under the confocal laser scanning microscope. ", "One representative resorbing osteoclast is shown.", "\n\nThe horizontal distances between the two sides of typical crescent-shaped actin rings were measured on 2D images for 65 single resorbing cells from pictures obtained under a fluorescence microscope (Eclipse 80i; Nikon, Tokyo, Japan).", "\n\nAffymetrix GeneChip Analysis and qRT-PCR {#Sec11}\n----------------------------------------\n\nTotal RNA was isolated from osteoclasts seeded on bone and dentin (after a 10-day preculture, as described above) after 14 days of culture in αMEM supplemented with 10 % FCS, 2 mM [l]{.smallcaps}-glutamine, 30 μg/mL gentamycin, 20 ng/mL M-CSF, and 2 ng/mL RANKL using a RNA Isolation Kit (Promega, Southampton, UK). ", "The RNA for microarray analyses of resorbing osteoclasts was isolated from those cultures which showed good resorption on bone and dentin substrates (verified by histomorphometry). ", "RNA for microarray analyses of nonresorbing osteoclasts was isolated from those cultures which showed no resorption on bone and dentin substrates. ", "For GeneChip analysis, processing of the RNA, such as quality control, cDNA amplification, labeling, hybridization, and scanning of the hybridized arrays, was performed on an Affymetrix Human Gene 1.0 ST Array by the Kompetenzzentrum für Fluoreszente Bioanalytik (Regensburg, Germany). ", "A signal ratio beyond 1.3-fold indicates gene upregulation \\[[@CR15]\\]. ", "For qRT-PCR, cDNA synthesis was performed on 1 μg RNA using the 1st Strand cDNA Synthesis Kit as described by the supplier (Roche). ", "The cDNA was then introduced into PCR amplification using FastStart SYBR-Green Master Mix on a real-time cycler (Rotorgene; Qiagen, Hilden, Germany). ", "PCRs were performed according to the following cycling program: 10 min of initial denaturation at 95 °C, followed by 60 cycles of 25 s denaturation at 95 °C, 45-second annealing at 62 °C, and 30-second extension at 72 °C.", "\n\nPrimer sequences were as follows: cathepsin K (forward) 5′-TGAGGCTTCTCTTGGTGTCCATAC-3′, (reverse) 5′-AAAGGGTGTCATTACTGCGGG-3′; RANK (forward) 5′-GCTCCTCCATGTACCAGTGAG-3′, (reverse) 5′-ACTGTCAGAGGTAGTAGTGCATT-3′; TRAP (forward) 5′- GACCACCTTGGCAATGTCTCTG-3′, (reverse) 5′- TGGCTGAGGAAGTCATCTGAGTTG-3′.\n\nAll PCRs were performed in triplicate. ", "Gene expression was normalized to 18Sr RNA.", "\n\nStatistical analysis was done by *t* test (Prism 4.0), and data are represented as mean ± SE.", "\n\nResults {#Sec12}\n=======\n\nCell Adhesion on Bone and Dentin {#Sec13}\n--------------------------------\n\nTo verify the adhesion of preosteoclasts on bone and dentin substrates in our culture system we visualized podosome patterns using immunofluorescence-labeled antibodies against two known and well-defined focal adhesion-associated molecules, vinculin and paxillin.", "\n\nAt the contact site between cells and substrate, vinculin was located mainly in the dot-like adhesion structures (podosomes) on dentin as well as on bone and showed a perfect colocalization with actin (Fig.", " [1](#Fig1){ref-type=\"fig\"}c, e). ", "In the main cell body this colocalization was lost and vinculin showed a strong accumulation in the cytoplasm, where as actin was localized mainly at the cell periphery (Fig.", " [1](#Fig1){ref-type=\"fig\"}d, f). ", "The same protein distribution pattern was observed for paxillin when cells were cultured on dentin or bone (data not shown). ", "Hence, we could not find a difference in the appearance of the dot-like cell adhesion patterns of podosomes between bone and dentin concerning those two adhesion molecules.", "Fig.", " 1Immunofluorescence for vincullin and actin on preosteoclasts on bone and dentin. ", "Signals: actin (*red*), vinculin (*green*), colocalization of vinculin and actin gives a brilliant yellow color (*white arrows*). **", "a** Actin staining of cells on dentin surface; image plane: cell attachment site to matrix. **", "b** Vinculin staining of cells on dentin surface; imaged plane: cell attachment site to matrix. **", "c** Merged image of **a** and **b**. **", "d** Merged image of actin and vinculin staining of cells seeded on dentin; image plane: middle of the cell body. **", "e** Merged image of actin and vinculin immunofluorescence of cells seeded on bone; image plane: cell attachment site to matrix. **", "f** Merged image of actin and vinculin staining of cells seeded on bone; image plane: middle of the cell body. ", "At attachment sites of cells to the substrate, vinculin and actin show a perfect colocalization in the dot-like adhesion sites (podosomes) on dentin as well as on bone. ", "This colocalization is lost in the cell body on both mineralized materials. *", "Scale bar* 50 μm\n\nCell adhesion on both materials was quantified and revealed approximately 11,400 adhered cells/cm² in case of bone and 17,200 cells/cm² in case of dentin, hence an increase in cell adhesion on dentin of about 50 % (Fig.", " [2](#Fig2){ref-type=\"fig\"}a).Fig.", " 2Histomorphometric analyses of osteoclastic resorption on bone and dentin, on rough and smooth surfaces, respectively. **", "a** Number of cells adhered on the surface 6 h after seeding. *", "n* = 6 different donors. ", "^\\#^ *p* \\< 0.05; \\**p* \\< 0.05. **", "b** Total resorbed areas (%). ", "^\\#\\#^ *p* \\< 0.01; \\*\\**p* \\< 0.01. **", "c** Number of pits per square centimeter. ", "^\\#\\#^ *p* \\< 0.01; \\*\\**p* \\< 0.01. **", "d** Mean pit size. ", "In case of **b**--**d**: *n* = osteoclasts from 16 different donors. *", "Bars* represent mean ± SEM; *hash* represents dentin_rough versus bone_rough; *asterix* represents dentin_smooth versus bone_smooth\n\nQuantification of Osteoclastic Resorption on Bone and Dentin {#Sec14}\n------------------------------------------------------------\n\nResorption activity of osteoclasts was analyzed by determining the following parameters: total resorbed area, average pit size, number of pits per square centimeter, mean pit length, and mean pit width on bone and dentin.", "\n\nQuantification of the total resorbed area revealed that 0.6 % of the surface was resorbed in bone, whereas 6.7 % of the surface was resorbed on dentin (Fig.", " [2](#Fig2){ref-type=\"fig\"}b), which represents an 11-fold higher osteoclastic resorption activity on dentin compared to bone.", "\n\nAnalyses of the number of pits on the two materials showed that 449 pits/cm² were found on rough bone, whereas on rough dentin we found 3,134 pits/cm² (Fig.", " [2](#Fig2){ref-type=\"fig\"}c).", "\n\nInterestingly, analyses of average pit size did not show a significant difference between bone and dentin. ", "We found that resorption pits exhibited a size of approximately 580 μm² on rough bone surfaces and of approximately 700 μm² on rough dentin surfaces (Fig.", " [2](#Fig2){ref-type=\"fig\"}d), which reflects the average work performed by each single osteoclast. ", "Detailed analysis of resorption pits revealed a mean pit length of 53 + 6.3 μm for pits/trails on rough bone and a mean pit length of 59 + 6.6 μm for pits/trails on rough dentin. ", "Values for pit width were 9.5 + 1.9 μm on bone and 11 + 1.9 μm on dentin (data obtained from 16 different donors). ", "The histograms in Fig.", " [3](#Fig3){ref-type=\"fig\"}a--d illustrate the distribution of length and width of resorption pits on dentin and bone and both showed similar characteristics on both materials.", " Fig.", " 3Histograms showing pit length (**a**) and pit width (**b**) distribution on dentin. ", "Histograms showing pit length (**c**) and pit width (**d**) distribution on bone. **", "a**--**d** *x*-axis represents absolute numbers of pits per category; *y*-axis represents dimensions in micrometers. **", "a, c** *Bars* 1--14 stand for 0--20, 20--40, 40--60, 60--80, 80--100, 100--120, 120--150, 150--180, 180--210, 210--240, 240--270, 270--300, 300--330, and \\>300 μm, respectively. **", "b, d** *Bars* 1--11 stand for 0--5, 5--10, 10--15, 15--20, 20--25, 25--30, 30--40, 40--50, 50--60, 60--70, and 70--80 μm, respectively. *", "Bars* represent mean ± SEM; *n* = 16 different donors. **", "e, f** Diagrams showing the depth/area relationship of resorption pits in osteoclast cultures from three different donors from two experiments (**e** experiment 1, **f** experiment 2). ", "Donor 1, *black symbols*; donor 2, *green symbols*; donor 3, *gray symbols*\n\nWe did not find a significant difference between rough and smooth surfaces in the parameters investigated, but we did observe a trend to higher levels on rough surfaces.", "\n\nThese results clearly demonstrate a strong material-dependent effect as well as a material-independent effect on osteoclastic resorption and show that dentin possesses a much higher potential than bone to generate resorbing osteoclasts (percent total resorbed area, number of pits per square centimeter). ", "But once the resorption process itself has started, it takes place quite independently from the material properties (average pit size, mean pit length, mean pit width, and histograms).", "\n\nResorption Pit Depth {#Sec15}\n--------------------\n\nWe used confocal laser scanning microscopy to measure the depth of resorption pits/trails from osteoclasts cultured on dentin from different blood donors. ", "Interestingly, osteoclasts from all donors showed that pit depth increased to a certain value and then stayed constant, but this maximal pit depth was different for each donor. ", "Reaching the maximal depth, no further increase in pit depth but just an additional increase in area was observed. ", "Figure [3](#Fig3){ref-type=\"fig\"}e shows resorption depths of single pits from three different donors; in the case of donor 1, osteoclasts created pits up to a depth of 35 μm, osteoclasts from donor 2 created pits up to a depth of 55 μm, and osteoclasts from donor 3 resorbed pits with a maximum depth of 68 μm. ", "Figure [3](#Fig3){ref-type=\"fig\"}f shows a second experiment from these donors, obtained from an independent blood sample, where osteoclasts from donor 1 created pits up to a depth of 32 μm, osteoclasts from donor 2 created pits up to a depth of 59 μm, and osteoclasts from donor 3 resorbed pits with a maximum depth of 62 μm. ", "These similar results indicate that varying pit depth is rather an intrinsic property of the cells than a matter of different culture conditions.", "\n\nMicroarray Analysis of Genes Expressed in Osteoclasts Cultured on Bone and Dentin {#Sec16}\n---------------------------------------------------------------------------------\n\nSince preosteoclasts seeded onto a mineralized substrate fuse and form mature resorbing cells \\[[@CR16]\\], we decided to use microarray analysis to determine whether increased resorption on dentin compared to bone was related more to fusion-associated or more to resorption-associated genes. ", "We found that genes related to cell fusion, such as CD9, purinergic receptor (P2RX7), and ADAM 8, and cytoskeleton-related genes like β-actin (ACTB), actinin (ACTN2), filamin A (FLNA), and tubulins (TUB-beta, TUB-alpha, MTMR2) were increased in cells cultured on dentin compared to bone. ", "Furthermore, genes typical for mature, resorbing osteoclasts, e.g., RANK, tartrate-resistant acid phosphatase (TRAP), carbonic anhydrase (CA2), and ATPase (ATP2A2), were also upregulated in osteoclasts cultured on dentin compared to bone (Fig.", " [4](#Fig4){ref-type=\"fig\"}a). ", "Genes associated with the apoptotic pathway (e.g., Fas ligand, Bcl2, BAX, BAD) were not regulated. ", "Caspases 3 and 7 were slightly upregulated, but no other members of the caspase family showed a changed expression level. ", "The regulation of the expression of some typical osteoclastic marker genes (cathepsin K, RANK, and TRAP) was verified in PCR analyses and showed as well an upregulation in resorbing compared to nonresorbing osteoclasts (Fig.", " [4](#Fig4){ref-type=\"fig\"}b). ", "Thus, genes involved in cell fusion and activity were elevated in osteoclasts cultured on dentin compared to bone, which indicates that the increased total resorption on dentin cannot be assigned to one mechanism but may reflect increased fusion as well as resorption activation.", "Fig.", " 4**a** Microarray analyses from osteoclastic cultures on bone and dentin. ", "Signal ratio beyond 1.3 gives the upregulation of genes in cultures on dentin compared to bone. **", "b** mRNA expression of cathepsin K, RANK, and TRAP in resorbing and nonresorbing osteoclasts cultured on dentin. *", "Bars* represent mean ± SEM, nonresorbing osteoclasts versus resorbing osteoclasts. ", "Values form nonresorbing osteoclasts were set to 1, and values from resorbing osteoclasts are expressed as *x*-fold. ", "\\*\\*\\**p* \\< 0.001\n\nResorbing Osteoclasts {#Sec17}\n---------------------\n\nTwo types of resorption traces could be distinguished after osteoclastic resorption. ", "First, single pits, which exhibit a round/elliptical shape, may result from the activity of one single, nonmigrating osteoclast. ", "Second, resorption trails most likely result from the resorption activity of an osteoclast migrating over the surface. ", "Both types of resorption traces display a sharp border between the resorbed area and the rest of the material and were found on dentin as well as on bone (Fig.", " [5](#Fig5){ref-type=\"fig\"}a, b). ", "The resorbing osteoclasts expressed a marker characterizing mature osteoclasts, the vitronectin receptor, and showed the typical F-actin ring within the cell, which represents the resorbing organelle. ", "The resorption organelles were round/elliptical, which were associated with single pits, or exhibited crescent-shaped or half-elliptical shapes, which were associated with osteoclasts forming trails (Fig.", " [5](#Fig5){ref-type=\"fig\"}c).Fig.", " 5Reflection microscopic image from osteoclastic resorption trail (**a**) and pits (**b**) on a dentin surface. **", "c** Immunofluorescence staining of actin (*red*) and vitronectin receptor (*green*). ", "Shown are resorbing osteoclasts on dentin, which organize their actin cytoskeleton into a typical belt or ring structure, thus forming the resorbing organelle. ", "\\*Moon-like or half-elliptical shape, \\~round/elliptical shape. **", "d** A pit-resorbing osteoclast on dentin after immunofluorescence staining. **", "c, d** *Red* actin staining of the cell, *green* calcein staining of dentin. **", "a**--**c** *Scale bar* 100 μm, **d** *Scale bar* 50 μM\n\n3D Analyses of a Trail-Resorbing Osteoclast {#Sec18}\n-------------------------------------------\n\nResorption pits appear under the microscope as round traces. ", "These structures are created by a stationary resorbing osteoclast sealing the whole (round) area, which is going to be resorbed (Fig.", " [5](#Fig5){ref-type=\"fig\"}d).", "\n\nResorption trails appear in reflected light microscopy as longitudinal resorption traces, suggesting that they are generated by horizontal resorption progression of the osteoclast. ", "To investigate how this resorption process occurs in more detail, we analyzed the 3D architecture of the actin ring of a resorbing osteoclast in an emerging trail on dentin using immunofluorescence staining and confocal laser scanning microscopy. ", "The results clearly show that, in the case of trail formation, one side of the resorption ring, which exhibits a crescent-like structure, attaches to the surface of the material slightly ahead of the matrix border (outside the trail margin). ", "The other side of the actin ring attaches to the wall inside the trail (Fig.", " [6](#Fig6){ref-type=\"fig\"}). ", "Figure [6](#Fig6){ref-type=\"fig\"} gives a series of pictures in *z*-dimension obtained by confocal laser scanning microscopy from the apical part of the resorbing osteoclast into the depth of the emerging resorption trail. ", "In these images, colocalization of the actin staining (red) and calcein staining (green) gives a brilliant yellow color. ", "The emerging resorption trail revealed two parts (Fig.", " [6](#Fig6){ref-type=\"fig\"}, column 1): one part being a \"ramp\" (green area within the trail margin) and the other part being a \"deep hole\" (black area within the trail margin), where resorption has already stopped. ", "The attachment of one part of the osteoclast to the surface outside the trail margin is visualized by the red region of the actin ring, slightly ahead in the direction of resorption. ", "The other part of the actin ring attaches to the wall inside the trail (yellow circle-like structure of the actin ring) (Fig.", " [6](#Fig6){ref-type=\"fig\"}, column 2, lane b). ", "From this pattern, the actin ring spans a narrow area and thereby encircles that part of the material which is going to be resorbed next. ", "In our experiments, the horizontal distances between the two walls of crescent-shaped actin rings were approximately 3--21 μm. ", "By going deeper, it is obvious that the actin ring clearly attaches along the \"ramp\" of the trail (\"movement\" of the yellow signal in Fig.", " [6](#Fig6){ref-type=\"fig\"}, column 2, lanes b--d), thus forming a hemisphere-like closed resorption organelle. ", "Due to this anatomical configuration of the actin ring, the material is resorbed in the form of a small layer from the surface to the depth. ", "Based on these 3D data, we propose the following model for osteoclastic resorption leading to trail formation: an osteoclast degrades a thin layer of the matrix from the surface to the depth (from the top to the bottom), moves on, and degrades the next thin layer from the surface to the depth (Fig.", " [7](#Fig7){ref-type=\"fig\"}). ", "The numerous repetitions of this cycle (a special sequential combination of vertical material degradation and horizontal movement) leads to the formation of the longitudinal resorption traces seen by microscopy. ", "Thus, the 3D configuration of the resorption organelle only allows a layer-by-layer degradation of the substrate material from the top to the bottom and not a purely horizontal resorption progression of the cell.", "Fig.", " 63D imaging of a resorbing osteoclast with confocal laser scanning microscopy. ", "Column 1 = calcein staining of dentin (*green*); column 2 = overlay pictures of actin staining (*red*) and calcein staining (yellow signal = overlay of red and green); *lane a* = depth per definition = 0 μm; depth of *lane b* = 2 μm; depth of *lane c* = 3 μm, depth of *lane d* = 4 μm relative to lane *a*. ", "\\*Resorption trailFig.", " 7Resorbing osteoclasts. **", "a** An osteoclast forming a resorption pit as proposed by the literature. **", "b** Scheme according to our model for osteoclastic trail formation. ", "Osteoclasts degrade the material layer by layer, starting resorption from the top and going in deep. ", "By cyclic repetition of this process a longitudinal resorption trace is formed. *", "Red bars* mark the actin ring attached to the mineralized matrix\n\nDiscussion {#Sec19}\n==========\n\nThe aim of this study was to describe the cellular mechanism of the osteoclastic resorption process in detail and to investigate the resorption behavior of osteoclasts on two widely used mineralized substrates, bone and dentin. ", "Bone is the continuously remodeled mineralized tissue in the human body, and dentin is widely used as an in vitro model substrate to study osteoclastic behavior, very often followed by extrapolation of the data obtained on dentin to osteoclastic behavior on bone. ", "Therefore, we first intended to characterize and compare osteoclastic resorption on these two mineralized materials. ", "Quantification of the resorption behavior revealed, on the one hand, a strong material-dependent effect illustrated by an 11-fold higher resorption on dentin (percent resorbed area) and a sevenfold higher number of pits per square centimeter on dentin compared to bone. ", "This material-dependent effect was also mirrored at the molecular level since genes associated with osteoclast migration, fusion, cytoskeletal organization, and resorption were upregulated in cells cultured on dentin compared to bone. ", "These elevated levels of fusion-related as well as maturation-related osteoclastic genes (cathepsin K and RANK were significantly upregulated, whereas TRAP showed a clear trend for higher expression in resorbing compared to nonresorbing osteoclasts) make it impossible to assign the material-dependent effect to either a pure cell fusion-specific or a pure resorption-specific effect. ", "Unfortunately, we could not study the effect of the substrates on gene expression at the protein level due to the limited amount of cells.", "\n\nOn the other hand, an important material-independent aspect was reflected by a similar average size of the pits on bone and dentin (with slightly higher, but not significantly different, levels on dentin) and comparable mean pit length and width and histogram distribution patterns.", "\n\nThe material chemistry of the substrate seems to have a minor effect on cell adhesion but exerts a major impact on the generation of osteoclasts (number of pits per square centimeter), whereas once the resorption process itself has started, it occurs quite independently of the material properties (average size of pits, mean pit length and width). ", "Interestingly, the resorption does not seem to depend on collagen orientation in the near surface region of the tissue since it appears randomly on osteonal as well as interstitial bone, which definitively exhibit different collagen orientation. ", "Vice versa, bone impairs osteoclastogenesis compared to dentin. ", "Azari et al. ", "\\[[@CR17]\\] described a similar observation, where different mineralized tissues evoked different effects on osteoclast formation and mainly affected their formation rather than their resorption. ", "Nevertheless, the resorption process itself is likely to be the same on bone and dentin. ", "Our observations suggest that dentin is a suitable model substrate for data acquisition and extrapolation to bone when studying general osteoclastic resorption processes. ", "However, addition of pharmacological substances other than M-CSF or RANKL or genetic manipulation of the preosteoclasts may influence or even abolish this observed material-dependent effect. ", "The striking quantitative difference in osteoclastic resorption between bone and dentin is interesting since bone and dentin are very similar in chemical composition as well as structural organization of collagen and mineral crystals at the micrometer and nanometer levels \\[[@CR18], [@CR19]\\]. ", "One possible explanation for the divergence in the observed resorption behavior on both materials may come from a difference in absolute amount of noncollagenous matrix proteins, e.g., osteopontin. ", "This protein is present in various concentrations in diverse bone types and is speculated to influence cell behavior \\[[@CR17]\\]. ", "In addition, osteocytic proteins, which are present in bone but are missing in dentin, may act on osteoclasts in the bone remodeling processes \\[[@CR20]--[@CR23]\\]. ", "Removal of organic components and osteocytic proteins from bone matrix was followed by an increased osteoclastic resorption in vitro \\[[@CR14]\\]. ", "Different osteoclastic resorption activity has also been described for numerous artificial substrates, e.g., hydroxyapatite, β-tricalcium phosphate, calcium phosphate, calcite, and carbonated apatite, including variation of cell adhesion rate on those materials, which we observed as well between bone and dentin \\[[@CR24]--[@CR27]\\]. ", "Osteoclastic activity is even influenced by extracts from natural mineralized substrates \\[[@CR28], [@CR29]\\]. ", "However, it is not understood why some substrates favor osteoclast adhesion and resorption while others do not. ", "Beyond those prominent material-dependent effects, we did not find a significant roughness-dependent effect in the micrometer range we offered to cells (just a tendency to higher levels on rough surfaces). ", "Geblinger et al. ", "\\[[@CR30]--[@CR32]\\] reported an increased half-life of the actin rings of resorbing RAW 264.7 osteoclast-like cells on rough artificial calcium substrates compared to smooth ones (roughness in the nanometer range), which could explain our observed tendency for higher resorption on the rough surfaces, as well as a very high dynamics of the sealing-zone being locally regulated by surface roughness. ", "However, topography-dependent higher resorption on rougher surfaces is described in the literature in osteoclast-like cell lines and osteoclasts generated from bone marrow \\[[@CR33]--[@CR36]\\]. ", "Nevertheless, the effects in cultures of primary osteoclasts may be due to the presence of osteoblastic cells or stromal cells, which are well known to strongly affect osteoclastic behavior \\[[@CR34]\\]. ", "Our osteoclast cultures were generated from peripheral blood; thus, they did not contain contaminating stromal cell types. ", "This allowed examination of the direct behavior of osteoclasts and not the indirect effects caused by the communication between osteoclasts and other cell types. ", "Besides the fact that osteoclasts are supposed to be significantly influenced by interactive signals from other cells, our data show that osteoclasts can, to a certain degree, act independently from mesenchymal cell types. ", "The material itself as well as the surface topography of the underlying substrate have the potential to directly guide the resorption behavior of osteoclasts (as reflected by the size and number of resorption lacunae and the resorbed area). ", "In the resorption process, actin ring formation is a prerequisite for an osteoclast to resorb; and in the case of bone as well as dentin, this process results in the same typical resorption traces, pits and trails, visible under reflected light microscopy. ", "Resorption pits correspond to \"reticulate patch resorption\" patterns, and resorption trails correspond to the \"longitudinal\" patterns, categorized by Gentzsch et al. ", "\\[[@CR37]\\]. ", "These resorption traces were also found in bone of femoral heads in vivo \\[[@CR37]\\]. ", "The 3D analyses of the resorption depth in our cultures showed that osteoclasts resorb up to certain maximum depth. ", "After reaching this depth, osteoclasts continue their resorption to further increase area but not depth. ", "This superficial resorption behavior of osteoclasts corresponds to the \"lacunar perforation type\" described in vivo \\[[@CR37]\\]. ", "Surprisingly, the resorption potential of the osteoclasts, generated from peripheral blood, strongly varied between the different donors; but nevertheless, it seems to be an intrinsic potential of the osteoclasts themselves. ", "This was reflected by the varying general resorption potential on the substrate surfaces, reflected by quite large error bars in the histograms, as well by the maximal depth of the resorption pits and pit volume. ", "Such a high variability in the resorption potential of osteoclasts was also observed by other authors \\[[@CR11], [@CR38]\\]. ", "We speculate that the individual, indefinable condition of each donor, probably reflected in the serum parameters but not further qualified in the case of our donors, played a significant role in this phenomenon since our donors were healthy individuals aged 19--55 years.", "\n\nThe resorption traces formed by osteoclasts seem to be identical not only between bone and dentin but also to other mineralized substrates since osteoclasts always form either pits or trails or fusing trails. ", "Beyond that, it is intriguing that on all materials and in osteoclasts from all species used in in vitro studies, the same actin ring formation patterns were observed \\[[@CR10]--[@CR13]\\]. ", "In the case of single pit formation, the resorption mechanism is known in the literature, which describes that the resorption direction is exclusively oriented to depth and the actin ring forms a circular or elliptical shape, enclosing the material in one plane \\[[@CR9]\\]. ", "Such a single pit may function as the initial step for trail formation. ", "The other shapes of actin rings observed, namely, crescent-shaped and half-elliptical, were associated with emerging resorption trails. ", "Saltel et al. ", "\\[[@CR39]\\] also observed round or crescent-shaped actin rings in osteoclasts seeded on hydroxyapatite or dentin. ", "Due to lacking information about the trail-forming process, we sought to elucidate the principal mechanism of how such a resorption trail is generated by an osteoclast. ", "A resorption trail is most probably produced by one osteoclast that migrates over the surface during the resorption process, whereas pits result from a noncontinuous process \\[[@CR40]\\]. ", "Based on the picture of a resorption trail visible under the microscope, one could speculate that such a longitudinal resorption trace may come from an osteoclast that resorbs to a certain depth and then continues resorption by a simple horizontal progression along the surface in a \"worm-like style.\" ", "Under confocal laser scanning microscopy we investigated actin rings which appeared as half-elliptical or crescent-shaped structures and were directly associated with an emerging trail. ", "A limitation of this study is that investigations were done on fixed cells, thus catching just one moment in the resorption process and not revealing dynamics in living cells. ", "Nevertheless, based on the observed 3D configuration of the actin ring due to trail architecture in case of resorbing osteoclasts we developed a model to explain how the resorption process leads to trail formation: during trail formation, one side of the actin ring is attached to the surface of the material, namely, outside the existing trail margin in the direction of resorption. ", "The other side of the ring attaches to the inner margin of the trail and reaches down along the material wall; thus, the closed resorption organelle encircles the region that is going to be resorbed next. ", "This 3D architecture of the resorption organelle allows the resorption of a thin layer of material from the surface to a depth (from top to bottom) which may lie, according to our analyses, in the range of 3--21 μm. ", "After reaching a certain pit depth, the cell stops resorption and the actin ring attaches again one step onward in the direction of resorption on the material surface, again followed by resorption of the material underneath. ", "By a cyclic repetition of this procedure, always starting resorption from the top and proceeding down to the depth, the cell degrades the material layer by layer. ", "Thus, the anatomical configuration of this kind of resorption organelle does not allow a simple horizontal resorption movement in a \"worm-like style\" but only a layer-by-layer degradation of the material from the top to the bottom, at the end appearing as a longitudinal trace under the microscope. ", "In our cultures we found only trail-resorbing osteoclasts exhibiting the described features. ", "Nevertheless, we cannot exclude that, in general, there may be vertically resorbing osteoclasts as well.", "\n\nConclusion {#Sec20}\n==========\n\nThe formation of resorption trails by osteoclasts occurs by an orchestrated combination of horizontal cell movement and vertical degradation of the material in thin layers.", "\n\nDentin is an appropriate substrate for studying osteoclast formation since resorption runs independently of the material (and is comparable on bone and dentin), once it has started. ", "It is the initiation of resorption which seems to be material-dependent and is different on bone and dentin. ", "Thus, only material-related conclusions extrapolated from dentin to bone (e.g., osteoclast formation kinetics) are not reliable. ", "Pharmacological substances or genetic manipulation of cells may abolish this material-dependent effect.", "\n\nThe authors have stated that they have no conflict of interest.", "\n\nThis research was funded by the Austrian Science Fund, Project P21524-B12.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Q:\n\nThe Puzzle of Locating Points in a Quadrilaterally-Faced Hexahedral Creature\n\nThe Disclaimer\nThis is NOT homework... I designed the story. ", "I thought a name MIT would be funny, while something along the line of TULSA or SU will still be decent. ", "I know the algorithm to Q3 and 3D version of Q4, and my major problem are the name of the local coordinate system, the terminology, the formulation of this mathematical question and possible generalization. ", "Insights are welcome.", "\nI'm with $10^3$ rep even though it's pretty weak, but at least I know when to tag homework questions and such. ", "I'm not even immune to homework investigators?", "\nThe Story\nLong long ago, in the far, far away mystical wonderland of $3$ dimensional Cartesian coordinate system lived many geometric creatures. ", "Nobody knew who first named the wonderland the Mystical Itchy Territory, but its geometric residents would from time to time complain the random itchiness concurring inside their body or on their surface.", "\nThe MIT creatures live under a strange rule: Every creature can see all geometric shapes and know the coordinates of any point, but when conveying information about a $n$-dimensional coordinate to others, e.g. $(3,4,5)$, it is only allowed to communicate with at most $n$ numbers in the interval $[-1,1]$.\n_Edit: The creatures want a solution like depicted in the picture below and do not prefer bijections drastically different to what's depicted. ", "A trivial answer like mapping every coordinate in $\\mathbb R$ to $[-1,1]$ using $\\frac2\\pi\\arctan(x)$ is not preferred by the creature, though it's appealing to me.", "\nThe 1D Ritual\nI just met this quadrilaterally-faced hexahedral creature, now my friend (photograph in picture (a)), who told me that his species have came up with a ritual to help locating the origin of itchiness on the edges so that others could scratch them.", "\nThe ritual is a simple convention plus an equation:\n\nThe Convention: Tell others the itchy edge $AB$, let $-1$ represent a vertex $A$, let $1$ represent the other vertex $B$, any point $P(x,y,z)$ on that edge will be represented by a number in $[-1,1]$, by the following equation.", "\nThe Equation: $\\displaystyle a=\\frac{x_A+x_B-2x}{x_A-x_B} \\text{or} \\frac{y_A+y_B-2y}{y_A-y_B} \\text{or} \\frac{z_A+z_B-2z}{z_A-z_B}$, whichever is defined.", "\n\nTo get the actual coordinates, they perform a simple linear operation (combination):\n$$P = \\frac{1-a}{2}A + \\frac{1+a}{2}B$$\nThe Questions\n\nQ1: What term describes this kind of mapping? ", "What's the combination called?", "\nQ2: Relaxing $a$ to $\\mathbb R$, what's this mapping called? ", "What's the combination called?", "\n\nSimilarly, for itches on the surface, he suggests that he could tell others which surface to scratch. ", "He wants to design another set of ritual similar to what's shown in Picture (c), however, he doesn't know how to represent points on his quadrilateral face in $[-1,1]^2$. Neither does he know how to represent any interior points in $[-1,1]^3$. \n\nQ3: Please help the creature-- given 4 vertices of a quadrilateral, map a point on the quadrilateral as the creature intended.", "\nQ4: Given all 8 vertices of this creature, upgrade the ritual. ", "If possible, generalize the result to $n$ dimensions following similar conventions.", "\nQ5: What about other geometric shapes?", "\n\nIllustration of the Mystical Itchy Territory\n\nA:\n\nQ1: If you change $[-1,1]$ to $[0,1]$, you've basically invented 1D Barycentric coordinates. ", "\nQ2: Then you have affine combinations.", "\nQ3: If the quadrilateral is not a parallelogram then I'm not so sure there's a completely canonical answer, but several things may be satisfying. ", "The algorithm you linked for Q4 is just one possibility. ", "Assuming the quadrilateral is convex, I might be inclined to say something like \"convert the $(x,y)$ to four coordinates for a convex combination of the vertices where basically we have a weighted version of something like $(2-y+x,x+y+2,2-x+y,2-x-y)$ (the x-forward vertices get the benefit of $x$: $x+1$ and the others get $1-x$, similarly for $y$).", "\nQ4: In this case, I would similarly convert to a convex combination in a way like that if the hexahedron is convex.", "\nQ5: Even these generalized barycentric coordinates depend on convexity; If a shape is not convex, I'm really not certain what I'd want an answer to look like...\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "1. ", "Introduction {#sec1-marinedrugs-16-00231}\n===============\n\nMarine sponge-associated microorganisms, known as one of the most prolific resources for the discovery of chemical and biological diversified secondary metabolites, have been and continue to be among the research interests of chemists and biologists worldwide \\[[@B1-marinedrugs-16-00231],[@B2-marinedrugs-16-00231],[@B3-marinedrugs-16-00231],[@B4-marinedrugs-16-00231],[@B5-marinedrugs-16-00231],[@B6-marinedrugs-16-00231],[@B7-marinedrugs-16-00231]\\]. ", "During the past decades, a myriad of structurally unique and pharmacologically interesting drug leads have been identified from the microorganisms derived from varieties of marine sponges, involving diterpenes inhibiting the growth of a panel of cancer cell lines from a fungus *Trichoderma harzianum* OUPS-111D-4 separated from a marine sponge *Halichondria okadai* \\[[@B8-marinedrugs-16-00231]\\], antibactetial and antifungal isocoumarins from a culture of the fungus *Pestalotiopsis heterocornis* associated with sponge *Phakellia fusca* \\[[@B9-marinedrugs-16-00231]\\], cytotoxic lactones from the sponge-derived fungus *Talaromyces rugulosus* \\[[@B10-marinedrugs-16-00231]\\], and cyclopentenones with *β*-amyloid fibrillization inhibitory effects from a sponge-derived fungus *Trichoderma* sp. ", "HPQJ-34 \\[[@B11-marinedrugs-16-00231]\\].", "\n\nAs part of our continuous effort to identify structurally and biologically interesting natural products from marine resources \\[[@B12-marinedrugs-16-00231],[@B13-marinedrugs-16-00231],[@B14-marinedrugs-16-00231]\\], the fungus *Gliomastix* sp. ", "ZSDS1-F7-2 from the marine sponge *Phakellia fusca* Thiele, which was collected from the South China Sea in March 2012, has been investigated with the discovery of a series of unusual macrolides gliomasolides A---E with cytotoxic effect against the growth of HeLa cell line \\[[@B15-marinedrugs-16-00231]\\]. ", "To further dig out bioactive metabolites from the remaining fractions of the same crude extract, we carried out systematically purification work, resulting in the discovery of four new metabolites (**1**--**4**), each having nine carbons in total, briefly named as C9 metabolites ([Figure 1](#marinedrugs-16-00231-f001){ref-type=\"fig\"}).", "\n\nInterestingly, these four C9 metabolites represented three kinds of structure-related skeletons. ", "Compound **1** was an unusual new γ-lactone which differed from other γ-lactones mainly by the presence of a methyl group in the γ position of the ester carbonyl. **", "2** represented a new δ-lactone, while compounds **3**--**4** were two new medium-chain fatty acids. ", "In view of their structure similarity, a plausible biosynthetic relationship was assumed. ", "As depicted in [Scheme 1](#marinedrugs-16-00231-sch001){ref-type=\"scheme\"}, compound **3** might shift the double bond and hydroxyl group by allylic alcohol rearrangement, followed by hydrogenation of the conjugated double bond to give **4**. ", "The intramolecular lactonisation of **3a** which was formed by *trans-cis* isomerization of **3**, at the γ position furnished 1, while cyclization of 3a at the δ position giving the δ-lactone **2a**, which might undergo Michael addition by water to give **2**. ", "The co-occurrence of macrolides gliomasolides A---E and four C9 metabolites in the same fermentation culture made us assume that these C9 metabolites might be biosynthetic building blocks toward the construction of more complex macrolides such as gliomasolides A---E or other unidentified polyketides. ", "This assumption was consistent with the widely accepted hypothesis of step by step functionalization of growing polyketide chains \\[[@B16-marinedrugs-16-00231],[@B17-marinedrugs-16-00231]\\]. ", "Biologically, these novel C9 metabolites exhibited no cytotoxic effect against HeLa cell line at concentrations up to 25 μg/mL, while **1** exhibited moderate antifouling activity against the settlement of *Balanus amphitrite* larvae with IC~50~ being 12.8 μg/mL and LC~50~ \\> 25 μg/mL. This paper reported the isolation, structural elucidation, biosynthetic relationship, and biological effects of four new C9 metabolites from the fungus *Gliomastix* sp. ", "ZSDS1-F7-2.", "\n\n2. ", "Results and Discussion {#sec2-marinedrugs-16-00231}\n=========================\n\nCompound **1** was obtained as a brown oil. ", "The molecular formula of **1** was determined to be C~9~H~12~O~3~ by high-resolution time-of-flight mass spectrometry (HR-TOF-MS), displaying ion peak \\[M + H\\]^+^ at *m*/*z* 169.0872 (calcd. ", "for C~9~H~13~O~3~^+^ at *m*/*z* 169.0865). ", "The infrared (IR) spectrum of compound **1** showed absorption bands for hydroxyl group (3487 cm^−1^) and carbonyl group (1746 cm^−1^). ", "Preliminary inspection of the ^1^H nuclear magnetic resonance (NMR) spectrum of **1** led to the clear identification of a singlet methyl group at δ~H~ 1.40 (3H, s, H-9), a doublet methyl at δ~H~ 1.70 (3H, d, *J* = 6.0 Hz, H-8) in the upfield area ([Table 1](#marinedrugs-16-00231-t001){ref-type=\"table\"}). ", "The presence of an oxygenated methine in **1**, was clearly suggested by the chemical shifts of δ~H~ 4.14 (1H, d, *J* = 6.9 Hz, H-5) and the corresponding δ~C~ 75.8 in the ^1^H and ^13^C NMR, respectively. ", "In the downfield region of the ^1^H NMR, the signals at δ~H~ 6.05 (1H, d, *J* = 5.4 Hz, H-2), 7.40 (1H, d, *J* = 5.4 Hz, H-3), 5.43 (1H, dd, *J* = 15.0, 6.9 Hz, H-6) and 5.78 (1H, dq, *J* = 15.0, 6.0 Hz, H-7), combined with the corresponding ^13^C NMR signals at δ~C~ 121.8 (C-2), 158.5 (C-3), 127.6 (C-6), 131.0 (C-7), supported the presence of two pairs of olefinic groups in **1**. ", "The linear fragment extending from C-5 to C-8, was established by the ^1^H-^1^H correlation spectroscopy (COSY) showing sequential correlations of between H-5 with H-6, H-6 with H-7, and H-7 with H-8, which was further supported by the correlations of from H-5 to C-7, H-8 to C-6/C-7 in heteronuclear multiple-bond correlation spectroscopy (HMBC) ([Figure 2](#marinedrugs-16-00231-f002){ref-type=\"fig\"}). ", "The fragment extending from C-1 to C-4 in **1**, was established by the HMBC correlations of from both H-2/H-3 to C-1/C-4, as shown in [Figure 2](#marinedrugs-16-00231-f002){ref-type=\"fig\"}. ", "Whereas, the connection between C-1 with C-4 via an oxygen atom to form the butenolide moiety was deduced by the high-resolution mass spectrometry (HRMS) spectrum referring the molecular formula of C~9~H~12~O~3~ to **1**, requiring the cyclization to satisfy the unsaturated degrees. ", "This assignment was also in agreement with the IR absorbance of carbonyl carbon at 1746 cm^−1^ which was found at a much higher wavenumber than the α,β unsaturated acid (around 1700 cm^−1^). ", "The arrangement of a singlet methyl group connected to the C-4, was determined by the correlations of from H-9 to C-4/C-3/C-5 in HMBC ([Figure 2](#marinedrugs-16-00231-f002){ref-type=\"fig\"}). ", "Furthermore, the connection of the moiety extending from C-5 to C-8, and the butenolide moiety extending from C-1 to C-4, to form the complete planar structure of **1**, as shown in [Figure 1](#marinedrugs-16-00231-f001){ref-type=\"fig\"}, was established by the HMBC correlations between H-5 and C-3/C-4/C-9, and between H-3 and C-4/C-5/C-9, respectively.", "\n\nThe stereochemistry of the double bond Δ^6,7^ was determined to be *trans* in view of the coupling constant of *J*~6,7~ = 15.0 Hz. ", "To determine the stereo-orientation of the hydroxyl group at C-5, the Mosher ester method was employed. ", "According to the procedure previously reported by our group, the (*S*)-MTPA (methoxy(trifluoromethyl)phenylacetic acid) ester was successfully obtained, unfortunately, in spite of modifying the reaction conditions several times, we failed to obtain the (*R*)-MTPA ester, which made our effort using the Mosher ester method in vain. ", "Pleasingly, the absolute configurations of both chiral carbons C-4/C-5, were successfully determined by the quantum chemical method using TDDFT (time-dependent density functional theory) calculations. ", "Theoretically, there are four configurations for the structure of **1**, being (4*R*, 5*S*)-**1**, (4*R*, 5*R*)-**1** and their enantiomers. ", "The absolute configuration of **1** was determined by comparisons of the calculated CD (circular dichroism) and OR (optical rotation) value with those of the corresponding experimental data. ", "The calculated CD spectra of both (4*R*, 5*S*)-**1** and (4*R*, 5*R*)-**1** were similar to the experimental spectrum of **1** ([Figure 3](#marinedrugs-16-00231-f003){ref-type=\"fig\"}), excluding the possibility of assigning their enantiomers to **1**. ", "Furthermore, the OR values of (4*R*, 5*S*)-**1** and (4*R*, 5*R*)-**1** were calculated at the B3LYP/6-311++g (2d, p) level using methanol as solvent. ", "The computed OR values of (4*R*, 5*S*)-**1** and (4*R*, 5*R*)-**1** were +99.6 and +241.6, respectively, which supported the assignment of (4*R*, 5*S*) stereochemistry to **1** in view of the information that the computed OR value of (4*R*, 5*S*)-**1** was more close to the experimental value (+88.3) than that of (4*R*, 5*R*)-**1**. ", "Thus, based on both the electronic circular dichroism (ECD) and OR calculations, the structure with absolute configuration of **1** was determined to be (*R*)-5-((*S*,*E*)-1-hydroxybut-2-en-1-yl)-5-methylfuran-2(5*H*)-one, trivially named gliomasolide F.\n\nCompound **2** was obtained as a brown oil. ", "Its molecular formula C~9~H~14~O~3~ was determined by HR-TOF-MS displaying ion peaks at *m*/*z* 171.1029 \\[M + H\\]^+^ (calcd. ", "for C~9~H~15~O~3~^+^: 171.1021) and 153.0932 \\[M − H~2~O + H\\]^+^ (calcd. ", "for C~9~H~13~O~2~^+^: 153.0916). ", "The IR spectrum suggested the presence of hydroxyl (3503 cm^−1^) and conjugated ester groups (1718 cm^−1^). ", "The NMR data of **2** was similar to that of prelactone C first isolated from the *Streptomyces* sp. ", "\\[[@B17-marinedrugs-16-00231]\\], with the major difference arising from the signals of CH-3, CH-4, CH-5, and CH~3~-9, as indicated in [Table S1](#app1-marinedrugs-16-00231){ref-type=\"app\"}. ", "The planar structure of **2** was unambiguously determined to be the same as that of prelactone C based on the comprehensive elucidation of the 2D NMR involving ^1^H--^1^H COSY, heteronuclear single quantum correlation (HSQC) and HMBC. ", "The relative stereochemistry of chiral carbons C-3/C-4/C-5 was established according to the nuclear Overhauser effect spectroscopy (NOESY) spectrum in which the correlations of H-3 with both H-4 and H-5, H-9 with both H-6 and H-8 were clearly identified ([Figure 4](#marinedrugs-16-00231-f004){ref-type=\"fig\"}), allowing the assignment of all-*cis* configurations for hydroxyl at C-3, methyl at C-4, and propenyl at C-5, as shown in [Figure 1](#marinedrugs-16-00231-f001){ref-type=\"fig\"}. ", "The absolute configurations of 3*S*, 4*S* and 5*S* were tentatively assigned to **2** based on the biogenetic point of view, in combination with the plausible biosynthetic relationship between **1** and **2** ([Scheme 1](#marinedrugs-16-00231-sch001){ref-type=\"scheme\"}). ", "Worthy of note, the carbon chemical shift of CH~3~-9 in **2** resonated at δ~C~ 5.9, significantly upfield shifted compared to that of its isomer prelactone C at δ~C~ 13.7 \\[[@B17-marinedrugs-16-00231]\\]. ", "We assumed that, due to the hydroxyl, propenyl, and methyl groups all being in *cis*-relationship, they were close to each other in spatial distance, making both the hydroxyl and propenyl groups exhibit strong gamma gauche effect which was generally observed causing an upfield shift of the resonating carbon \\[[@B18-marinedrugs-16-00231],[@B19-marinedrugs-16-00231]\\], resulting in significant shield effect on methyl. ", "Therefore, the chemical structure of **2** was tentatively elucidated, trivially named gliomasolide G.\n\nBased on NMR analysis, compounds **3** and **4** were found to be mixed in one thin-layer chromatography (TLC) fraction, with a rough 1:1 ratio, which were then subjected to prep-high-performance liquid chromatography (HPLC) for purification. ", "However, in spite of trying varieties of HPLC conditions, these two compounds could not be separated well. ", "After carefully examining the NMR spectra and the HRMS data, we suspected that this mixture should consist of a pair of medium-chain fatty acids, inspiring us to esterify them before processing separation. ", "Fortunately, after esterification using benzyl bromide, their corresponding esters were successfully separated by silica gel column chromatography, which were then subjected to LiOH solution to remove the benzyl group, giving the pure compounds **3** and **4** ([Scheme 2](#marinedrugs-16-00231-sch002){ref-type=\"scheme\"}).", "\n\nCompound **3** was obtained as a yellow oil, and its molecular formula C~9~H~14~O~3~ was established by the ^1^H, ^13^C NMR data, in combination with the HRMS displaying ion peaks at *m*/*z* 153.0924 \\[M − H~2~O + H\\]^+^ (calcd. ", "for C~9~H~13~O~2~^+^: 153.0916). ", "The IR displayed typical linear α,β-unsaturated carbonyl carbon absorption at 1697 cm^−1^, in agreement with the observation of chemical shift of δ~C~ 171.2 (C-1) in the ^13^C NMR spectrum. ", "The ^1^H, ^13^C NMR data, indicated the presence of four olefinic protons and carbons, one oxygenated methine, and two doublet methyls ([Table 2](#marinedrugs-16-00231-t002){ref-type=\"table\"}). ", "The ^1^H--^1^H COSY correlations sequentially extending from H-2 to H-9, combined with the correlations of from H-2/H-3 with C-1, H-9 with C-3/C-5, H-5 with C-9/C-7, and H-8 with C-6/C-7 in HMBC, clearly constructed the planar structure of **3**, shown in [Figure 1](#marinedrugs-16-00231-f001){ref-type=\"fig\"}. ", "The geometric configurations of both the double bonds Δ^2,3^, Δ^6,7^ were determined to be *trans* by the coupling constants, being 15.0 Hz for both *J*~2,3~ and *J*~6,7~. The relative configurations, with hydroxyl and methyl CH~3~-9 being assigned as *cis*, was established by comparison of ^13^C NMR data between **3** and the similar moiety of reveromycins, a series of polyketide spiroketals from *Streptomyces* sp. ", "\\[[@B20-marinedrugs-16-00231]\\]. ", "The reveromycins contained a medium-chain acid, being very similar to **3**, as its structure moiety. ", "As shown in [Figure 5](#marinedrugs-16-00231-f005){ref-type=\"fig\"}, the carbon chemical shifts of C-4 and C-5 in all reveromycins resonated at \\~44.0 and \\~76.9 ppm in CD~3~OD, respectively, almost the same as those corresponding signals in **3** with C-4 and C-5 at δ~C~ 43.9 and 76.9, respectively. ", "The absolute configurations 4*S*/5*S*, were tentatively assigned in view of the biogenetic and biosynthetic relationships between **1** and **3**. ", "Therefore, the chemical structure of compound **3** was achieved, being (2*E*,4*S*,5*S*,6*E*)-5-hydroxy-4-methylocta-2,6-dienoic acid, trivially named gliomacid A.\n\nCompound **4**, structurally similar to **3**, has nine carbons in total, involving one carbonyl, two olefinic carbons and one oxygenated methine, as revealed by ^13^C NMR. ", "The HRMS displayed ion peaks at *m*/*z* 155.1073 \\[M − H~2~O + H\\]^+^ (calcd. ", "for C~9~H~15~O~2~^+^: 155.1072), giving a molecular formula C~9~H~16~O~3~ to **4**. ", "Corresponding to the ^13^C NMR and HRMS, there are two more protons in the ^1^H NMR compared with **3**. ", "According to the detailed 2D NMR analysis ([Figure 2](#marinedrugs-16-00231-f002){ref-type=\"fig\"}), the planar structure of **4** was established as shown in [Figure 1](#marinedrugs-16-00231-f001){ref-type=\"fig\"}. ", "The stereochemistry of C-4 was assumed to be the same as that of 3 based on the biogenetic and biosynthetic viewpoint, whereas the stereochemistry of C-7 remained unknown currently. ", "The *cis* geometric configuration of the double bond Δ^5,6^ was determined by the peak pattern of the olefinic protons H-5/H-6 which overlapped to form what looks like a broad singlet with coupling constant of *J*~5,6~ obviously less than 15 Hz. ", "Compound **4**, therefore, was elucidated to be (4*S*,*Z*)-7-hydroxy-4-methyloct-5-enoic acid, trivially named gliomacid B.\n\nAll the isolates were evaluated for cytotoxic activity against the proliferation of HeLa cell line and the antifouling effect against the settlement of *Balanus amphitrite* larvae. ", "Unfortunately, none of the tested compounds **1**--**4** showed cytotoxicity at the concentrations up to 25 μg/mL. Pleasingly, compound **1** exhibited a non-toxic moderate inhibitory effect against the settlement of *Balanus amphitrite* larvae with IC~50~ being 12.8 μg/mL and LC~50~ \\> 25 μg/mL, whereas **2**--**4** displayed no anti-fouling effect at the concentrations up to 25 μg/mL.\n\n3. ", "Experimental Section {#sec3-marinedrugs-16-00231}\n=======================\n\n3.1. ", "General Experimental Procedures {#sec3dot1-marinedrugs-16-00231}\n------------------------------------\n\nOptical rotation was measured on a JASCO P-2000 digital polarimeter (Jasco, Tokyo, Japan). ", "The ultraviolet (UV) spectrum was recorded on a Shimadzu UV2401PC spectrophotometer (Shimadzu, Kyoto, Japan). ", "IR spectra were recorded on a Perkin-Elmer 16 PC Fourier transform--infrared (FT--IR) spectrometer (Perkin-Elmer, Boston, MA, USA). ", "NMR spectra were recorded on Varian Inova-500 NMR spectrometer (Toso, Tokyo, Japan) and Varian Mercury VX 300 spectrometer (Varian, Japan) using TMS (Tetramethylsilane) as internal standard, the chemical shifts were reported in ppm relative to CD~3~OD (δ~H~ 3.31 and δ~C~ 49.00) or CDCl~3~ (δ~H~ 7.26 and δ~C~ 77.16). ", "High-resolution mass spectra (HRMS) were performed on QSTAR XL mass spectrometry system (Applied Biosystems, Foster City, CA. ", "USA). ", "The preparative HPLC was performed on Waters systems (Waters, Manchester, UK) involving Waters 2545 binary gradient module, Waters 2996 PDA detector, MassLynx V4.1 workstation, and XBridge RP18 column (19 × 300 mm, 5 µm). ", "Column chromatography (CC) was performed with silica gel (230--400 mesh, Merck, Darmstadt, Hessen, Germany) or octadecyl silane (ODS) (Fuji Silysia Chemical Ltd. Kasugai, Aichi, Japan). ", "TLC was performed on aluminium sheet precoated with silica gel G~60~ (Merck, Darmstadt, Hessen, Germany). ", "Spots were visualized under UV light or by spraying with 5% H~2~SO~4~ in EtOH followed by heating.", "\n\n3.2. ", "Fungal Material {#sec3dot2-marinedrugs-16-00231}\n--------------------\n\nThe fungal strain, *Gliomastix* sp. ", "ZSDS1-F7-2, was isolated from the sponge *Phakellia fusca* Thiele collected from the Xisha Islands of China in 2012. ", "The sponge was identified by Prof. Jinhe Li at the Institute of Oceanology, Chinese Academy of Sciences. ", "A voucher specimen of the fungus (No. ", "12071301) was deposited in the Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences. ", "The fungus was identified using a molecular biological protocol by DNA amplification and sequencing of the 18S rRNA gene (GenBank Accession No. ", "KR054959). ", "By comparison with the GenBank database, the most similar strain was *Gliomastix murorum* YNS1116-4, with a sequence identity of 99% (95% query coverage). ", "So the fungus strain ZSDS1-F7-2 belonged to the genus *Gliomastix*, and was designated as *Gliomastix* sp.", "\n\n3.3. ", "Fermentation, Extraction and Isolation {#sec3dot3-marinedrugs-16-00231}\n-------------------------------------------\n\nThe strain *Gliomastix* sp. ", "ZSDS1-F7-2 was cultured in 100 mL Erlenmeyer flasks each containing 25 mL of malt medium (20 g/L of malt extract (Oxoid), 1 g/L of peptone (BD Difco), and 30 g/L of sea salt (Anhui Hongsifang Co., Ltd., CNSG, Anhui, China), to give the seed culture (20 × 100 mL flasks), which was transferred to the 1000 mL Erlenmeyer flask containing solid rice medium (200 g of rice (North-eastern rice, COFCO), 200 g water, 6 g sea salt (Anhui Hongsifang Co., Ltd., CNSG, Anhui, China, 20 × 1 L flasks). ", "After incubation at 25 °C under daylight for 2 months, the culture was broken up with a spatula and extracted with 95% EtOH (3 × 10 L). ", "The combined extract was filtered and evaporated under vacuum to give 95% EtOH extract (105.1 g), which was suspended in water (1 L) and extracted successively with petroleum ether (1 L × 3), EtOAc (1 L × 3), and *n*-BuOH (1 L × 3). ", "The EtOAc fraction (70 g) was subjected to a chromatography column (CC) on silica gel (400 g; 9.0 cm diam × 50 cm height), eluted with a step gradient of petroleum ether (PE) in EtOAc (10--100%), and then with MeOH--EtOAc (10--30%), to yield 10 fractions (Fr. ", "A-J). ", "Fr. ", "B (5.0 g) was further subjected to octadecyl silane (ODS) CC (60 g; 3.0 cm diam. ", "× 16 cm height), eluted with a gradient solution of methanol in water (10--100%) to furnish 10 fractions (Fr. ", "B1-Fr. ", "B10). ", "Then, Fr. ", "B4 (0.2 g) was purified by preparative high-performance liquid chromatography (HPLC) (25% acetonitrile--H~2~O, 15.0 mL/min) to yield compounds **1** (19.5 mg), **2** (5.3 mg). ", "Fr. ", "B6 (0.3 g) was purified by preparative HPLC (30% acetonitrile-H~2~O, 15.0 mL/min) to yield a mixture (18.9 mg) containing both compounds **3** and **4**. ", "To the solution of this mixture (15.0 mg) in dried DMF (1 mL), was added K~2~CO~3~ (40 mg), followed by benzyl bromide (16 μL), then this was stirred at room temperature for 8 h, then quenched with saturated NaHCO~3~ aqueous (2 mL), extracted with DCM (3 mL × 2), washed sequentially by brine (5 mL × 2) and water (5 mL); the residue obtained after evaporation was purified by silica gel CC, eluting with 15% EtOAc/PE, to give the benzyl ester of **3** (6.5 mg, ^1^H NMR recorded at 300 MHz in CDCl~3~: δ~H~ 1.06 (3H, d, *J* = 6.9), 1.70 (3H, d, *J* = 6.3), 2.52 (1H, m), 4.01 (1H, m), 5.18 (2H, s), 5.47 (1H, m), 5.70 (1H, m), 5.90 (1H, d, *J* = 15.9), 7.03 (1H, dd, *J* = 15.9, 6.9), 7.38 (5H, m)), and the benzyl ester of 4 (3.0 mg, 1H NMR recorded at 300 MHz in CDCl3: δH 0.99 (3H, d, *J* = 6.6), 1.24 (3H, d, *J* = 6.3), 1.66 (2H, m), 2.13 (1H, m), 2.34 (2H, t, *J* = 7.5), 4.23 (1H, m), 5.11 (2H, s), 5.46 (2H, m), 7.36 (5H, m)). ", "The separated benzyl esters **3** (3.0 mg), was dissolved in methanol/water (1 mL/0.5 mL), followed by the addition of LiOH (2.1 mg), the mixture was stirred at room temperature for 4 h, then quenched with 1 M HCl aqueous (2 mL), extracted with DCM (3 mL × 2), washed with brine (3 mL × 2) and water (3 mL), and the combined DCM layer was evaporated to obtain the residue which was subjected to CC, eluted with 30% EtOAc/PE to give **3** (2.0 mg). ", "The compound **4** (1.2 mg) was obtained from the separated benzyl esters **4** by the same procedure.", "\n\nGliomasolide F (**1**): brown oil; $\\left\\lbrack \\alpha \\right\\rbrack_{D}^{25}$ +88.1 (*c* = 5.53, CH~3~OH); IR (film) ν~max~ 3487, 2938, 1746, 1450, 1377, 1111, 1027, 820 cm^−1^; UV (CH~3~OH) λ~max~ (log *ε*) 210 (3.75) nm; CD λ~max~ (Δ*ε*) 260 (18.9); ^1^H and ^13^C NMR data see [Table 1](#marinedrugs-16-00231-t001){ref-type=\"table\"}; HR-TOF-MS *m*/*z* 169.0872 \\[M + H\\]^+^ (calcd. ", "for C~9~H~13~O~3~^+^: 169.0865).", "\n\nGliomasolide G (**2**): brown oil; $\\left\\lbrack \\alpha \\right\\rbrack_{D}^{25}$ −38.7 (*c* = 0.87, CH~3~OH); IR (film) ν~max~: 3503, 2966, 1718, 1459, 1249, 1051, 966, 844 cm^−1^; UV (CH~3~OH) λ~max~ (log *ε*): 244 (3.32) nm; ^1^H and ^13^C NMR data see [Table 1](#marinedrugs-16-00231-t001){ref-type=\"table\"}; HR-TOF-MS *m*/*z* 171.1029 \\[M + H\\]^+^ (calcd. ", "for C~9~H~15~O~3~^+^: 171.1021), 153.0932 \\[M − H~2~O + H\\]^+^ (calcd. ", "for C~9~H~13~O~2~^+^: 153.0916).", "\n\nGliomacid A (**3**): brown oil; $\\left\\lbrack \\alpha \\right\\rbrack_{D}^{25}$−409.7 (*c* 0.08, MeOH); IR (film) ν~max~ 3394, 2917, 1697, 1652, 1398, 967 cm^--1^; UV (CH~3~OH) *λ*~max~(log *ε*) 232 (3.86) nm; ^1^H and ^13^C NMR data see [Table 2](#marinedrugs-16-00231-t002){ref-type=\"table\"}; HR-TOF-MS *m*/*z* 153.0924 \\[M − H~2~O + H\\]^+^ (calcd. ", "for C~9~H~13~O~2~^+^: 153.0916).", "\n\nGliomacid B (**4**): brown oil; $\\left\\lbrack \\alpha \\right\\rbrack_{D}^{25}$ +76.8 (*c* 0.09, MeOH); IR (film) ν~max~ 3382, 2923, 1707, 1651, 1379, 1059 cm^--1^; UV (CH~3~OH) *λ*~max~(log *ε*) 228 (2.95) nm; ^1^H and ^13^C NMR data see [Table 2](#marinedrugs-16-00231-t002){ref-type=\"table\"}; HR-TOF-MS *m*/*z* 155.1073 \\[M − H~2~O + H\\]^+^ (calcd. ", "for C~9~H~15~O~2~^+^: 155.1072).", "\n\n3.4. ", "Computation Section {#sec3dot4-marinedrugs-16-00231}\n------------------------\n\nConformational studies were performed using the Amber and MMFF94S force field, respectively. ", "The geometries with relative energy less than 5.5 kcal/mol were selected and calculated at B3LYP/6-31G(d)//B3LYP/3-21G(d) level to obtain global minima. ", "Conformers within an energy range of 3 kcal/mol from the global minima were subjected to geometrical optimization (DFT/B3LYP/6-31G(d)) in the gas phase, combined with calculation of vibrational modes to confirm these minima. ", "No imaginary frequencies were found. ", "After conformational search, 10 conformations for (4*R*, 5*S*)-**1**, and 8 conformations for (4*R*, 5*R*)-**1** with low energy were found. ", "For these conformations, ECD spectra were calculated at the B3LYP/6-311+G(d,p) level in MeOH (SCRF/IEFPCM). ", "OR values were calculated at the B3LYP/6-311++G(2d,p) level. ", "Each calculated ECD spectra and OR values was assigned a Boltzmann weight according to the energy of the minimized conformers at 298.15 K and overlaid prior to comparison with the experimental results. ", "All of the DFT (density functional theory) calculations reported in this study were performed with the Gaussian 09 package \\[[@B21-marinedrugs-16-00231]\\].", "\n\n3.5. ", "Cytotoxicity Test {#sec3dot5-marinedrugs-16-00231}\n----------------------\n\nThe cytotoxicity against HeLa cervical cancer cell line was determined using the MTT \\[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide\\] method. ", "Briefly, the HeLa cells were cultured in Dulbecco's modified Eagle\\'s medium (DEME) (Invitrogen, Carlsbad, CA, USA) supplemented with 10% FCS (fetal calf serum) (Invitrogen, Carlsbad, CA, USA) in a 96-well plate at a density of 1 × 10^4^ cells per well and incubated for 20 hours, then the cells were treated with testing samples at various concentrations and then incubated at 37 °C for 48 hours in a 5% CO~2~ atmosphere. ", "The supernatant was removed, followed by the addition of 25 μL of MTT (2.5 mg mL^−1^ in PBS (phosphate buffered saline)) to each well. ", "After incubation at 37 °C for 4 h, 100 μL of dimethyl sulfoxide (DMSO) was added to each well and incubated for another 20 min. ", "The absorbance of each well was then measured at 570 nm using a Thermo scientific Multiskan FC multiplate photometer (Waltham, MA, USA).", "\n\n3.6. ", "Antifouling Effect {#sec3dot6-marinedrugs-16-00231}\n-----------------------\n\nThe antifouling assay was evaluated according to the procedure reported previously \\[[@B13-marinedrugs-16-00231]\\]. ", "Briefly, fresh cyprids of the barnacle *Balanus amphitrite* were used in the testing. ", "Larval settlement assays were examined using 24-well polystyrene plates with Sea-Nine 211^TM^ (4,5-dichloro-2-*n*-octyl-4-iso-thiazolin-3-one) being served as positive control. ", "The tested samples and Sea-Nine 211^TM^ were dissolved with a small amount of dimethyl sulfoxide (DMSO) and then diluted with 0.22 μm filtered seawater (FSW) to achieve the final concentrations of 25.0, 12.5, 6.25, 3.13, and 1.56 µg/mL. About 15−20 competent larvae were added to each well containing 1 mL of test solution in triplicate, with wells having only FSW, DMSO, and larvae being served as negative control. ", "The plates were incubated at 25 °C for 48 h, followed by examination under a microscope to count settled, unsettled larvae, and where appropriate, potential toxic effects were recorded. ", "The number of settled larvae was expressed as a percentage of the total number of larvae per well. ", "The EC~50~ was calculated as the concentration where 50% of the larval individuals were inhibited to settle as compared to the control, while LC~50~ was calculated as the concentration where 50% of the larval population was dead.", "\n\n4. ", "Conclusions {#sec4-marinedrugs-16-00231}\n==============\n\nAs part of our continuous effort to explore the biologically and structurally interesting metabolites from marine resources, we carried out a systematical investigation on the secondary metabolites from the sponge-associated fungus *Gliomastix* sp. ", "ZSDS1-F7-2, leading to the discovery of four new structurally related metabolites, each having nine carbons in total, therefore briefly named as C9 metabolites. ", "Their structures involving absolute configurations were successfully elucidated by the detailed analyses of NMR, HRMS, quantum chemistry calculations, biosynthetic relationship, and by comparison with reported literature. ", "Biological assay revealed that these C9 metabolites showed no cytotoxic effect against the HeLa cell line, whereas one γ-lactone named gliomasolide F (1) exhibited moderate anti-fouling activity against the settlement of the barnacle *Balanus Amphitrite.* ", "Furthermore, based on their structure similarity, a plausible biosynthetic relationship between these C9 metabolites was assumed. ", "Interestingly, the co-isolation of unusual macrolides gliomasolides A---E and these four look like simple C9 metabolites, from the same fermentation extract of the marine fungus *Gliomastix* sp. ", "ZSDS1-F7-2, and strongly inspired our assumption that these C9 metabolites might represent the early steps of the polyketide pathway toward gliomasolides A---E or other macrolides that remained unknown within the fermentation extract. ", "For a more detailed understanding of the role of these C9 metabolites in the macrolides biosynthesis, incorporation experiments will be carried out in our laboratory in the future.", "\n\nThe following are available online at <http://www.mdpi.com/1660-3397/16/7/231/s1>, Table S1: ^1^H and ^13^C NMR data of compounds **2** and prelactone C; Computational data, HRMS, IR and NMR spectra of compounds **1**--**4**.", "\n\n###### \n\nClick here for additional data file.", "\n\nJ.Z. designed the research plan, elucidated the chemical structures and wrote the paper; Z.Y. carried out the isolation and purification process; Y.L. performed the biological activities test; L.Z. assisted in the purification work; H.L. assisted in the biological activities test; B.Z. and Y.L. contributed to the revision of the paper; L.L. contributed to the quantum chemistry calculation, compounds isolation, and wrote partial sections of the paper; S.X. assisted in the chemical structures elucidation, prepared the draft paper, and conceived the project.", "\n\nThis work was financially supported by the National Natural Science Foundation of China (No. ", "41506156), Natural Science Fundation of Guangdong Province (No. ", "2016A030310095), and Natural Science Fundation of Jiangxi Province (No. ", "20171BCB24011).", "\n\nThe authors declare no conflict of interest.", "\n\nFigures, Schemes and Tables\n===========================\n\n{#marinedrugs-16-00231-f001}\n\n{#marinedrugs-16-00231-sch001}\n\n{#marinedrugs-16-00231-f002}\n\n{#marinedrugs-16-00231-f003}\n\n{#marinedrugs-16-00231-f004}\n\n{#marinedrugs-16-00231-sch002}\n\n{#marinedrugs-16-00231-f005}\n\nmarinedrugs-16-00231-t001_Table 1\n\n###### \n\n^1^H (300 MHz) and ^13^C (75 MHz) nuclear magnetic resonance (NMR) data of compounds **1** in CDCl~3~ and **2** in CD~3~OD.", "\n\n --------------------------------------------------------------------------------\n No. ", " 1 2 \n ----- ---------------------------- ------- ----------------------------- -------\n 1 \\- 172.8 \\- 173.4\n\n 2 6.05 (d, *J* = 5.4) 121.8 2.42 (dd, *J* = 18.3, 9.0)\\ 36.4\n 2.81 (dd, *J* = 18.3, 6.6) \n\n 3 7.40 (d, *J* = 5.4) 158.5 4.20 (m) 67.4\n\n 4 \\- 90.9 2.16 (m) 38.9\n\n 5 4.14 (d, *J* = 6.9) 75.8 4.81 (dd, *J* = 6.9, 2.1) 83.2\n\n 6 5.43 (dd, *J* = 15.0, 6.9) 127.6 5.66 (dd, *J* = 15.3, 6.9) 128.6\n\n 7 5.78 (dq, *J* = 15.0, 6.0) 131.0 5.84 (dq, *J* = 15.3, 6.3) 130.6\n\n 8 1.70 (d, *J* = 6.0) 17.9 1.75 (d, *J* = 6.3) 17.9\n\n 9 1.40 (s) 20.1 0.92 (d, *J* = 7.2) 5.9\n --------------------------------------------------------------------------------\n\nmarinedrugs-16-00231-t002_Table 2\n\n###### \n\n^1^H (500 MHz) and ^13^C (75 MHz) NMR data of compounds **3**--**4** in CD~3~OD.", "\n\n No 3 4 \n ---- ---------------------------- ------- --------------------- -------\n 1 \\- 171.2 \\- 179.1\n 2 5.79 (d, *J* = 15.5) 123.7 2.25 (m) 33.9\n 3 6.89 (dd, *J* = 15.5,7.5) 151.5 1.57 (m), 1.62 (m) 33.4\n 4 2.43 (m) 43.9 2.13 (m) 37.4\n 5 3.93 (m) 76.9 5.47 (m) 136.2\n 6 5.44 (dd, *J* = 15.5, 7.5) 132.8 5.47 (m) 134.8\n 7 5.68 (dq, *J* = 15.5, 6.5) 128.8 4.18 (m) 69.3\n 8 1.70 (d, *J* = 6.5) 17.9 1.20 (d, *J* = 6.5) 23.7\n 9 1.06 (d, *J* = 7.0) 15.4 1.01 (d, *J* = 6.5) 20.9\n" ]

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[ "As Invisible Children’s Kony2012/stopKony campaign goes viral, Sisters of Resistance share links that criticize the paternalistic, racist, “white savior” nature of the “not for profit” organization (as well as a trailer for a documentary about US interference in Africa.)", "\n\nIn advocating further US military intervention in Uganda, with no reference to the political economic context, or underlying systemic causes of the conflict, let alone the fact corporations prolong and profit from it, Kony2012 furthers a racist, imperialist Western agenda which cannot be understood without reference to Africom.", "\n\nAfrican people are presented as “invisible” and incapable, while the Hollywood narrative of the “white American good guy saving the world and getting the bad guy” is perpetuated at a time when US global dominance is crumbling.", "\n\nIf the founders of Invisible Children were serious, they would take down the arms companies, corporations and governments that fund, profit from, cause and prolong the conflict (read more about cobalt, corporations and Central Africa here).", "\n\nWe got trouble.", "\n\nInvisible Children has been condemned time and time again. ", "As a registered not-for-profit, its finances are public. ", "Last year, the organization spent $8,676,614. ", "Only 32% went to direct services (page 6), with much of the rest going to staff salaries, travel and transport, and film production. ", "This is far from ideal for an issue which arguably needs action and aid, not awareness, and Charity Navigator rates their accountability 2/4 stars because they lack an external audit committee. ", "But it goes way deeper than that.", "\n\nThe group is in favour of direct military intervention, and their money supports the Ugandan government’s army and various other military forces. ", "Here’s a photo of the founders of Invisible Children posing with weapons and personnel of the Sudan People’s Liberation Army. ", "Both the Ugandan army and Sudan People’s Liberation Army are riddled with accusations of rape and looting, but Invisible Children defends them, arguing that the Ugandan army is “better equipped than that of any of the other affected countries”, although Kony is no longer active in Uganda and hasn’t been since 2006 by their own admission.", "\n\n******************\n\nThoughts on Kony 2012 and White Saviours vs. Allies\n\nby Alex Snider\n\nI watched the Kony 2012 video this morning and I have to say the White saviour, colonial overtones made me extremely uncomfortable. ", "Not to mention the lack of any consultation or even reference to any of the Ugandan groups who have been actively fighting against Kony for years. ", "Even the way Invisible Children denies granting the two (!) ", "Ugandan politicians further identification in the video. ", "What party are they from? ", "What role in government do they play? ", "Why was there no mention of the president? ", "Or of any other adult Ugandans? ", "Why weren’t Ugandans given the opportunity to speak for themselves? ", "Why were they instead treated as props for the self-aggrandizing filmmaker and his friends? ", "Merely showing images of nameless mutilated children, flashing them before the audience’s eyes reduces and erases the children’s humanity. ", "This type of stomach-turning pity-porn is no way to bring attention to a cause. ", "This is no way to treat those you wish to help.", "\n\nI could go on about the problems with the video: the lack of Ugandan culture; the weird inclusion of the narrator’s very young son and how the video placed him at the centre of the narrative as the ideal future; the fact that it took nearly 9 minutes for Joseph Kony and the LRA to even be mentioned; the pro-military stance; and the basis that no one else could possibly have heard or cared about the LRA before Invisible Children ever before. ", "The video is the very definition of the White Man’s Burden.", "\n\n******************\n\nStop Kony, yes. ", "But don’t stop asking questions\n\nInvisible Children has had some success already: late last year, President Barack Obama committed 100 US troops to provide “advice and assistance” to the Ugandan army in removing Joseph Kony from the battlefield. ", "The President’s move came in part due to the NGO’s tremendous advocacy efforts. ", "Everyone agrees that this a hugely important issue, but Invisible Children’s methods have come in for searing criticism; most scathingly, they have been attacked as “neo-liberal, do-good Whiteness”. ", "Elsewhere, Foreign Affairs has provided some important context on this matter, in relation to Uganda’s strategic importance to the USA. ", "I would also recommend the Twitter feed of Laura Seay, who was moved to comment this morning that “[Solomme Lemma] is tweeting links to great community-based organizations working in Northern Uganda. ", "Give there if you really want to help. ", "I understand the anger and resentment at Invisible Children’s approach, which with its paternalism has unpleasant echoes of colonialism. ", "I will admit to being perturbed by its apparent top-down prescriptiveness, when so much diligent work is already being done at Northern Uganda’s grassroots.", "\n\n********************\n\n@DynamicAfrica, @InnovateAfrica and @TexasinAfrica have been tweeting criticism and analysis as well as promoting the important work already being done by grassroots Ugandan organisations. ", "For further information on the context of US imperialism in Africa please see:\n\nAFRICOM was created for two main reasons, oil and China. ", "I have documented where US officials have stated this at numerous places in this blog. ", "For a more detailed discussion see Understanding AFRICOM: A Contextual Reading of Empire’s New Combatant Command Part I, Part II and Part III.", "\n\n[…]\n\nKony is a handy cover for the real reasons for US interest in the region, which are all about African resources.", "\n\nYou can see links to more information and documentation in these posts:\nUganda – Stepping On the Mission Creep Accelerator\nIf Uganda Has Oil It Must Need The Pentagon’s Democracy\nor via this search: http://crossedcrocodiles.wordpress.com/?s=lra”\n\nSOLID! ", "i remember when i got involved w/the “global night commute” (circa 2006) related to “invisible children” how i felt that it was some typical white savior shit and even challenged a few of the organizers about the ad they used for the action. ", "anyhow, thanks for posting this piece!" ]

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[ "Q:\n\nhow to find out Fully qualified name IntelliJ project\n\nI have an IntelliJ project with 2 scala objects, as below:\ncloudera@quickstart tlf]$ ll\ntotal 8\n-rwxrw-r-- 1 cloudera cloudera 1601 May 2 15:45 AnalyzeGraphTlf.scala\n-rwxrw-r-- 1 cloudera cloudera 1868 May 2 13:35 FormatDataTlf.scala\n[cloudera@quickstart tlf]$ ls\nAnalyzeGraphTlf.scala FormatDataTlf.scala\n[cloudera@quickstart tlf]$ pwd\n/home/cloudera/ideaProjects/grafoTelefonos/src/main/scala/tlf\n\nHow can I know the fully qualified name of the package?", "\n\nA:\n\nAccording to convention that IDEA follows (and maven, and most Java & Scala developers do) all Scala sources goes to \n${projectDir}/src/main/scala\nJava sources to:\n${projectDir}/src/main/java\nAnd so on...\nin case Your Scala sources goes to:\nhome/cloudera/ideaProjects/grafoTelefonos/src/main/scala\nFull qualified name of the package begins after '/scala' . ", "In your case it is 'tlf'\nAnd in addition fully qualified name of class AnalyzeGraphTlf.scala is 'tlf.", "AnalyzeGraphTlf'\nNote that Full qualified name reflects directory structure and use '.' (", "dot) as a separator.", "\n\n" ]

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[ "Saucy Sue\n\nSaucy Sue (1922– July 1937) was a British Thoroughbred racehorse and broodmare, best known for winning two Classics in 1925. ", "The filly won eight times from ten races in a racing career which lasted from July 1924 until October 1925. ", "She was the top-rated British two-year-old of either sex in 1924, when she was unbeaten in three races. ", "In her first two races the following year she won the 1000 Guineas over one mile at Newmarket and The Oaks over one and a half miles at Epsom Downs Racecourse a month later. ", "Saucy Sue took her unbeaten run to seven by winning the Coronation Stakes at Royal Ascot and the Nassau Stakes at Goodwood. ", "She was defeated in her next two races and was retired from racing at the end of the season after a final win in the Atalanta Stakes at Sandown Park.", "\n\nBackground\nSaucy Sue was a bay mare with a white blaze and one white sock on her left hind foot. ", "She was bred by her owner Waldorf Astor, 2nd Viscount Astor, an American-born politician and newspaper proprietor. ", "Saucy Sue's sire, Swynford, was a successful racehorse and stallion, winning the St Leger Stakes in 1910 and becoming British Champion sire in 1923. ", "Her dam, Good and Gay, was a daughter of Lord Astor's broodmare Popinjay, and therefore a half-sister of the Caulfield Cup winner Magpie. ", "Popinjay's other descendants have included the 2000 Guineas winners Pay Up and Shadeed, the St Leger winners Book Law and Provoke, and the Kentucky Derby and Belmont Stakes winner Swale.", "\n\nAstor sent the filly into training with Alec Taylor, Jr. at his stables at Manton in Wiltshire. ", "The Bloodstock Breeders'Review described her as \"somewhat plain-looking\" at rest but also said that she possessed \"a wonderful action and a great, sweeping stride\". ", "Before her win in the Oaks, one correspondent called her \"greyhoundish\" in appearance, but with \"immense power\".", "\n\nRacing career\n\n1924: two-year-old season\nIn 1924 Saucy Sue was unbeaten, winning all three of her races by wide margins. ", "She began by winning the five furlong Lavant Stakes at Goodwood in July. ", "In October she won the Bretby Stakes at Newmarket and the Criterion Stakes at the same course two weeks later. ", "She reportedly won the latter race very easily at odds of 1/4 and was described as \"one of the smartest two-year-olds in England\".", "\n\nAt the end of the season, at the instructions of the Jockey Club, the inaugural Free Handicap, a rating of the year's best juveniles was published. ", "Saucy Sue was assigned top weight of 127 pounds, one pound ahead of the leading colt Picaroon, who had won the Middle Park Stakes and was also trained by Alec Taylor. ", "The Manton stables housed another leading two-year-old filly in the form of the Cheveley Park Stakes winner Miss Gadabout: like Saucy Sue she was owned and bred by Lord Astor and was a grand-daughter of Popinjay.", "\n\n1925: three-year-old season\nSaucy Sue began her three-year-old season in the 1000 Guineas over Newmarket's Rowley Mile course on 3 May. Ridden by the Australian jockey Frank Bullock, she started at odds of 1/4 against ten opponents, making her the shortest priced favourite since 1904. ", "She was never in any danger of defeat and won by six lengths from Miss Gadabout, with Firouze Mahal two lengths further back in third. ", "According to descriptions of the race she won with her ears pricked and her mouth hanging open as her jockey struggled to restrain her. ", "The win gave the forty-year-old Bullock a first classic win in what was to be his final season as a jockey. ", "After the race he described Saucy Sue was the most remarkable horse he had ever ridden and said that she had won without ever traveling at more than half-speed.", "\n\nTwenty-six days later, Saucy Sue was made 30/100 favourite for the Oaks in a field of twelve fillies. ", "Ridden again by Bullock she pulled hard in the early stages as her jockey tried to restrain her and ran wide at the turn into the straight as her bit slipped through her mouth. ", "Once Bullock allowed her to gallop freely however, she quickly went clear of the field and won by very easily by eight lengths from Miss Gadabout, who was in turn eight lengths clear of the rest. ", "Her winning time of 2:38.2 was more than two seconds faster than that recorded by the Derby winner Manna over the same course and distance two days earlier. ", "Following the win, she was described in the press as the best filly seen in Britain since Pretty Polly.", "\n\nAt Royal Ascot in June, Saucy Sue was brought back in distance to one mile for the Coronation Stakes and started at odds of 1/10. ", "Carrying a weight of 136 pounds, she won the race by ten lengths \"in a canter\" from Inca and two others. ", "A heel injury forced Saucy Sue to miss a run against colts and older horses in the Eclipse Stakes at Sandown in July, but she returned later in the month to win the Nassau Stakes over ten furlongs at Goodwood.", "\n\nOn 12 September, Saucy Sue was stepped up in distance for the Park Hill Stakes over fourteen and a half furlongs at Doncaster Racecourse. ", "Taylor's original intention had been to run the filly in the St Leger at the same meeting, but plans were revised after she was beaten by Picaroon in a trial race at Manton. ", "She was beaten for the first time as she finished third of the four runners, beaten twelve lengths by the Aga Khan's filly Juldi. ", "In her next race she finished third to the colts Conquistador and Warden of the Marches in the Royal Stakes at Newmarket on 17 October, leading some commentators to offer the opinion that she had been over-rated as a result of wins against an unusually weak crop of three-year-old fillies. ", "Saucy Sue ended her career with a win in late October as she defeated five opponents in the ten furlong Atalanta Stakes at Sandown. ", "Saucy Sue's earnings of £22,155 for the year enabled Lord Astor to claim the title of British flat racing Champion Owner for the 1925 season.", "\n\nAssessment and honours\nIn their book, A Century of Champions, based on the Timeform rating system, John Randall and Tony Morris rated Saucy Sue a \"superior\" winner of the 1000 Guineas and Oaks and the twentieth best filly trained in Britain or Ireland in the 20th century.", "\n\nStud record\nAs a broodmare, Saucy Sue produced a good colt in Truculent, sired by Teddy, who won the Royal Standard Stakes at Manchester Racecourse and made a promising start as a breeding stallion before dying in 1937 at the age of ten.", "\n\nPedigree\n\nReferences\n\nCategory:1922 racehorse births\nCategory:1937 racehorse deaths\nCategory:Racehorses bred in the United Kingdom\nCategory:Racehorses trained in the United Kingdom\nCategory:Thoroughbred family 1-n\nCategory:1000 Guineas winners\nCategory:Epsom Oaks winners" ]

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[ "Conventional packaged microelectronic devices can include a singulated microelectronic die, an interposer substrate or lead frame attached to the die, and a molded casing around the die. ", "The die generally includes an integrated circuit and a plurality of bond-pads coupled to the integrated circuit. ", "The bond-pads are typically coupled to terminals on the interposer substrate or lead frame, and supply voltage, signals, etc., ", "are transmitted to and from the integrated circuit via the bond-pads. ", "In addition to the terminals, the interposer substrate can also include ball-pads coupled to the terminals by conductive traces supported in a dielectric material. ", "Solder balls can be attached to the ball-pads in one-to-one correspondence to define a “ball-grid array.” ", "Packaged microelectronic devices with ball-grid arrays are generally higher grade packages having lower profiles and higher pin counts than conventional packages using lead frames.", "\nPackaged microelectronic devices such as those described above are used in cellular phones, pagers, personal digital assistants, computers, and many other electronic products. ", "To meet the demand for smaller electronic products, there is a continuing drive to increase the performance of packaged microelectronic devices, while at the same time reducing the height and the surface area or “footprint” of such devices on printed circuit boards. ", "Reducing the size of high performance devices, however, is difficult because the sophisticated integrated circuitry requires more bond-pads, which results in larger ball-grid arrays and thus larger footprints. ", "One technique for increasing the component density of microelectronic devices within a given footprint is to stack one device on top of another.", "\nOne conventional stacking process includes placing a plurality of singulated first dies in a fixture and stacking a plurality of singulated second dies onto corresponding first dies. ", "The stacked first and second dies can then be heated to reflow solder bumps on the second dies and securely attach the second dies to corresponding first dies. ", "The stacked assemblies of first and second dies are then taken out of the fixture and mounted on an interposer substrate (e.g., in a “flip-chip” arrangement). ", "Another reflow process can be used to securely attach the individual stacked die assemblies to the interposer substrate. ", "The stacked die assemblies on the interposer substrate can then be encapsulated and singulated.", "\nThe conventional stacking process described above, however, has several drawbacks. ", "For example, the process includes a large number of steps and accordingly can be relatively expensive. ", "The large number of steps can also reduce the throughput of finished devices. ", "Another drawback of the conventional process described above is that the stacked die assemblies can have a relatively large footprint and occupy a significant amount of vertical space (i.e., high profile) because the dies are stacked on an interposer substrate.", "\nAnother conventional stacking process includes forming a plurality of first dies on a first support member (e.g., a film frame) and a plurality of second dies on a second support member (e.g., a film frame). ", "The individual first and second dies can be tested while on the support members with a probe device. ", "After testing, the first and second dies are singulated and mounted directly onto an interposer substrate in a stacked configuration. ", "This stacking process, however, also includes several drawbacks. ", "For example, although the dies are tested before singulation to ensure that they function properly, the dies must still undergo a variety of fabrication and packaging processes (e.g., singulation, bumping, mounting) after testing. ", "If the dies become inoperable and/or damaged after these rigorous packaging processes, the entire packaged device (rather than just the bad die) is generally discarded. ", "Accordingly, there is a need to improve the processes for packaging microfeature devices." ]

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[ "Apple Watchに対応するアプリの中から、毎週オススメの1本を選んで紹介していく「Apple Watchアプリ探訪」。", "\n\n腹筋は人体のなかでも特に重要な筋肉の部位。日常的な動作に欠かせないのはもちろんのこと、臓器を正しい位置に保持するコルセットのような役割も果たしており、筋肉量が衰えると肥満体でなくてもポコリとお腹が飛び出してくる原因ともなります。", "\n\nバランスよく腹筋を鍛えるためには複数のエクササイズを組み合わせるのが効果的ですが、エクササイズの動作、正しい姿勢を覚えるのは難しいものです。そこでオススメしたいのが、Apple Watchアプリ『Runtastic Six Pack 腹筋を割る筋トレでお腹痩せ運動』なのです。", "\n\nApple Watchアプリ『Runtastic Six Pack 腹筋を割る筋トレでお腹痩せ運動』\n\n本アプリはほかのApple Watchアプリと同様に、まずiPhoneで初期設定を行います。", "\n\nそしてトレーニングメニューを選びます\n\nトレーニングメニューは、35エクササイズを10日間かけて行う“1.筋トレの旅に出発”、60エクササイズを15日間かけて行う“2.テンションをあげていきましょう”、115エクササイズを25日間かけて行う“3.驚きの結果を体験”の3種類があります。2と3はApp内課金（600円）が必要なので、まずは“1.筋トレの旅に出発”から始めてはいかがでしょうか？", "\n\nこのあとエクササイズを指導する“音声コーチパック”をダウンロードするのですが、ひとつ残念なお知らせがあります。", "\n\n実はトレーナーに女性の“Angie”を選んでも、音声コーチパックに“日本語 女性”は選べないんですね。つまりエクササイズの動作見本はAngie、指示する声はDanielとちょっとチグハグなことになります。", "\n\nとはいえエクササイズ自体に支障はありません。最後にApple Watchにアプリをインストールしましょう。", "\n\nこれで準備はすべて終了です。Apple Watchのホーム画面から『Runtastic Six Pack』を立ち上げれば、下記のようなメニューが表示されるので、“次のトレーニング”をタップしましょう。", "\n\n『Runtastic Six Pack』をApple Watchにインストールする最大のメリットは、エクササイズメニューを手首で確認できることです。エクササイズ時の音声と音楽はiPhoneから再生されるので、iPhoneを同じ部屋に置いておく必要はありますが、エクササイズの動きを確認する際にiPhoneをわざわざ目の前に掲げなくて済むのは非常にお手軽です。", "\n\n辛いエクササイズ中にiPhoneを持つのは億劫です\n\nApple Watchなら手首を返すだけで動作を確認できます\n\n現在のバージョンでは、心拍数計にApple Watchを選択できないなど不満もありますが、無課金でも腹筋トレーニングの入門アプリとしては必要十分な機能を備えている『Runtastic Six Pack 腹筋を割る筋トレでお腹痩せ運動』。ワタシ同様にぽっこりお腹が気になる方は、まずは無課金でトレーニングを始めてみてはいかがでしょうか？", "\n\nRuntastic Six Pack 腹筋を割る筋トレでお腹痩せ運動 開発：runtastic 価格：無料（App内課金あり、600円） ダウンロードリンク\n\n" ]

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[ "The weirdest words from the 2013 Scripps National Spelling Bee\n\nCould you spell any of these unusual words?", "\n\nBen Nuckols\nOXON HILL, Md. — A look at some unusual, difficult or otherwise noteworthy words from the 2013 Scripps National Spelling Bee.", "\n\nKNAIDEL — a small mass of leavened dough cooked by boiling or steaming. ", "The winning word for 2013 was from German-derived Yiddish, a source of much amusement to champion Arvind Mahankali, 13, of Bayside Hills, N.Y., who finished third in 2012 and 2011 after misspelling German-derived words. ", "This time, he had little trouble.", "\n\nCYANOPHYCEAN — a blue-green alga. ", "Runner-up Pranav Sivakumar, 13, of Tower Lakes, Ill., was bounced by this word, missing it by a single letter. ", "He thought the final “a” was an “i.”\n\nLANSCENET — a card game, similar to pharaoh, played in central Europe. ", "Aspiring comedy writer Amber Born, 14, of Marblehead, Mass., seemed confident about this word until she was given an alternate pronunciation and deadpanned, “That is cause for panic.” ", "She let out a big sigh and spelled it right.", "\n\nKABURI — a land crab common in mangrove swamps from the West Indies to southern Brazil. ", "Chetan Reddy’s run in the finals was over as soon as he asked for the language of origin and was told, “unknown.” ", "With little helpful information, Chetan, 13, of Plano, Texas, pursed his lips before guessing “c-a-b-u-r-r-i.”\n\nMELOCOTON — a peach grafted on a quince root stalk. ", "Grace Remmer, 14, of St. Augustine, Fla., who spells quickly when she knows a word, asked for the definition twice and the etymology twice. ", "She was off by two letters, and that was the end of her fourth and final National Spelling Bee appearance. “", "Thank you, everyone,” she said, and left the stage to a standing ovation.", "\n\nGALERE — a group of people having a marked common quality or relationship. ", "Derived from French and old Catalan, this word nearly bounced champion Arvind Mahankali from the finals. ", "He asked for the etymology twice, shifted his body back and forth and stroked his chin. ", "He started with “g-a,” and then asked to start again, getting it right with seconds to spare.", "\n\nDORYLINE — a type of migratory tropical ant that is blind except for the functional males. ", "In the finals, Christal Schermeister, 13, of Pembroke Pines, Fla., stood silently for a long time, trying to figure it out. “", "Can I have the definition again, please?” ", "she asked, her voice cracking a bit. ", "She went with “d-o-r-a-l-i-n-e” and was eliminated.", "\n\nSMELLFUNGUS — a critic or faultfinder, taken from a novel by 18th-century absurdist Laurence Sterne. ", "Gokul Venkatachalam, 12, of Chesterfield, Mo., spelled it correctly.", "\n\nMALACOPHILOUS — adapted to pollination by snails. “", "I don’t know if that’s possible,” Amber Born said. ", "After spelling the word correctly, she leapt for joy and dashed back to her seat.", "\n\nCYANOPE — a person with fair hair and brown eyes. ", "Caleb Miller, 13, of Calhoun, La., asked if it came from the Greek word “ops,” meaning eye. ", "Told yes, he responded, “Thank goodness.” ", "He still misspelled the word, going with p-s-i-a-n-o-p-e. Told the correct spelling, he said, “Oh, you’ve gotta be kidding me.”", "\n\nBILBOQUET — a device having a cup or spike at the top of a stick to which is attached a ball on a string. ", "This word looked like it might trip up 11-year-old Vanya Shivashankar of Olathe, Kan., the sister of the 2009 champion and one of the favourites. ", "She paused while pretending to write the word on her hand, a common technique among spellers. ", "But she got it right and advanced to the finals.", "\n\nCABOTINAGE — behaviour befitting a second-rate actor. ", "There was no acting from Eva Kitlen, 14, of Niwot, Colo., who struggled with this word, breathing quickly into the microphone, before getting it wrong. “", "Can I maybe get a different word?” ", "she asked. “", "I hope you get a different word,” pronouncer Jacques Bailly responded. ", "She did not.", "\n\nTENERAMENTE — a musical direction meaning “tenderly.” ", "Grace Remmer, who plays violin, chuckled with relief after being asked to spell this word, which helped propel her to the finals. ", "She still asked Bailly to use it in a sentence, which turned out to be a gem: “The piano teacher repeatedly encouraged the Incredible Hulk to try to play the lullaby teneramente.”", "\n\nOLEACRANON — the clinical term for the funny bone. ", "Emily Keaton, 14, of Pikeville, Ky., missed this word by adding an “h” after the “c.” She jumped back with surprise at the sound of the bell that ended her spelling bee career. ", "Emily was a five-time National Spelling Bee contestant." ]

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[ "---\nabstract: 'The [*IJCAI–18 Proceedings*]{} will be printed from electronic manuscripts submitted by the authors. ", "The electronic manuscript will also be included in the online version of the proceedings. ", "This paper provides the style instructions.'", "\nauthor:\n- |\n First Author$^1$, Second Author$^2$, Third Author$^3$\\\n $^1$ First Affiliation\\\n $^2$ Second Affiliation\\\n $^3$ Third Affiliation\\\n [email protected], [email protected], [email protected]\nbibliography:\n- 'ijcai18.bib'\nnocite:\n- '[@abelson-et-al:scheme]'\n- '[@bgf:Lixto]'\n- '[@brachman-schmolze:kl-one]'\n- '[@gottlob:nonmon]'\n- '[@gls:hypertrees]'\n- '[@levesque:functional-foundations]'\n- '[@levesque:belief]'\n- '[@nebel:jair-2000]'\ntitle: 'IJCAI–18 Formatting Instructions'\n---\n\nIntroduction\n============\n\nThe [*IJCAI–18 Proceedings*]{} will be printed from electronic manuscripts submitted by the authors. ", "These must be PDF ([*Portable Document Format*]{}) files formatted for 8-1/2$''$ $\\times$ 11$''$ paper.", "\n\nLength of Papers\n----------------\n\nAll paper [*submissions*]{} must have a maximum of six pages, plus at most one for references. ", "The seventh page cannot contain [**anything**]{} other than references.", "\n\nThe length rules may change for final camera-ready versions of accepted papers, and will differ between tracks. ", "Some tracks may include only references in the last page, whereas others allow for any content in all pages. ", "Similarly, some tracks allow you to buy a few extra pages should you want to, whereas others don’t.", "\n\nIf your paper is accepted, please carefully read the notifications you receive, and check the proceedings submission information website[^1] to know how many pages you can finally use (and whether there is a special references-only page or not). ", "That website holds the most up-to-date information regarding paper length limits at all times.", "\n\nWord Processing Software\n------------------------\n\nAs detailed below, IJCAI has prepared and made available a set of LaTeX macros and a Microsoft Word template for use in formatting your paper. ", "If you are using some other word processing software (such as WordPerfect, etc.), ", "please follow the format instructions given below and ensure that your final paper looks as much like this sample as possible.", "\n\nStyle and Format\n================\n\nLaTeX and Word style files that implement these instructions can be retrieved electronically. (", "See Appendix \\[stylefiles\\] for instructions on how to obtain these files.)", "\n\nLayout\n------\n\nPrint manuscripts two columns to a page, in the manner in which these instructions are printed. ", "The exact dimensions for pages are:\n\n- left and right margins: .75$''$\n\n- column width: 3.375$''$\n\n- gap between columns: .25$''$\n\n- top margin—first page: 1.375$''$\n\n- top margin—other pages: .75$''$\n\n- bottom margin: 1.25$''$\n\n- column height—first page: 6.625$''$\n\n- column height—other pages: 9$''$\n\nAll measurements assume an 8-1/2$''$ $\\times$ 11$''$ page size. ", "For A4-size paper, use the given top and left margins, column width, height, and gap, and modify the bottom and right margins as necessary.", "\n\nFormat of Electronic Manuscript\n-------------------------------\n\nFor the production of the electronic manuscript, you must use Adobe’s [*Portable Document Format*]{} (PDF). ", "A PDF file can be generated, for instance, on Unix systems using [ps2pdf]{} or on Windows systems using Adobe’s Distiller. ", "There is also a website with free software and conversion services: [http://www.ps2pdf.com/]{}. ", "For reasons of uniformity, use of Adobe’s [*Times Roman*]{} font is strongly suggested. ", "In LaTeX2e, this is accomplished by putting\n\nin the preamble.[^2]\n\nAdditionally, it is of utmost importance to specify the American [**letter**]{} format (corresponding to 8-1/2$''$ $\\times$ 11$''$) when formatting the paper. ", "When working with [dvips]{}, for instance, one should specify [-t letter]{}.", "\n\nTitle and Author Information\n----------------------------\n\nCenter the title on the entire width of the page in a 14-point bold font. ", "The title should be capitalized using Title Case. ", "Below it, center author name(s) in a 12-point bold font. ", "On the following line(s) place the affiliations, each affiliation on its own line using a 12-point regular font. ", "Matching between authors and affiliations can be done using superindices. ", "Additionally, a comma-separated email addresses list using a 12-point regular font is also allowed. ", "Credit to a sponsoring agency can appear on the first page as a footnote.", "\n\n### Blind Review\n\nIn order to make blind reviewing possible, authors must omit their names and affiliations when submitting the paper for review. ", "In place of names and affiliations, provide a list of content areas. ", "When referring to one’s own work, use the third person rather than the first person. ", "For example, say, “Previously, Gottlob  has shown that…”, rather than, “In our previous work [@gottlob:nonmon], we have shown that…” Try to avoid including any information in the body of the paper or references that would identify the authors or their institutions. ", "Such information can be added to the final camera-ready version for publication.", "\n\nAbstract\n--------\n\nPlace the abstract at the beginning of the first column 3$''$ from the top of the page, unless that does not leave enough room for the title and author information. ", "Use a slightly smaller width than in the body of the paper. ", "Head the abstract with “Abstract” centered above the body of the abstract in a 12-point bold font. ", "The body of the abstract should be in the same font as the body of the paper.", "\n\nThe abstract should be a concise, one-paragraph summary describing the general thesis and conclusion of your paper. ", "A reader should be able to learn the purpose of the paper and the reason for its importance from the abstract. ", "The abstract should be no more than 200 words long.", "\n\nText\n----\n\nThe main body of the text immediately follows the abstract. ", "Use 10-point type in a clear, readable font with 1-point leading (10 on 11).", "\n\nIndent when starting a new paragraph, except after major headings.", "\n\nHeadings and Sections\n---------------------\n\nWhen necessary, headings should be used to separate major sections of your paper. (", "These instructions use many headings to demonstrate their appearance; your paper should have fewer headings.). ", "All headings should be capitalized using Title Case.", "\n\n### Section Headings\n\nPrint section headings in 12-point bold type in the style shown in these instructions. ", "Leave a blank space of approximately 10 points above and 4 points below section headings. ", "Number sections with arabic numerals.", "\n\n### Subsection Headings\n\nPrint subsection headings in 11-point bold type. ", "Leave a blank space of approximately 8 points above and 3 points below subsection headings. ", "Number subsections with the section number and the subsection number (in arabic numerals) separated by a period.", "\n\n### Subsubsection Headings\n\nPrint subsubsection headings in 10-point bold type. ", "Leave a blank space of approximately 6 points above subsubsection headings. ", "Do not number subsubsections.", "\n\n### Special Sections\n\nYou may include an unnumbered acknowledgments section, including acknowledgments of help from colleagues, financial support, and permission to publish.", "\n\nAny appendices directly follow the text and look like sections, except that they are numbered with capital letters instead of arabic numerals.", "\n\nThe references section is headed “References,” printed in the same style as a section heading but without a number. ", "A sample list of references is given at the end of these instructions. ", "Use a consistent format for references, such as that provided by BibTeX. The reference list should not include unpublished work.", "\n\nCitations\n---------\n\nCitations within the text should include the author’s last name and the year of publication, for example [@gottlob:nonmon]. ", "Append lowercase letters to the year in cases of ambiguity. ", "Treat multiple authors as in the following examples: [@abelson-et-al:scheme] or [@bgf:Lixto] (for more than two authors) and [@brachman-schmolze:kl-one] (for two authors). ", "If the author portion of a citation is obvious, omit it, e.g., Nebel . ", "Collapse multiple citations as follows: [@gls:hypertrees; @levesque:functional-foundations].", "\n\nFootnotes\n---------\n\nPlace footnotes at the bottom of the page in a 9-point font. ", "Refer to them with superscript numbers.[^3] Separate them from the text by a short line.[^4] Avoid footnotes as much as possible; they interrupt the flow of the text.", "\n\nIllustrations\n=============\n\nPlace all illustrations (figures, drawings, tables, and photographs) throughout the paper at the places where they are first discussed, rather than at the end of the paper. ", "If placed at the bottom or top of a page, illustrations may run across both columns.", "\n\nIllustrations must be rendered electronically or scanned and placed directly in your document. ", "All illustrations should be in black and white, as color illustrations may cause problems. ", "Line weights should be 1/2-point or thicker. ", "Avoid screens and superimposing type on patterns as these effects may not reproduce well.", "\n\nNumber illustrations sequentially. ", "Use references of the following form: Figure 1, Table 2, etc. ", "Place illustration numbers and captions under illustrations. ", "Leave a margin of 1/4-inch around the area covered by the illustration and caption. ", "Use 9-point type for captions, labels, and other text in illustrations.", "\n\nAcknowledgments {#acknowledgments .unnumbered}\n===============\n\nThe preparation of these instructions and the LaTeX and BibTeX files that implement them was supported by Schlumberger Palo Alto Research, AT&T Bell Laboratories, and Morgan Kaufmann Publishers. ", "Preparation of the Microsoft Word file was supported by IJCAI. ", "An early version of this document was created by Shirley Jowell and Peter F. Patel-Schneider. ", "It was subsequently modified by Jennifer Ballentine and Thomas Dean, Bernhard Nebel, and Daniel Pagenstecher. ", "These instructions are the same as the ones for IJCAI–05, prepared by Kurt Steinkraus, Massachusetts Institute of Technology, Computer Science and Artificial Intelligence Lab.", "\n\nLaTeX and Word Style Files {#stylefiles}\n==========================\n\nThe LaTeX and Word style files are available on the IJCAI–18 website, [http://www.ijcai-18.org/]{}. ", "These style files implement the formatting instructions in this document.", "\n\nThe LaTeX files are [ijcai18.sty]{} and [ijcai18.tex]{}, and the BibTeX files are [named.bst]{} and [ijcai18.bib]{}. ", "The LaTeX style file is for version 2e of LaTeX, and the BibTeX style file is for version 0.99c of BibTeX ([*not*]{} version 0.98i). ", "The [ijcai18.sty]{} file is the same as the [ijcai07.sty]{} file used for IJCAI–07.", "\n\nThe Microsoft Word style file consists of a single file, [ijcai18.doc]{}. ", "This template is the same as the one used for IJCAI–07.", "\n\nThese Microsoft Word and LaTeX files contain the source of the present document and may serve as a formatting sample.", "\n\nFurther information on using these styles for the preparation of papers for IJCAI–18 can be obtained by contacting [[email protected]]{}.", "\n\n[^1]: <https://proceedings.ijcai.org/info>\n\n[^2]: You may want also to use the package [latexsym]{}, which defines all symbols known from the old LaTeX version.", "\n\n[^3]: This is how your footnotes should appear.", "\n\n[^4]: Note the line separating these footnotes from the text.", "\n" ]

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[ "Sofa Tables\n\nOur side tables fit nicely almost anywhere; behind a couch, in a hallway, or against a wall in any room. ", "Available with 1″ thick top, plank-style or smooth top with breadboard ends. ", "Available in a variety of sizes, you can choose turned or tapered legs. ", "All our table tops are hand planed and finished in a variety of stains, colors, and combinations. ", "Drawers, as well as a shelf below, can be added to help with storage needs.", "\n\nAll lumber is purchased in maximum width and in the rough from local lumberyards. ", "It is carefully selected and milled in our shop. ", "This allows us optimal use of our wood selection, ensuring most of the wood is used in both width and thickness, so there is little waste. ", "We strive to leave as much of the natural character in each piece created. ", "Then we distress and sand all edges for an aged, worn unique one of a kind look. ", "All painted pieces are also distressed and sanded for a worn look.", "\n\nOur bases feature mortise and tenon joinery as well as newer techniques such as metal brackets and machine threaded inserts and bolts. ", "Sliders and other hardware are used to allow for wood movement, which is so critical in solid wood furniture.", "\n\nDetermining the best Size Carolina Farmhouse Coffee or End Table for your space:\n\nCreating your living space in your house is one of the most important things you can do to personalize it and make it a “home”. ", "This includes creating the right balance of furniture and negative space. ", "Do you have a clean, modern aesthetic, or have more of a bohemian vibe in mind? ", "As you look around your room, consider the amount of space you have to work with and choose your table size accordingly. ", "Take good measurements and factor in the furniture you have in the room such as couches, entertainment centers, decorative pieces, as well as envisioning any pieces you may add down the road." ]

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[ "# -*- coding: utf-8 -*-\n#\n# || ____ _ __\n# +------+ / __ )(_) /_______________ _____ ___\n# | 0xBC | / __ / / __/ ___/ ___/ __ `/_ / / _ \\\n# +------+ / /_/ / / /_/ /__/ / / /_/ / / /_/ __/\n# || || /_____/_/\\__/\\___/_/ \\__,_/ /___/\\___/\n#\n# Copyright (C) 2018 Bitcraze AB\n#\n# This program is free software; you can redistribute it and/or\n# modify it under the terms of the GNU General Public License\n# as published by the Free Software Foundation; either version 2\n# of the License, or (at your option) any later version.", "\n#\n# This program is distributed in the hope that it will be useful,\n# but WITHOUT ANY WARRANTY; without even the implied warranty of\n# MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. ", " See the\n# GNU General Public License for more details.", "\n# You should have received a copy of the GNU General Public License\n# along with this program; if not, write to the Free Software\n# Foundation, Inc., 51 Franklin Street, Fifth Floor, Boston,\n# MA 02110-1301, USA.", "\n\n\"\"\"\nDialog box used to configure anchor positions. ", "Used from the LPS tab.", "\n\"\"\"\nimport logging\n\nimport cfclient\nfrom PyQt5 import QtWidgets\nfrom PyQt5 import uic\nfrom PyQt5.QtCore import QAbstractTableModel, QVariant, Qt\nfrom PyQt5.QtGui import QBrush, QColor\nfrom PyQt5.QtWidgets import QInputDialog, QFileDialog\nimport yaml\nimport os\n\n__author__ = 'Bitcraze AB'\n__all__ = ['AnchorPositionDialog']\n\nlogger = logging.getLogger(__name__)\n\n(anchor_postiong_widget_class, connect_widget_base_class) = (\n uic.loadUiType(\n cfclient.module_path + '/ui/dialogs/anchor_position_dialog.ui')\n)\n\n\nclass AnchorPositionConfigTableModel(QAbstractTableModel):\n def __init__(self, headers, parent=None, *args):\n QAbstractTableModel.__init__(self, parent)\n self._anchor_positions = []\n self._headers = headers\n self._latest_known_anchor_positions = {}\n\n self._green_brush = QBrush(QColor(200, 255, 200))\n self._red_brush = QBrush(QColor(255, 200, 200))\n\n def rowCount(self, parent=None, *args, **kwargs):\n return len(self._anchor_positions)\n\n def columnCount(self, parent=None, *args, **kwargs):\n return len(self._headers)\n\n def data(self, index, role=None):\n value = self._anchor_positions[index.row()][index.column()]\n if index.isValid():\n if index.column() == 0:\n if role == Qt.", "CheckStateRole:\n return QVariant(value)\n elif index.column() == 1:\n if role == Qt.", "DisplayRole:\n return QVariant(value)\n else:\n if role == Qt.", "DisplayRole:\n return QVariant('%.2f' % (value))\n elif role == Qt.", "EditRole:\n return QVariant(value)\n elif role == Qt.", "BackgroundRole:\n return self._get_background(index.row(), index.column())\n\n return QVariant()\n\n def setData(self, index, value, role=Qt.", "EditRole):\n if not index.isValid():\n return False\n\n self._anchor_positions[index.row()][index.column()] = value\n return True\n\n def headerData(self, col, orientation, role=None):\n if orientation == Qt.", "Horizontal and role == Qt.", "DisplayRole:\n return QVariant(self._headers[col])\n return QVariant()\n\n def flags(self, index):\n if not index.isValid():\n return None\n\n if index.column() == 0:\n return Qt.", "ItemIsEnabled | Qt.", "ItemIsUserCheckable\n elif index.column() == 1:\n return Qt.", "ItemIsEnabled\n else:\n return Qt.", "ItemIsEnabled | Qt.", "ItemIsEditable\n\n def add_anchor(self, anchor_id, x=0.0, y=0.0, z=0.0):\n if not self._id_exist(anchor_id):\n self.layoutAboutToBeChanged.emit()\n self._anchor_positions.append([0, anchor_id, x, y, z])\n self._anchor_positions.sort(key=lambda row: row[1])\n self.layoutChanged.emit()\n\n def replace_anchors_from_latest_known_positions(self):\n self.replace_anchor_positions(self._latest_known_anchor_positions)\n\n def replace_anchor_positions(self, anchor_positions):\n self.layoutAboutToBeChanged.emit()\n self._anchor_positions = []\n for id, position in anchor_positions.items():\n self.add_anchor(id, x=position[0], y=position[1], z=position[2])\n self.layoutChanged.emit()\n\n def get_anchor_postions(self):\n result = {}\n for row in self._anchor_positions:\n result[row[1]] = (row[2], row[3], row[4])\n return result\n\n def anchor_postions_updated(self, anchor_positions):\n self.layoutAboutToBeChanged.emit()\n self._latest_known_anchor_positions = anchor_positions\n self.layoutChanged.emit()\n\n def remove_selected_anchors(self):\n self.layoutAboutToBeChanged.emit()\n self._anchor_positions = list(filter(\n lambda row: row[0] == 0, self._anchor_positions))\n self.layoutChanged.emit()\n\n def _id_exist(self, anchor_id):\n for anchor in self._anchor_positions:\n if anchor[1] == anchor_id:\n return True\n return False\n\n def _get_background(self, row, col):\n id = self._anchor_positions[row][1]\n if id in self._latest_known_anchor_positions:\n current_value = self._anchor_positions[row][col]\n latest_value = self._latest_known_anchor_positions[id][col - 2]\n\n if abs(current_value - latest_value) < 0.005:\n return self._green_brush\n else:\n return self._red_brush\n\n return QVariant()\n\n\nclass AnchorPositionDialog(QtWidgets.", "QWidget, anchor_postiong_widget_class):\n\n def __init__(self, lps_tab, *args):\n super(AnchorPositionDialog, self).__init__(*args)\n self.setupUi(self)\n\n self._current_folder = os.path.expanduser('~')\n\n self._lps_tab = lps_tab\n\n self._headers = ['', 'id', 'x', 'y', 'z']\n self._data_model = AnchorPositionConfigTableModel(self._headers, self)\n self._table_view.setModel(self._data_model)\n\n self._table_view.verticalHeader().setVisible(False)\n\n header = self._table_view.horizontalHeader()\n header.setSectionResizeMode(0, QtWidgets.", "QHeaderView.", "ResizeToContents)\n header.setSectionResizeMode(1, QtWidgets.", "QHeaderView.", "ResizeToContents)\n header.setSectionResizeMode(2, QtWidgets.", "QHeaderView.", "Stretch)\n header.setSectionResizeMode(3, QtWidgets.", "QHeaderView.", "Stretch)\n header.setSectionResizeMode(4, QtWidgets.", "QHeaderView.", "Stretch)\n\n self._add_anchor_button.clicked.connect(\n self._add_anchor_button_clicked)\n self._remove_anchors_button.clicked.connect(\n self._data_model.remove_selected_anchors)\n self._get_from_anchors_button.clicked.connect(\n self._get_from_anchors_button_clicked)\n self._write_to_anchors_button.clicked.connect(\n self._write_to_anchors_button_clicked)\n self._close_button.clicked.connect(self.close)\n self._load_button.clicked.connect(\n self._load_button_clicked)\n self._save_button.clicked.connect(\n self._save_button_clicked)\n\n def _add_anchor_button_clicked(self):\n anchor_id, ok = QInputDialog.getInt(\n self, \"New anchor\", \"Enter id\", min=0, max=255)\n if ok:\n self._data_model.add_anchor(anchor_id)\n\n def _get_from_anchors_button_clicked(self):\n self._data_model.replace_anchors_from_latest_known_positions()\n\n def _write_to_anchors_button_clicked(self):\n anchor_positions = self._data_model.get_anchor_postions()\n self._lps_tab.write_positions_to_anchors(anchor_positions)\n\n def anchor_postions_updated(self, anchor_positions):\n self._data_model.anchor_postions_updated(anchor_positions)\n\n def _load_button_clicked(self):\n names = QFileDialog.getOpenFileName(self, 'Open file',\n self._current_folder,\n \"*.yaml;;*.*\")", "\n\n if names[0] == '':\n return\n\n self._current_folder = os.path.dirname(names[0])\n\n f = open(names[0], 'r')\n with f:\n data = yaml.load(f)\n\n anchor_positions = {}\n for id, pos in data.items():\n anchor_positions[id] = (pos['x'], pos['y'], pos['z'])\n self._data_model.replace_anchor_positions(anchor_positions)\n\n def _save_button_clicked(self):\n anchor_positions = self._data_model.get_anchor_postions()\n data = {}\n for id, pos in anchor_positions.items():\n data[id] = {'x': pos[0], 'y': pos[1], 'z': pos[2]}\n\n names = QFileDialog.getSaveFileName(self, 'Save file',\n self._current_folder,\n \"*.yaml;;*.*\")", "\n\n if names[0] == '':\n return\n\n self._current_folder = os.path.dirname(names[0])\n\n if not names[0].endswith(\".yaml\") and names[0].find(\".\") ", "< 0:\n filename = names[0] + \".yaml\"\n else:\n filename = names[0]\n\n f = open(filename, 'w')\n with f:\n yaml.dump(data, f)\n" ]

{ "pile_set_name": "Github" }

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[ "Q:\n\nIs there a way to merge the input and its placeholder classes in CSS?", "\n\nI have a simple input element as following:\n\nI styled the element and its placeholder text as follows:\ninput {\n height: 40px;\n width: 600px;\n}\n\ninput::placeholder {\n padding: 10px;\n line-height: 1.5em;\n color: #959595;\n font-size: 14px;\n}\n\nCan I merge these two into one block in CSS? ", "Is that possible?", "\nThanks\n\nA:\n\nDepends on what you mean!", "\n// input.css\ninput, input::placeholder {\n height: 40px;\n width: 600px;\n padding: 10px;\n line-height: 1.5em;\n color: #959595;\n font-size: 14px;\n}\n\nI'd recommend using something like SASS for easy control. (", "variables and such)\n// input.scss\ninput {\n height: 40px;\n width: 600px;\n &::placeholder {\n padding: 10px;\n line-height: 1.5em;\n color: #959595;\n font-size: 14px;\n }\n}\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Emergence of drug resistance-associated mutations in HIV-1 subtype C protease gene in north India.", "\nA major cause of anti-retroviral therapy (ART) failure is the drug resistance-associated mutations in polymerase gene of HIV-1. ", "Paucity of data regarding potential drug resistance to protease inhibitors (PIs) prompted us to carry out this study. ", "Drug resistance (DR) genotyping of the entire protease gene was performed in 104 HIV-1 ART-naive and first-line ART-experienced patients. ", "The DR pattern was analyzed using the Stanford HIV-DR database, International AIDS Society-USA mutation list and REGA algorithm version 8.0. ", "Subtyping was done using Mega 4 and REGA HIV-1 subtyping tool-v2.01. ", "Majority of our sequences 98 (96%) were subtype C and remaining four (3.92%) were subtype A1. ", "In three (2.9%) DE patients, major DR-associated mutation at D30 N and M46I positions were detected. ", "Approximately 70% polymorphisms as minor mutations were observed in protease gene, of which 14 distinct amino acids changes were linked to partial DR such as G16E, K20R, M36I, D60E, I62V, L63P, I64M, H69K, T74A/S, V77I, V82I, I85V, L89M, and I93L. The two major and several minor mutations detected in this study confer low/intermediate levels of resistance to most PIs independently or together. ", "Our results conclude that resistance testing in HIV-1-infected patients should be performed before the initiation of PI therapy for better therapeutic outcome in this region. ", "This information not only will shed light on the extent of current DR in HIV strains but also will aid in patient treatment and drug designing." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "1. ", "Field of the Invention\nThe present invention relates to the fixation of heavy metal contaminants present in soil using microwave radiation. ", "More particularly, it relates to a method for fixing and rendering non-leachable the heavy metal contaminants present in soil contaminated with heavy metal containing oily wastes such as refinery waste oil streams.", "\n2. ", "Description of the Related Art\nThe treatment of metal- and oil-contaminated soils is the subject of much ongoing research. ", "This is so because of the limits on the amount of hazardous wastes which can be discharged into the environment and the requirement that contaminated sites be cleaned up. ", "Microwave radiation has been investigated as useful in remediation/clean-up activities, see for example \"Microwave Treatment of Hazardous Wastes: Removal of Volatile and Semi-Volatile Organic Contaminants From Soil\" Windgasse et al, Journal of Microwave Power and Electromagnetic Energy, Vol. ", "26, No. ", "1, 1992, pp. ", "23-32; \"Microwave Treatment of Hazardous Wastes: Fixation of Chromium in Soil\", Sedhom et al, Journal of Microwave Power and Electromagnetic Energy, Vol. ", "27, No. ", "2, 1992, pp. ", "81-86; \"Microwave Treatment of Hazardous Wastes: Remediation of Soils Contaminated by Non-Volatile Organic Chemicals Like Dioxins\", Zhu et al, Journal of Microwave Power and Electromagnetic Energy, Vol. ", "27, No. ", "1, 1992, pp. ", "54-61.", "\nNumerous patents also address the use of microwave radiation energy in decontaminating soil contaminated with heavy metals and/or oily wastes. ", "See U.S. Pat. ", "No. ", "5,209,604; U.S. Pat. ", "No. ", "5,193,934; U.S. Pat. ", "No. ", "5,190,405; U.S. Pat. ", "No. ", "5,169,263; U.S. Pat. ", "No. ", "5,110,364; U.S. Pat. ", "No. ", "5,076,727." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "\n\nSo You're A Startup: How To Create & Maintain An Advisory Board - meangeme\nhttp://velocity.uwaterloo.ca/startups/startup-create-advisory-board\n\n======\npg\nThe high bit is don't, unless you're working in some specialized industry\nwhere credentials count for a lot.", "\n\n~~~\ndebacle\nWhat about scaling (in the non technical sense)? ", "There are some vital\nancillary (oxymoron?) ", "roles in a large scale company that a lot of founders\nwill likely be bad at (support, administration, etc).", "\n\nObviously these are Good Problems to Have, but how do you best obtain that\nknowledge?", "\n\n" ]

{ "pile_set_name": "HackerNews" }

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[ "Q:\n\nInteger comparison with Twig Symfony 4\n\nI'm trying to do some comparisions using Twig on Symfony, in order to show a text with different style, but I'm getting a strange result. ", "The value comes from my entity (Context) function :\n public function getDaysToExpire(): int\n {\n $creationDate = $this->created_at;\n $duration = $this->duration;\n $finalDate = $creationDate->modify('+' . ", "$duration . ' ", "days');\n $currentDate = new \\DateTime();\n $difference = $currentDate->diff($finalDate);\n\n return $difference->days;\n }\n\nIt's working as expected and returning an integer as result.", "\nOn my Twig I have :\n{% if context.getDaysToExpire > 5 %}\n <p class=\"context-days\">Jours restants : {{ context.getDaysToExpire }}</p>\n{% else %}\n <p class=\"context-days\">Jours restants : <span class=\"bolder\">{{ context.getDaysToExpire }}</span></p>\n{% endif %}\n\nIf I don't use if clauses, I get the correct value from context.getDaysToExpire. ", "However, with this code I get an strange result : + 30 for the first condition and + random values for the second one.", "\nWhat I'm doing wrong ?", "\n\nA:\n\nThis should work\npublic function getDaysToExpire(): int\n{\n $creationDate = clone $this->created_at; // prevent modification on $this->created_at\n $duration = $this->duration;\n $finalDate = $creationDate->modify('+' . ", "$duration . ' ", "days');\n $currentDate = new \\DateTime();\n $difference = $currentDate->diff($finalDate);\n\n return $difference->days;\n}\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "WITH THE RESCUE of Captain Richard Phillips from a pirate-filled lifeboat in the Indian Ocean, President Obama has survived the first dramatic crisis of his administration with colors flying. ", "All the world was watching to see how a new, untested president would react to one of the most elemental tests of any president: how to handle the public kidnapping of an American citizen being held for ransom. ", "The deeper crises he faces are long-term ones and will not be resolved so easily, but the success of Easter Sunday will make it all a little easier politically.", "\n\nObama was lucky that it was only one American, and not a whole embassy full as in Tehran 30 years ago - a crisis that ended with the hostages being released after 444 days and a failed rescue mission, but ended any chance that President Carter would have a second term.", "\n\nObama was lucky, too, in that he was dealing with pirates beyond the law of any nation, not a sovereign state, and on the open ocean and not among the warrens of a hostile town. ", "The whole incident was over in a matter of days, not months.", "\n\nIt takes nothing away from the skill of the US Navy Seal sharpshooters to say there was a good deal of luck that the incident did not end in tragedy. ", "If the pirates had not gotten careless and showed themselves - perhaps they thought they were protected by darkness - there might have been days of national mourning for an undoubted hero.", "\n\nObama's handling of the affair went beyond luck, however. ", "He didn't heed the advice of those on the left who said the pirates were only businessmen of sorts and that ransom should be paid, as is the custom. ", "Nor did he bluster and threaten the way Teddy Roosevelt famously did over the kidnapping of an American, Ion Perdicaris, by a Moroccan bandit named Mulai Ahmed Raisuli 105 years ago. ", "The statement that America wanted \"Perdicaris alive or Raisuli dead\" electrified the Republican convention in Chicago that year, and if there was any hesitation over TR's renomination before, there was none after.", "\n\nTR sent warships to Tangier, but the matter was resolved when the Moroccan government paid the ransom. ", "That Perdicaris had renounced his American citizenship years before was kept a secret. ", "The Perdicaris incident was recalled in right-wing blogs last week before the Phillips rescue, almost wishing that Obama would be found wanting. ", "But Obama never said \"Captain Phillips alive or Somali pirates dead.\" ", "As it was, he got both.", "\n\nThere could not be two more different men than Roosevelt, the greatest political showman of his age, and no-drama Obama. ", "But by sensibly not urging a surrender to pirate demands, and leaving it to the officers of the USS Bainbridge to decide when and if to use lethal force, Obama won the day. ", "US bombers are not raining down death on Somali villages, nor is a shameful tribute being paid - neither overreaction, nor under-reaction. ", "There was a certain symmetry, too, in the rescue ship USS Bainbridge being named for William Bainbridge, one of the American Navy officers who helped suppress piracy on the Barbary Coast of Africa 200 years ago.", "\n\nThe Somali problem persists, however, and, as the pirates threaten, they may seek revenge against Americans or other foreigners. ", "Memories of \"Black Hawk Down\" and the failure of other expeditionary forces in Somalia stay the hands of those who would go in with Marines and clear the pirates out. ", "Casualties among noncombatants would be high, and Somalia is the quintessential failed state with little chance of beneficial change anytime soon.", "\n\nAn answer could lie in a convoy system for merchant ships, which would make it easier for navies to guard them than with shipping spread out and uncoordinated over vast stretches of ocean. ", "Perhaps an exclusion zone far out to sea in which fishing vessels would be banned might help, as pirates use fishing boats to stalk their prey.", "\n\nThe current situation of pirates getting richer and richer on ransoms, and ranging farther and farther out to sea to disrupt shipping and taking hostages, however, is no longer acceptable, and never should have been.", "\n\nyes, yes, julie understand: absolutely no matter what, you right and your side win.", "\n\nwhatever make you feel better, dipshit.", "\n\nno...it simple really...you think aye am a republican. ", "and aye am not. ", "aye don't like republicans...aye do find them to have helped indigo agenda though...aye don't like dems either...and they need to come together...moderates need to bring more liberals into the fold...esp.on national security issues.", "\n\n\"w\" was a pub...but aye appreciate his wrangler politiques\n\nand \"'bam\" is a crat...and aye appreciate his good cop politics...\n\nget it?", "\n\nboth have destroyed the \"dovesellers\" like yourself...get it, bigotboy?", "\n\nyou know who aye didn't want in the c.i.c. ", "position, right...your girl hiliary...and she is not." ]

{ "pile_set_name": "Pile-CC" }

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[ "Q:\n\nInput only to bottom line of terminal\n\nI made a command-line chat client with Java, that sends the messages from stdin to the server and, at the same time, receives messages from the server to stdout at the same time. ", "It's likely that somebody may send a message while you're writing one, so I want the bottom line of the terminal always reserved for input, so that output appears above it.", "\nI hope you understand my question and I apologize in advance if you don't.", "\n\nA:\n\nThe JCurses library will do exactly what you need. ", "\nhttp://sourceforge.net/projects/javacurses/\nIt's a Java implementation of ncurses from the *nix operating systems. ", "On Windows, you'll need to include the .dll files, on most linux distros, you don't need to do anything except include the jar in your classpath.", "\nThe reason you need a library to build a \"command line gui\" is because standard java is not capable of manipulating the local command line in this fashion. ", "This is likely due to how Java is not built for a specific platform - but that's just a guess.", "\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "\n889 P.2d 1212 (1995)\n119 N.M. 290\nDIVERSIFIED DEVELOPMENT & INVESTMENT, INC., ", "Plaintiff-Appellant,\nv.\nHelga HEIL and Dorothy S. Holmberg, co-personal representatives of the Estate of Anne Pickard, deceased, and the Estate of Anne Pickard, Defendants/Third-Party-Plaintiffs-Appellees,\nand\nPatrick Hurley and Lee Welsh, Defendants/Third-Party-Defendants-Appellees.", "\nNo. ", "21320.", "\nSupreme Court of New Mexico.", "\nJanuary 25, 1995.", "\n*1215 Dubois, Caffrey, Cooksey & Bischoff, P.A., William J. Cooksey, Albuquerque, for appellant.", "\nFreedman, Boyd, Daniels, Peifer, Hollander, Guttmann & Goldberg, P.A., Joseph Goldberg and K. Lee Peifer, Albuquerque, for appellees Helga Heil et al.", "\nRodey, Dickason, Sloan, Akin & Robb, P.A., Bruce Hall and Edward Ricco, Albuquerque, for appellee Patrick Hurley.", "\nGallagher, Casados & Mann, P.C., Nathan Mann, Albuquerque, for appellee Lee Welsh.", "\n\nOPINION\nRANSOM, Justice.", "\nDiversified Development & Investment, Inc., sued the estate of Anne Pickard and its personal representatives, Helga Heil and Dorothy Holmberg, (collectively, \"the Estate\") for breach of contract, misrepresentation, and prima facie tort in connection with a contractual option to purchase real estate. ", "After the Estate filed a third-party claim for indemnification and legal malpractice against its attorney, Patrick Hurley, Diversified Development filed a claim against Hurley for breach of contract, misrepresentation, and prima facie tort, and asked for punitive damages. ", "Before ruling on a motion filed by Diversified Development to compel discovery, the district court granted summary judgments in favor of the Estate and Hurley.", "\nDiversified Development appeals pursuant to SCRA 1986, 12-102(A)(1) (Repl. ", "Pamp.1992) (count sounding in contract). ", "We find that the court erred in granting summary judgment before ruling on the motion to compel discovery. ", "We therefore reverse the judgment in favor of the Estate on Diversified Development's claim that Hurley had actual authority to grant an extension of the purchase option. ", "Further, we hold that the trial court should compel discovery of certain communications between the Estate and Hurley. ", "Finally, we find that Diversified Development raised a genuine issue as to Hurley's actual or apparent authority to communicate whether the Estate agreed to an extension of the option deadline. ", "We therefore hold that, on remand, Diversified Development may pursue its theory that Hurley's statements thus could bind the Estate.", "\nFacts. ", "In March 1990 Diversified Development executed an agreement with New Jersey residents Heil and Holmberg in which Diversified Development was given a six-month option to purchase approximately sixteen acres of unimproved Albuquerque real estate for $575,000. ", "The agreement empowered Diversified Development to extend the purchase option for an additional six months upon written notification to the Estate. ", "Diversified Development exercised this right to an extension in a letter delivered to Hurley from Diversified Development's attorney, Ray Baehr. ", "This extension gave Diversified Development until March 31, 1991, to exercise the purchase option.", "\nIn February 1991 Diversified Development asked Lee Welsh, a real estate agent for the Estate, to determine whether the Estate would consider modifications to the agreement's financing terms. ", "Diversified Development's president, Chester Hearn, testified that Welsh assured him he had talked to Heil and Holmberg and that they were receptive to \"some modifications of the financing arrangements.\" ", "Diversified Development emphasized to Welsh that it wished to retain the right to exercise the original purchase option if financing modifications could not be worked out.", "\nIn a letter sent to Welsh, Heil, Hurley, and Baehr dated March 22, 1991, Diversified Development put its financing modification request in writing. ", "In this letter Hearn reaffirmed Diversified Development's intent to purchase the parcel of land and requested a ninety-day extension of the existing option pending execution of the modified agreement. ", "Baehr testified that during the week of March 25 he telephoned Hurley to inquire about the status of the March 22 extension request and to set up a meeting before the March 31 option deadline to discuss whether the Estate would accept the alternative financing proposal. ", "He testified that Hurley was not able to meet with him but assured him that \"a few days one way or another [will] not make any difference\" and \"these *1216 ladies are not going to hold [Diversified Development] to the [option deadline.]\"", "\nHurley conceded only that on March 29 he told Baehr he had talked to Heil and that the Estate \"probably [would] agree to an extension—possibly more.\" ", "He stated that Heil told him it would be after the March 31 deadline before she could say whether the Estate was amenable to accepting an alteration of the option. ", "Heil insisted that Hurley had no authority to tell Baehr that the Estate \"probably [would] agree to an extension\" but acknowledged that Hurley did have authority to discuss an extension.", "\nBaehr and Hurley agreed to meet on April 4. ", "At this meeting Diversified Development and Baehr discussed the March 22 financing proposal with Hurley and Welsh and inquired whether the option would have to be exercised as written. ", "Hearn testified that at the conclusion of the meeting he asked for a written extension but Hurley insisted that one was not necessary because Diversified Development would get an answer on the financing proposal in a few days. ", "Hearn also stated that Hurley assured Diversified Development it could exercise the original purchase option if the Estate did not agree to financing modifications.", "\nBetween April 4 and April 25 Hurley had several conversations with Heil about the proposed modifications. ", "Hurley did not know that the Estate would not extend the option, however, until either April 25 or May 2. ", "On May 1 Heil and Holmberg faxed a letter directly to Baehr rejecting the proposed financing modifications and stating that the Estate was \"reviewing [its] options\" and would attempt to obtain a better price for the land. ", "On May 8 Welsh told Hearn that the Estate considered the purchase option to have expired.", "\nOn May 9 Diversified Development deposited earnest money in the amount called for by the option agreement into escrow and notified Hurley, Welsh, and Heil that it was exercising the original purchase option. ", "On May 11 the Estate instructed the escrow agent to return the earnest money to Diversified Development and to record a termination statement. ", "Approximately three months later the Estate accepted a purchase offer for $800,000 from another buyer.", "\nProceedings. ", "On February 25, 1993, following minimal pretrial discovery, Diversified Development filed a motion to compel production of memos written by Hurley detailing his conversations with Heil about the March 22 extension request. ", "Hurley refused to produce these memos, claiming attorney-client privilege. ", "The motion to compel also sought production of withheld portions of Heil's telephone diary detailing conversations with Welsh and Hurley. ", "Hurley joined in Diversified Development's motion, arguing that Heil had waived the attorney-client privilege by bringing an action against him and by offering evidence of some of the communications. ", "The court held a motion hearing on March 11 but did not rule.", "\nThe Estate and Hurley filed motions for summary judgment on February 15 and 19 respectively. ", "On March 26 and 29 those motions were heard and on April 6 the court issued a letter decision ruling in favor of the Estate and Hurley. ", "The court stated that it assumed Diversified Development's motion to compel discovery to be moot as a result of its ruling. ", "The trial court found it undisputed that Hurley lacked actual or apparent authority either to make final decisions for the Estate or to grant an extension. ", "Based on this finding, the court determined that there was no support for the contract claim. ", "The court also determined that \"Hurley made no misrepresentations for which his principals could be held liable.\" ", "Finally, the court found as a matter of law that the facts of the case did not support the prima facie tort claim.", "\nWith regard to Diversified Development's claims against Hurley, the court determined that Diversified Development could not state a contract claim because Hurley was not a principal and commented that the nature of the extension was too nebulous to represent a \"meeting of the minds as to what the duties and obligations of the parties were.\" ", "The court also determined that recovery against Hurley for prima facie tort was not supported by the facts, and that Hurley's representations were unactionable opinions upon which Diversified Development could not reasonably *1217 have relied. ", "Finally, the court found that Hurley had no duty to disclose to Diversified Development his lack of authority to grant an extension.", "\nThe motion to compel discovery. ", "The major issue in this case is whether Hurley had actual or apparent authority to bind the Estate to an extension of time within which Diversified Development could exercise the purchase option. ", "Diversified Development argues that because it was denied the opportunity to discover facts defining the nature and scope of Hurley's authority, it did not have the ability to defeat summary judgment motions by the Estate and Hurley. ", "The Estate counters that Diversified Development waived any objection to the court's decision by failing to object to the court's mootness ruling when summary judgment was granted. ", "On the merits, the Estate claims an attorney-client privilege against discovery.", "\n—Diversified Development preserved the issue. ", "To preserve an issue for appeal, \"it must appear that a ruling or decision by the district court was fairly invoked.\" ", "SCRA 1986, 12-216(A) (Repl.", "Pamp.1992); see also SCRA 1986, 1-046 (Repl. ", "Pamp.1992). ", "The purpose of requiring a party to invoke a ruling or decision by the district court is to alert the trial judge to a claim of error and give the judge an opportunity to correct any mistake. ", "Madrid v. Roybal, 112 N.M. 354, 356, 815 P.2d 650, 652 (Ct.", "App.), ", "cert. ", "denied, 112 N.M. 308, 815 P.2d 161 (1991); see also Cockrell v. Cockrell, 117 N.M. 321, 323-24, 871 P.2d 977, 979-80 (1994) (holding that challenge to sufficiency of evidence was not brought to the attention of trial court and thus was not preserved).", "\nIn its response to the Estate's motion for summary judgment Diversified Development requested \"that the Court's decision on Summary Judgment be continued pursuant to SCRA 1986, 1-056(F) [ (Repl.", "Pamp.1992) (allowing a trial judge to deny a motion for summary judgment when it appears that the party opposing the motion needs more discovery to obtain facts supporting his position) ], until such time as the Motion to Compel Discovery is decided.\" ", "Diversified Development further argued, as it had done previously and more extensively in a memorandum in support of the motion to compel, that its \"ability to fully demonstrate the extent of the dispute as to Hurley's authority [had] been hampered\" by the Estate's claim of attorney-client privilege. ", "Thus Diversified Development argued that a decision on summary judgment should be delayed until the motion to compel was decided.", "\nBy requesting the trial judge to stay his ruling on the motions for summary judgment until he had ruled on the motion to compel, by citing Rule 1-056(F), and by incorporating its prior argument that further discovery was essential to support its claims that Hurley had authority to bind the Estate, Diversified Development presented the judge with all the information necessary to make an informed decision whether the motion to compel should be decided prior to the motions for summary judgment. ", "Diversified Development thus preserved the discovery issue.", "\n—Attorney-client privilege does not extend to a client's grant of actual authority. ", "Although appellate courts generally do not address the merits of a discovery motion before the trial court has had an opportunity to do so, see Garrett v. City of San Francisco, 818 F.2d 1515, 1519 n. 4 (9th Cir.1987), for purposes of judicial economy and because the parties have briefed the issue, we will address the merits of the Estate's claim of privilege. ", "Diversified Development and Hurley urge that no privilege existed between Hurley and the Estate. ", "Alternatively, they urge that the Estate waived any privilege by bringing a third-party claim against Hurley. ", "The Estate counters that communications between itself and Hurley should be exempt from discovery under the attorney-client privilege set out in SCRA 1986, 11-503(B) (Repl.", "Pamp.1994).", "\nRule 11-503(B) states that \"[a] client has a privilege to refuse to disclose and to prevent any other person from disclosing confidential communications made for the purpose of facilitating the rendition of professional legal services to the client.\" ", "Rule 11-503(A)(4) defines a \"confidential communication\" as one \"not intended to be disclosed to third *1218 persons.\" ", "It follows from the unambiguous definition of confidential communications and from Rule 11-503 that the Estate may refuse to disclose only those communications made for the purpose of facilitating legal services and not intended to be disclosed to others.", "\nDiversified Development seeks to discover the instructions given to Hurley by the Estate and the nature and scope of his authority in regard to the purchase option deadline. \"[", "C]ourts have held that the [attorney-client] privilege does not protect the instructions or authority given by the client to his attorney....\" Paul R. Rice et al., ", "Attorney-Client Privilege in the United States § 6:22, at 467-68 (1993); see id. § 6:22, at 468 n. 35 (citing cases that have held that a client's instructions to his or her attorney and the scope of the authority granted are not protected by attorney-client privilege). ", "Explaining the reason for this rule, one federal court has stated that \"the client's grant of authority to the attorney to settle [is not protected by the attorney-client privilege] since this must be communicated to the other party to the settlement.\" ", "Willard C. Beach Air Brush Co. v. General Motors Corp., 118 F.Supp. ", "242, 244 (D.N.J. 1953), aff'd 214 F.2d 664 (3d Cir.1954). ", "Thus the attorney-client privilege does not prohibit Hurley from disclosing what the Estate authorized him to agree upon with or communicate to Diversified Development.", "\n—Incomplete discovery precluded summary judgment on actual authority claim. ", "Generally, \"a court should not grant summary judgment before a party has completed discovery, ... particularly when further factual resolution is essential to determine the central legal issues.\" ", "Sun Country Sav. ", "Bank of N.M. v. McDowell, 108 N.M. 528, 534, 775 P.2d 730, 736 (1989) (citations omitted). ", "Diversified Development may have been able to discover material facts in Hurley's memos and in the withheld portions of Heil's telephone diary defining the nature and scope of Hurley's authority. ", "The court should have examined those documents and allowed Diversified Development to discover those portions detailing the Estate's instructions to Hurley and the scope of his authority in connection with the extension of the option deadline. ", "See Garrett, 818 F.2d at 1519 (\"It was error for the trial court to have granted defendants' motion for summary judgment without first having determined the merits of plaintiff's pending [motion to compel discovery].\"); ", "Snook v. Trust Co. of Georgia Bank of Savannah, 859 F.2d 865, 871 (11th Cir. ", "1988) (\"By failing to rule on the motion to compel, the district court deprived the plaintiffs' of their right to utilize the discovery process to discover the facts necessary to justify their opposition to the [summary judgment] motion.\"). ", "Summary judgment was therefore improper on Diversified Development's claim that Hurley had actual authority to grant an extension of the option deadline.", "\nHurley did not have apparent authority to agree upon an extension. ", "In Romero v. Mervyn's, 109 N.M. 249, 253, 784 P.2d 992, 996 (1989), we stated that \"a principal... is responsible for the acts of the agent when the principal has clothed the agent with the appearance of authority.\" ", "Apparent authority arises from manifestations by the principal to the third party \"and can be created by appointing a person to a position that carries with it generally recognized duties.\" ", "Id. Because the facts necessary to prove apparent authority would be known by Diversified Development without further discovery, we decide whether summary judgment was appropriate on the issue of Hurley's apparent authority to grant an extension of the option deadline.", "\nThe record establishes that the purchase agreement could be modified only in writing. ", "The record further establishes that the Estate did not communicate directly with Diversified Development or its attorney prior to the May 1 letter rejecting the proposed financing modifications. ", "As an attorney himself, Baehr knew or should have known that an attorney does not have implied authority to approve the modification of an agreement. ", "See Augustus v. John Williams & Assoc., ", "Inc., 92 N.M. 437, 438-39, 589 P.2d 1028, 1029-30 (1979) (stating rule that attorney does not have implied authority to compromise client's cause of action (quoting Nehleber v. Anzalone, 345 So.2d 822, 822-23 (Fla. Dist.", "Ct.", "App.1977))); see, e.g., Torrao v. Cox, *1219 26 Mass.App.", "Ct. ", "247, 525 N.E.2d 1349, 1353 (1988) (stating that attorney has no power, absent express authority, to bind principal by his assent to modification of principal's contract). ", "Hurley's assertion that \"these ladies are not going to hold [Diversified Development] to [the purchase option deadline],\" without more, did not indicate Hurley was authorized to make the decision and did not absolve Baehr and Diversified Development of the duty to make further inquiry as to the extent of Hurley's authority. ", "See Warren A. Seavey, Handbook of the Law of Agency § 22(B), at 44 (1964) (\"Persons dealing with an agent ... cannot hold the principal liable for unauthorized acts of an agent which are not normally permitted to an agent in such a position.\"); ", "Comstock v. Mitchell, 110 N.M. 131, 132, 793 P.2d 261, 262 (1990) (stating that third party has duty to \"use reasonable diligence and prudence to ascertain whether the agent is acting within the scope of his powers\" (quoting 3 Am.", "Jur.2d Agency § 82 (1986))). ", "Therefore summary judgment on the issue of apparent authority to agree to an extension was appropriate.", "\nFor similar reasons, it was unreasonable for Diversified Development to infer from Hurley's above-quoted assertion that it could place any reliance on an implied representation by Hurley that he was binding the Estate. ", "Thus summary judgment was appropriate on Diversified Development's misrepresentation claim against Hurley.", "\nDiversified Development may pursue whether Hurley's statements bound the Estate to an extension. ", "Diversified Development argues that the facts it has adduced raise a question whether Hurley could bind the Estate by representing to Diversified Development that the Estate itself agreed to an extension. ", "As we understand the facts, Hurley's authority to bind the Estate may spring from two sources. ", "First, it may be argued that Hurley could bind the Estate because he had actual or apparent authority to perform discretionary acts on behalf of the Estate such as granting an extension of the option deadline. ", "We have held that summary judgment on the issue of Hurley's actual authority to grant an extension was premature in light of the pending motion to compel discovery. ", "Further, we have held that the Estate did not place Hurley in such a position that he had apparent authority to grant an extension.", "\nSecond, it may be argued that Hurley had actual or apparent authority to make binding statements representing the position of the Estate. ", "It is unclear whether Diversified Development actually argued this issue below, and consequently it is also unclear whether the trial court, as part of its grant of summary judgment, ruled that Hurley did not have speaking authority. ", "In response to questions from this Court, the parties have supplied us with briefs on this issue. ", "Because we have ruled that summary judgment was premature and are remanding this case for further discovery, and because we find that the trial court could not rule against Diversified Development as a matter of law on the issue of speaking authority under the facts presented here, Diversified Development would not be prohibited from claiming on remand that Hurley had speaking authority. ", "We therefore take this opportunity to clarify the law on this issue for purposes of aiding the trial court.", "\nAn agent's statements may bind the principal if the agent is authorized to speak. ", "When a principal gives a person authority (either actual or apparent) to do certain acts, those acts become binding on the principal because they are treated as the acts of the principal. ", "Cf. ", "Albuquerque Concrete Coring Co. v. Pan Am World Servs., ", "Inc., 118 N.M. 140, 146, 879 P.2d 772, 778 (1994) (holding corporation liable for act of managing agent because acts of agent are acts of corporation). ", "In the case of speaking authority, an agent who actually has been authorized to speak, or has been cloaked with the authority to speak, may bind his or her principal to perform the acts about which he or she speaks. ", "Speaking authority differs from authority to do acts within one's discretion such as entering into a binding modification of the principal's contract with a third party. ", "Thus an agent with speaking authority may not agree to a modification of the principal's contract but may represent the principal's position on the modification of the *1220 contract and thereby bind the principal to that modification.", "\nFor the statements, representations, or admissions of a purported agent to be binding on the principal, the fact of agency must first be established. ", "2 Floyd R. Mechem, A Treatise on the Law of Agency § 1774, at 1348 (2d ed. ", "1914). \"[", "T]he unauthorized statements of an agent to the third party concerning the existence or extent of his authority cannot be relied upon to establish apparent authority.\" ", "Comstock v. Mitchell, 110 N.M. 131, 134, 793 P.2d 261, 264 (1990) (Ransom, J., specially concurring). ", "Once the principal has manifested to a third party that another individual is his or her agent, however, statements by that agent regarding the extent of authority may bear upon whether, without further inquiry of the principal, the third party reasonably relied upon a belief about the extent of the agent's authority. ", "Even then, before the agent's extrajudicial statements concerning the extent of authority may be relied upon to excuse further inquiry, the principal first must have placed the agent in a position that would give rise to a belief in a reasonably prudent third party that the authority of the agent would extend as far as represented by the agent. ", "Thus once agency has been established, the statements, representations, or admissions made by the agent to a third party will bind the principal only if the agent was actually or apparently authorized to make the particular statements or was actually or apparently authorized to make statements on the particular subject. ", "See Restatement (Second) of Agency § 286 (1957).", "\nIn this case Hurley's agency is not disputed. ", "Hence the only question remaining is whether the facts presented an issue regarding the existence of actual or apparent speaking authority. ", "Even if the trial court was to be the finder of fact, it could not have used the summary judgment procedure to resolve a disputed issue of fact. ", "See Bergerson Plumbing & Heating, Inc. v. Poole, 111 N.M. 525, 528, 807 P.2d 223, 226 (1991) (holding that \"[a] trial court should not summarily cut to a dispositive issue without trial on the merits, even when the trial court believes the ultimate disposition is foreseeable\"). ", "If Diversified Development raised facts that, if proven, might have been interpreted in such a way as to entitle it to judgment, the court must have conducted a trial on the merits. ", "See id.\n—Actual authority to speak. ", "Actual speaking authority may be express or implied. ", "See Restatement (Second) of Agency § 7 cmt. ", "c (1957). ", "Express speaking authority will exist when the principal has told the agent that he or she may make certain statements, representations, or admissions. ", "Id. Implied speaking authority will exist when the principal appoints the agent to a position that normally carries with it the authority to make certain statements and from which position the agent reasonably believes that he is authorized to make such statements. ", "Similarly, implied speaking authority will exist when the principal expressly authorizes the agent to do an act that necessarily requires the making of statements. ", "See Warren A. Seavey, Handbook of the Law of Agency § 105(C), at 190 (1964) (\"To the extent that statements are made as part of an authorized transaction, ... a statement is authorized if the agent has reason to believe that the principal desires him to make it.\").", "\nHeil testified that Hurley had actual authority to discuss an extension of the purchase option deadline. ", "By informing Hurley that it would not make the decision whether to agree to the financing modifications until after the March 31 purchase option deadline, the Estate gave Hurley reason to believe that it was authorizing a \"grace period\" during which the original option could be exercised. ", "On remand the factfinder thus should determine whether Hurley reasonably believed Heil and Holmberg desired him to communicate to Diversified Development a temporary extension of the option agreement. ", "If Hurley had such a reasonable belief, the Estate would be bound by Hurley's statement that \"these ladies are not going to hold [Diversified Development] to the [option deadline]\" regardless of whether the Estate intended Hurley to grant an extension. ", "See Restatement (Second) of Agency § 26 cmt. ", "a (1957) (\"[T]he manifestation and not the intention of the principal is important; hence, *1221 whenever the principal manifests to the agent that the agent is to act on his account, [actual] authority exists although the principal is not in fact willing that he should do so.\").", "\n—Apparent authority to speak. ", "Whether an agent has apparent speaking authority is a question that must be determined by the trier of fact in light of the agent's duties and responsibilities. ", "See Hartman v. Port of Seattle, 63 Wash.2d 879, 389 P.2d 669, 673-74 (1964); cf. ", "Kasper v. Buffalo Bills, 42 A.D.2d 87, 345 N.Y.S.2d 244, 250-51 (1973) (adopting rule that statements made by agent will bind principal if agent had authority to speak and remanding for determination of agent's authority and responsibilities). ", "Further, evidence of the appearance of authority as created by the actions and words of the principal is always admissible to show that the agent has authority to speak. ", "See Restatement (Second) of Agency § 286 cmt. ", "b (1957); see also Sigel v. Boston & M.R.R., 107 N.H. 8, 216 A.2d 794, 806-07 (1966) (finding sufficient evidence of speaking authority to create a jury question when negotiations over proposed railroad crossing repair were initiated by defendant, defendant's representatives were vice presidents in charge of purchasing, and duties of defendant's representatives included resolving matters in relation to the company negotiated with).", "\nAs an attorney and negotiator for the Estate, Hurley had apparent authority to communicate the position of the Estate in terms of offer and acceptance. ", "Further, prior to the negotiations over the extension of the option deadline, the Estate always had communicated its wishes to Diversified Development through Hurley, and, prior to the May 1 letter faxed directly to Baehr, the Estate never had communicated directly with Diversified Development. ", "Finally, the Estate did not reject Diversified Development's proposed financing modifications or respond to Diversified Development's extension request, other than through Hurley, prior to the expiration of the option. ", "Thus because of Hurley's position, and because of the Estate's behavior toward Diversified Development in relation to the option deadline, we conclude that there was an issue of fact whether Hurley had apparent authority to speak.", "\nEven if the evidence discloses that Hurley's representations that the Estate would not hold Diversified Development to the option deadline were not correct, his misrepresentations could still be binding on the Estate. ", "Seavey, Handbook of the Law of Agency § 60, at 109; cf. ", "Wallo v. Rosenberg, 331 S.W.2d 8, 13-14 (Mo.Ct.", "App.1960) (holding that agent's fraudulent representations about the occupancy rates and expenses of a hotel were binding on the principal in an action to rescind a real estate contract). ", "The question is whether Hurley's statements reasonably could be understood as representations of the Estate's position. ", "When a speaking agent makes a statement that is susceptible to more than one reasonable interpretation, the principal cannot complain that a third party relied on one reasonable interpretation over another. ", "Thus, if the Estate placed Hurley in a position from which Diversified Development could reasonably conclude that he had authority to communicate the Estate's position on the proposed extension request, the Estate cannot complain to the third party that its agent acted contrary to its wishes.", "\nReasonableness of interpretation is a question of fact. ", "We have discussed the binding nature of a representation by an agent with speaking authority. ", "We hasten to distinguish that issue from the issue whether Diversified Development reasonably interpreted Hurley's statements as representations of the Estate's extension of a grace period for exercise of this purchase option. ", "From statements such as \"a few days one way or another would not make any difference\" and \"[t]hese ladies are not going to hold you to the line\" there is raised a genuine issue of material fact whether Diversified Development did reasonably rely on Hurley's statements as a representation of the Estate's position.", "\nStatute of frauds not a bar. ", "As a contract for the sale of land, the contract between Diversified Development and the Estate is governed by the statute of frauds and must be in writing. ", "See Robinson v. Black, 73 N.M. 116, 118-19, 385 P.2d 971, 973 *1222 (1963). ", "The Estate argues that because the contract falls within the statute of frauds, the oral modification of the option agreement, to be enforceable, had to be in writing. ", "We disagree and conclude that Hurley could bind the Estate to an extension of the option deadline by orally conveying the Estate's agreement to an extension.", "\nRelying on this Court's prior decisions in Dave Zerwas Co. v. James Hamilton Construction Co., 117 N.M. 724, 876 P.2d 653 (1994), and Yrisarri v. Wallis, 76 N.M. 776, 418 P.2d 852 (1966), the Estate argues that an oral modification of the option deadline is unenforceable because of the statute of frauds. ", "In Yrisarri this Court held that parole evidence was not admissible to \"contradict, vary, modify, or add to a written agreement.\" ", "76 N.M. at 779, 418 P.2d at 854 (quoting Maine v. Garvin, 76 N.M. 546, 550-51, 417 P.2d 40, 43 (1966)). ", "In Zerwas we stated that \"a modification to an agreement within the Statute of Frauds must be in writing ... because it is, in essence, a new agreement.\" ", "117 N.M. at 726, 876 P.2d at 655.", "\nWhile we believe Yrisarri and Zerwas correctly stated the general law, we must reconcile those cases with other New Mexico law. ", "In Kingston v. Walters, 16 N.M. 59, 64, 113 P. 594, 595 (1911), we held that \"a subsequent verbal modification of the time of performance fixed by a written agreement for the sale of real estate will be regarded ... as valid.\" ", "This holding recognized that parties to a written contract controlled by the statute of frauds may orally modify the contract and the modification will be enforced if one of the parties materially changes its position in reasonable reliance on the subsequent oral agreement. ", "Id. at 64-65, 113 P. at 595; see Restatement (Second) of Contracts § 150 (1979) (stating that statute of frauds does not bar enforcement of subsequent oral modification if enforcement of original terms would be unjust in view of one party's material change in position). ", "We believe these holdings may be reconciled insofar as the extension of the option agreement in Kingston did not so alter the real estate sale agreement as to create, in effect, a new agreement. ", "As in Kingston, the oral modification between Diversified Development and the Estate, if authorized, would be enforceable notwithstanding the statute of frauds.", "\nThe court erred in dismissing Diversified Development's prima facie tort claim against the Estate. ", "In recognizing prima facie tort as a cause of action in Schmitz v. Smentowski, 109 N.M. 386, 394, 785 P.2d 726, 734 (1990), we stated that the cause of action was intended to provide \"a remedy for plaintiffs who have been harmed by a defendant's intentional and malicious acts\" and who have no other legal remedy. ", "For liability under this cause of action to attach, a defendant's conduct must be both wrongful and unjustifiable. ", "Id. at 394-95, 785 P.2d at 734-35. ", "Because the court entered judgment before ruling on the motion to compel, the evidence of intent was not fully developed. ", "The withheld portions of Heil's telephone diary may have established the Estate's knowledge and intent; therefore dismissal of the cause of action before ruling on the motion to compel was premature. ", "There being no genuine issue of material fact in this regard on the part of Hurley, however, summary judgment was properly granted in his favor on this issue.", "\nConclusion. ", "We reverse the judgments in favor of the Estate except the judgment based on Hurley's lack of apparent authority to grant an extension. ", "We affirm the judgments in favor of Hurley. ", "The case is remanded to the trial court for further proceedings consistent with this opinion.", "\nIT IS SO ORDERED.", "\nBACA, C.J., and FROST, J., concur.", "\n" ]

{ "pile_set_name": "FreeLaw" }

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[ "/*\n * Copyright 2015 the original author or authors.", "\n * @https://github.com/scouter-project/scouter\n *\n * Licensed under the Apache License, Version 2.0 (the \"License\");\n * you may not use this file except in compliance with the License.", "\n * You may obtain a copy of the License at\n *\n * http://www.apache.org/licenses/LICENSE-2.0\n *\n * Unless required by applicable law or agreed to in writing, software\n * distributed under the License is distributed on an \"AS IS\" BASIS,\n * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.", "\n * See the License for the specific language governing permissions and\n * limitations under the License.", "\n *\n */\n\npackage scouterx.webapp.layer.controller;\n\nimport io.swagger.annotations.", "Api;\nimport scouterx.webapp.framework.client.server.", "ServerManager;\nimport scouterx.webapp.framework.util.", "ZZ;\nimport scouterx.webapp.layer.service.", "GlobalKvStoreService;\nimport scouterx.webapp.model.", "KeyValueData;\nimport scouterx.webapp.request.", "SetKvBulkRequest;\nimport scouterx.webapp.request.", "SetKvRequest;\nimport scouterx.webapp.request.", "SetKvTTLRequest;\nimport scouterx.webapp.view.", "CommonResultView;\n\nimport javax.inject.", "Singleton;\nimport javax.ws.rs.", "Consumes;\nimport javax.ws.rs.", "GET;\nimport javax.ws.rs.", "PUT;\nimport javax.ws.rs.", "Path;\nimport javax.ws.rs.", "PathParam;\nimport javax.ws.rs.", "Produces;\nimport javax.ws.rs.", "QueryParam;\nimport javax.ws.rs.core.", "MediaType;\nimport java.util.", "List;\n\n/**\n * @author Gun Lee ([email protected]) on 2017. ", "8. ", "27.", "\n */\n@Path(\"/v1/kv\")\n@Api(\"GlobalKeyValueStore\")\n@Singleton\n@Produces(MediaType.", "APPLICATION_JSON)\npublic class GlobalKvStoreController {\n\n private final GlobalKvStoreService kvStoreService = new GlobalKvStoreService();\n\n /**\n * get value by key from scouter key-value store\n */\n @GET\n @Path(\"/{key}\")\n @Consumes(MediaType.", "APPLICATION_JSON)\n public CommonResultView<String> get(@PathParam(\"key\") String key, @QueryParam(\"serverId\") int serverId) {\n String result = kvStoreService.get(key, ServerManager.getInstance().getServerIfNullDefault(serverId));\n return CommonResultView.success(result);\n }\n\n /**\n * store key & value onto scouter key-value store\n */\n @PUT\n @Consumes(MediaType.", "APPLICATION_JSON)\n public CommonResultView<Boolean> set(SetKvRequest request) {\n kvStoreService.set(request.getKey(), request.getValue(), request.getTtl(),\n ServerManager.getInstance().getServerIfNullDefault(request.getServerId()));\n return CommonResultView.success(true);\n }\n\n /**\n * set ttl onto scouter key-value store\n */\n @PUT\n @Path(\"/{key}/:ttl\")\n @Consumes(MediaType.", "APPLICATION_JSON)\n public CommonResultView<Boolean> set(@PathParam(\"key\") String key, SetKvTTLRequest request) {\n\n kvStoreService.setTTL(key, request.getTtl(),\n ServerManager.getInstance().getServerIfNullDefault(request.getServerId()));\n\n return CommonResultView.success(true);\n }\n\n /**\n * get values by keys from scouter key-value store\n */\n @GET\n @Path(\"/{keys}/:bulk\")\n @Consumes(MediaType.", "APPLICATION_JSON)\n public CommonResultView<List<KeyValueData>> getBulk(@PathParam(\"keys\") final String keyBySeparator,\n @QueryParam(\"serverId\") final int serverId) {\n List<KeyValueData> resultList = kvStoreService.getBulk(ZZ.splitParam(keyBySeparator),\n ServerManager.getInstance().getServerIfNullDefault(serverId));\n return CommonResultView.success(resultList);\n }\n\n /**\n * store key-values on scouter key-value store\n */\n @PUT\n @Path(\"/:bulk\")\n @Consumes(MediaType.", "APPLICATION_JSON)\n public CommonResultView<List<KeyValueData>> setBulk(SetKvBulkRequest request) {\n List<KeyValueData> resultList = kvStoreService.setBulk(request.toMap(), request.getTtl(), ServerManager.getInstance().getServerIfNullDefault(request.getServerId()));\n return CommonResultView.success(resultList);\n }\n}\n" ]

{ "pile_set_name": "Github" }

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[ "Q:\n\nHow to add multiple file extensions to the Files: input field in the Foreach loop container SSIS\n\nHow could I add multiple file extensions to the Files: input field in the Foreach loop container in SSIS 2008.", "\nI have currently entered as *.zip OR .csv see image... but it doesn not work only works if I have one value like *.zip\n\nA:\n\nI don't think you can specify two file type extensions in a For each Loop container , you should use *.* ", "and you can filter for a specific extensions by using the following steps:\n\nadd a Variable of type boolean (ex: User::Flag)\nadd a script task inside the container and mark Filename variable as Readonly , Flag variable as ReadWrite\n\nInside the script write the following script\nPublic Sub Main()\n\n Dim strFile As String = Dts.", "Variables.", "Item(\"Filename\").Value.", "ToString\n\n Select Case IO.Path.", "GetExtension(strFile).ToLower\n Case \".csv\", \".zip\"\n Dts.", "Variables.", "Item(\"Flag\").Value = True\n\n Case Else\n Dts.", "Variables.", "Item(\"Flag\").Value = False\n End Select\n\n Dts.", "TaskResult = ScriptResults.", "Success\nEnd Sub\n\nAdd an expression to the Script task output connector like shown below\n\nOr you can achieve it by using a Third-party components like Foreach File Enumerator with regex\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Prime Minister Benjamin Netanyahu said some countries will only wake up to the Iranian threat when nuclear missiles fall on European soil, after the European Union on Monday declared that recent Iranian violations of a nuclear deal are not significant enough to necessitate reimposing sanctions.", "\n\nNetanyahu urged the EU to act immediately against Iran, and in a video posted on his social media invoked the memory of Britain’s failed attempt to appease Nazi Germany on the eve of World War II.", "\n\n“The response by the European Union to the Iranian violations [of the nuclear deal] reminds me of the European appeasement of the 1930s,” Netanyahu said in the Hebrew-language clip. “", "Also then, there was someone who buried his head in the sand and didn’t see the approaching danger.”", "\n\nGet The Times of Israel's Daily Edition by email and never miss our top stories Free Sign Up\n\n“It seems that there are those in Europe who won’t wake up until Iranian nuclear missiles fall on European soil, and then, of course, it will be too late. ", "In any case, we will continue to do everything necessary to prevent Iran from obtaining nuclear weapons,” added to the prime minister.", "\n\nכנראה שיש כאלה באירופה שלא יתעוררו עד שיפלו על אדמת אירופה טילים גרעיניים איראניים. ", "אז זה כבר יהיה מאוחר מדיי. ", "אנחנו בכל מקרה נעשה הכל כדי למנוע מאיראן נשק גרעיני. ", "pic.twitter.com/HDEfE88PS1 — Benjamin Netanyahu (@netanyahu) July 15, 2019\n\nEuropean diplomats met in Brussels to discuss the 2015 nuclear deal on Monday and balked at the prospect of renewed sanctions against the Islamic Republic, even though Tehran has openly broken the uranium enrichment cap set by the accord.", "\n\nEarlier this month, Iran announced that it had exceeded a 300 kilogram stockpile limit for 3.67% enriched uranium and had started enriching to 4.5% fissile purity.", "\n\nNuclear experts are concerned that Iran’s enrichment moves could shorten the year-long period it would need to produce the 90% enriched uranium required for a nuclear weapon.", "\n\nIran’s non-compliance is not “considered to be significant non-compliance,” EU foreign policy chief Federica Mogherini said at a press conference, as the European foreign ministers held crisis talks on saving the beleaguered nuclear deal.", "\n\n“For the time being, none of the parties to the agreement has signaled their intention to invoke this article,” Mogherini said, referring to the process by which global and United Nations sanctions could be restored on Iran.", "\n\nBlue and White party leader MK Benny Gantz, the leader of the opposition, also urged the EU to recognize and act against the global threat of a nuclear-armed Iran.", "\n\n“This evening it is important to remind our European friends that Iran is a global problem that threatens world peace,” Gantz tweeted. “", "On this issue, there is no [dividing] politics. ", "Israel cannot allow Iran nuclear capabilities — and neither can you.”", "\n\nThe European Union is desperately trying to prevent the deal unraveling completely, seeing it as the best way to stop Tehran acquiring atomic weapons, and the issue was top of the agenda as ministers from the bloc met in Brussels.", "\n\nThe 28 EU foreign ministers insisted that recent Iranian actions surpassing uranium enrichment thresholds set by the 2015 deal did not necessarily condemn the whole agreement.", "\n\n“We note that technically all the steps that have been taken — and that we regret have been taken — are reversible. ", "So we hope and we invite Iran to reverse the steps,” Mogherini said.", "\n\n“The deviations are not significant enough to think that Iran has definitively broken the agreement,” said Spanish Foreign Minister Josep Borrell, who is in line to succeed Mogherini this fall.", "\n\nBut Iran piled fresh pressure on Europe on Monday, demanding concrete measures to give it relief from US sanctions, and threatening to return its nuclear program to where it was before the curbs imposed by the 2015 deal.", "\n\n“If the Europeans and the Americans don’t want to carry out their duties… we will decrease our commitments and… reverse the conditions to four years ago,” said Iran’s atomic energy agency spokesman Behrouz Kamalvandi, quoted by IRNA state news agency.", "\n\nThe EU currently has few direct measures for offsetting US economic sanctions against Tehran that have crippled the country’s economy, and the bloc faces US threats to target any EU companies that attempt to trade with Iran.", "\n\nNoting that Iran was “still a good year away” from potentially developing a nuclear bomb, British Foreign Secretary Jeremy Hunt said there was still a “small window to keep the deal alive.”", "\n\nEven if Britain, France, Germany, and the rest of the EU held out a helping hand to Iran, the diplomatic puzzle was made more difficult Monday, when France’s foreign ministry said a researcher with dual French-Iranian nationality had been arrested in Iran.", "\n\nIt said the French government was seeking information about Fariba Adelkhah and consular access to her “without delay,” but added there has been “no satisfactory response to its demands as of today.”", "\n\nIranian opposition websites based abroad have said Abdelkhah disappeared in June.", "\n\nAnd while the EU nations were looking to deescalate tensions in the Persian Gulf region, they also put the blame on the Trump administration for quitting the nuclear deal last year, imposing sanctions and trying to keep European nations from trading with Iran.", "\n\nFrench Foreign Minister Jean-Yves Le Drian said that Iran’s recent moves to surpass mutually agreed limits from the deal were only “a bad reaction following a bad decision — which was the US decision to withdraw from the accord and put sanctions into place.”", "\n\nChina, another signatory to the global agreement, said that US pressure was the root cause of recent developments and called on the Trump administration to step in and fix the diplomatic quagmire.", "\n\nChinese foreign ministry spokesman Geng Shuang said it was “better for the one who made the trouble to fix it.”", "\n\nFacing economic hardship, Iran had called on the other parties to the agreement — Germany, France, Britain, China, Russia and the EU — to come up with enough economic incentives to effectively offset the US sanctions.", "\n\nWhile the Europeans were still hoping to find an amicable solution, the United States instead called on them to turn their backs on Iran.", "\n\nGordon Sondland, the US ambassador to the EU, told the BBC that “our European friends should join the US in unequivocally condemning Iran’s actions with respect to their malign activities, not just in the Strait of Hormuz, but throughout the world.”", "\n\nBut EU foreign ministers first and foremost want to get Iran to respect the terms of the deal again. ", "At their regular monthly meeting, the EU foreign ministers sought to drum up further support for the bloc’s proposed barter-type system to trade with Tehran and get around possible US sanctions. ", "Ten nations are already on board with the idea, and Borrell said Spain was among them.", "\n\nTehran said Sunday it was ready to negotiate with the United States if Washington lifts the economic sanctions. ", "President Hassan Rouhani’s official website quoted him as saying, “The moment you stop sanctions and bullying, we are ready to negotiate.”" ]

{ "pile_set_name": "OpenWebText2" }

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[ "Lucenay-l'Évêque\n\nLucenay-l'Évêque is a commune in the Saône-et-Loire department in the region of Bourgogne in eastern France.", "\n\nGeography \nThe city lies in the Morvan massif, on the shores of the Ternin, a tributary to the Arroux.", "\n\nSee also\nCommunes of the Saône-et-Loire department\nParc naturel régional du Morvan\n\nReferences\nINSEE\n\nCategory:Communes of Saône-et-Loire" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "Q:\n\nFiltering listview of custom POJO's by their fields\n\nI have a POJO:\npublic class RoomData implements Parcelable {\n private String objectId, name, building, floor, imageUrl;\n private boolean hasPc, hasProjector, hasTelepresence, hasWhiteboard;\n private boolean dataReady = false;\n private ArrayList<MeetingData> meetingData = new ArrayList<MeetingData>();\n private int capacity;\n private ArrayList<BeaconData> beacons = new ArrayList<BeaconData>();\n private DateTime nextAvailableStart, nextAvailableEnd;\n private boolean availableNow = false;\n private ArrayList<Interval> meetingDuringIntervals = new ArrayList<Interval>();\n}\n\nthat is populated into a custom ListView/ListAdapter.", "\nI want to know how I can filter that list by the fields of my POJO. ", "For instance if I construct a RoomFilter object, that states that my capacity integer should be higher than X. How can I implement this? ", "I can only find links to filtering by primitive data types...\nHere is my custom Adapter class:\npublic class BeaconAdapter extends BaseAdapter {\n private Context context;\n private ArrayList<BLEDeviceAdvertisement> beaconArrayList = new ArrayList<BLEDeviceAdvertisement>();\n\n private static LayoutInflater inflater = null;\n\n //BeaconAdapter for the custom ListView\n public BeaconAdapter(Context context, ArrayList<BLEDeviceAdvertisement> beaconArrayList) {\n this.beaconArrayList = beaconArrayList;\n this.context = context;\n inflater = (LayoutInflater) context.getSystemService(Context.", "LAYOUT_INFLATER_SERVICE);\n }\n\n @Override\n public int getCount() {\n return beaconArrayList.size();\n }\n\n @Override\n public BLEDeviceAdvertisement getItem(int position) {\n return beaconArrayList.get(position);\n }\n\n @Override\n public long getItemId(int position) {\n return position;\n }\n\n //Custom getview for the custom layout beacon_row_item.", "\n @Override\n public View getView(int position, View convertView, ViewGroup parent) {\n View myCustomView = convertView;\n\n if (myCustomView == null)\n myCustomView = inflater.inflate(R.layout.beacon_row_item, null);\n\n return myCustomView;\n }\n\n}\n\nA:\n\nAfter OP's request I post my comment as an answer for future reference, giving more details. ", "Here are some possible solutions:\n\nDestructive update: Loop through the list, filtering out what you don't need. ", "Implement adapter based on this list.", "\nVirtual view: Implement logic for a \"virtual view\" over the original list. ", "Here you keep only the original list, but in all adapter's methods you skip items that don't match the filter. ", "For instance, in getItem(int pos) you loop through the list keeping a counter, but you increment it only if the item matches the filter: when the counter equals pos you return the item. ", "Similar for the other methods.", "\nConcrete View: Use an additional list to keep the \"view\" over the original list, so to cache the computation done in 2. ", "When the filter is set/updated, a loop through the original list builds the \"view\" and then you implement the adapter based on the \"view\". ", "More time efficient, but also more memory consumed.", "\n\n" ]

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[ "Introduction {#sec1}\n============\n\nMerkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy with an estimated 2488 cases per year in the United States with an exponential increase in incidence.[@bib1] MCC patients have a high (approximately \\>30%) risk for locoregional recurrences and distant metastases after resection.[@bib2], [@bib3], [@bib4], [@bib5], [@bib6] For patients who have localized disease with clinically negative draining lymph nodes (American Joint Committee on Cancer \\[AJCC\\] eighth edition stage I-IIIA), initial treatment typically consists of wide excision of the primary tumor and sentinel lymph node biopsy (SLNB).[@bib7] Surgery is then often followed by adjuvant conventionally fractionated postoperative radiation therapy (cPORT) (50 Gy in 25 fractions).[@bib2], [@bib3], [@bib4], [@bib5], [@bib6] ^,^ [@bib8]\n\nFor patients with MCC of the head and neck (H&N), cPORT provides a locoregional control benefit over observation alone, even among the most favorable low-risk cases.[@bib3] ^,^ [@bib4] However, acute toxicity in the sensitive regions of the H&N can be substantial (eg, skin erythema and desquamation, painful mucositis, xerostomia, altered taste, anorexia, weight loss). ", "In addition, patients often face logistical challenges in attending a protracted course of radiation therapy (RT) for 5 weeks. ", "Logistical considerations are of particular relevance with the increased risk of infection, complications, and death that may occur over a protracted radiation course during the COVID-19 pandemic.[@bib9], [@bib10], [@bib11]\n\nPreviously, a study found durable local control for gross disease with 8-Gy single-fraction RT (SFRT) among patients with metastatic MCC with minimal toxicity,[@bib12] reflecting the radiosensitivity of MCC. ", "Here, we present the preliminary results of using SFRT treatment in a postoperative, curative setting for patients with H&N disease.", "\n\nMethods and Materials {#sec2}\n=====================\n\nTwelve patients were identified from an institutional review board-approved prospective registry of 1459 patients with MCC based on the following inclusion criteria: (1) localized MCC of the H&N with clinically negative lymph nodes treated in the initial or recurrent setting (AJCC eighth edition stage I-II), (2) surgical resection with or without SLNB, (3) no residual gross disease, (4) received postoperative 8-Gy SFRT, (5) \\>90 days of follow-up after SFRT, and (6) no prior RT to the H&N region. ", "Patients provided consent for SFRT after an informed discussion. ", "The patients who opted for this regimen were typically elderly with multiple comorbidities or with significant logistical difficulties and were otherwise willing to forgo RT despite having an indication for cPORT. ", "No tumor-related selection criteria were applied. ", "RT was delivered using electrons (6-8 MeV prescribed to 90% isodose line with a bolus) or photons to the entire surgical bed plus 3- to 5-cm margins as illustrated in [Figure 1](#fig1){ref-type=\"fig\"} . ", "Patients had RT to the primary site alone in 11 of 12 patients, and 1 patient received elective nodal irradiation using an en-block technique (patient no. ", "9). ", "The patient who received elective nodal RT was immunosuppressed and had a large primary (stage IIB) in close proximity to the first echelon draining lymph nodes.", "Figure 1(A-B) Patient no. ", "5 is an 81-year-old immunosuppressed man with a history of clinical stage I Merkel cell carcinoma of the right cheek status post-wide local excision with negative margins and a technically failed sentinel lymph node biopsy who elected to undergo adjuvant 8-Gy SFRT to his primary surgical tumor bed site with electrons. ", "Four months after SFRT, he exhibited out-of-field regional failure in the lymph nodes in (C) the parotid, (D) level 2A, and (E) level 5. ", "He was successfully salvaged with surgical resection followed by adjuvant conventional fractionated proton radiation therapy. ", "He never failed within his initial SFRT field. *", "Abbreviation:* SFRT = single-fraction radiation therapy.", "\n\nNegative margins were defined as no tumor at the inked edge. ", "In-field recurrences were defined by an event that occurred within the 50% isodose line. ", "Local recurrences were defined by an event that occurred within 2 cm of the primary tumor's surgical bed. ", "Regional recurrences were defined by an event that occurred beyond 2 cm of the primary tumor's surgical bed and within the in-transit pathways or lymph nodal regions of the head and neck that drain the primary site. ", "Common Terminology Criteria for Adverse Events (CTCAE) v5 was employed to grade acute toxicity \\<90 days and late toxicity ≥90 days after SFRT. ", "Time to event was calculated from the date of resection before SFRT.", "\n\nThe cumulative incidence of in-field and out-of-field locoregional recurrence was estimated with death considered a competing risk. ", "Patients who did not experience an event during follow-up were right-censored at the time of last follow-up. ", "Confidence intervals (CIs) for the rate of recurrence at different timepoints were calculated using conventional standard error formulas except when the estimate rate was 0%. ", "In those cases, CIs were calculated using the Clopper--Pearson exact method. ", "All statistical calculations were conducted with the statistical computing language R (version 3.6.1; R Foundation for Statistical Computing, Vienna, Austria).", "\n\nSurveillance consisted of follow-up visits with physical examination including complete skin and lymph nodes every 3 to 6 months for 3 years, then every 6 to 12 months thereafter.[@bib7] Patients who were seropositive for the Merkel cell polyomavirus oncoprotein antibodies had titers obtained at the follow-up visits, prompting repeat imaging if a notable rise occurred.[@bib1] Computed tomography imaging of the neck, chest, abdomen, and pelvis was performed based on clinical indications or recurrence risk-based assessment approximately every 4 months for the first year, then every 6 to 12 months.[@bib1]\n\nResults {#sec3}\n=======\n\nWe identified 12 patients with stage I-II H&N MCC treated from 2017 to 2019. ", "Pathologic staging was obtained in the majority of patients (n = 8 of 12), and the remaining patients were clinically staged due to either a failed SLNB (n = 2 of 12) or excisional biopsy alone due to their advanced age and comorbidities (n = 2 of 12). ", "Patient demographics and treatment characteristics are summarized in [Table 1](#tbl1){ref-type=\"table\"} . ", "The patient cohort had a median age of 81 years (range, 58-96 years) with 25% (n = 3 of 12) being immunosuppressed and 8% (n = 1 of 12) positive microscopic margins (R1 resection).Table 1Demographics and treatment summary table of the patient cohortPatient IDAge, yStage (AJCC eigth edition)SexImmune-suppressedType of immune suppressionSettingECOGSite of RTField size, EQ SQLate toxicity gradeSurgery typePath margin statusRecurrence status185p-IFNo-Initial0Glabella81WLE and SLNBNegativeNone296c-IMNo-Initial1Right cheek3.30Excisional biopsyNegativeNone386c-IFYesCLLInitial3Left ear10.20Excisional biopsyPositiveNone464p-IFNo-Initial0Left cheek8.50WLE and SLNBNegativeNone581c-IMYesHairy cell leukemiaInitial0Right cheek60WLE and failed SLNBNegativeRegional671p-IMNo-Initial0Left lip/cheek80WLE and SLNBNegativeNone782c-IFNo-Initial0Right cheek70WLE and failed SLNBNegativeNone868p-IFNo-Initial0Left nose100WLE and SLNBNegativeNone970p-IIBMYesCMLInitial2Left cheek/elective neckPTV 342 cm^3^0WLE and SLNBNegativeNone1083p-IMNo-Initial0Nose8.50WLE and LN dissectionNegativeNone1158p-IFNo-Recurrent0Left scalpN/A[∗](#tbl1fnlowast){ref-type=\"table-fn\"}N/A[∗](#tbl1fnlowast){ref-type=\"table-fn\"}WLE[†](#tbl1fndagger){ref-type=\"table-fn\"}NegativeNone1280p-IIBMNo-Recurrent0Left upper lip8.41WLE[†](#tbl1fndagger){ref-type=\"table-fn\"}NegativeNone[^2][^3][^4]\n\nTen patients (no. ", "1-10) were treated in the de novo setting. ", "Two patients (no. ", "11-12) were treated in the recurrent setting after they experienced a local recurrence at the primary site alone. ", "They had prior wide local excision and SLNB or neck dissection followed by observation in the initial setting. ", "No patients had a history of prior radiation therapy to the H&N region or received systemic therapy. ", "The documented rationale for patients pursuing SFRT after an informed consent included: logistics for all patients (no. ", "1-12) with 16% living within 30 miles of our academic institution; potential for decreased acute side effects (patients no. ", "7-9); and significant medical comorbidities (patient no. ", "9).", "\n\nAt a median follow-up time of 19 months (range, 8-34 months), there were no local recurrences. ", "Eleven of 12 patients received radiation to the postoperative bed alone, and one of these patients (no. ", "5) experienced a recurrence in the regional draining lymph nodes that were not treated with PORT. ", "Patient no. ", "5 was also immunosuppressed but had clinical stage I disease with negative surgical margins and a failed SLNB ([Fig 1](#fig1){ref-type=\"fig\"}). ", "The patient was successfully salvaged with a neck dissection and postoperative conventional fractionated radiation therapy. ", "Thus, there was 1 out-of-field recurrence and no in-field recurrences. ", "The overall out-of-field locoregional recurrence rate at 1 year was 8.3% (95% CI, 1.3%-54.4%) and 0% (95% CI, 0.0%-26.5%) in-field ([Fig 2](#fig2){ref-type=\"fig\"} ).Figure 2Freedom from in-field (100%) and out-of-field (92%) locoregional recurrence in patients treated with single-fraction radiation therapy.", "\n\nNo patient developed distant metastatic disease. ", "There was 1 patient death during the follow-up period owing to significant cardiac comorbidities, which were present before the MCC diagnosis. ", "No patient experienced any radiation-related toxicity greater than grade 1 (CTCAE v5).", "\n\nDiscussion {#sec4}\n==========\n\nWe present a preliminary experience of treating localized MCC in the H&N region with a single fraction of 8 Gy in the postoperative setting. ", "With a median follow-up of 19 months, there were no in-field or local failures. ", "This compares favorably to the results of historical H&N MCC series of cPORT. ", "Takagishi et al reported a 5-year local recurrence rate of 26.3% with surgery alone versus 0% with adjuvant cPORT (*P* = .02) in patients with H&N MCC, suggesting a benefit for PORT over observation alone in patients with favorable pathologic stage I tumors with negative surgical margins and negative sentinel node biopsy and without immunosuppression.[@bib3] The median time to local recurrence was 11 months. ", "Compared with the patients reported by Takagishi et al, this study had patients with worse prognostic features, including recurrent tumors (n = 2), stage II (n = 2), failed or no sentinel node biopsy (n = 4), positive margin (n = 1), and immunosuppression (n = 3). ", "Strom et al also showed a significant improvement in 3-year local control (89.4% vs 68.1%; *P* = .005) and regional control (95% vs 66.7%; *P* = .008) among 113 patients with clinical stages I-IIIB H&N MCC who received cPORT versus observation, respectively.[@bib4]\n\nOther series have reported on the efficacy of RT for the treatment of MCC of the H&N region.[@bib13] ^,^ [@bib14] Lok et al reported a 10% crude rate of locoregional failures (4% local and 6% regional) at a median follow-up of 51 months among 48 patients with H&N MCC (clinical stages I-III and recurrent) treated with cPORT.[@bib13] Bishop et al demonstrated excellent 5-year local and regional control outcomes (96% and 92%, respectively) for 102 patients with MCC of the H&N region (clinical stages I-III and recurrent) treated with definitive radiation therapy (61%) or cPORT (39%) to the postoperative bed and ipsilateral neck.[@bib14]\n\nOur study, albeit with a small sample size, had patients with the highest percentage of immunosuppression of 25% (n = 3 of 12) compared with other H&N series reported rates of 0 to 10%.[@bib3] ^,^ [@bib4] ^,^ [@bib13] ^,^ [@bib14] The only regional recurrence noted in this study was in an immunosuppressed patient, who developed an out-of-field recurrence in the regional lymph nodes. ", "This patient also had a failed sentinel lymph node biopsy. ", "However, there was no radiologic evidence of regional nodal disease at the time of SFRT. ", "This is consistent with the observation noted in the literature that immunosuppression is a negative prognostic factor associated with an increased probability of recurrence and death from MCC.[@bib15] ^,^ [@bib16]\n\nThere were no observed acute or late toxicities \\>grade 1 (CTCAE v5) within this cohort after SFRT. ", "A previous study demonstrating the durability of SFRT for gross metastatic MCC in all anatomic sites similarly demonstrated no acute or late toxicities when treating tumors in the H&N region with a median follow-up of 9 months.[@bib12] In regard to acute toxicity after cPORT, Lok et al reported 10% and 2% rates of Radiation Therapy Oncology Group grade 3 dermatitis and mucositis, respectively.[@bib13] For late toxicity after cPORT, Bishop et al reported a 5% Radiation Therapy Oncology Group grade ≥3 or greater event rate (4 ocular, 1 mandible).[@bib14]\n\nIn addition to the minimal toxicity, another attractive feature of this 8-Gy SFRT approach is that it would not significantly interfere with salvaging a potential in-field failure given the low dose of radiation therapy.", "\n\nThis study is limited by its retrospective design, a small sample size, and a relatively short follow-up period of 19 months, although with MCC most locoregional recurrences occur within 1 year. ", "Patient selection was not based on any specific tumor-related factors. ", "All patients expressed logistical considerations as the primary reason for preferring SFRT to cPORT. ", "These data apply to treatment of the primary site in patients with localized H&N MCC. ", "The safety and efficacy of SFRT for patients with higher-stage MCC with clinical or pathologic node-positive disease (AJCC eighth edition stage III) remains unknown. ", "It is possible that the biology of the primary site and regional nodes may differ. ", "Moreover, there was only 1 patient in this study who received elective nodal RT. ", "Caution should be applied with using this approach for elective nodal RT for an aggressive primary in the setting of a failed or no SLNB.", "\n\nThis study suggests that favorable in-field locoregional control may be achieved with SFRT, including in a patient who had microscopically positive margins. ", "In addition, consistent with MCC typically being very radiosensitive, SFRT using a lower biologically equivalent dose (BED~α/ß\\ =\\ 10~) of 14.4 Gy compared with 50 Gy with cPORT was able to achieve promising in-field local control. ", "Despite the lower BED of SFRT, the similar local control may be explained by emerging data demonstrating that higher dose per fraction may potentiate a greater immune-mediated effect compared with conventionally fractionated RT.[@bib17], [@bib18], [@bib19] This is relevant given MCC is a highly immunogenic malignancy.[@bib20] Ongoing work will refine the ideal patient population for postoperative SFRT. ", "To the best of our knowledge, this is the first study to demonstrate promising outcomes with single-fraction postoperative radiation therapy in localized MCC of the H&N region. ", "This approach can also address a need to shorten the course of radiation therapy while maintaining excellent oncologic outcomes during the COVID-19 pandemic.[@bib9], [@bib10], [@bib11]\n\nConclusion {#sec5}\n==========\n\nThis study provides preliminary data for prospective evaluation to determine the long-term durability and toxicity of postoperative SFRT for MCC of the H&N region. ", "Further work is needed to identify which patients with MCC may benefit from abbreviated versus protracted postoperative radiation therapy.", "\n\nThis work was presented at the Society of Investigative Dermatology in May 2019.", "\n\nSources of support/Funding: NIHP01-CA225517; P30-CA015704 and the UW MCC patient gift fund.", "\n\nDisclosures: Dr Paul Nghiem reports grant support (Bristol-Meyers Squibb) and consulting fees (EMD Serono, Pfizer, Sanofi/Regeneron, 4SC). ", "Dr Shailender Bhatia reports Advisory board participation (with honoraria) from Genentech, EMD Serono, Bristol-Myers Squibb and Sanofi Genzyme; and research funding to his institution (University of Washington) from Oncosec, EMD Serono, Merck, BMS, NantKwest, Immune Design, Novartis, Nektar and Exicure. ", "All other authors have no disclosures to declare.", "\n\n[^1]: M.M.C. and S.K.S. contributed equally to this work.", "\n\n[^2]: *Abbreviations:* AJCC = American Joint Committee on Cancer; c = clinical; CLL = chronic lymphocytic leukemia; CML = chronic myelogenous leukemia; ECOG = Eastern Cooperative Oncology Group; EQ SQ = equivalent square of radiation therapy field (cm); LN = lymph node; p = pathologic; PTV = planning target volume; RT = radiation therapy; SLNB = sentinel lymph node biopsy; WLE = wide local excision.", "\n\n[^3]: N/A denotes \"not available\" due to radiation treatment at an outside institution.", "\n\n[^4]: WLE denotes surgical procedure performed in the recurrent setting after WLE and ipsilateral SLNB or neck dissection followed by observation in the initial setting.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "A veteran public school teacher has announced plans to run against a GOP state lawmaker who vowed to vote against all education funding during the Oklahoma teachers strike.", "\n\nCyndi Ralston, who has worked in education for 30 years, announced on Tuesday that she will be running as a Democrat to represent Oklahoma’s 12th District, the Tulsa World reported.", "\n\nADVERTISEMENT\n\nShe wrote in a Facebook post that she was spurred to make her announcement after Rep. Kevin McDugle said he would not vote “for another stinking [education] measure when they're acting the way they're acting.\"", "\n\nOklahoma teachers are on their third day of a statewide strike in protest for more resource funding and better pay.", "\n\nMcDugle said he didn’t care if the teachers were “pissed” at him.", "\n\n\"You're losing support of people who supported you all year long,\" McDugle said in a now-deleted post. \"", "Now you're going to come here and act like this after you got a raise?", "\n\nHe later apologized, according to the Tulsa World.", "\n\n“If Kevin McDugle won’t fight for teachers and students, then I will,\" Ralston wrote in the post. \"", "If Kevin McDugle won’t back parents over oil companies, I will. ", "If Kevin McDugle won’t treat his constituents with respect and dignity, I will.\"", "\n\nRalston was originally going to wait until after she officially filed to run but said the “events of the day” moved her.", "\n\nShe filed her intention to run last week with the Ethics Commission, the Tulsa World reported.", "\n\nOklahoma teachers filled the state Capitol on Tuesday during their walkout. ", "They’re demanding a $10,00 raise over three years and a $5,000 increase for support staff." ]

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[ "#region License\r\n\r\n/*\r\n * Copyright © 2002-2011 the original author or authors.", "\r\n *\r\n * Licensed under the Apache License, Version 2.0 (the \"License\");\r\n * you may not use this file except in compliance with the License.", "\r\n * You may obtain a copy of the License at\r\n *\r\n * http://www.apache.org/licenses/LICENSE-2.0\r\n *\r\n * Unless required by applicable law or agreed to in writing, software\r\n * distributed under the License is distributed on an \"AS IS\" BASIS,\r\n * WITHOUT WARRANTIES OR CONDITIONS OF ANY KIND, either express or implied.", "\r\n * See the License for the specific language governing permissions and\r\n * limitations under the License.", "\r\n */\r\n\r\n#endregion\r\n\r\n#region Imports\r\n\r\nusing System;\r\nusing NUnit.", "Framework;\r\nusing Spring.", "Util;\r\n\r\n#endregion\r\n\r\nnamespace Spring.", "Objects.", "Factory.", "Config\r\n{\r\n\t/// <summary>\r\n\t/// Unit tests for the DelegateFactoryObject class.", "\r\n\t/// </summary>\r\n\t/// <author>Rick Evans</author>\r\n\t[TestFixture]\r\n\tpublic sealed class DelegateFactoryObjectTests\r\n\t{\r\n\t\t[Test]\r\n\t\tpublic void StaticDelegateWithInstanceMethod()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tfob.", "DelegateType = typeof (PopHandler);\r\n\t\t\tfob.", "TargetType = typeof (OneThirstyDude);\r\n\t\t\tfob.", "MethodName = \"HandlePop\";\r\n\t\t\tfob.", "IsSingleton = false;\r\n\t\t\tfob.", "AfterPropertiesSet();\r\n Assert.", "Throws<ArgumentException>(() => fob.", "GetObject());\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void StaticDelegate()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tfob.", "DelegateType = typeof (PopHandler);\r\n\t\t\tfob.", "TargetType = typeof (OneThirstyDude);\r\n\t\t\tfob.", "MethodName = \"StaticHandlePop\";\r\n\t\t\tfob.", "IsSingleton = false;\r\n\t\t\tfob.", "AfterPropertiesSet();\r\n\t\t\tPopHandler popper = (PopHandler) fob.", "GetObject();\r\n\t\t\tAssert.", "IsNotNull(popper);\r\n\t\t\tAssert.", "AreEqual(fob.", "MethodName, popper.", "Method.", "Name);\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void InstanceSingletonDelegate()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tfob.", "DelegateType = typeof (PopHandler);\r\n\t\t\tOneThirstyDude dude = new OneThirstyDude();\r\n\t\t\tfob.", "TargetObject = dude;\r\n\t\t\tfob.", "MethodName = \"HandlePop\";\r\n\t\t\tfob.", "AfterPropertiesSet();\r\n\t\t\tPopHandler popper = (PopHandler) fob.", "GetObject();\r\n\t\t\tAssert.", "IsNotNull(popper);\r\n\t\t\tAssert.", "AreEqual(fob.", "MethodName, popper.", "Method.", "Name);\r\n\t\t\tstring soda = \"The Drink Of Champions\";\r\n\t\t\tpopper(this, soda);\r\n\t\t\tAssert.", "AreEqual(soda, dude.", "Soda);\r\n\t\t\tPopHandler other = (PopHandler) fob.", "GetObject();\r\n\t\t\tAssert.", "IsTrue(ReferenceEquals(popper, other));\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void InstancePrototypeDelegate()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tfob.", "IsSingleton = false;\r\n\t\t\tfob.", "DelegateType = typeof (PopHandler);\r\n\t\t\tOneThirstyDude dude = new OneThirstyDude();\r\n\t\t\tfob.", "TargetObject = dude;\r\n\t\t\tfob.", "MethodName = \"HandlePop\";\r\n\t\t\tfob.", "IsSingleton = false;\r\n\t\t\tfob.", "AfterPropertiesSet();\r\n\t\t\tPopHandler one = (PopHandler) fob.", "GetObject();\r\n\t\t\tPopHandler two = (PopHandler) fob.", "GetObject();\r\n\t\t\tAssert.", "IsFalse(ReferenceEquals(one, two));\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void ObjectType()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tAssert.", "IsNotNull(fob.", "ObjectType, \"Should never be null (should default to typeof(Delegate)) \");\r\n\t\t\tAssert.", "AreEqual(typeof (Delegate), fob.", "ObjectType, \"Not defaulting to typeof(Delegate).\");", "\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void MissingDelegateType()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n Assert.", "Throws<ArgumentException>(() => fob.", "AfterPropertiesSet());\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void BadDelegateType()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tfob.", "DelegateType = DBNull.", "Value.", "GetType();\r\n Assert.", "Throws<ArgumentException>(() => fob.", "AfterPropertiesSet());\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void NullMethodName()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n fob.", "DelegateType = typeof (EventHandler);\r\n fob.", "TargetType = typeof (OneThirstyDude);\r\n Assert.", "Throws<ArgumentException>(() => fob.", "AfterPropertiesSet());\r\n }\r\n\r\n [Test]\r\n public void EmptyMethodName()\r\n {\r\n DelegateFactoryObject fob = new DelegateFactoryObject();\r\n fob.", "DelegateType = typeof (EventHandler);\r\n fob.", "TargetType = typeof (OneThirstyDude);\r\n fob.", "MethodName = string.", "Empty;\r\n Assert.", "Throws<ArgumentException>(() => fob.", "AfterPropertiesSet());\r\n }\r\n\r\n [Test]\r\n public void WhitespacedMethodName()\r\n {\r\n DelegateFactoryObject fob = new DelegateFactoryObject();\r\n fob.", "DelegateType = typeof (EventHandler);\r\n fob.", "TargetType = typeof (OneThirstyDude);\r\n fob.", "MethodName = \"\\n\";\r\n Assert.", "Throws<ArgumentException>(() => fob.", "AfterPropertiesSet());\r\n }\r\n\r\n\t\t[Test]\r\n\t\tpublic void MissingATarget()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tfob.", "DelegateType = typeof (EventHandler);\r\n\t\t\tfob.", "MethodName = \"I Love You Laura Palmer, I Really Do\";\r\n Assert.", "Throws<ArgumentException>(() => fob.", "AfterPropertiesSet());\r\n\t\t}\r\n\r\n\t\t[Test]\r\n\t\tpublic void ChokesIfBothTargetTypeAndTargetObjectSupplied()\r\n\t\t{\r\n\t\t\tDelegateFactoryObject fob = new DelegateFactoryObject();\r\n\t\t\tfob.", "DelegateType = typeof (PopHandler);\r\n\t\t\tfob.", "TargetType = typeof (OneThirstyDude);\r\n\t\t\tfob.", "TargetObject = new OneThirstyDude();\r\n\t\t\tfob.", "MethodName = \"I Love You Laura Palmer, I Really Do\";\r\n Assert.", "Throws<ArgumentException>(() => fob.", "AfterPropertiesSet());\r\n\t\t}\r\n\t}\r\n}" ]

{ "pile_set_name": "Github" }

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[ "\n381 S.E.2d 241 (1989)\nSTATE of West Virginia\nv.\nGuy F. WILKINSON.", "\nNo. ", "18634.", "\nSupreme Court of Appeals of West Virginia.", "\nMay 16, 1989.", "\n*242 Stuart Calwell, Calwell, McCormick & Peyton, Charleston, for Guy F. Wilkinson.", "\nRichard M. Riffe, Asst. ", "Atty. ", "Gen., Charleston, for the State.", "\n*243 PER CURIAM:\nThe defendant in this proceeding, Guy F. Wilkinson, was convicted in the Circuit Court of Putnam County on July 27, 1987, of driving under the influence of alcohol, second offense. ", "He was sentenced to one year in the Putnam County Jail. ", "On appeal he claims that the trial court erred in denying him a continuance of his trial date. ", "He also claims that the court erred in permitting the prosecuting attorney to introduce evidence relating to an earlier conviction of driving under the influence of alcohol and evidence relating to the results of a breathalyzer test. ", "After reviewing the record this Court can find no reversible error. ", "Accordingly, the judgment of the Circuit Court of Putnam County is affirmed.", "\nIn the early morning hours of March 4, 1987, a Nitro City patrolman, Gregory D. Winter, observed the defendant's vehicle weaving back and forth on Route 25 as it approached 40th Street. ", "At one point the car went off the road onto the berm and then moved across the dividing line of two north bound lanes of traffic. ", "Officer Winter stopped the car and asked the defendant, who was driving, to get out.", "\nWhen the defendant got out, the officer noticed a \"large odor of alcohol coming from the vehicle.\" ", "Officer Winter administered a field sobriety test consisting of the performance of various walking exercises, balance exercises, and physical dexterity exercises. ", "As a result of the field sobriety test, Officer Winter placed the defendant under arrest for driving under the influence of alcohol. ", "Officer Winter then took the defendant to the Nitro Police Department where the defendant submitted to a breathalyzer test on an Intoxilyzer 5000 machine. ", "During that test the defendant did not exhale an optimum-sized breath sample into the machine. ", "The machine, nonetheless, measured the alcohol content of the sample which was available. ", "It showed that the defendant was intoxicated. ", "The result of the test, however, was labelled a \"deficient sample\" because it was based on less than an optimum breath sample.", "\nThe defendant had previously been convicted of driving under the influence of alcohol, and at the police station he informed Officer Winter that he had been sick, that he had injuries to his back and neck. ", "There is also some indication that he had lung disease.", "\nThe defendant was tried for driving under the influence of alcohol, second offense, before a Putnam County magistrate on April 28, 1987. ", "At the conclusion of that trial the defendant was found guilty and released on bond. ", "He later filed an appeal in the Circuit Court of Putnam County on May 15, 1987.", "\nA trial de novo before a jury was scheduled in the circuit court for July 27, 1987. ", "Several weeks before that date the defendant visited the medical offices of Elias Haikal for the purpose of obtaining breathing tests to determine his physical ability to successfully complete a breathalyzer test. ", "As a result of the physical examination, the defendant, according to the documents in the present proceeding, proposed to call Dr. Haikal to testify at his July 27, 1987 trial. ", "He, however, did not include Dr. Haikal's name on his proposed witness list, and he did not subpoena Dr. Haikal to attend the trial.", "\nOn July 23 or July 24, 1987, just prior to the July 27, 1987 trial date, the defendant learned that his aunt, who was suffering from cancer, was scheduled for surgery on July 27, 1987, the proposed trial date. ", "The aunt, who lived with the defendant, was blind and dependent upon the defendant for care. ", "Her physician requested that the defendant be present on the day of surgery. ", "After learning of this development, the defendant contacted his attorney and requested that the trial in the circuit court be continued to some day other than the day of his aunt's surgery. ", "The defendant's attorney contacted the prosecuting attorney's office and learned that the circuit judge was out of town and could not entertain a motion for continuance prior to trial.", "\nOn the morning of trial, July 27, 1987, the defendant learned that his medical expert, Dr. Haikal, who had been out of town over the weekend, due to a change in airline *244 scheduling could not attend trial on July 27, 1987. ", "He, therefore, moved for a continuance based on Dr. Haikal's unavailability for trial. ", "He also moved for a continuance because of the medical emergency involving the aunt.", "\nIn spite of the circumstances, the trial court denied a continuance, and a jury trial was conducted. ", "At the conclusion of the trial the defendant was found guilty of driving under the influence of alcohol, second offense. ", "On July 29, 1987, he was sentenced to the Putnam County Jail for a period of one year.", "\nIn the present proceeding the defendant's first contention is that the trial court erred in denying him a continuance of the trial date. ", "The defendant argues that he should have been granted a continuance for two reasons. ", "First, he claims that on the morning of trial he learned that his medical expert, who had been out of state over the weekend of July 25, 1987, due to a change in airline scheduling, would be unable to attend trial on July 27, 1987. ", "Second, he claims that the court should have granted a continuance because of his aunt's physician's request that he be present for the surgery on his aunt which was scheduled for the early morning hours of July 27, 1987.", "\nIn State v. Bush, 163 W.Va. ", "168, 255 S.E.2d 539 (1979), this Court discussed the granting of continuances in criminal trials. ", "The Court concluded in syllabus point 2 that:\nA motion for continuance is addressed to the sound discretion of the trial court, and its ruling will not be disturbed on appeal unless there is a showing that there has been an abuse of discretion.", "\nThe Court also indicated that whether there has been an abuse of discretion in denying a continuance must be decided on a case-by-case basis.", "\nIn the present case, the defendant argues that had Dr. Haikal been present at trial, he would have had evidence to rebut the arresting officer's conclusions as to his failure to give a full sample on the breathalyzer test.", "\nGenerally, to warrant a continuance on the basis of the absence of material witness it is necessary that the party seeking the continuance use due diligence to procure the attendance of the witness. ", "It is also incumbent upon the party to show the materiality and importance of the witness's proposed testimony to the issues to be tried. ", "State v. Burdette, 135 W.Va. ", "312, 63 S.E.2d 69 (1950). ", "If the facts upon which the motion for continuance is based are not before the court, the party seeking the continuance must support his motion by a sufficient affidavit showing such facts. ", "State v. Vance, 168 W.Va. ", "666, 285 S.E.2d 437 (1981). ", "Mere conclusionary statements by the affiant without more are not sufficient. ", "State v. Whitecotten, 101 W.Va. ", "492, 133 S.E. 106 (1926).", "\nIn the case presently before the Court, the defendant did not include Dr. Haikal's name on his witness list, and Dr. Haikal was not subpoenaed to attend the trial. ", "In fact, there is some indication that the first time that the State was made aware of Dr. Haikal was on the morning of trial. ", "The defendant did not file an affidavit relating to the unavailability of Dr. Haikal or to the character of his proposed testimony.", "\nUnder the circumstances of the case, this Court cannot conclude that the defendant used due diligence to procure the attendance of Dr. Haikal or established the materiality and importance of his evidence as is required under our law.", "\nIt also appears that the defendant was aware of his aunt's operation on Thursday before the trial scheduled on Monday. ", "The defendant and the prosecutor discussed the matter on Friday, yet no formal affidavit was prepared setting forth the circumstances. ", "There is also some evidence that surgery was not actually performed on the aunt on the trial day.", "\nOverall, after reviewing the record this Court believes that the defendant has failed to show that the trial court abused its discretion in refusing to grant a continuance.", "\n*245 The defendant also argues that the trial court erred in permitting the prosecuting attorney to introduce during his trial evidence of his earlier conviction for driving under the influence of alcohol. ", "He argues that evidence of prior crimes is not generally admissible in a criminal case, and he asserts that the prejudicial effect of the prosecutor's informing the jury of his prior conviction for drunk driving led the jury to believe that if the defendant drove once under the influence, he would do it again.", "\nIn note 1 of a similar case, State v. Cozart, ___ W.Va. ___, ", "352 S.E.2d 152 (1986), this Court stated:\nThe defendant also argues the trial court erred in allowing the State to admit evidence that he had been convicted of driving under the influence of alcohol on two prior occasions. ", "In support of this argument, the defendant cites State v. McAboy, 160 W.Va. ", "497, 236 S.E.2d 431 (1977), where we held that a defendant in a criminal case who elects to testify may have his credibility impeached by showing prior convictions of perjury or false swearing.", "\nThe defendant's credibility is not the issue in the present case ... The issue is whether the defendant was guilty of a third offense of driving under the influence of alcohol, in violation of W.Va. ", "Code, 17C-5-2(i) (1983). ", "Obviously, where a prior conviction is a necessary element of the current offense charged or is utilized to enhance the penalty after a jury finding that the defendant has committed such prior offense, it is admissible for jury purposes and McAboy is not applicable.", "\nIn the later case of State v. Barker, ___ W.Va. ___, ", "366 S.E.2d 642 (1988), the Court refused to reverse a conviction where the assertion was that the trial court erred in admitting evidence of his prior convictions for driving under the influence of alcohol.", "\nIn the present case, the defendant was charged with second offense driving under the influence. ", "Obviously, it was necessary for the State to prove that he was convicted a first time in order to prove the second offense. ", "As indicated in State v. Cozart, supra, evidence of the first offense was clearly admissible under the circumstances.", "\nThe defendant lastly claims that the trial court erred in permitting evidence of a breathalyzer test, based on a deficient sample, to go to the jury and in permitting an unqualified police officer to testify as to the meaning of a \"deficient\" sample.", "\nIt appears that when the State administered the breathalyzer test, the defendant failed to give the machine a full sample. ", "During trial the State sought to introduce the breathalyzer results into evidence. ", "Defense counsel protested on the ground that the State had not established a proper foundation for the admission of the evidence. ", "The State then adduced evidence showing that the test had been conducted in compliance with the rules and regulations issued by the Department of Health in regard to the Intoxilyzer 5000. ", "The State also adduced the testimony of Officer Gregory D. Winter of the Nitro Police Department, who had performed the Intoxilyzer test upon the defendant. ", "Officer Winter testified that he had been given special training on the Intoxilyzer 5000 and that his training indicated that the fact that a sample as a \"deficient\" sample did not affect the validity of the results.", "\nIn syllabus point 4 of State v. Dyer, 160 W.Va. ", "166, 233 S.E.2d 309 (1977), this Court stated that:\nIn the trial of a person charged with driving a motor vehicle on the public streets or highways of the state while under the influence of intoxicating liquor, a chemical analysis of the accused person's blood, breath or urine, in order to be admissible in evidence in compliance with provisions of W.Va.", "Code, 17C-5A-5, \"must be performed in accordance with methods and standards approved by the state department of health.\" ", "When the results of a breathalyzer test, not shown by the record to have been so performed and administered, are received in the trial evidence on which the accused is convicted, the admission of such evidence is prejudicial error and the conviction will be reversed.", "\n*246 In the case presently before the Court, there is evidence that the intoxilyzer test results introduced against the defendant resulted from a test performed in accordance with the methods and standards approved by the State Department of Health. ", "There was also evidence from Gregory D. Winter, the individual who performed the test and who had special training on the Intoxilyzer 5000 machine, that the test results were valid, according to the training which he received, even though a deficient sample was taken.", "\nIn view of all the evidence presented, this Court cannot conclude that the defendant has established that admission of the intoxilyzer results was prejudicial.[*]", "\nFor the reasons stated, the judgment of the Circuit Court of Putnam County is affirmed.", "\nAffirmed.", "\nNOTES\n[*] In at least one case where substantial expert evidence was adduced, an appellate court recognized that a deficient sample does not result in more than a very minimal variation in the alcohol reading of a breathalyzer machine. ", "State v. Kieley, 413 N.W.2d 886 (Minn.1987). ", "The Court concluded that admission of a deficient sample did not constitute error. ", "In spite of this, there is some suggestion that a deficient sample utilized by an Intoxilyzer 5000 machine might, under certain special circumstances, result in inaccurate readings. ", "See 3 R. Erwin, Defense of Drunken Driving Cases § 24A.12[8] (3d ed. ", "1989). ", "In the case presently before the Court, the defendant offered no evidence showing that the specialized circumstances mentioned in that authority were present at the time he took the Intoxilyzer 5000 test, and no expert evidence relating to the invalidity of the results obtained was produced.", "\n" ]

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[ "Egmont Publishing, which put its U.S. division up for sale in October, has announced plans to close the unit. ", "The move, the Danish publisher said in a release, comes after the division failed to establish a \"market leading position\" in the States, and attempts to sell the unit failed.", "\n\nThe U.S. division of Egmont, which published children's titles in the elementary, middle grade and teen categories, was established in 2008. ", "Now, the division's spring 2015 list (distributed by Random House) will mark its last, and its office will close on January 31. ", "Egmont USA's six staffers' final day in the office will be January 30.", "\n\nRob McMenemy, CEO of Egmont Publishing International, said the U.S. business, ultimately, \"does not fit\" with the company's strategy, as it has not been able to become a market leader in the States. ", "He added that Egmont was \"hoping to succeed with selling the business, unfortunately this has turned out not to be possible.”" ]

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[ "No difference in terms of content when compared to this album but tracks are ordered very differently - the reason for this is because the Steam folder was just arranged in alphabetical order, something which the Bandcamp release replicated but other digital storefronts altered." ]

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[ "Well you may not be surprised to see Emily Giovannithere...you all know her....she is the Color Challenge Queen! ", "I'm super excited to be in this for the next six months with her! ", "I can't wait to get to know her better!!", "\n\nI had the hardest time keeping this HUGE secret and I had to flat out LIE to Jennifer Meyer a couple of weeks ago on the phone....sorry Jennifer...hope you can forgive me ;)\n\nOnto my cards!", "\n\nThis first one was for Monday's Try a New Technique. ", "Beate had written a fabulous tutorial on SCS for this GRID technique. ", "It's super easy but gives wonderful results. ", "I'd gotten my new SU! ", "stuff last week and wanted to give them a whirl. ", "I'm not sure I like the new colours just yet...\n\nJulee had her Mojo sketch posted first thing Monday morning and I couldn't wait to get at it. ", "I had this monkey already stamped and coloured from another project I'd been working on. ", "He is so adorable! ", "These Summertime Fun stamps from CC Designs can be purchased at All That Scraps.", "\n\n55 comments:\n\nCONGRATULATIONS, girlie! ", "I was so excited when I found out you were picked, and I'm still excited (note how early I'm up today??..hehe!). ", "You're an awesome addition to the dirt pile, you're super talented, and are so deserving. ", "Big Hugs to ya, Dawn!!", "\n\nI think I like new colors, I especially like the new dp, this card is nice. ", "Julee's sketch card is cute as well. ", "I tried last night but was too tired to get the circles balanced. ", "I try again later in the week. ", "Maybe it was me / not the card off balance! ", "HA!", "\n\nHEY DAWN !!! ", "I just went to SCS a few minutes ago and was so excited to see the Dirty Dozen was open and imagine my wonderful surprise to see that you are the newest member !!!! ", "Congratulations, girlie !!!! ", "I'm so happy for you !!!! ", "Way to go :)\n\nDawn, I heard you yelling and had to come over to make sure you were all right! ", "WOWZERS!! ", "Congratulations to you! ", "Fabulous news! - ", "but of course - what took \"them\" so long!!?? ", "haha! ", "Aren't secrets like that just wonderful??!! ", "In a sadistic sort of way!", "\n\nOh girl! ", "I am so super excited for you! ", ":D You deserve it! ", "Your work is always amazing and I am (obviously) not the only one who notices! ", "Hehe! ", "I just can't tell you how excited I am for you! ", ":D Congratulations! ", "Also, I love both of your cards! ", "I too can't decide if I like the new in colors or not. ", "They definitely didn't catch my eye right away. ", "Hopefully over time I will start to love them! ", "Both of your cards are fantastic though! ", "I love your monkey card! ", "That dp is fantastic and your coloring is wonderful!", "\n\nCongratulations on your new assignment to the Dirty Girls! ", "You so deserve it. ", "I am a daily blurfer of your blog, and enjoy everything you post. ", "Fortunately, I AM a Fan Club member, so I am off to see all of your wonderful creations for this month, and will look forward to your future creations there, too.", "\n\nSo can I finally say I told you so again (see here: http://stampinwhenican.blogspot.com/2007/12/this-one-is-from-diane-dd2njoy.html)...you even laughed at my prediction. ", "I am so darn omniscient, I scare me! ", "See, you were always a dirty girl (they just didn't know that I had already nominated you for the title!).", "\n\nCongrats to you Dawn! ", "I've been following your work for some time... back when you weren't on any design team and now look .... design teams and a dirty girl! ", "I did see the gallery and love what you created this month.", "\n\nSuch an exciting day for you, Dawn! ", "You were BORN to be a Dirty Girl !!!! ", "I know you're going to have a BLAST in the prestigous role! ", "There are so many stampers out there that admire your work ... you are truly a leader in the industry! ", "These cards are why! ", "They're incredible!", "\n\nCongrats Dawn!! ", "No worries about the hitting the reject button :) because I could leave a 100 comments on your site everyday because your cards always make me so happy and make me go \"WOW\"! ", "You've got great style Ms.Dawn! ", "You will make the Dirty Dozen proud!!! ", "Much love,Sankari :)\n\nOMG!!! ", "I was sooooo happy for you when I signed on to SCS today! ", "I can't think of a dirtier girl than you! (", "you know what I mean) They won't be sorry to have such talent on their team! ", "BTW, I grew up in Edmonton but I now live in Québec. ", "I still love the Eskies but have been since converted to a Habs Fan. ", "I hope you won't hold it against me! ", "LOL! ", "Go HABS go! ", "Congrats on your fantastic news! ", "You rule!", "\n\nOMG! ", "YEAH!! ", "Dawn Im like a proud mama! ", "LOL! ", "I have seen you grow into such a fabulous stamper, and am so proud of you! ", "The dirty girl status is well earned. ", "Have fun because the time will FLY by.", "Now I hope to get some time to go check out the DD gallery! ", "How exciting. ", "CONGRATS and hugs my friend!!", "\n\nDawn ~ wooooo-hoooooo for you!!! ", "OMG, how exciting is that! ", "Being a Dirty girl is a well deserved honor for you. ", "Your work is amazing and you will have no trouble at all fitting in with the ultimate design team...the dirty dozen!!! ", "You go girl :0)!!!!!", "\n\nThe stamps with the quotes on them are really cool....and I love that summery look with the red, white, green and the DREAMS sentiment. ", "I guess I really love the red look for summer like those cherry ones you had done before." ]

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[ "Q:\n\nError when trying to include multiple js sources: Check your javascripts.joinTo config\n\nI'm trying to set up a basic app using phoenix-elixir and brunch, but am getting the following error:\n\n23 Mar 10:18:10 - warn: node_modules/phoenix/priv/static/phoenix.js compiled, but not written. ", "Check your javascripts.joinTo config\n 23 Mar 10:18:10 - warn: node_modules/phoenix_html/priv/static/phoenix_html.js compiled, but not written. ", "Check your javascripts.joinTo config\n\nThis is what I have in branch-config.js:\nfiles: {\n javascripts: {\n joinTo: {\n \"js/app.js\": /^(web\\/static\\/js)/,\n \"js/script.js\": /^(web\\/static\\/js)/\n }\n }\n // ...\n}\n\nThis is my folder structure:\nweb/\n static/\n js/\n app.js\n script.js\n\nI do see script.js being included (I see it compiled into priv/static/js and also as a source in dev tools) but functions inside it don't exhibit the behaviour I'd expect them to do. ", "They do work if I add the contents of script.js to app.js.", "\nInterestingly css works fine if I do...\nstylesheets: {\n joinTo: \"css/app.css\",\n joinTo: \"css/style.css\"\n},\n\nIf I format js similarly to css, there is no error, but, again, functions inside it won't kick in...\njavascripts: {\n joinTo: \"js/app.js\",\n joinTo: \"js/script.js\"\n}\n\nDo I need to add script.js to the vendor folder instead? ", "Is app.js the only js script that can be used inside web/js? ", "I feel I may be missing a setting somewhere.", "\nEDIT:\n\n$ mix phoenix.new -v\n Phoenix v1.1.4\n$ brunch -v\n 2.1.3\n\nA:\n\nIf you want your js files joined into one app.js file, just leave the config as the default\nfiles: {\n javascripts: {\n joinTo: {\n \"js/app.js\": /^(web\\/static\\/js)/\n }\n }\n // ...\n}\n\nThis means all files in web/static/js will be concatenated into app.js. ", "What's happening is basically you're telling brunch to join all javascripts into two different files which confuses it.", "\n\n" ]

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[ "Ann Arbor Symphony to perform at South Lyon farmers market\n\nSouth Lyon’s Farmers Market is ready to give residents and loyal customers a chance to hear the Ann Arbor Symphony Orchestra and give kids a chance to play instruments.", "\n\nA small ensemble performance and an “instrument petting zoo” will be available from 9 a.m. to 2 p.m. this Saturday at the market on the northwest corner of Liberty and Lafayette streets in downtown.", "\n\n“It’s special to the market, because we’ve tried to make music part of every market day,” said South Lyon Farmers Market Manager Mary Novrocki. “", "We’ve had some great musicians and to have the Ann Arbor Symphony there is an especially good thing. ", "We haven’t had a chance to hear this type of music at the market.”", "\n\nThe symphony ensemble will play from 11-12:30 p.m. Jack Hartwig will perform at other times during the day.", "\n\nThe symphony will also provide an “instrument petting zoo.” ", "While it’s geared toward children, instruments will be available to anyone who is interested in getting their hands on violins, cellos, flutes, clarinets, trumpets and trombones.", "\n\nThe symphony is pairing with farmers markets throughout the state in a three-year program, Taste of Music, which is funded by the Community Foundation of Southeast Michigan.", "\n\n“We’re excited that we can we can be in front of a new audience that’s not our typical audience,” explained Sarah Ruddy, Ann Arbor Symphony director of education and outreach. “", "We like that they’re bringing classical music in a fun environment and they show them how fun it can be.”", "\n\nAdded Navrocki: “It’s another nice event that people can come to downtown. ", "For me that’s one of the main reasons the market exists, other than to offer fresh produce and hand-crafted items.”", "\n\nFor concert or educational programming information, contact the symphony at 734-994-4801 or email [email protected]." ]

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[ "Comments on this Embassy\n\nWe are leading Manufacturer exporter of India engaged in Ceramic and Porcelain Tiles [With Inkjet Printing Technology] with years of experience in this field.", "\n\nWe shall be grateful to you if you could provide us the names and contact details of the buyers/agents/importers of these products. ", "Also please mail us the names and addresses of the Trade Associates.", "\n\nWe wish to sell our products in worldwide Countries.", "\n\nYou can visit our website also for our innovative activities - www.sunheart.in.", "\n\nAwaiting your positive reply soon.", "\n\nRegards,\nMs Janki\[email protected]\n\nsridhar.s\n\nFri, 29 Jul 2016 08:00 EDT\n\nnatural essential oilsRespected sir\n\nI Like to take this opportunity to introduce our company SRILAB which is a leading export company in south india and dealing in various agro products like (Eg.", "High Quality essential oil,Herbs etc). ", "And we like to do Export these items to world wide in near future. ", "so i kindly request you send us your Valuable imports data to the following address and help us in built a trade relationship with your country.", "\n\nI want to introduce you to Vaibhav International Pvt Ltd (VIPL). ", "Vaibhav International Pvt Ltd has been in the market circles since 1977 which was formerly known as Vaibhav Plastics. ", "Our company is globally engaged in petrochemical trading with sourcing, storage and distribution. ", "With an age-old loyalty to our customers, we have been focusing on plastics, chemicals, agro and the automobile industries.", "\n\nI am pleased to introduce that we are also into exports of wide variety of items including the Ceramic Tiles, Bathroom Tiles, Floor Tiles, Living Room Tiles, Wall Tiles. ", "We have been dealing in these items for the last 5 years and exporting a variety of items to many Asian and Foreign countries.", "\n\nWe are one of the recognized exporting houses in India. ", "We believe that your company imports these items from India. ", "We shall be glad to have business relations with you. ", "We assume you better competitive rates and good quality products.", "\n\nPlease feel free to keep in touch with us about any of your business related requirements/queries.", "\n\nRegards,\nGaurav Dave\n(Marketing Executive)\n\nJayur Shah\n(Director)\nEmail id: [email protected]\n\n(Send me the list of Importers of Tiles)\n\nswarup\n\nWed, 13 Apr 2016 01:03 EDT\n\nmanagement jobI am looking for MBA jobs in marketing , i dont have any exp\[email protected]\n\nI am Sivaranjith from India & I would like to Export Coconut shells,charcoal,Activated carbon, coconut related products buyer required products to Italy.", "\nI request you to please furnish the Importers & required product list data of the same ASAP.", "\nIt will be more helpful & thank-you\n\nInstitution of Engineers (India)The Institution of Engineers (India), 8 Gokhale Road, Kolkata (IEI) is the National organization of Engineers in India. ", "The Institution of Engineers (India) has over one million members in 15 engineering disciplines in 114 centers or chapters in India and overseas; it is the world's largest multi-disciplinary engineering professional society in engineering and technology world. ", "The Institution of Engineers (India) was established in 1920 in Kolkata, West Bengal and is acclaimed to have pioneered non-formal education in Engineering. ", "The Institution of Engineers (India) was incorporated by Royal Charter in 1935. ", "It is currently headquartered in 8 Gokhale Road, Kolkata - 700020.", "\nMembership categories : -\n1. ", "Fellow - F.I.E.\n2. ", "Member - M.I.E.\n3. ", "Associate member - A.M.I.E.\n4. ", "Graduate - Grad.", "I.E.\n5. ", "Associate - A.I.E.\n6. ", "Chartered Engineer - C.Eng.", "\n7. ", "Professional Engineer - P.Eng.", "\n8. ", "International Professional Engineer - Int.", "PEng.", "\n9. ", "Senior Technician Member - ST\n10. ", "Technician Member –T\nApplication forms for Corporate Membership FIE/MIE/AMIE are available to download from the website. ", "Hard copy of the application form duly filled in along with the requisite documents duly attested by FIE/MIE/AMIE as specified in the form must be sent to the Headquarters. ", "The application form must be signed by the supporter(s), who is a member of the IEI in the Category of FIE/MIE/AMIE, quoting the valid membership number. ", "All the copies of documents accompanying the membership form must be attested by one of the supporters who has signed the membership form. ", "For more details (Membership Eligibility, fees & payment options) visit. ", "For attestation of membership form & document contact me.", "\n\nKishor Patel\n\nTue, 4 Aug 2015 06:26 EDT\n\nOsis SanitarywaresRespected Sir,\n\nWe are one of the leading manufacturer and exporter of all kinds of Tiles and Sanitarywares . ", "Eg.", "Wall Tiles,Floor Tiles, Ceramic Tiles, Porcelain Tiles etc.", "\n\nWe shall be grateful to you if you could provide us the names and contact detail of the buyers/agents/importers of these products.", "\nPlease, also mail us the names and addresses of the Trade Associations\nI wish to sell our products in world wide Countries.", "\n\nPost a comment on this page\n\nWe invite you to share your experiences with the Indian Embassy — obtaining visas and other services, locating the building, and so on. ", "Your comments may be seen by the public, so please do not include private information.", "\n\nYour name\n\nEmail\n\nHeadline\n\nYour messageMax 2000 characters\n\nThis web site is not operated by the Embassy and your comments and questions will not necessarily be seen by its staff. ", "Please note that this is not a forum for broad debate about the foreign policy of India, and such topics will be deleted." ]

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[ "Direct dynamics study on the reaction of N2H4 with F atom: a hydrogen abstraction reaction?", "\nWe present a systematic direct ab initio dynamics investigation of the reaction between N2H4 and F atom, which is predicted to have three possible reaction channels. ", "The structures and frequencies at the stationary points and the points along the minimum energy paths (MEPs) of all reaction channels were calculated at the UB3LYP/6-31+G(d,p) level of theory. ", "Energetic information of stationary points and the points along the MEPs was further refined by means of the CCSD(T)/aug-cc-pVTZ method. ", "The calculated results revealed that the first two primary channels (N2H4+F-->N2H3+HF) are equivalent and occur synchronously via the formation of a pre-reaction complex with Cs symmetry rather than via the direct H abstraction. ", "The pre-reaction complex then evolves into a hydrogen-bonding intermediate through a transition state with nearly no barrier and a high exothermicity, which finally makes the intermediate further decompose into N2H3 and HF. ", "Another reaction channel of minor role (N2H4+F-->NH2F+NH2) was also found during the calculations, which has the same Cs pre-reaction complex but forms NH2F and NH2 via another transition state with high-energy barrier and low exothermicity. ", "The rate constants of these channels were calculated using the improved canonical variational transition state theory with the small-curvature tunneling correction (ICVT/SCT) method. ", "The three-parameter ICVT/SCT rate constant expressions of k(ICVT/SCT) at the CCSD(T)/aug-cc-pVTZ//UB3LYP/6-31+G(d,p) level of theory within 220-3000 K were fitted as (7.64x10(-9))T (-0.87) exp(1180/T) cm3 mole-1 s-1 for N2H4+F-->N2H3+HF and 1.45x10(-12)(T/298)(2.17) exp(-1710/T) cm3 mole-1 s-1 for N2H4+F-->NH2F+NH2." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "/*\r\n ==============================================================================\r\n\r\n This file is part of the JUCE library.", "\r\n Copyright (c) 2017 - ROLI Ltd.\r\n\r\n JUCE is an open source library subject to commercial or open-source\r\n licensing.", "\r\n\r\n By using JUCE, you agree to the terms of both the JUCE 5 End-User License\r\n Agreement and JUCE 5 Privacy Policy (both updated and effective as of the\r\n 27th April 2017).", "\r\n\r\n End User License Agreement: www.juce.com/juce-5-licence\r\n Privacy Policy: www.juce.com/juce-5-privacy-policy\r\n\r\n Or: You may also use this code under the terms of the GPL v3 (see\r\n www.gnu.org/licenses).", "\r\n\r\n JUCE IS PROVIDED \"AS IS\" WITHOUT ANY WARRANTY, AND ALL WARRANTIES, WHETHER\r\n EXPRESSED OR IMPLIED, INCLUDING MERCHANTABILITY AND FITNESS FOR PURPOSE, ARE\r\n DISCLAIMED.", "\r\n\r\n ==============================================================================\r\n*/\r\n\r\nnamespace juce\r\n{\r\n\r\nResizableCornerComponent::ResizableCornerComponent (Component* const componentToResize,\r\n ComponentBoundsConstrainer* const constrainer_)\r\n : component (componentToResize),\r\n constrainer (constrainer_)\r\n{\r\n setRepaintsOnMouseActivity (true);\r\n setMouseCursor (MouseCursor::BottomRightCornerResizeCursor);\r\n}\r\n\r\nResizableCornerComponent::~ResizableCornerComponent()\r\n{\r\n}\r\n\r\n//==============================================================================\r\nvoid ResizableCornerComponent::paint (Graphics& g)\r\n{\r\n getLookAndFeel()\r\n .drawCornerResizer (g, getWidth(), getHeight(),\r\n isMouseOverOrDragging(),\r\n isMouseButtonDown());\r\n}\r\n\r\nvoid ResizableCornerComponent::mouseDown (const MouseEvent&)\r\n{\r\n if (component == nullptr)\r\n {\r\n jassertfalse; // You've deleted the component that this resizer is supposed to be controlling!", "\r\n return;\r\n }\r\n\r\n originalBounds = component->getBounds();\r\n\r\n if (constrainer !", "= nullptr)\r\n constrainer->resizeStart();\r\n}\r\n\r\nvoid ResizableCornerComponent::mouseDrag (const MouseEvent& e)\r\n{\r\n if (component == nullptr)\r\n {\r\n jassertfalse; // You've deleted the component that this resizer is supposed to be controlling!", "\r\n return;\r\n }\r\n\r\n Rectangle<int> r (originalBounds.withSize (originalBounds.getWidth() + e.getDistanceFromDragStartX(),\r\n originalBounds.getHeight() + e.getDistanceFromDragStartY()));\r\n\r\n if (constrainer !", "= nullptr)\r\n {\r\n constrainer->setBoundsForComponent (component, r, false, false, true, true);\r\n }\r\n else\r\n {\r\n if (Component::Positioner* const pos = component->getPositioner())\r\n pos->applyNewBounds (r);\r\n else\r\n component->setBounds (r);\r\n }\r\n}\r\n\r\nvoid ResizableCornerComponent::mouseUp (const MouseEvent&)\r\n{\r\n if (constrainer !", "= nullptr)\r\n constrainer->resizeEnd();\r\n}\r\n\r\nbool ResizableCornerComponent::hitTest (int x, int y)\r\n{\r\n if (getWidth() <= 0)\r\n return false;\r\n\r\n const int yAtX = getHeight() - (getHeight() * x / getWidth());\r\n\r\n return y >= yAtX - getHeight() / 4;\r\n}\r\n\r\n} // namespace juce\r\n" ]

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[ "Let's take the cast of jersey shore and send them on a highly experimental space mission!", "\n\n494 shares" ]

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[ "/* SPDX-License-Identifier: GPL-2.0 */\n#ifndef __NVKM_DISP_CONN_H__\n#define __NVKM_DISP_CONN_H__\n#include <engine/disp.h>\n\n#include <core/notify.h>\n#include <subdev/bios.h>\n#include <subdev/bios/conn.h>\n\nstruct nvkm_conn {\n\tstruct nvkm_disp *disp;\n\tint index;\n\tstruct nvbios_connE info;\n\n\tstruct nvkm_notify hpd;\n\n\tstruct list_head head;\n};\n\nint nvkm_conn_new(struct nvkm_disp *, int index, struct nvbios_connE *,\n\t\t struct nvkm_conn **);\nvoid nvkm_conn_del(struct nvkm_conn **);\nvoid nvkm_conn_init(struct nvkm_conn *);\nvoid nvkm_conn_fini(struct nvkm_conn *);\n\n#define CONN_MSG(c,l,f,a...) do { \\\n\tstruct nvkm_conn *_conn = (c); \\\n\tnvkm_##l(&_conn->disp->engine.subdev, \"conn %02x:%02x%02x: \"f\"\\n\", \\\n\t\t _conn->index, _conn->info.location, _conn->info.type, ##a); \\\n} while(0)\n#define CONN_ERR(c,f,a...) CONN_MSG((c), error, f, ##a)\n#define CONN_DBG(c,f,a...) CONN_MSG((c), debug, f, ##a)\n#define CONN_TRACE(c,f,a...) CONN_MSG((c), trace, f, ##a)\n#endif\n" ]

{ "pile_set_name": "Github" }

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[ "This is the third year in a row Baltimore has topped the list, which is compiled based on treatment data from the metro areas where Orkin performed the most bed bug treatments in 2018. ", "Nearby Washington, D.C., nabbed second place on the list." ]

{ "pile_set_name": "OpenWebText2" }

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[ "1. ", "Field of the Invention\nThe invention is related to controlling borders between packet based networks, and in particular, to border control systems and methods.", "\n2. ", "Description of the Prior Art\nCurrent Voice over Internet Protocol (VoIP) networks route voice communications using the IP format. ", "Essentially, voice communications are converted into packets and transported through IP networks. ", "In an example of a typical VoIP call from an on-net subscriber to an off-net destination, the subscriber to the VoIP network utilizes a phone program on a personal computer connected to the Internet. ", "An application on the computer converts voice communications to packets and transmits the voice packets to the Internet. ", "The packets are then routed to a gateway on a standard switched telephone network such as the public switched telephone network (PSTN). ", "The voice packets are then routed through the PSTN to the destination for the call.", "\nIn an example of a typical VoIP call from an on-net subscriber to another on-net subscriber, both users utilize phone programs on their personal computers connected to the Internet. ", "In this case, voice communications are converted to packets and transmitted over the Internet in accordance with routing instructions in the packet headers. ", "The packets are routed in the same fashion as any other type of packet, such as a packet carrying email.", "\nProblematically, VoIP calls suffer from low quality of surface and reliability. ", "In both examples of the prior art, VoIP calls are either dumped to the nearest gateway and then routed on the PSTN, or the calls are routed over the Internet and suffer from low quality. ", "In either case, intelligent routing decisions are not made to choose an optimal route, gateway, or otherwise.", "\nOne solution in the prior art to solve the persistent problems of low quality and reliability involves implementing dedicated VoIP networks. ", "Unfortunately, stand alone dedicated VoIP networks are only able to provide high quality of service for a call between two subscribers to the dedicated VoIP service. ", "If a call must reach the PSTN, dedicated VoIP networks do not possess intelligent gateway selection capabilities. ", "Additionally, for a call that must transit between two competitive dedicated VoIP networks, intelligent border control capabilities do not exist.", "\nPacket voice networks, such as VoIP networks, utilize border controllers to control traffic exchanged across various packet networks. ", "Often times, numerous border controllers are employed between two packet networks. ", "A typical border controller may consist of a firewall and an application server, for example. ", "Packet switches typically perform call setup processing for calls across two packet networks, including choosing the particular border controller for a call.", "\nFor calls originating from a host packet network and destined for another competitive packet voice network, the host packet switch is responsible for choosing the border controller for the call. ", "The host packet switch is also responsible for querying a corresponding packet switch in the destination packet network for the network address of the called party. ", "The host packet switch is further responsible for alerting the destination switch of the identity of the chosen border controller. ", "The host packet switch also notifies the calling device of the chosen border controller.", "\nProblematically, requiring a host switch to interface with the destination switch inefficiently places processing burdens on the host switch that could be better directed towards other purposes. ", "Requiring a host switch to choose a border controller also inefficiently burdens the switch. ", "Furthermore, requiring host switches to communicate with several border controllers potentially opens security holes to the packet network of the host switch. ", "Requiring the host switch to notify the destination switch of the chosen border controller creates additional potential security holes into the host packet network. ", "Thus, improved operations between competitive networks is desired." ]

{ "pile_set_name": "USPTO Backgrounds" }

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[ "/*******************************************************************************\n * \n * Copyright (c) 1993 Intel Corporation\n * \n * Intel hereby grants you permission to copy, modify, and distribute this\n * software and its documentation. ", " Intel grants this permission provided\n * that the above copyright notice appears in all copies and that both the\n * copyright notice and this permission notice appear in supporting\n * documentation. ", " In addition, Intel grants this permission provided that\n * you prominently mark as \"not part of the original\" any modifications\n * made to this software or documentation, and that the name of Intel\n * Corporation not be used in advertising or publicity pertaining to\n * distribution of the software or the documentation without specific,\n * written prior permission.", "\n * \n * Intel Corporation provides this AS IS, WITHOUT ANY WARRANTY, EXPRESS OR\n * IMPLIED, INCLUDING, WITHOUT LIMITATION, ANY WARRANTY OF MERCHANTABILITY\n * OR FITNESS FOR A PARTICULAR PURPOSE. ", " Intel makes no guarantee or\n * representations regarding the use of, or the results of the use of,\n * the software and documentation in terms of correctness, accuracy,\n * reliability, currentness, or otherwise; and you rely on the software,\n * documentation and results solely at your own risk.", "\n *\n * IN NO EVENT SHALL INTEL BE LIABLE FOR ANY LOSS OF USE, LOSS OF BUSINESS,\n * LOSS OF PROFITS, INDIRECT, INCIDENTAL, SPECIAL OR CONSEQUENTIAL DAMAGES\n * OF ANY KIND. ", " IN NO EVENT SHALL INTEL'S TOTAL LIABILITY EXCEED THE SUM\n * PAID TO INTEL FOR THE PRODUCT LICENSED HEREUNDER.", "\n * \n ******************************************************************************/\n\n\t.file \"memcmp.s\"\n#ifdef\t__PIC\n\t.pic\n#endif\n#ifdef\t__PID\n\t.pid\n#endif\n/*\n * (c) copyright 1988,1993 Intel Corp., all rights reserved\n */\n/*\n\tprocedure memcmp (optimized assembler version for the 80960K series)\n\n\tresult = memcmp (src1_addr, src2_addr, max_bytes)\n\n\tcompare the byte array pointed to by src1_addr to the byte array\n\tpointed to by src2_addr. ", " Return 0 iff the arrays are equal, -1 iff \n\tsrc1_addr is lexicographically less than src2_addr, and 1 iff it is \n\tlexicographically greater. ", " Do not compare more than max_bytes bytes.", "\n\n\tUndefined behavior will occur if the end of either source array\n\tis in the last two words of the program's allocated memory space. ", "\n\tThis is so because memcmp fetches ahead. ", " Disallowing the fetch ahead \n\twould impose a severe performance penalty.", "\n\n\tStrategy:\n\n\tFetch the source strings by words and compare the words until either \n\ta differing word is found or max_bytes is exhausted. ", " In the former \n\tcase, move through the words to find the differing byte and return \n\tplus or minus one, appropriately. ", " In the latter case, return zero \n\t(equality).", "\n\n\tTactics:\n\n\t1) Do NOT try to fetch the words in a word aligned manner because,\n\tin my judgement, the performance degradation experienced due to \n\tnon-aligned accesses does NOT outweigh the time and complexity added \n\tby the preamble that would be necessary to assure alignment. ", " This \n\tis supported by the intuition that most source arrays (even more \n\ttrue of most big source arrays) will be word aligned to begin with.", "\n\n\t2) Rather than decrementing max_bytes to zero, I calculate the\n\taddress of the byte after the last byte of the source_1 array, and\n\tquit when the source byte pointer passes that. ", " \n*/\n\n\t.globl _memcmp\n\t.globl __memcmp\n\t.leafproc _memcmp,__memcmp\n\t.align 2\n\n_memcmp:\n#ifndef __PIC\n\tlda\t.Lrett,g14\n#else\n\tlda\t.Lrett-(.+8)(ip),g14\n#endif\n__memcmp:\n\tmov\tg14,g13\t\t# preserve return address\n\tldconst 0,g14\t\t# conform to register conventions\n\tcmpibge\t0,g2,Lequal_exit\t# quit if max_bytes <= 0\n\taddo\tg0,g2,g2\t# calculate byte addr of byte after last in src1\n\n.Lwloop:\n\tcmpo\t g0,g2\t\t\n\tld\t(g0), g5\t# fetch word of source_1\n\tbge \t Lequal_exit\t# quit (equal) if max_bytes exhausted\n\tld\t(g1), g3\t# fetch word of source_2\n\taddo 4,g0,g0\t# post-increment source_1 byte ptr\n\taddo 4,g1,g1 \t# post-increment source_2 byte ptr\n\tcmpobe\t g5,g3,.", "Lwloop\t# branch if source words are equal\n\n\tldconst 0xff,g4\t\t# byte extraction mask\n\tsubo 4,g0,g0\t# back up src1 pointer\n\n.Lcloop: and\tg4,g5,g7 \t# extract and compare individual bytes\n\tand\tg4,g3,g6\n\tcmpobne\tg7,g6,.diff\t# branch if they are different\n\tshlo\t8,g4,g4\t\t# position mask for next extraction\n\taddo\t1,g0,g0\n\tcmpobl\tg0,g2,.", "Lcloop\t# quit if max_bytes is exhausted\n\nLequal_exit:\n\tmov\t0,g0\n\tbx\t(g13)\n.Lrett:\t\n\tret\n\n.diff:\tbl\t.neg\t\t# arrays differ at current byte. ", " \n\t\t\t\t/* return 1 or -1 appropriately */\n mov 1,g0\n\tbx\t(g13)\n.neg:\tsubi 1,0,g0\n.Lexit: \t\n\tbx\t(g13)\n\n/* end or memcmp */\n" ]

{ "pile_set_name": "Github" }

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[ "Enhanced temporal non-linearities in human object-related occipito-temporal cortex.", "\nTo what extent does neural activation in human visual cortex follow the temporal dynamics of the optical retinal stimulus? ", "Specifically, to what extent does stimulus evoked neural activation persist after stimulus termination? ", "In the present study, we used functional magnetic resonance imaging (fMRI) to explore the resulting temporal non-linearities across the entire constellation of human visual areas. ", "Gray-scale images of animals, houses and faces were presented at two different presentation rates - 1 and 4 Hz - and the fMRI signal was analyzed in retinotopic and in high order occipito-temporal visual areas. ", "In early visual areas and the motion sensitive area MT/V5, a fourfold increase in stimulus presentation rate evoked a twofold increase in signal amplitude. ", "However, in high order visual areas, signal amplitude increased only by 25%. ", "A control experiment ruled out the possibility that this difference was due to signal saturation ('ceiling') effects. ", "A likely explanation for the stronger non-linearities in occipito-temporal cortex is a persistent neuronal activation that continues well after stimulus termination in the 1 Hz condition. ", "These persistent activations might serve as a short term (iconic) memory mechanism for preserving a trace of the stimulus even in its absence and for future integration with temporally correlated stimuli. ", "Two alternative models of persistence (inhibitory and excitatory) are proposed to explain the data." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Mathematical analysis of a weather-driven model for the population ecology of mosquitoes.", "\nA new deterministic model for the population biology of immature and mature mosquitoes is designed and used to assess the impact of temperature and rainfall on the abundance of mosquitoes in a community. ", "The trivial equilibrium of the model is globally-asymptotically stable when the associated vectorial reproduction number (R0) is less than unity. ", "In the absence of density-dependence mortality in the larval stage, the autonomous version of the model has a unique and globally-asymptotically stable non-trivial equilibrium whenever 1 andlt;R0 andlt;RC0 (this equilibrium bifurcates into a limit cycle, via a Hopf bifurcation at R0=RC0). ", "Numerical simulations of the weather-driven model, using temperature and rainfall data from three cities in Sub-Saharan Africa (Kwazulu Natal, South Africa; Lagos, Nigeria; and Nairobi, Kenya), show peak mosquito abundance occurring in the cities when the mean monthly temperature and rainfall values lie in the ranges [22-25]0C, [98-121] mm; [24-27]0C, [113-255] mm and [20.5-21.5]0C, [70-120] mm, respectively (thus, mosquito control efforts should be intensified in these cities during the periods when the respective suitable weather ranges are recorded)." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "\n\nCounting Bloom Filter: Efficient d-left implementation in Go - jaytaylor\nhttps://github.com/seiflotfy/dlCBF\n\n======\njsherer\nOdd: \"This implmentation (sic) currently does not implement the counter\nfeature.\"", "\n\n" ]

{ "pile_set_name": "HackerNews" }

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[ "Staying home amid the coronavirus lockdown has had many people dreading the indoors. ", "One family, however, is having the time of their life after their little toddler was caught playing with dog food. ", "Her parents interrogated the child in question, and she is seen confidently keeping her facade that she is innocent.", "\n\nThe 38-year-old mother, Sarah, who hails from Jacksonville, Florida, questioned her daughter Lilyana after she saw her taking food from their dog's bowl.", "\n\nBeing afraid of getting into trouble, the little one was quick to deny the claim, although she was seen in the act.", "\n\nThe mother was able to catch the hilarious encounter on video as the toddler continued to lie her way out.", "\n\nThe heated argument\n\nSarah asked her daughter if she touched the food, where the child was still hesitant to be honest even when her father, Tim, joined the conversation.", "\n\nThe little kid just kept on repeating the line, \"No, I didn't touch the food!' ", "as confidently and 'truthfully' as she could.", "\n\nThe toddler continuously repeated her statement that she did not touch the dog food.", "\n\nThe family kept going back and forth between questions and getting the same response from their child.", "\n\nThe parents struggled to maintain their strictness during their daughter's sudden outburst.", "\n\nLilyana exuded the confidence of a lawyer in putting up her case of innocence, desperately trying to convince her parents she wasn't guilt, as they otherwise believed. ", "She repeatedly walks back and forth while answering the questions switching from looking at her mother to her father.", "\n\nAfter her attempt at redemption, Lilyana could be seen walking away without a shred of guilt after being drawn to the television, ending the debacle prematurely without a conclusion.", "\n\nThe ecstatic mother uploaded the video of the confrontation on Facebook and quickly amassed more than 280,000 shares and 28,000 comments.", "\n\nRead Also: Tom Hanks and Rita Wilson Donates Blood for the Development of 'Hank-ccine', a Coronavirus Vaccine\n\nUsers were quick to share their amusement regarding the event and commented on their thoughts on how hilarious the child is.", "\n\nOthers commented about how some people might think that children of Lilyana's age can't have the ability to lie. ", "Another user pointed out the child's future in law with her credible and convincing defense.", "\n\nThe reason behind the confrontation\n\nSarah commented about her video explaining the events that led to the confrontation. ", "She said she was washing the dishes as their little daughter came and tried to get a knife where Tim quickly reprimanded her.", "\n\nAfter her chore, Sarah saw Lilyana go over to their dog, Jude's bowl, and grab a handful of food. ", "The mother then asked her daughter why she did so, and that's how the argument started.", "\n\nThe mother shared that the little toddler doesn't argue confidently like that, but like most kids, only try to get what they want as much as they can.", "\n\nSarah just thought to herself, 'What 21-month-old doesn't try?' ", "as the parents continued to tease her that led to not touching the food at all.", "\n\nShe also added they immediately went out to ride her bike and play with bubbles after she got distracted by the TV.", "\n\nRead Also: [Viral Video] Cops Prank Lockdown Violators by Forcing them into an Ambulance where a \"Sick\" Police Officer was Waiting" ]

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[ "Introduction\n============\n\nFor every given solid surface, breaking of periodicity in one dimension will result in a change in the electronic states near and at the surface, since the lack of nearest neighbours on one side of the surface atoms causes a sensible local rearrangement of the surface structure and chemical bonds. ", "We investigate here aluminum, which as a bulk material is a paradigmatic jelliumlike metal: cohesion and bonding are dominated by electron–gas features, where the ions can be considered roughly speaking as a perturbation.", " [@pseudo] What happens at an Al surface, however, is much less intuitive: does the surface behave essentially like a jellium surface, or do surface atoms play a preminent role? ", "Here we investigate this issue and we show how a sharp answer is provided by a tool which is a very innovative one in condensed matter physics. ", "So far, bonding features at a crystal surfaces have been investigated by studying either the charge density or the local density of states. ", "Instead, we are using here the so–called “electron localization function” (ELF),[@Becke_90; @Silvi_94; @Savin_97] which has become recently very popular in the field of quantum chemistry.", "\n\nWe study here three basic choices for the orientation of the Al surface: (110), (100), and (111), schematically shown in Fig.", " \\[f:Fig1\\]. ", "These high–symmetry surfaces have a rather different packing of the surface atoms: this is also visible in Fig.", " \\[f:Fig1\\], where the same scale has been used for the three surfaces. ", "Some correlation between packing and bonding properties is obviously expected, but what is surprising is that the three chosen surfaces span the whole range of possibilities, with (110) and (111) being at the two very extreme ends: while the Al(110) surface prominently displays well characterized Al atoms, Al(111) is essentially a weakly perturbed jellium surface. ", "The atomiclike vs. jelliumlike character of the electron distribution is perspicuously shown by the immediate graphical language of ELF.", "\n\nSeveral appealing features make ELF the tool of choice in the present study: ELF is a pure ground–state property, as the density is, but it “magnifies” by design the bonding features of a given electron distribution. ", "Furthermore, ELF is dimensionless, and allows to compare the nature of bonding on an absolute scale. ", "ELF provides in a very simple way a quantitative estimate of the “metallicity” of a given bond, or more generally of a given valence region of the system. ", "From our ELF calculations it is clear how in the bulk metal the valence electrons display a free–electron nature: actually, outside the core region, the charge density basically behaves as a free–electron gas. ", "This jelliumlike behaviour of the crystalline system must be contrasted with the opposite extreme of the isolated atom, where the valence–shell region is characterized by very different ELF values. ", "Through a series of ELF contour plots, we will show in the following how this free–atom behaviour is almost entirely reproduced by the topmost atoms of the least packed metal surface studied, namely Al(110). ", "We stress that ELF discriminates an atomiclike valence–electron distribution from a jelliumlike distribution in a sharp quantitative way.", "\n\nWe are adopting here a fully [*ab–initio*]{} method, which has become the “standard model” in modern first–principles studies of simple metals, covalent semiconductors, simple ionic solids, and many other disparate materials:[@Cohen_91] namely, density functional theory (DFT)[@Lundqvist_83] with norm–conserving pseudopotentials.[@Pickett_89] This framework is the natural choice for a real solid system as the one chosen for this work, although the ELF has been originally introduced and mostly applied, in the quantum–chemistry litterature, as an all–electron tool. ", "Anyhow, we will demonstrate that the use of the pseudopotential approximation makes the ELF particularly meaningful, since getting rid of the core electrons and focussing solely on the bonding electrons notably simplifies the final outcome.", "\n\nIn a recent very interesting paper, Fall [*et al.*]{}", " [@Fall_98] have investigated the trend in the Al work function for the same three orientations as considered here. ", "They provide an explanation of the trend in terms of “face–dependent filling of the atomiclike $p$ states at the surface”. ", "The ELF is an orbital–independent tool, yet it provides a concomitant message: we show that there is indeed a face–dependent filling of the electronic states localized in the surface region.", "\n\nThe present paper is organized as follows. ", "In Sec. ", "II we introduce the ELF definition, reviewing its foundamental properties and features. ", "In Sec. ", "III we discuss the use of the pseudopotential approximation for our ELF analysis. ", "In Sec. ", "IV we present our results carried out for the three aluminum surfaces. ", "Finally, in Sec. ", "V we draw a few conclusions.", "\n\nDefinitions\n===========\n\nThe ELF has been originally proposed by Becke and Edgecombe, [@Becke_90] as a convenient measure of the parallel–spin electron correlation. ", "Starting from the short–range behavior of the parallel–spin pair probability, they defined a new scalar function, conveniently ranging from zero to one, that uniquely identifies regions of space where the electrons are well localized, as occurs in bonding pairs or lone–electron pairs. ", "This tool has immediately shown its power to visualize the chemical bonding and the electron localization. ", "The ELF is defined as $$\\mbox{ELF}=\\frac\n1{1+[D({\\bf r})/D_h({\\bf r})]^2}, \\label{e:ELF}$$ in which $D({\\bf r})$ and $D_h({\\bf r})$ represent the curvature of the parallel–spin electron pair density for, respectively, the actual system and a homogeneous electron gas with the same density as the actual system at point [**r**]{}. ", "By definition, ELF is identically one either in any single–electron wavefunction or in any two–electron singlet wavefunction: in both cases the Pauli principle is ineffective, and the ground wavefunction is nodeless or, loosely speaking, “bosonic”. ", "In a many–electron system ELF is close to one in the regions where electrons are paired to form a covalent bond, while is small in low–density regions; ELF is also close to one where the unpaired lone electron of a dangling bond is localized. ", "Furthermore, since in the homogeneous electron gas ELF equals 0.5 at any density, values of this order in inhomogeneous systems indicate regions where the bonding has a metallic character.", "\n\nSavin [*et al.*]{}", " [@Savin_92] have proposed another illuminating interpretation of the same quantity, showing how $D$ can be simply calculated in terms of the local behaviour of the kinetic energy density, thus making no explicit reference to the pair distribution function. ", "This is particularly convenient in our case, since the pair density is outside the scope of DFT. ", "Owing to the Pauli principle, the ground–state kinetic energy density of a system of fermions is no smaller than the one of a system of bosons at the same density: ELF can be equivalently expressed in terms of the extra contribution to the kinetic energy density due to the Pauli principle. ", "The Savin [*et al.*]{} ", "reformulation also provides a meaningful physical interpretation: where ELF is close to its upper bound, electrons are strongly paired and the electron distribution has a local “bosonic” character.", "\n\nFollowing Ref.", " , $D({\\bf r})$ is the Pauli excess kinetic energy density, defined as the difference between the kinetic energy density and the so–called von Weizsäcker kinetic energy functional: [@Dreizler] $$D({\\bf r})=\\frac 12\\nabla _{{\\bf\nr}}\\nabla _{{\\bf r^{\\prime }}}\\rho ({\\bf r}, {\\bf r^{\\prime }})\\bigg |_{{\\bf\nr}={\\bf r^{\\prime }}}-\\frac 18\\frac{|\\nabla n({\\bf r})|^2}{n({\\bf r})}\n\\label{e:D}$$ where $\\rho $ is the one–body reduced (spin–integrated) density matrix. ", "The von Weizsäcker functional provides a rigorous lower bound for the exact kinetic energy density [@Dreizler] and is ordinarily indicated as the “bosonic” kinetic energy, since it coincides with the ground–state kinetic energy density of a non–interacting system of bosons at density $n({\\bf r})$. Therefore, $D$ is positive semidefinite and provides a direct measure of the local effect of the Pauli principle. ", "The other ingredient of Eq.", " (\\[e:ELF\\]) is $D_{h}({\\bf r})$, defined as the kinetic energy density of the homogeneous electron gas at a density equal to the local density: $$D_h({\\bf r})=\\frac 3{10}(3\\pi ^2)^{\\frac 23}n({\\bf\nr})^{\\frac 53}. ", " \\label{e:D_h}$$ It is obvious to verify that the ELF is identical to one in the ground state of any one– or two–electron systems, while is identical to 0.5 in the homogeneous electron gas at any density.", "\n\nAs commonly done in many circumstances—including in other ELF investigations[@Savin_92]—we approximate the kinetic energy of the interacting electron system with the one of the noninteracting Kohn–Sham (KS) one. ", "We therefore use the KS density matrix: $$\\rho ({\\bf\nr},{\\bf r^{\\prime }})= 2 \\sum_i\\phi_i^{KS} ({\\bf r})\\phi _i^{*KS}( {\\bf\nr^{\\prime }}), \\label{e:rho}$$ where $\\phi _i^{KS}({\\bf r})$ are the occupied KS orbitals. ", "Such approximation is expected to become significantly inaccurate only in the case of highly correlated materials.", "\n\nIsolated Pseudo–Atom\n====================\n\nThe original ELF definition is an all–electron one, and has the remarkable feature of naturally revealing the entire shell structure for heavy atoms. ", "Such a feature is of no interest here, since only one electronic shell (the $sp$ valence one) is involved in the bonding of Al atoms in any circumstances. ", "The pseudopotential scheme simplifies the landscape, since only the electrons of the relevant valence shell are dealt with explicitly: the ELF message comes out therefore much clearer, with basically no loss of information.[@Kohout_97] In the spatial regions occupied by core electrons, the pseudo–electronic distribution shows a depletion and ELF assumes very low values. ", "Outside the ionic cores, in the regions relevant to chemical bonding, the norm conservation endows the pseudocharge density with physical meaning, as widely discussed in the modern pseudopotential literature.[@Cohen_91; @Pickett_89] The pseudo ELF carries therefore—in the material of interest here—the same information as the all–electron ELF, while it removes irrelevant and confusing features due to the inner, chemically inert, shells.", "\n\nFor an isolated pseudo–atom we have by construction only a single valence shell, clearly displayed by a single and very prominent ELF maximum. ", "In Fig.", " \\[f:Fig2\\] we report our result carried out for an isolated Al atom: in the picture one immediately remarks the spherical region associated to the ELF maximum (0.91), where the charge density is almost bosonic. ", "The black cloud in Fig.", " \\[f:Fig2\\] indicates the strong localization of the electronic valence shell and perspicuously distinguishes the [*free*]{} aluminum pseudo–atom from the crystalline one.", "\n\nIndeed looking at the following Figs.", " \\[f:Fig3\\]–\\[f:Fig5\\], and inspecting the bulk regions of them, the ELF plots quantitatively demonstrate that the valence electrons have a predominant free–electron nature, with a jelliumlike (or Thomas–Fermi) ELF value. ", "The ion cores only provide an “exclusion region” for electrons (white circles in the plots), but basically do not alter the jelliumlike nature of the electron distribution outside the core radii: in this sense we may regard the ion cores as a “weak” perturbation.[@pseudo] Actually, the maximum value attained by ELF between nearest–neighbor atoms in bulk Al is only 0.61 and—outside the core radii—there is a widespread grey region, where ELF is almost constant and close to 0.5, thus indicating a jelliumlike electronic system. ", "This peculiar behaviour will help us in the following to understand the bonding pattern occurring at different Al surfaces.", "\n\nAluminum Surfaces\n=================\n\nAll the calculations in this work use a state–of–the–art set of ingredients: a plane–wave expansion of the KS orbitals with a 16 Ry kinetic–energy cut–off, a set of Monkhorst–Pack[@Monkhorst_76] special points for the Brillouin zone integration, with a Gaussian broadening of 0.01Ry and a norm–conserving pseudopotential in fully non–local form.[@Kleinman_82] The calculations for the (111) surface were performed using a 9+6 supercell (9 planes of Al, 6 equivalent planes of vacuum) and 37 [**k**]{}–points in the irreducible Brillouin zone. ", "The corresponding values used for the (100) surface are an 8+6 supercell and 46 [**k**]{}–points, and for the (110) surface an 8+8 supercell and 48 [**k**]{}–points. ", "We have preliminarily investigated the effect of surface ionic relaxation on ELF, and found it negligible. ", "Similar insensitiveness was found in Ref.", "  upon other surface electronic properties: we therefore present results for the unrelaxed surfaces. ", "As shown above in Fig.", " \\[f:Fig1\\], the three surfaces have a different packing: the packing increases from Al(110) to Al(100) to Al(111). ", "A measure of this packing is the number of nearest neighbors in the surface plane, called coordination in the following: this number is 2, 4, and 6 for the three surfaces, respectively.", "\n\nIn Fig.", " \\[f:Fig3\\] we report two ELF contour plots along two non–equivalent planes passing through the topmost (twofold coordinated) atom of the Al(110) surface. ", "Along a direction orthogonal to the surface and passing through the surface atom, our calculated ELF attains the maximum value of 0.86, thus indicating that the Pauli principle has little effect. ", "Comparing Fig.", " \\[f:Fig3\\] to \\[f:Fig2\\], where the ELF maximum has the close value of 0.91, we quantitatively see see how much the surface atom actually behaves as a free–atom in the outer direction. ", "A slightly different electronic distribution is present at the four–fold coordinated Al(100) surface in Fig.", " \\[f:Fig4\\]. ", "In this case the ELF maximum—along the same direction—attains the lower value of 0.80 and shows therefore an electron distribution with a less pronounced atomiclike character.", "\n\nThe almost black regions around the surface atoms in Figs.", " \\[f:Fig3\\] and \\[f:Fig4\\] are also clearly visible in the top views of Fig.", " \\[f:Fig6\\], where the contour plots are drawn in the outermost atomic plane. ", "In this plane the maxima occur midway between nearest-neighbors atoms and assume the values of 0.77, 0.74, and 0.67 in order of increasing packing. ", "This decrease of electron pairing shows a trend from covalent–like to metallic–like bonding between nearest neighboring surface atoms; bonding to the underlying bulk atoms is instead metallic in all cases.", "\n\nFinally, in Fig.", " \\[f:Fig5\\] we have the extreme case of the six–fold coordinated Al(111) surface. ", "The absolute ELF maximum is only 0.73 and lies in a low–symmetry point, slightly off the outermost atomic plane. ", "Along the direction orthogonal to the surface and passing through the surface atom, the ELF maximum is only 0.65: this behaviour clearly marks an almost smooth decay from the bulk—where the electrons exhibit a prevailing jelliumlike distribution—to the vacuum region. ", "Also in the top view of Fig.", " \\[f:Fig6\\] there is no evidence of electron pairing between surface atoms, with a wide spread region of almost uniform ELF, close in value to 0.5. ", "We can therefore summarize the result by saying that the Al(111) surface is essentially a jellium surface perturbed by the atomic cores, in a pseudopotential sense:[@pseudo] the perturbation obviously originates an “exclusion region” (white plots within the core radii), but besides this has little effect on the electron distribution in the bulk [*and*]{} at the (111) surface.", "\n\nThe values of the maxima in the direction orthogonal to the surface and passing through the surface atom in the three cases (0.91, 0.80, and 0.65, as reported above) can be interpreted as a measure of the occupation of the atomiclike states protruding from the surface. ", "We recall in fact that ELF is identically equal to 1 for any one– or two–electron system: high ELF values indicate a strong localization of the wavefunction. ", "Our numbers show an analogous trend as the one pointed out by Ref.", " , where it is shown that the filling of atomic $p_\\perp$ orbitals, protruding from the surface, decreases indeed with increasing packing, [*i.e.*]{} going from (110) to (100) to (111).", "\n\nConclusions\n===========\n\nIn conclusion, we have shown how the ELF at the surfaces of a paradigmatic $sp$–bonded metal distinctly reveals the rearrangements in the electron distribution due to the surface formation and to the changes in the local coordination. ", "We have shown that ELF, in a modern DFT–pseudopotential framework, is a powerful tool to investigate—without using any spectral information—the chemical bonding pattern: this makes the method appealing in order to deal with much more complicated systems.", "\n\nFinally, to put this work in a wider perspective, we notice in the current literature a quest for other innovative tools which address localization and bonding,[@Silvestrelli98; @rap107] and whose relationships to ELF have not been investigated yet.", "\n\nV. Heine, in [*Solid State Physics*]{}, edited by H. Ehrenreich, F. Seitz, and D. Turnbull, vol [**24**]{} (Academic, New York, 1970), p.1; M.L. Cohen and V. Heine, [*ibid.*]{} ", "p.250.", "\n\nA. D. Becke, K. E. Edgecombe, J. Chem. ", "Phys. [**", "92**]{}, 5397 (1990).", "\n\nB. Silvi, A. Savin, Nature [**371,** ]{}683 (1994).", "\n\nA. Savin, R. Nesper, S. Wengert and T. F. Fässler, Angew. ", "Chem. ", "Int. ", "Ed. ", "Engl. [**", "36**]{}, 1808 (1997).", "\n\nM.L. Cohen, in [*Electronic Materials*]{}, edited by J.R. Chelikowsky and A. Franciosi (Springer, Berlin, 1991), p.57.", "\n\nedited by S. Lundqvist and N. H. March (Plenum, New York, 1983).", "\n\nW. E. Pickett, Comput. ", "Phys. ", "Rep. [**9**]{}, 115 (1989).", "\n\nC. J. Fall, N. Binggeli, and A. Baldereschi, Phys. ", "Rev. B [**58**]{}, R7544 (1998).", "\n\nA. Savin, O. Jepsen, J. Flad, O. K. Andersen, H. Preuss and H. G. von Schneiring, Angew. ", "Chem. ", "Int. ", "Ed. ", "Engl. [**", "31**]{}, 187 (1992).", "\n\nR.M. Dreizler and E.K.U. Gross, [*Density Functional Theory: an Approach to the Quantum Many-body Problem*]{} (Springer, Berlin, 1990).", "\n\nM. Kohout and A. Savin, J. Comp. ", "Chem. [**", "18**]{}, 1431 (1997).", "\n\nH. J. Monkhorst and J. D. Pack, Phys. ", "Rev. B [**13**]{}, 5188 (1976).", "\n\nL. Kleinman and D. Bylander, Phys. ", "Rev. Lett. [**", "48**]{} 1425 (1982).", "\n\nP. L. Silvestrelli, N. Marzari, D. Vanderbilt and M. Parrinello, Solid State Commun.", " [**107**]{}, 7 (1998).", "\n\nR. Resta and S. Sorella, Phys. ", "Rev. Lett. [**", "82**]{}, 370 (1999).", "\n" ]

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[ "1. ", "Field of the Invention\nThe present invention relates to a fastener means which utilizes the attraction of a permanent magnet and which comprises an attraction member and a member to be attracted. ", "More particularly, in order to converge the magnetism of one of the magnetic poles, a projection made of ferromagnetic material is provided on a plate to be attached on the surface of the magnetic pole. ", "The plate at the magnetic pole and the permanent magnet are firmly fixed by firmly pressing the projection into a hole provided in the direction of the magnetic pole of the permanent magnet to thereby form an attraction member. ", "The member to be attracted is made of ferromagnetic material and is made attachable/detachable with respect to the surface of the other pole of the permanent magnet. ", "By attaching the attraction member and the attracted member to the body and the flap of a handbag respectively, a fastener means is obtained. ", "The fastener means may be attached to a body and a door of a case, or to both ends of a belt or a chain, or on a jacket at the position of a hook or a button, for opening and closing the door, fastening belts, connecting the chain, fastening cloths, etc.", "\n2. ", "Description of the Related Art\nFastener means utilizing the attraction of a permanent magnet are diversified in structure and use.", "\nOne of such fastener means is embodied by U.S. Pat. ", "No. ", "4,021,891. ", "The fastener means according to said invention features a ferromagnetic member which is attached fixedly or detachably to each respective magnetic pole of a magnet, thereby containing the magnetic fields of the poles within the respective plates. ", "At the same time, a hole is provided in the direction of the magnetic pole so that a ferromagnetic projection arranged inside the hole forms a passage of low magnetism connecting the ferromagnetic plates.", "\nAs a result, the magnetic flux of the permanent magnet is converged on the ferromagnetic projection in the hole, minimizing the magnetic flux leakage and thus providing a fastener means with firm attraction.", "\nCertain improvements have been made to U.S. Pat. ", "No. ", "4,021,891 and these are shown in U.S. Design Pat. ", "Nos. ", "247,467 and 247,468. ", "U.S. Pat. ", "No. ", "4,453,294 for a fastener means shows an additional improvement U.S. Pat. ", "No. ", "4,489,361, discloses an additionally improved fastener means with higher shielding effect against magnetic leakage.", "\nIn the above mentioned patents, the ferromagnetic plate is attached to one of the magnetic poles either by a non-magnetic case, or by attaching the plate directly to the permanent magnet by an adhesive.", "\nUse of a non-magnetic case as a means to attach the ferromagnetic member for the purpose of converging the magnetic flux is advantageous in that the non-magnetic case covers the outer surface of the magnet and, therefore, both protects the magnet against damage and offers a better appearance. ", "However, the presence of the non-magnetic case causes a magnetic gap between the surface of the attraction member and the member to be attracted, equivalent to the thickness of the case. ", "This prevents the magnetic flux of the attraction member from effectively reaching the member to be attached and causes flux leakage of the flux outside the fastener means.", "\nManufacturing difficulty is a second problem of the above mentioned means. ", "The non-magnetic case is usually manufactured by press-holding. ", "Thereafter, it is necessary to fix the permanent magnet and ferromagnetic plate within the case. ", "This involves the handling of the several components, as well as troublesome assembling steps, and leads to a high cost for the final product.", "\nIn order to overcome both the magnetic gap and the production cost problems, one possible solution is to directly attach a ferromagnetic member to one of the magnetic poles of a permanent magnet with an adhesive. ", "This eliminates the magnetic gap that is formed by a non-magnetic case, thereby improving the attraction between the magnet and the member to be attracted. ", "However, in order to fabricate a fastener of this type, it is necessary to apply an adhesive, align the positions of a permanent magnet and the ferromagnetic plate, press the two members together in a manner that does not cause the adhesive to be squeezed out, and maintain the pressure between the two members until the adhesive is completely set. ", "Once again, because of the numerous productions steps, the production cost becomes high. ", "Furthermore, there is no ready method to check the condition of adhesion between the permanent magnet and the ferromagnetic plate, which results in a danger that the adhesion between the two members may be or may become ineffective and ultimately result in the parts separating from each other by subsequent impact.", "\nAnother fastener means, such as that disclosed in U.S. Pat. ", "No. ", "4,700,436, includes a permanent magnet made of synthetic resin, utilizes a unique design wherein the ferromagnetic member is integrally buried inside the magnet. ", "As a result, there is no need to attach the ferromagnetic member to one of the magnetic poles of the magnet. ", "Nor is it necessary to attach the ferromagnetic member by means of a non-magnetic case. ", "As a result, the problems encountered in the construction and/or manufacture of the prior art fastener means were solved.", "\nHowever, the fastener means mentioned above has serious drawbacks. ", "In particular, since the permanent magnet is made from synthetic resin by injection-molding extreme care must be exercised in incorporating the ferromagnetic member inside the resin. ", "The procedure requires the use of a high degree of skill in carrying out a number of troublesome steps. ", "Furthermore, the ferromagnetic member incorporated inside the magnet is likely to be at an undesired angle, making it difficult to establish firm attraction between the attraction member and the member to be attracted." ]

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[ "Puppy\n\nAlmost, at least. ", "Sorry to jump off the fashion train, but dogs are near and dear to my heart. ", "Having grown up with these tender, little (sometimes) creatures, I can honestly say that they really do exhibit human qualities, at least to my untrained eye. ", "But, thanks to neuroscientist, Gregory Berns, of Emory University we now have the scientific proof to back it up.", "\n\nOver the past two years, Berns has conducted a series of MRI testing on canines, including his own pup, to test their capacity for love and attachment. ", "Research dictated that our furry friends indeed have the inherent ability to feel and display these characteristics that are largely reserved only for humans. ", "In Bern’s op-ed article published in The New York Times, he explained that because dogs cannot speak, research has obviously been more difficult, but with the help of a trainer and MRIs they were able to look “directly at their brains and bypass[…] the constraints of behaviorism, […]” which in turn tells “us about dogs’ internal states.” ", "Because of these findings, Berns urges dog-owners and lawmakers alike to see man’s best friend as a class of people and not property. ", "Perhaps, this is a long-awaited stepping stone for animal rights. ", "At the very least, it is an important reminder that pets, big and small, become part of our family and as one of my favorite quotes illustrates:" ]

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[ "The only other 29er I have ridden is a Specialized Epic (full suspension) so they were very different beasts. ", "I've been on Dekerf's for a decade now, and I'm probably a lifer, assuming Chris keeps making bikes. ", "This Team SST rides like my Dekerf Generation did, and that is a good thing.", "\n\nThe only other 29er I have ridden is a Specialized Epic (full suspension) so they were very different beasts. ", "I've been on Dekerf's for a decade now, and I'm probably a lifer, assuming Chris keeps making bikes. ", "This Team SST rides like my Dekerf Generation did, and that is a good thing.", "\n\nI used to have a Dekerf Implant which I loved, shame I sold it, but there are discussion afoot regarding a new build sometime soon...\n\nChris welded thousands of Rocky Mountains when he worked there, that doesn't make any of those frames DeKerf's either though. ", "I don't see why some people think that having a particular welder join the tubes makes that frame then one of his brand of frames.", "\n\nAs to the lack of DeKerf manufacturers forum, probably the same reason there isn't one for say Eclipse (which has only sold tens of thousands of bikes around canada), or Tomac, or True North, or Cube, or Ghost, or (shall I go on?)", "\n\nI don't post to generate business for myself or make like I'm better than sliced bread" ]

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[ "In Part 1 of this teardown, we ventured inside 3 of Nintendo’s first controllers: the NES, Super Nintendo, and (our favorite) the N64. ", "Now we’re making our way towards the present with Part 2, looking at the Gamecube, Wii Mote and finally the latest Wii U Gamepad.", "\n\n(Honorable mentions go out to the Virtual Boy controller and the Power Glove, which didn't make it into this teardown as some of Nintendo’s more... eccentric ideas.)", "\n\nAt the end of Part 1, we saw huge leaps on both the design and engineering fronts from the Super Nintendo controller to the N64 so let’s see how these next 3 controllers stack up.", "\n\nGamecube Controller\n\nWith the Gamecube controller, Nintendo has shifted to a two-prong ergonomic design with “wing grips.” ", "This controller also has 2 joy sticks instead of just the 1 we found in the N64, as well as 11 other buttons.", "\n\nAlso, where the N64 introduced an external Rumble Pak add-on, the Gamecube controller now has a built-in rumble motor.", "\n\nOpening up the controller, we find 2 potentiometers and 2 vertical breakout boards, which connect to the left and right bumpers. ", "In the center is the haptic feedback motor (read: vibration).", "\n\nWhen the bumpers are pressed, the potentiometers measure not only which bumper was pressed, but also the acceleration of the press. ", "The result is an experience of pressure sensitivity that creates a much more granular input than a simple I/O button. ", "The bumpers themselves also have big springs inside, wrapped around a large boss which allows the grey plastic piece to retract every time while the black piece remains stationary. ", "Simple but effective!", "\n\nTaking a closer look at the main PCB, we see that everything has been miniaturized.", "\n\nThere’s also a lot more complexity going on, and this is our first 2-sided board. ", "Here’s what we see:\n\nMultiple breakout boards\n\n‍145U2584 chip\n\n6.3V 7uF capacitor\n\n(+ we love open source and the incredibly smart hackers out there. ", "Check out this article for more info on the hacking the PCB.)", "\n\nAdditionally, the joysticks are now using potentiometers to directly measure the movement of the stick by the change in resistance, vs. the N64 optical joystick, which had old-school gears and encoder wheels.", "\n\nWiimote\n\nThe Wiimote! ", "Forever tied to hilarious and unfortunate images of this thing jammed into walls and television screens after a rousing game of Wii bowling.", "\n\nWith the Wii remote controller comes a major shift in design and usability, packed with tech that’s starting to look much closer to what we see in consumer electronics today.", "\n\nLooking inside the main controller, the ratio of wall thickness to boss thickness is finally starting to resemble the norm for consumer electronics — a much sleeker design.", "\n\nInside, we find:\n\n‍a small speaker\n\n‍ADXL330 accelerometer\n\n‍a small vibrating motor for haptic feedback\n\nan IR sensor\n\n‍BCM2042 Broadcom Bluetooth chip\n\nproprietary connectors\n\nmassive 4V 3300uF capacitor\n\nWhy, oh why, does a remote this small need a capacitor so large, you ask? ", "One theory is that the capacitor acts as a small power supply in case the AA batteries compress the springs enough to temporarily disconnect the batteries from the system, while engaged in a vigorous Wii golf match, for example.", "\n\nThe second part of the Wiimote is the unique standalone nunchuk. ", "We think the coolest part here is the strain relief mechanism, showing the best strain relief design we’ve seen so far. ", "When you pull on the wire, the force is actually applied to the plastic housing, vs. the cables and connectors. ", "Really great design here.", "\n\nAlso, the joystick is once again getting even smaller. ", "The ever-shrinking joystick!", "\n\nThat’s it for the Wiimote. ", "Next up, the most modern controller of them all: the Wii U gamepad.", "\n\nWii U Gamepad\n\nHere we are, at the end of rainbow road, with the latest Wii U gamepad and a major shift in design once again. ", "Interesting to note that we started with a boxy design (NES), and now we’ve come full circle (but bigger and with rounded corners + a touchscreen, of course).", "\n\nThe jump in complexity is also massive — you can tell by the sheer number of components captured above that there’s a lot going on in this very large television-like controller.", "\n\nSide note: we're still not entirely sold on the value this little screen adds to the gaming experience...more features does not always = a better product.", "\n\nAs we open up the controller, we see the screws are covered with stickers, instead of rubber pads. ", "This is common for handheld products, whereas tabletop products will generally use rubber pads to hide screws.", "\n\nOpening up the controller, we find a ton of connectors, which is a significantly more expensive option over soldering, but much easier for assembly. ", "The trade-off here is BOM (Bill of Materials) vs. ease of assembly.", "\n\nThe main PCB is, of course, by far the most complex we’ve seen yet, with a lot of components:\n\nSTMicroelectronics UIC-WUP MCE GH226\n\nSTMicroelectronics MSA3D 01F\n\nTexas Instruments TSC 2046I Low Voltage I/O Touch Screen Controller\n\nInvenSense ITG-3280 Gyroscope\n\nMicron 25Q256A 256 Mb Serial Flash\n\nDRC-WUP 811309J31 1217LU603\n\nTexas Instruments AIC3012 Audio Converter\n\nTexas Instruments 1010007\n\nOh, how far we’ve come since the humble NES.", "\n\nOn this smaller board, we see 3 dome switches, which sit beneath the bottom row buttons (tv, home, power). ", "Dome switches don’t last as long or feel as nice as conductive rubber pads, but they’re less expensive, and since these buttons aren’t used for gameplay and therefore aren’t pressed as often, it’s a good alternative. ", "The controller also has 2 pretty low cost speakers and 2 custom Wi-Fi antennas with an off-the-shelf wireless chip.", "\n\nIn previous controller generations, Nintendo used rigid PCBs for conductive pads, but now the tech has advanced, so to save room they can use flex boards, instead.", "\n\nThe joystick is our favorite mechanism throughout this teardown. ", "The joystick is, once again, even smaller and now it has a new action as well; you can push down on the z axis as well as left, right, up, down in the x and y axes. ", "This new action actually just combines the old joystick switch with a new tact switch — yay for modular design!", "\n\nSo there you have it. ", "We’ve made our way from the very first NES through the Wii U and found a lot of neat mechanisms along the way.", "\n\nIf you enjoyed this teardown and want to hang out with us again for the next one, be sure to subscribe here to get the next edition in your inbox.", "\n\nAnd if you’re building something cool yourself, you can learn more about our hardware development platform here.", "\n\nUntil next time!" ]

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[ "Communications services (e.g., fiber optic connectivity and service; copper connectivity and service) are being extended to more and more customers, both commercial and residential. ", "With the increase in use of copper and fiber cables in the communications industry, it is desirable to provide devices with increased termination density. ", "By density, it is meant the number of locations per unit volume or unit area for providing connection on a particular communications device.", "\nWith the increased density of communications connections in telecommunications devices, quick identification of the individual connection ports, e.g., for service or for other purposes, presents a challenge, especially in low-light environments. ", "A system for quick identification of the individual ports in a high density distribution environment is desirable." ]

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[ "Article content continued\n\nAlthough Brazil has a history of government corruption, 2014 had seen the imprisonment of the key figures in the Mensalão “Big Monthly” payments scandal in 2003 that enveloped key figures in the Lulu administration. ", "After more than 10 years, powerful politicians and party officials involved were finally serving prison sentences, and the impunity that Brazilian political figures have traditional enjoyed seems to be gone. ", "But the Petrobras scandal is much more serious than the Mensalão, both because of its impact on key sectors of the economy and because it involves foreign bond and shareholders in Petrobras, as well as foreign companies that were allegedly involved in the kickbacks.", "\n\nThe Petrobras scandal is the entirely predictable result of the interventionist economic policies adopted by the Lula-Dilma governments. ", "With regard to the Pre-Sal, these policies mandated Petrobras as the sole operator and imposed a 30 percent local content requirement on equipment and construction associated with the development. ", "This limited competition for contracts to Brazilian suppliers inflated costs and allowed Brazilian companies to form a bidding cartel, enabling the Petrobras directors to demand bribes for awarding contracts.", "\n\nPetrobras’ problems have come at a time when growth in the Brazilian economy has stalled because of the decline in resource prices. ", "For example, the price of iron ore, a major export, has fallen by 47 percent this year and shares in Vale have declined by over 37 percent. ", "Economic growth over the past decade has been driven by a boom in consumer spending, as lower and middle income classes received higher incomes and a decline in interest rates allowed them to purchase consumer durables. ", "The resulting increase in consumer debt levels combined with a slowing economy has brought the consumer spending boom to an end." ]

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[ "\nElon Musk Deletes Own, SpaceX and Tesla Facebook Pages After #deletefacebook - middle1\nhttps://techcrunch.com/2018/03/23/elon-musk-deletes-own-spacex-and-tesla-facebook-pages-after-deletefacebook/\n======\nsubmeta\nI always felt like doing this (deleting my facebook account), but fear of\nmissing out always kept me from doing it. ", "Whenever I seriously considered\nleaving the platform, I had a vague sense that I would \"not belong to the\nherd\" anymore, that I would lose the option to contact friends / family\nmembers, that I would be left outdoors.", "\n\nThe other day I made the step. ", "I deleted my account. ", "Before I did I exported\nall my data.", "\n\nTwo days past and I have a strange sense of freedom. ", "Previously I would check\nmy FB feed a dozen times a day. ", "Although I deleted the app years ago, never\nreally used Messenger, always had to use different browsers than Safari on my\niPhone because FB would not let me read/use messages in Safari, instead it\nwanted me to install Messagner. ", "So previously I would check my feed many times\na day to kill time. ", "I was a \"lurker\". ", "Never posted anything since years, just\nused it as a news reader. ", "And glanced over the things that my contacts posted.", "\nIt gave me an illusionary feeling of connectedness, when in fact I could not\nbe more disconnected from real contacts, quality contacts, and most of all:\nfrom myself by fleeing into a dull activity, by entering \"the matrix\", killing\ntime.", "\n\nToday I felt like in my childhood, going to appointments, not killing time on\nmy way to my appointment, having seen my surroundings like back in those days\nwithout so many distractions. ", "A wonderful feeling.", "\n\nI hope this platform dies, rather quickly. ", "Because it harms society and\nindividuals more than we are aware of.", "\n\nEdit: Grammar\n\n~~~\nlphnull\nIn your opinion, what is your criteria for declaring that a platform is \"bad\nfor you\" and \"an unhealthy habit\"?", "\n\nPersonally, I spend ALOT of my free time lurking 4chan's /g/ \"technology\"\nboard, 4chan's /ck/ cooking board, and a carefully curated list of my favorite\nfood and technology related subreddits on Reddit. ", "I personally consider my\naddictions to be quite healthy because I learn and absorb a tremendous amount\nof information from sites that focus more on \"actual content that matters\" and\nless on worshiping the same small group of narcissistic acquaintances that\ncongregate on platforms where \"disliking\" content is frowned upon.", "\n\nSure there's a lot of stupid crap on 4chan and reddit is full of corporate and\ngovernment shills, but the internet has grown SO MUCH lately that the signal\nto noise ratio isn't as bad as it was in the early 2000s. ", "My only problem\nnowadays is that I don't have enough time in a day to read/watch/comment on\nall the important stuff I find on the net. ", "Compare that to the early 2000's,\nwhen useful information on the internet was so scarce, that I had to use\nminesweeper in my highschool computer labs to pass the time.", "\n\nI for one am happy at how much content there is on the internet now. ", "If you're\nsmart, you can curate your own nonstop stream of \"useful\" content without that\nmuch effort. ", "Problem is that you have to reject content that is curated by big\nbusinesses like Facebook and Instagram and Twitter and program your own method\nof retrieving things that matter.", "\n\nPeople will always complain about the exponential growth of information. ", "Look\nat newspapers and the printing press. ", "I'm sure that people reacted the same\nway towards pocket watches and newspapers as people nowadays are reacting to\nsmartphones and social media. ", "Some people just have addictive personalities in\ngeneral, and will blame not being productive on whoever's in charge of\n\"information\" at any given moment.", "\n\n~~~\nThriptic\nNot the parent, but I would say that a platform should somehow add value to\nyour life to be \"good for you\". ", "HN, Reddit (depending on where you go), other\nsites etc can entertain, teach, and connect you with interesting people.", "\nSocial networks I've found are value detractors for me because:\n\nA. I don't care what 95% of people I am connected with are doing, and I\nregularly talk to the people I care about anyway.", "\n\nB. I can't have any meaningful discussions on them\n\nC. They are dominated by high volume posters who tend to be very opinionated.", "\nVery opinionated people tend to have extreme opinions which are usually wrong\nand aren't particularly interesting to me.", "\n\nD. The networks present a false sense of reality which lowers happiness.", "\nEveryone always posts their highlight reel which makes you feel like the whole\nworld is killing it constantly and you aren't.", "\n\n~~~\ndragonwriter\n> The networks present a false sense of reality which lowers happiness.", "\n> Everyone always posts their highlight reel which makes you feel like the\n> whole world is killing it constantly and you aren't.", "\n\nIf this is what happens in your feed, you have a shallower and less genuine\nset of social media connections than I do. ", "I get highlights, sure, but just as\nmuch lowlights, and quotidian events that don't meet either description.", "\n\nI suspect that the people who connect with networks of people who do exclusive\nself-image-burnishing social media posts would also connect with people that\nprovide the same kind of fronts in other venues (including in-person), though\nI'll also grant that _if_ you tend to connect predominantly with such people,\nsocial media magnifies their effect, as it's easier to consistently present an\nimage online than in person.)", "\n\n~~~\nhrasyid\n> you have a shallower and less genuine set of social media connections\n\nI don't think you have to be \"shallow\" to be biased towards posting\nhighlights.", "\n\nYou spend a nice vacation in Asia? ", "Your kid managed an important\naccomplishment? ", "Found a restaurant that's awesome? ", "Aren't these the kind of\nthings that you naturally have the tendency to share?", "\n\nIn contrast, you spent your saturday doing nothing at home? ", "Your kid did an\naverage thing? ", "You ate food that's just \"okay\"? ", "Am I shallow if I don't like\nposting these things? ", "Sure some of the days I might want to post about some\naverage or bad things, but I think I'm still biased towards the highlights\n\n------\nmajestik\nFYI here’s a link to delete your Facebook account:\n[https://www.facebook.com/help/delete_account](https://www.facebook.com/help/delete_account)\n\nEarlier I had “deactivated” my account thinking it would get deleted, but then\nI learned I have to visit this page to actually delete it.", "\n\n~~~\nmarknadal\nDeleting Facebook now, without good alternatives, might cause more problems\nthan good.", "\n\nInstead, we should first model what the future of social networking should\nlook like:\n\n[https://hackernoon.com/a-new-kind-of-social-network-\nemotiona...](https://hackernoon.com/a-new-kind-of-social-network-emotional-\nintelligence-e45dcddb1bdb)\n\nThen I am curious to hear people's thoughts on:\n\n\\- Mastodon\n\n\\- Secure Scuttlebutt\n\n\\- Steemit\n\netc.", "\n\n~~~\nreitanqild\nMany of us use Telegram.", "\n\nOthers use Signal.", "\n\nSignal advantages: tptacek thinks the crypto is good.", "\n\nSignal disadvantage: It wont work with limited permissions on your phone\naccording to some people on HN.", "\n\nTelegram advantage: somewhat more userfriendly. ", "Larger userbase. ", "Works even if\nyou limit its permissions.", "\n\nTelegram disadvantage: every cryptographer seems to think their crypto is bad.", "\nUncertainty wrt their relations with Russian government. (", "I think they are\nenemies but some think they are very good friends or blackmailed into\ncooperation.)", "\n\n~~~\nchappi42\n> Many of us use Telegram.", "\n\nAnd some friends and me use Threema. ", "Very old fashioned: you pay some money\nand get a product. ", "But I wouldn't want to switch.", "\n\n~~~\ntheyinwhy\nImho threema is the best client overall. ", "Very fast, very reliable, great UI,\ngood crypto. ", "Designed for company usage. ", "Security whise however I guess Signal\nhas the upper hand.", "\n\nThey both audit their crypto:\n\nThreema audit:\n[https://threema.ch/es/faq/code_audit](https://threema.ch/es/faq/code_audit)\n\nSignal audit:\n[https://eprint.iacr.org/2016/1013.pdf](https://eprint.iacr.org/2016/1013.pdf)\n\n------\niooi\nWhile I don't normally give much weight to Business Insider, they have an\ninteresting theory [1] that this is related to Zuckerberg's nasty comments\nabout SpaceX after the rocket carrying Facebook's 85M satellite blew up.", "\n\nMust feel pretty good for Elon considering how much press this is getting.", "\n\n[1] [http://www.businessinsider.com/elon-musk-deletes-tesla-\nspace...](http://www.businessinsider.com/elon-musk-deletes-tesla-spacex-\nfacebook-pages-2018-3)\n\n~~~\ndandelany\nSounds overblown to me. ", "Zuck's statement was: “As I’m here in Africa, I’m\ndeeply disappointed to hear that SpaceX’s launch failure destroyed our\nsatellite that would have provided connectivity to so many entrepreneurs and\neveryone else across the continent.”", "\n\nI don't see anything nasty about that. ", "It _was_ SpaceX's failure.", "\n\n~~~\nkemiller\nIt's passive-aggressive. ", "A bit like deleting one's facebook profile I guess.", "\n\n~~~\ntoomuchtodo\nA bit of a different though. ", "Elon did not intentionally destroy the Falcon 9\nin question, and SpaceX worked very hard to determine what caused the issue\nand rectify it for future flights. ", "Zuckerberg knew for _years_ what was going\non with user data, and gave zero f __*s until they were caught.", "\n\nSubstantially easier to throw shade (passive aggressively even) from the moral\nhigh ground.", "\n\n~~~\nkoheripbal\nElon cares tremendously about bad press. ", "He's specifically banned all\nreporters from filming launch or recovery attempts in case there are failures.", "\n\nYou'll notice that there are NO social media posts whenever there's a accident\n(of which there have been many).", "\n\nZuck drawing attention to it must have really pissed Elon off.", "\n\n~~~\ntoss1\nUm, except when Elon posts video compilations of their failures... (seems to\nme they're pretty open)\n\n[https://www.youtube.com/watch?v=-2PWKdQzuU8](https://www.youtube.com/watch?v=-2PWKdQzuU8)\n\n~~~\njccooper\nThey do that in a carefully controlled way, well after the event is too cold\nfor the news cycle. ", "And even then, some events that are too dicey-looking are\nnever seen.", "\n\nMark, this is not a criticism. ", "Given the way the media handles such things\n(i.e. sensationally and with minimal or just plain wrong context) it's really\nfor the best.", "\n\n~~~\nmarcell\nI'm confused--aren't the launches broadcast live via webstream?", "\n\n~~~\njccooper\nYes, but landings at sea tend to cause the video feed to go away, and it\ndoesn't come back if anything goes wrong.", "\n\n------\ntaytus\nI read his tweets and I thought he was just joking. ", "New level of respect for\nElon.", "\n\n~~~\njusticezyx\nNew level of marketing probably more accurate\n\n~~~\nd23\nFacebook pages are in and of themselves avenues for marketing. ", "Stop being so\ndamn cynical about every single thing people do. ", "It is possible, believe it or\nnot, for people to have personal values and beliefs that extend beyond the\nceaseless desire for money.", "\n\n~~~\nlorenzorhoades\nI think the OP above is being practical as opposed to cynical. ", "TBH, most of\nthe demographic that followed him on FB also have insta and twitter. ", "Most of\nthe people i know in my age group (college age - 24) don't even use FB\nanymore. ", "Theres a little joke that as soon as your parents start to use the\nplatform its time to jump ship. ", "On top of that, its created articles like this\n- which has led to even more publicity. ", "I also wasn't aware that any of these\nFB pages existed but i follow them all on insta and twitter.", "\n\n~~~\nantisocial\nMy thoughts exactly, practicality as opposed to cynicism.", "\n\nAlso, what are his personal values? ", "Who knows? ", "Why does he bore the\nunderground with abandon even when he acknowledges that the environmental\nimpacts are not completely know. ", "One study says autonomous vehicles can be as\neffective for congestion easing as his underground tunnels.", "\n\nHis transportation is the next level of dependency he is creating and we are\nturning a blind eye to. ", "As these corporations' services get too essential\n(through lobbying), there won't be any choice to #delete_boring.", "\n\nI respect him for what he has achieved, but too much celebrity worship is\nsomething we should all be watchful of.", "\n\n~~~\nskellera\nI believe that future cities shouldn’t require roads. ", "The amount of space\nwasted on roads and parking can be used for better things.", "\n\nAnd if anyone hasn’t noticed (this gets brought up all the time), Musk is\ncommercializing everything needed for colonization of the moon/Mars. ", "Electric\nmotors, solar energy, underground infrastructure, and space travel.", "\n\n~~~\nzentiggr\nConsidering his big picture goal is \"humans on more than one world\", this\nmakes perfect sense. ", "And isn't 100% obvious.", "\n\n~~~\nTeMPOraL\nHe's been talking about Mars since day one. ", "It's just some people refuse to\nlisten / believe that he really means it.", "\n\n------\ndeviationblue\nI don't think #deletefacebook is a backlash against the results of the 2016\nelections. ", "To me it seems that it's more about it now being socially\nacceptable to dislike Facebook and social media in general. ", "Some may have\nalways innately disliked it, but never had the follow through with any desire\nto get rid of it, or had to keep it for business/appearances.", "\n\n~~~\noneweekwonder\n> socially acceptable to dislike Facebook and social media in general.", "\n\nI then find it ironic that it is using #hashtag in the movements name then.", "\n\n~~~\nreitanqild\nHashtags has been popular before Facebook and in a number of other media.", "\n\n~~~\nfrostwhale\nCorrect me if I'm wrong, but it dates back to C? ", "And # is used as includes /\nother first compiler steps? ", "And the hashtag on twitter is a reference to this.", "\n\n~~~\ncorrigible\nI was under the impression that it was popularized by IRC #channels\n\n~~~\nkardos\nI thought it was to make keyword searches work on twitter\n\n~~~\ncmrdporcupine\nSure but that notation looks obviously inspired by IRC to me.", "\n\n~~~\nfernandotakai\nwhen i started using twitter back in 2008, that's how it felt to me -- that #\ntags were basically irc rooms and twitter itself was just a big async irc\n\n------\nnsx147\nI always had respect for the fact that Apple just never used Facebook...except\nfor claiming the profile it seems.", "\n\n[https://www.facebook.com/apple](https://www.facebook.com/apple)\n\n~~~\nslig\nThey do use it\n[https://www.facebook.com/applemusic/](https://www.facebook.com/applemusic/)\n\n~~~\ntotalZero\n\n > Typically replies within an hour\n \n\nDamn.", "\n\n~~~\nchrisper\nMost companies have that... it's often just a bot.", "\n\n------\nnextstep\nBoycotts are one of the most effective methods consumers have to enact change.", "\n\n~~~\nshaki-dora\nI can't think of a successful boycott. ", "I believe the largest attempt I\nwitnessed was against BP when they just sank an old oil platform, including\nall sorts of toxins and petrochemicals.", "\n\nI think that made a single-digit dent in their revenue.", "\n\nPolitics and law enforcement are far better tools to get corporations to\nbehave. ", "They solve the coordination problem, they can far easier track\nchanging and long chains of ownership, and they allow you to delegate the\nresearch work to someone you trust.", "\n\n~~~\nbonaldi\nWhat do you mean by successful? ", "Usually the point is not to dent revenue, it's\nto cause behaviour change. ", "And there is a long list of boycotts that have\nachieved that.", "\n[http://www.ethicalconsumer.org/boycotts/successfulboycotts.a...](http://www.ethicalconsumer.org/boycotts/successfulboycotts.aspx)\n\n~~~\nBartweiss\nLooking at that list, I see two main categories.", "\n\nOne are outcomes dubiously tied to boycotts - did Sea World change their orca\nproblem to protect revenues, or because they feared legal intervention?", "\n\nThe second is indirect outcomes, where the bad actor and the boycott-ee are\ndifferent. ", "If you threaten a purchaser over a supplier, or a supplier over a\npurchaser, they can hope to change behavior with no major loss of revenue.", "\nIt's a very different situation than changing the actual bad behavior. (", "And in\nmany of these cases the bad behavior was unchanged, some external company just\ndissociated from it.)", "\n\nThere do seem to be some solid successes there, for instance with product\nsafety, food source sustainability, or sweatshop labor. ", "But even there, I'm\ncurious whether the threat of boycott was a primary influence compared to the\nother activist campaigns around it.", "\n\n~~~\ndragonwriter\n> One are outcomes dubiously tied to boycotts - did Sea World change their\n> orca problem to protect revenues, or because they feared legal intervention?", "\n\nThey feared legal intervention due to the public attention drawn by the\nboycott.", "\n\nAffecting revenue of a targeted actor directly is not the only mechanism by\nwhich boycotts are intended to have an effect.", "\n\n~~~\nBartweiss\nI agree that revenue hits are not the only (and usually not the primary)\neffect of boycotts.", "\n\nBut what I'm questioning is \" _due to the public attention drawn by the\nboycott._ \" ", "Was the consumer boycott actually a major reason SeaWorld feared\nlegal action?", "\n\nWhen _Blackfish_ came out, a lot of musicians cancelled planned SeaWorld\nconcerts, which had a visible and immediate revenue impact. ", "Share prices\ndropped 33%, even though revenue only dropped ~1%; presumably shareholders\nfeared the possibility of legal action. ", "And a range of state and federal\nCongressmen introduced bills on regarding orca captivity, explicitly citing\n_Blackfish_ as a motivator.", "\n\nBoycotts are certainly correlated with major corporate and legal changes, but\nI'm skeptical that they're a significant cause. ", "Examples like SeaWorld make me\nthink that boycotts and policy changes have common causes (e.g. Blackfish),\nbut the boycotts aren't themselves very impactful.", "\n\nThe Chicago Tribune had a clever bit about the gun-seller boycotts, arguing\nthat boycotts only matter as a way to keep the topic in the news, and it\nbasically doesn't matter whether people actually participate. ", "That's basically\nmy guess, also.", "\n\n[http://www.chicagotribune.com/g00/news/opinion/zorn/ct-\npersp...](http://www.chicagotribune.com/g00/news/opinion/zorn/ct-perspec-zorn-\nnra-boycott-fedex-apple-amazon-0228-20180227-story.html)\n\n------\ngrinsekatze\nI abandoned Facebook instead of deleting my account.", "\n\nI treat Facebook like a big phone book now and left a public status on my\nprofile with an email address that forwards mail to my real email address for\npeople that want to get in touch with me.", "\n\nThe main reason I did not delete my account is that there is one other person\nwith exactly my name and very questionable values, judging the public content\nof his profile. ", "This really sucks. ", "My name is not common and unfortunately he\nmarried a distant cousin of mine and now has my name.", "\n\nNow I don’t like the idea of people looking for me accidentally getting in\ntouch with him thinking they are contacting me. ", "Unlikely with his current\nprofile picture in place, but still a possibility in the future.", "\n\n------\nem3rgent0rdr\nFacebook can be an essential promotional tool for many. ", "If you're rich or an\nalready successful company, then you can handle the loss by not being on\nFacebook. ", "But if you're poor or just starting up a new venture, then it is\nharder to afford not being on Facebook.", "\n\n~~~\ntaytus\nI'm poor and starting a new venture. ", "I don't have FB. ", "If my success depends on\nme/my company having FB presence, then my business sucks. ", "How this idea of FB\nbeing the \"place to be\" got so much traction is beyond me.", "\n\n~~~\ntoufka\nYep. ", "LinkedIn as well. ", "Still without one, and starting strong. ", "Very much\nrealize I must put my data where my mouth is.", "\n\nSimilarly, I'll be far less likely to hire one who has Facebook on their\nresume.", "\n\n~~~\ndgellow\n> Similarly, I'll be far less likely to hire one who has Facebook on their\n> resume.", "\n\nCould you explain why? ", "I don’t see an obvious reason to avoid ex-Facebook\nemployees\n\n~~~\ntoufka\nFrom my personal interactions, and with my personal perspective of how\nFacebook has publicly conducted itself over the years, having worked at\nFacebook would immediately raise red flags in my mind about the philosophical\nperspective of the potential employee for having worked 'at will' at the\ncompany. ", "Context certainly matters, but it would be become a point of\nconversation. ", "Not all that different from a health-professional being wary of\nhiring someone who used to work for a tobacco company.", "\n\nTo me it would indicate the possibility that the person might not want to\nunderstand the wider implications of their work, might understand those\nimplications but not care about them so long as they are personally or\nsocially enriched, or might just agree with the duplicitous nature of the\ncompany. ", "There are of course circumstances to account for, and everyone's\nreasons are different - but the above rationalizations would raise red flags\nfor me - especially in my industry where thinking about wider implications of\nour work is absolutely critical.", "\n\n------\njayess\nDoes anyone know if it works if you change your location to Europe and then\ndelete your account to take advantage of the better privacy protections?", "\n\n~~~\novulator\nI've lived in America all my life, but since I signed up for Facebook 10 years\nago my hometown/current city has always been listed as a place in Portugal.", "\nFor a long time all my adds were served in Portuguese, but that changed years\nago to English. ", "My guess is they know where you really are.", "\n\n~~~\nSymbiote\nKnowing it enough to serve ads is one thing.", "\n\nKnowing it enough to be sure under European privacy rules, especially the new\nGDPR ones, is another. ", "I doubt one person's data is worth the risk Facebook\nwould take by keeping it.", "\n\n~~~\nThrustVectoring\nAnd if you said you were a a European Citizen (or even just neglecting to\nmention that you aren't), would Facebook really check?", "\n\n------\njliptzin\nFor Facebook to truly die someone needs to come up with a bare bones social\nnetwork that has all the basics - friends lists, photos, address book,\nmessaging, groups. ", "Charge $1 a month. ", "No sleazy tracking you everywhere on the\ninternet, no ads, no newsfeed filled with garbage clickbait ads and conspiracy\ntheories. ", "This would be insanely profitable assuming it reaches some critical\nmass.", "\n\n~~~\nd4l3k\nExcept it probably won't ever happen. ", "Charging anything turns off the vast\nmajority of users.", "\n\n~~~\nsteaknsteak\nDefinitely. ", "People are reluctant to buy $1 or $2 mobile apps that would be\nreally useful, even though they would never notice the money was gone. ", "Just\nbecause most apps are free. ", "Also, most people lose more than they gain by\ndeleting their facebook or anything else. ", "Tech people tend to care about\nprivacy because of all of the terrible implications and possibilities that\ncome with all your personal info being freely bought and sold, but the vast\nmajority of people will never (at least consciously) suffer any ill effects of\ngovernment tracking or targeted ads.", "\n\n~~~\nseanwilson\nWhatsApp is free for the first year then a small amount each year to continue.", "\nMaybe that works.", "\n\n~~~\nnarsil\nI believe this is no longer the case and WhatsApp is free to use now.", "\n\nRegardless, the free trial -> paid version is a popular model, even if 1 year\nis a long \"trial\"\n\n~~~\nseanwilson\nI'm curious how the \"first year for free\" business model works out. ", "I'm\nguessing smaller companies couldn't survive on that as it's too long to wait\nuntil you start getting revenue?", "\n\nI paid a few dollars for WhatsApp once or twice to keep it working after the\nfirst year. ", "It was such a small amount I didn't care. ", "I remember some of my\nfriends freaking out about it though, like they were being tricked.", "\n\n------\nwonder_bread\nCan anybody who lives in the valley speak to whether people really hate\nZuckerberg enough over there to the point where this seems like a rational\nthing to do? ", "I live out in Mass and while the 'scandal' has definitely been\nfront page news, for a company to do this (especially with a well-known\nentrepreneur) would be decidedly odd.", "\n\n~~~\njf\nI live in the valley, have several friends at Facebook, etc. ", "I don't know\nanybody who hates Zuckerberg. ", "I don't hate him. ", "But I am very upset with\nFacebook-the-company and Facebook-the-system. ", "What bothers me most is that, to\nthe best that I can tell, Facebook-the-company and especially Facebook-the-\nsystem just _do not care_ about me or you as individuals.", "\n\nI have a thread on Twitter that goes into more detail here:\n[https://twitter.com/jf/status/976250584213803008](https://twitter.com/jf/status/976250584213803008)\n\n~~~\nnetsharc\nTalking about Facebook on Twitter seems to be the height of irony...\n\n(I hate Twitter, although if you ask me to substantiate why, I would probably\ncome up with the oft-repeated talking points of echo chamber, Russian bots,\nrage mobs, etc, etc.)", "\n\n~~~\njf\nIrony bordering on hypocrisy!", "\n\nIf we were to compare reasons why we dislike Twitter, I expect that we'd have\na lot to agree on. ", "I tried to leave Twitter too, but found that I couldn't\nbecause I still get too much value from Twitter. ", "I still hope that someday the\nwinds will shift to a system that brings me the joy I got from Twitter between\n2008 and 2016.", "\n\n~~~\nvinhboy\nHi jf, I missed you facebook. :)", "\n\n~~~\njf\nMe too! ", "Not having Facebook prevented me from asking you what you think of\nthis claim:\n[https://www.reddit.com/r/AskReddit/comments/7s36ub/what_cons...](https://www.reddit.com/r/AskReddit/comments/7s36ub/what_conspiracy_theory_do_you_100_buy_into_and_why/dt1vg6j/)\n\n~~~\nvinhboy\nLOL... that comment is hilarious because it touches one key truth about\nVietnamese culture...\n\nWhen you ask a Vietnamese person if they can do something, they ALWAYS say\nthey can, even if they have no clue what it is. ", "Especially Vietnamese men. ", "We\nhave this weird need to always pretend like we know everything.", "\n\nIt's similar to the TV sitcom stereotype of how all men think they can fix a\nleaking pipe, even if they have no clue how to do it.", "\n\nGood stuff... I'll see you around jf.", "\n\n------\nguiambros\nIf you're considering doing the same but is still on the fence, here's an\nalternative: News Feed Eradicator [1].", "\n\nIt still gives you access to messages, but eliminates the news feed, so it\nbreaks your habit of going there to \"check what's new\".", "\n\nGo ahead and give it a try. ", "If after 30 days you still miss the news feed, you\ncan just disable the extension. ", "But I bet you won't even notice...\n\nps: but don't forget to delete the mobile app. ", "Conveniently FB offers you a\nseparate app just for messages, if desired.", "\n\n[1] [https://chrome.google.com/webstore/detail/news-feed-\neradicat...](https://chrome.google.com/webstore/detail/news-feed-eradicator-\nfor/fjcldmjmjhkklehbacihaiopjklihlgg)\n\n~~~\nigornadj\nYou can accomplish the same thing by unfollowing everyone in your friends\nlist. ", "My news feed is always empty, it's great.", "\n\n------\ntambourine_man\nAnd yet, still a heavy Instagram user.", "\n\nAs long we keep guessing which companies are “bad” and which aren't, we are\nnot solving the problem. ", "We need open, decentralized standards and protocols.", "\nWe can then choose the fashionable front end client du jour.", "\n\n------\nRaphmedia\nContext:\n\nElon Musk: \"What’s Facebook?\"", "\n-[https://twitter.com/brianacton/status/976231995846963201](https://twitter.com/brianacton/status/976231995846963201)\n\n~~~\njessaustin\nISTM Acton's statement is more surprising than Musk's. ", "They gave that dude a\npile of money, not very long ago.", "\n\n~~~\nurmish\nWho would turn down that amount of money. ", "Also, I think he didn't join\nfacebook after the acquisition.", "\n\n~~~\njessaustin\nHe remained there for three years. ", "A founder that _didn 't_ agree to stay on\nfor a respectful period would get dinged on the price. ", "He probably didn't want\nto do that to co-founders.", "\n\n------\nsidyapa\nLike apple, facebook has very successfully created an ecosystem which makes it\nvery very hard for you to escape and remain sane. ", "I used 4 products from\nfacebook - the website(deleted), instagram, messenger(deleted), whatsapp\nbecause all of my contacts are on either of them. ", "I do not have an alternative\ncurrently where I can be assured of finding any of my contact to connect and\nshare stuff with.", "\n\n~~~\nslantyyz\n>> facebook has very successfully created an ecosystem which makes it very\nvery hard for you to escape and remain sane.", "\n\nReally? ", "Ok granted, I'm probably \"old\" for an HN user, but to me Facebook is a\nsystem that creates an artificial sense of connectedness. ", "I don't consider\nthat an essential service.", "\n\nDo we all need to be connected to everyone and know what they're doing at all\ntimes? ", "I've drifted away from friends I had 20, 30, 40 years ago, and that's\nperfectly OK. ", "If people are important to you, you will find a way to stay\nconnected. ", "It's not the end of the world if you lose touch. ", "It was a perfectly\nnormal phenomena before social media, and it will be after social media as\nwell.", "\n\nAs I've gotten older, I've noticed that I prefer fewer, deeper relationships\nthan having a large number of shallow relationships. ", "That's why I tend to use\nemail/instant messaging with only my close friends/family. ", "I have a Facebook\npresence, but it's only there to maintain weaker connections to people outside\nof my core social circle.", "\n\n~~~\nsidyapa\nThere is something greater than a social circle, the economic circle. ", "It might\nnot be for you but lot my contacts have transactional relationships with me,\ni.e., they have my details because they know I can offer something they have\navailed in the past and might someday need in the future, they trust me. ", "And\nsame goes for me, if someday I need my friend Tushaar's video and audio skills\nfor some project I should be able to look him up instantly and message him\nrather than asking around helplessly within my social circle for his contact.", "\n\n------\ngnicholas\nWhile it might seem a big deal to give up a platform with millions of\nfollowers (2.6M, apparently), it's much less of a sacrifice for a company that\nhas a large presence on Instagram (which the article notes Musk has said is\n\"borderline\", and he's not deleting) and Twitter. ", "Also, they're in the news\nall the time, both for their victories and failures.", "\n\nSo this is a great way for Musk to brand Tesla, SpaceX, and himself, without\nactually giving up much in terms of his social media reach.", "\n\n------\nshady-lady\nAn unbelievable amount of bots on that twitter thread responding to a fake\nEthereum giveaway by not 1, but 2 * fake Brian Action a/c's:\n\n[https://imgur.com/a/yv1Hm](https://imgur.com/a/yv1Hm)\n\nvery nearly believed it was legit too..\n\n*fake twitter handle of brianhacton (h) & brianpacton (p)\n\n~~~\nshady-lady\nnot surprising that there are even more of these fake look-a-like a/cs:\n\nbrianlacton (l) brianmacton (m) brianzacton (z)\n\nIs it really that hard for Twitter to detect a fake look-a-like a/c given\nthat:\n\na) the display name is the same for all fakes\n\nb) they all have limited posts, all posting the same link\n\nc) the bad actors do seem to be making ever so slight changes to (full square)\nprofile pics in an avoidance attempt- ref\n[https://imgur.com/a/QruDm](https://imgur.com/a/QruDm) ??", "\n\nI've personally clicked report scam on the initial a/cs I listed along with\nall the fake a/c's that liked/replied duplicitously.", "\n\n------\nmixmastamyk\nInteresting considering I've not been happy about the lack of privacy\nregarding driving/location metrics by Tesla automobiles. ", "Has that improved\nany?", "\n\n~~~\ncryptoz\nThere is a very big difference in the privacy problems posed by Facebook\ncompared to Tesla. ", "Equating the two is a clear false equivalence.", "\n\nEdit: I'm no longer allowed to post on HN. ", "I guess my posts are considered\nlow-quality and not welcome here. ", "Here is my response to the comment below,\nregardless. ", "Thanks for continually banning me, downvoters.", "\n\n\\--\n\n> Why does that bother you?", "\n\nBecause you exclusively use logical fallacies in these posts to make points\nthat make no logical sense.", "\n\n> whether Tesla will start caring about privacy as well\n\nThis implies Tesla does not care about privacy. ", "That simply is not true. ", "If\nyou have a concern, voice it in some logical manner, not in some accusatory\nalready-made-up-your-mind tone about how so-and-so doesn't care about your\nprivacy.", "\n\n\\--\n\nEdit 2: Does Elon really babble on Twitter about people's speeds and driving\nlocations? ", "I don't think so. ", "And surely if you drive a car then you know that\nthe people in the city/state/federal government offices and other tracking\ncorporations also know where you go at all times anyway. ", "Having a Tesla and\ndriving it does not meaningfully invade your privacy in any fashion more than\ndriving any other car does.", "\n\n~~~\nfancyfacebook\nI think it's worth bringing up, one of the reasons I didn't buy a Tesla was\nbecause I didn't want the CEO immediately blabbing all over twitter about\nexactly how fast I was driving or how many times I left my lane if there\nhappened to be some sort of accident.", "\n\nThey seem to take the same attitude as Facebook, mainly: we own all your data\nand you have zero rights to anything in the car.", "\n\n------\nalcover\nThis will deeply count in facebook's demise I think.", "\n\nTech people act as prescribers to the rest. ", "When they use something new, it\nthen propagates to the population. ", "Abandoning is the same.", "\n\nNow Elon Musk is mystically revered by tech people. ", "Then transitively, his\nexample will accelerate tech peoples' condamnation of facebook, then everyone\nlistening to techies advice.", "\n\n~~~\nseanwilson\n> Tech people act as prescribers to the rest\n\nAny good examples of this? ", "I don't find this at all. ", "Hackernews for example is\nalways very against Facebook, ads and tracking user behaviour. ", "As far as I can\nsee, none of my less technical friends want to know more details about any of\nthis or care in the slightest.", "\n\nMost of the time if my non-technical friends are asking for technology advice,\nit's advice to help them follow the crowd e.g. my friends wouldn't ask me what\nsocial network to use, they'd ask me how to install Facebook on their phone.", "\nIf I started ranting about privacy stuff for something all their friends used,\nthey'd just dismiss it as me being overly concerned.", "\n\n~~~\nalcover\n\n Any good examples of this?", "\n \n\nNot really I must admit. ", "It's more that when the tide turns, people ask\ntechies why and what to do.", "\n\nIn FB case they'll ask you what is so bad about it and you'll come up with a\nsolid answer. ", "They'll repeat your word around and the tide will gain momentum\n?", "\n\nLinux. ", "My parents got a laptop with Windows 8. ", "We couldn't make sense of it. ", "I\npitched Ubuntu, installed it and they never turned back.", "\n\nWhen their friends evoke problems with their computers, they will hear about\nUbuntu from my folks.", "\n\n------\nBadassFractal\nThings I like about Facebook:\n\n* seeing what events in the area my friends are going to, helps me know what's happening around me and going there\n\n* facebook groups for some friends / professional organizations\n\n* following bands / band tours so I can get updates about them\n\nDon't really care about anything else on there. ", "Can I keep just the good parts\nsomehow?", "\n\n~~~\nnotananthem\nThe problem here is just adding anonymized (so international traveling bands\naren't stopped at customs) tour schedules to something like bandcamp won't do.", "\nMusic is generally served on some type of forum, that's how it grows and\npermeates. ", "For me, the ever-aging metal/punk/hardcore scenes are fairly\npresent on facebook- the older crowd stays because they have jobs to worry\nabout and are technophobic/terrible at computers (mostly). ", "The younger crowd\nis the innovative one, and tries new things. ", "Currently a bunch of friends are\nall leaving facebook and I'm a crotchity old 30-something being like \"well\nralph where the fuck am I going to find your tour schedule?\"", "\n\nThere's been every sort of private forum for these things city by city and the\nproblem is basically the drama that comes with it, that's why people like\nfacebook because the architecture of conversations is so spread out you can\navoid something that would otherwise get someone trolling.", "\n\nI guess its something to really respect about the service is its ability to\nhave so many people with such public opinions online and friends with each\nother. ", "That's what you need for stuff like music related tours/bands/etc,\nprofessional circles where all sorts of people come together, school programs\n(me.. night school MBA), etc.", "\n\n------\nsoundpuppy\nFacebook won't die by a movement like this, it'll die when users adopt\nalternatives.", "\n\n------\nbeaconstudios\nwould it not be better for the #deletefacebook movement to delete all data and\npost a single protest message instead? ", "Future users clicking through to the\nSpaceX or Tesla pages from links on the net won't know why they did this.", "\n\n------\npleasecalllater\nDeletes the profile, Facebook keeps the data :)\n\n~~~\nnothis\nThey’re forced to delete the data as well aren’t they? ", "Or is that just in the\nEU?", "\n\n~~~\ndglass\nI just downloaded all the data that FB has on me. ", "It's quite surprising to see\nevery single message and wall post I have made and others have made to me.", "\n\nOne thing I realized is that even if I delete my account, facebook will still\nstore my communication with other people in case they request to download\ntheir information too. ", "So I'm not sure if it would ever get deleted unless\nboth parties delete their accounts? ", "For my info to truly get deleted, all of\nmy contacts would have to delete their accounts too.", "\n\n~~~\niamdave\n>I just downloaded all the data that FB has on me.", "\n\nWhere can one do this?", "\n\n~~~\ndglass\n[https://www.facebook.com/settings](https://www.facebook.com/settings) at the\nbottom where it says \"Download a copy of your Facebook data.\"", "\n\n~~~\niamdave\nAha cheers!", "\n\n------\nstunt\nI don’t have FB account for more than 5 years (for both privacy reasons and\nalso cos it felt wasting my time for a platform that doesn’t add any value to\nmy life) and today I’m very happy about that.", "\n\nIt is kinda funny how people are reacting just now because I am pretty sure\npeople already knew what was happening to their data anyway. ", "It was obvious,\nthere was so many discussions around it. ", "So it’s a lie if you say you didn’t\nknow they are using your data.", "\n\nBut everybody chose to stay just because everyone else was there. (", "most)People\ndon’t dare to move alone and that’s very sad and stupid.", "\n\n------\nexodust\nPerhaps this will result in a re-booted demand for custom websites that\nreplace Facebook business pages, or at least take on more responsibilities and\ntasks that would otherwise be left to FB.", "\n\nOver the years I've seen many businesses including those I've worked for (as\nfrontend developer) putting effort into Facebook and diminishing effort into\ntheir own websites (the kind that I make for a living).", "\n\nIt surprised and disappointed me over the years as I saw organisations move in\nand start paying Facebook to promote posts. ", "The misguided assumption that user\nbehaviour was better quality because of the real name policy (not true); and\nthat \"everyone was on it\". ", "There's also a mistaken perception that Facebook is\ngood for long form or archived topics, such as factual content, but this is\nnot correct. ", "It's awful for anything other than recent buzz.", "\n\nWe seem to have lots of nice new web technology standards, but there's an\nabsence of something approaching a \"social profile\" or system whereby users\nand businesses can create, manage, share, follow, and control 100% the data in\nsome social context web mechanism, decoupled from a closed platform with CEO\nat the top. ", "I don't pretend to have the solution on how that might be\npossible.", "\n\n------\nfancyfacebook\nI deleted Facebook after the Beacon fiasco, but I think I'm gonna go ahead and\nmove off google today. ", "Mainly just gmail.", "\n\nI wonder if there will be a backlash against cloud services more generally?", "\nCould we see people return to buying their own servers and hiring network\nengineers again? ", "Everyone I talk to is so concerned about where their data\nlives now, I could see it happening.", "\n\n~~~\napotatopot\nWhat email service are you switching to?", "\n\n~~~\nFezzik\nFor email I highly recommend FastMail. ", "It is $30 a year and their spam filters\nare better than Gmail's. ", "They also have a sleek web interface. ", "The annual fee\nalso includes good looking calendar and document storage features, but I have\nonly dabbled with using those so I do not know how good they are.", "\n\nNotes from a happy user with no relationship to the company.", "\n\n~~~\nmaxxxxx\nHow is Fastmail on Android?", "\n\n~~~\ngkya\nMy experience is from a couple years ago, but the app was not all that good.", "\nNo trouble though, as K-9 mail is a quite nice OSS mail client for Android,\nit's probably the only mobile app that I've used and am nearly satisfied with\nthe experience.", "\n\n------\nkakarot\nThat's my boy! ", "We need more tech leaders to take this stance.", "\n\n------\ncobbzilla\nThis is excellent. ", "We need more high-profile people to do this. ", "It's not so\nhard!", "\n\nAfter years off all personal/social media, I recently joined the mastodon\nfediverse; it's really a breath of fresh air, I'm enjoying it.", "\n\n------\nterraforming\nI never had the impression that Musk cared much about privacy but I seem to be\nwrong. ", "Or perhaps it has more to do with the current POTUS and his impact in\nthe environment. ", "Either way, I am happy for his decision.", "\n\n------\nfoobaw\nConsidering that Elon and Mark constantly disagreed on subjects like AI, this\nisn't surprising.", "\n\nAlso notable is that typical Tesla customers probably don't rely on Facebook\nanyway so this should not have consequences.", "\n\n------\nbooleandilemma\nOne of the best things to come out of all this controversy surrounding FB will\nbe that people will no longer look at me like I have two heads when I tell\nthem I don’t have a FB account.", "\n\n------\nnunez\nI don't think that this matters nearly as much as a major advertiser like\nJohnson and Johnson or pseudo celebrity Instagram followers pulling out.", "\n\n------\nejanus\nI don't work at FB and I don't have their shares either . ", "But to me this is\nlooking like punishment beating because it is linked to Trump victory at the\npolls. ", "We all know that FB is in the business of selling data in one form or\nother. ", "And we also know that FB is human and is subjected errors and mistakes.", "\nBut deleting FB , leaving FB , pulling adverts from FB may not change the\nfundamental.", "\n\n------\ncodebook\nI will not use any service that requires to specify my personal info such as\nreal name, address, phones anymore unless it is tightly coupled to my offline\nlife (financial, hiring). ", "Even email can link many scattered info into one and\nguess who I am, but at least it gives a lot more complexity than one single\nsource has my info.", "\n\n------\nmxschumacher\nInteresting, especially considering that Facebook is/was a customer of SpaceX:\n[https://www.wsj.com/articles/spacex-rocket-test-hit-by-\nexplo...](https://www.wsj.com/articles/spacex-rocket-test-hit-by-\nexplosion-1472738051)\n\n~~~\ngreglindahl\nNo, Facebook was planning on being a customer of Spacecom, the satellite\nowner. ", "Spacecom is SpaceX's customer.", "\n\n------\nmalloreon\nhopefully people deleting facebook don't flee to instagram and think their\nsomehow safe from facebook.", "\n\n~~~\nmalloreon\nI am ashamed that I missed seeing my obvious error in 'their/they're' usage\nlong enough that I cannot edit the parent of this post.", "\n\n------\novercast\n#deletefacebook really isn't going to go anywhere, outside of a vocal minority\nthat don't rely on it. ", "The train stops once the general population realizes\nthey can no longer login to their favorite sites without it. ", "Social Auth is a\nthing, and it's MASSIVE.", "\n\n~~~\nanonytrary\nI am seriously considering disallowing OAuth in my apps for a few reasons:\n\n \n \n 1. ", "It would be impossible for the user to voluntarily give up rights to information they may not understand.", "\n \n 2. ", "It would be impossible for the app to act on behalf of a user.", "\n \n 3. ", "True early adopters are not deterred by the lack of quick sign-in if they truly love the product.", "\n \n 4. ", "Signing up with email is easy today, and browsers make logging in an automatic and smooth process.", "\n \n 5. ", "Emails already act as zero-permission identities.", "\n \n\nFor me, emails are the root of my internet activity. ", "Everything I do is\ntethered to email, not Facebook or Twitter. ", "Going to my email to click a\nverification link is trivial and takes a few seconds; well designed email-\nverification can be seamless. ", "It might even take me _more_ time to read and\ngrok all of the permissions the app is asking for.", "\n\nFurthermore, I don't have to worry about having a user account system that has\nto be ready to deal with N different OAuth tokens. ", "Personally, I have found\nOAuth to be a very inelegant technology.", "\n\nNext time I build a website that has accounts, I will try and market the\n_lack_ of \"signing in with Facebook\" as a boon to the user. ", "OAuth is a\nslippery tool for collusion, something I never want my customers to be victims\nof. ", "I cannot advocate for technology that is primarily used to extract\ninformation from passive people.", "\n\nMaking the rules so hard to read that the average person just says \"yes\" was\nunethical in 1492, and it's unethical now.", "\n\n------\nwwarner\nScreen shot from my twitter feed\n[https://twitter.com/warnerw/status/976431809889210368](https://twitter.com/warnerw/status/976431809889210368)\n\n------\nkolbe\nThat is cool. ", "I wonder if he can kick his Instagram addiction, though.", "\n\n------\nmindfulplay\nThis is great but... This is deleting FB pages not actually deleting FB ads.", "\nFacebook doesn't care about FB pages anymore now that they can track people\nclosely for ad targetting.", "\n\n------\nthelittleone\nI want to delete my FB profile but I'm reluctant because it opens the door for\nsomeone to start a new profile with my name and pictures. ", "Perfect for social\nengineering.", "\n\n------\ndownandout\nMy guess is that they just made the pages private and will quietly bring them\nback after realizing how much traffic they lose as a result, and/or after a\nshareholder lawsuit is filed alleging that Musk is squandering a valuable\ncompany asset on a whim, based on his own political views. ", "Tesla is especially\nvulnerable to such shareholder lawsuits, given that it had millions of “fans”\non the platform. ", "Arguably Musk just took an asset worth tens of millions of\ndollars, that technically belongs to his shareholders, and set it on fire.", "\nThat won’t fly, even amongst the most liberal investors.", "\n\n~~~\ndannyw\nIf you think that the FB page is worth that much to Tesla and SpaceX, I’d like\nto sell you some Facebook pages...\n\n~~~\ndownandout\nYou don’t think a fan page liked by nearly 3 million people, many of whom are\ncustomers or potential customers for a $100,000+ car, is worth at least $10M\nin sales to them? ", "That’s only ~100 sales. ", "I’d bet just about anything that the\nTesla FB Page has helped drive at least that many sales. ", "People look at\ncomments to see what other customers feel about the car etc.", "\n\n------\nshmerl\nGood! ", "Time for Facebook refugees to switch to decentralized social networks,\nthat respect their privacy and don't treat their profiles as a product.", "\n\n------\nJerry64545\nElon and Mark were not getting along well as far as i can tell from reading\npast news. ", "My guess is Mark and Bezos might be getting along well.", "\n\n------\nsergiotapia\nOut of the loop here, are people mad at Facebook for third-party apps that use\ntheir oauth data sharing API?", "\n\n~~~\nAjedi32\nAs far as I can tell, yes that's exactly what's happening.", "\n\nThe HN crowd has, of course, hated Facebook for a long time now for a variety\nof reasons completely unrelated to that, but that was the incident that seems\nto have triggered all this.", "\n\n~~~\nsergiotapia\nIn that case, people are just looking for anything to rabble about. ", "Facebook\ndid nothing wrong here.", "\n\n------\njoelrunyon\nIs there a way to bulk-download photos?", "\n\nThat's about the only FB related item I care about.", "\n\n~~~\nKarunamon\nPhotos you uploaded are included in the \"download your Facebook data\" archive.", "\n\n[https://www.facebook.com/help/131112897028467/](https://www.facebook.com/help/131112897028467/)\n\n------\nmiddle1\nJust checked myself in google. ", "It looks he really did. ", "No Facebook page opened\n\n------\nabalone\n<gif of SpaceX rocket blowing up Facebook satellite>\n\n------\nsweetp\nthis pushed me over the edge to delete my account too.", "\n\nfacebook is toxic\n\n------\nalexnewman\nAnd I just bought some more tesla stock\n\n------\nada1981\nSpaceXBook?", "\n\nElon ought to boot up a social media company.", "\n\n~~~\nCommunitivity\nElon Musk is already using #Mastodon. ", "I suspect he has possibly supported it\nin other ways as well, through public praise and/or contributions.", "\n\n[https://mastodon.social/users/elonmusk/followers](https://mastodon.social/users/elonmusk/followers)\n\n~~~\nterraforming\nCan you check when he created the account? ", "He hasn't made any \"toot\" yet, so\nhe might've just created the account so no one would pretend to be him?", "\n\n~~~\nCommunitivity\nUnfortunately, AFAIK there is no way to check that if he hasn't tooted. ", "Also,\nbear in mind it might not be him..might be a fake account, but then I'd\nsuspect it would have been used more.", "\n\n------\nasdsa5325\nWhy is this news?", "\n\n------\n908087\nIs he still on Instagram? ", "If he is, he's still supporting Facebook.", "\n\n~~~\ndanso\nPeople quitting FB but staying on Instagram is still going to hurt FB. ", "Part of\nFB’s strength is the massive network effects.", "\n\n------\nnugi\nElon, whatever your reasons, I applaud this.", "\n\nNow delete insragram.", "\n\n------\nMikusR\nProbably Tesla workers were using it to talk about unionization.", "\n\n~~~\nslig\nHe deleted his company's Fan Pages, which are basically used to do marketing\n(\"Check out our new car\", \"Coming soon on 2019\", etc). ", "It's not a discussion\ngroup or a forum.", "\n\n------\nakerro\nHey, Elon, why don't you build a better Facebook? ", "Call it, \"the better\ninterplanetary Facebook\".", "\n\n~~~\ncvaidya1986\nActually Elon might do that. ", "He really launches stuff he believes in rather\nquickly.", "\n\n" ]

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[ "[Study on Metagonimus yokogawai(Katsurada, 1912) in Korea VII. ", "Electron microscopic observation on the tegumental structure]\nThis study was performed to observe the chronological changes in the tegumental structure of M. yokogawai using scanning electron microscope. ", "The subjected worms were excysted metacercariae obtained from sweetfish, and 2-day, 1-week and 4-week old worms experimentally reared in albino rats. ", "The results are as follows: The tegument of excysted metacercariae showed many transverse shallow rugae, which were more remarkable in posterior half body, i.e., posterior to ventral sucker. ", "The whole surface was armed with many scale-like spines; 7~8 pointed ones on anterior body and 2~3 pointed on posterior body. ", "The ciliated knob-like papillae (Type I) were abundant around oral and ventral suckers, which grouped 2, 3 or 4 in number in most cases. ", "A few round swellings of tegument (Type II) were observed only on oral sucker. ", "The tegumental surface of 2-day old worms showed deeper rugae, and the anterior half covered with knob-like processes of distal cytoplasm and the posterior half with cobblestone-like ones. ", "Interspinous space became more wide and 9 pointed spines appeared on anterior dorsal surface. ", "The sensory papillae enlarged but not changed in their distribution. ", "The tegument of 1-week old worms revealed knob-like cytoplasmic processes in posterior half body and velvety ones around oral sucker. ", "The scale-Iike spines of anterior half body changed remarkably to the slender ones of posterior body at the level of ventral sucker. ", "In dorsal surface, the arrangement of the Type I papillae were bilaterally symmetrical. ", "The tegument of 4-week old worms were finely differentiated and the posterior tegument covered with velvety cytoplasmic processes. ", "The spines had remarkably grown in length and width but the density remained nearly unchanged. ", "The papillae also became larger but their morphology and distribution were not different from younger worms. ", "However, the round elevation of cytoplasmic ridges (Type III papilla) appeared bilaterally on inner wall of oral sucker, approximately 8 in number. ", "From the above results, it is considered that the tegument of juvenile M. yokogawai continued to differentiate until 4 weeks after infection." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Treatment of lupus nephritis.", "\nRenal involvement in systemic lupus erythematosus patients is a severe disease manifestation characterized by various clinical and histopathological alterations. ", "The revised International Society of Nephrology/Renal Pathology Society 2003 classification defines the subclasses of lupus nephritis (LN) according to their pathological glomerular patterns, which has a crucial impact on the prognosis and treatment options for LN patients. ", "There are widely accepted therapeutic agents available, such as cyclophosphamide, mycophenolate mofetil, azathioprine and corticosteroids. ", "Several trials have tried to determine a gold standard for induction and maintenance therapy in LN, and the place of newer drugs, biologicals, has been investigated. ", "We review recently reported data on current treatment regimens in LN, in particular in the context of the International Society of Nephrology/Renal Pathology Society 2003 classification." ]

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[ "Q:\n\nНакладываются элементы flex-контейнера друг на друга\n\nПриветствую! ", "Верстаю меню с помощью flexbox и столкнулся с проблемой, что если я поставлю flex-wrap: wrap;, то элементы наслаиваются друг на друга. ", "Это скорее всего из-за padding'а у моей ссылки, как это исправить? ", "Вот код:\nТак выходит:\n\n@charset \"UTF-8\";\r\n \r\n* {\r\n margin: 0; \r\n padding: 0; \r\n font-family: Arial;}\r\nhtml {\r\n height: 100%; \r\n unicode-bidi: embed;\r\n direction: ltr;}\r\nbody {\r\n background-color: #6C238D;}\r\n.menu {\r\n position: fixed;\r\n top: 0;\r\n width: 100%;\r\n background-color: #4F1373;\r\n padding: 10px 0px;}\r\n.menu ul {display: flex;\r\n justify-content: space-between;\r\n align-items: center;\r\n align-content: center;\r\n list-style: none;\r\n flex-direction: row;\r\n margin: 5px 0px;\r\n flex-wrap: wrap;}\r\n.menu ul li {flex-grow: 1;\r\n text-align: center;\r\n flex-basis: auto;\r\n font-size: 1.2em;}\r\n.menu li a {\r\n text-decoration: none;\r\n color: #EAE6E6;\r\n padding: 5px 12px;\r\n background-color: #37196F;\r\n border: 2px outset #301B4F;\r\n -webkit-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n -moz-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n -ms-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n -o-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67); \r\n box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n }\r\n \r\n.menu li a:hover {\r\n color: #BE962F;\r\n border: 2px inset #301B4F;}\n<div class=\"menu\">\r\n <ul>\r\n <li><a href=\"#\">This page</a></li>\r\n <li><a href=\"#\">Another page</a></li>\r\n <li><a href=\"#\">And another page</a></li>\r\n </ul>\r\n</div>\n\nА по дефолту так: \n\nХотелось бы, чтоб оно ровненько подвинулось вниз, при уменьшении экрана, а выходит так:\n\nA:\n\nКогда инлайн-элементам добавляется паддинг, то это не влияет на их «внешнюю коробку» и из-за этого они могут налазить друг на друга. ", "Тут достаточно добавить ссылкам стиль display: inline-block.", "\n\n@charset \"UTF-8\";\r\n \r\n* {\r\n margin: 0; \r\n padding: 0; \r\n font-family: Arial;}\r\nhtml {\r\n height: 100%; \r\n unicode-bidi: embed;\r\n direction: ltr;}\r\nbody {\r\n background-color: #6C238D;}\r\n.menu {\r\n position: fixed;\r\n top: 0;\r\n width: 100%;\r\n background-color: #4F1373;\r\n padding: 10px 0px;}\r\n.menu ul {display: flex;\r\n justify-content: space-between;\r\n align-items: center;\r\n align-content: center;\r\n list-style: none;\r\n flex-direction: row;\r\n margin: 5px 0px;\r\n flex-wrap: wrap;}\r\n.menu ul li {flex-grow: 1;\r\n text-align: center;\r\n flex-basis: auto;\r\n font-size: 1.2em;}\r\n.menu li a {\r\n text-decoration: none;\r\n color: #EAE6E6;\r\n padding: 5px 12px;\r\n background-color: #37196F;\r\n display: inline-block;\r\n border: 2px outset #301B4F;\r\n -webkit-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n -moz-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n -ms-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n -o-box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67); \r\n box-shadow: 0px 0px 13px 3px rgba(48,17,48,0.67);\r\n }\r\n \r\n.menu li a:hover {\r\n color: #BE962F;\r\n border: 2px inset #301B4F;}\n<div class=\"menu\">\r\n <ul>\r\n <li><a href=\"#\">This page</a></li>\r\n <li><a href=\"#\">Another page</a></li>\r\n <li><a href=\"#\">And another page</a></li>\r\n </ul>\r\n</div>\n\n" ]

{ "pile_set_name": "StackExchange" }

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[ "Comparative evaluation of various immunodiagnostic tests for the diagnosis of Taenia solium cysticercosis in pigs, using fractionated antigens.", "\nThe sensitivity and specificity of double immunodiffusion (DID), indirect haemagglutination test (IHA), immunoelectrophoresis (IEP), counterimmunoelectrophoresis (CIEP) and enzyme-linked immunosorbent assay (ELISA) were evaluated and compared using saline extracted of Taenia solium larval scolex and its Sephadex G-200 fractionated 1st and 2nd peak as antigens. ", "Various immunodiagnostic tests gave different results with different antigens. ", "Highest sensitivity (92.5%) was obtained with 84.6% sensitivity was obtained with IHA and CIEP respectively using scolex antigen. ", "CIEP gave better results as compared to IEP. ", "Crude antigen gave high sensitivity but less specificity. ", "It was concluded that CIEP can be used as a field test for the anti-mortem diagnosis and ELISA can be employed for laboratory confirmation of T. solium cysticercosis in pigs using fractionated 1st peak antigen." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "Sylvi Listhaug: Vil ha dobbel og firedobbel straff for kriminalitet på Holmlia og andre belastede områder\n\n– Det nytter ikke med kos, klapp og klem på gjengkriminelle, sier Frp-nestleder Sylvi Listhaug.", "\n\n– Vi ønsker å føre en tøffere politikk enn de andre partiene, sier Frps innvandringstalsmann Jon Engen-Helgheim og første nestleder Sylvi Listhaug. ", "Olav Olsen\n\n29. ", "apr. ", "2019 18:27 Sist oppdatert 30. ", "april 2019\n\nI en tidligere versjon av denne artikkelen uttalte professor Bård Anders Andreassen ved Juridisk fakultet (UiO) seg som om Frp foreslo «dobbeltstraff» i juridisk forstand. ", "Det de snakker om er straffeskjerpelse, ikke en dobbeltstraff eller gjentagende straffeutmåling, i juridisk forstand. ", "Saken er derfor oppdatert.", "\n\nFrp vil ha dobbel straffelengde for kriminalitet begått i bestemte områder. ", "Er den kriminelle i tillegg medlem av en gjeng, vil Frp at vedkommende skal få firedobbel straff.", "\n\n– Vi er inspirert av at Danmark har innført dette. ", "Det har bidratt til bedre forhold i belastede områder. ", "Vi mener vi bør gjøre det samme her, sier Sylvi Listhaug.", "\n\nHun leder Frps innvandrings- og integreringsutvalg, som legger frem sin første rapport på helgens landsmøte.", "\n\nHer er forslagene:\n\nSkjerpet straffesone med dobbelt straff etter dansk modell i særlig utsatte boligområder eller i sentrumsområder som har høy dokumentert kriminalitetshyppighet.", "\n\nOslo sentrum bør defineres som en skjerpet straffesone, trolig sammen med en rekke andre områder i hovedstaden.", "\n\nDobbel straff for handlinger utført av medlemmer i gjenger.", "\n\nFire-dobbel straff for gjengmedlemmer som begår kriminelle handlinger i definerte straffesoner.", "\n\nEtablere flere plasser i ungdomsfengsel. ", "Etablere forsterkede lukkede barnevernsinstitusjoner. ", "Opprette hurtigdomstol for rask behandling av gjengkriminelle.", "\n\nNulltoleranse, høye bøter og fengsel for utagerende oppførsel mot politiet.", "\n\nDe ønsker også å fotfølge hardbarkede kriminelle etter mønster av Malmö-politiet.", "\n\n– Politiet er i hælene på dem for ikke å gi dem arbeidsro, sier Listhaug.", "\n\nFakta Disse sitter i partiutvalget Leder: Sylvi Listhaug, 1. ", "nestleder i Frp. ", "Nestleder: Jon Helgheim Innvandringspolitisk talsmann i Frp. ", "Medlemmer: Per-Willy Amundsen (stortingsreresentant), Christian Tybring-Gjedde (stortingsreresentant), Himanshu Gulati (stortingsreresentant), Kari Kjønaas Kjos (stortingsreresentant), Aina Stenersen (Oslo Frp), Silje Diserud (Innlandet Frp), Andreas Brännström (Fremskrittspartiets ungdom). ", "Vis mer\n\nPå spørsmål om hvordan de belastede områdene skal defineres, svarer Listhaug:\n\n– De må utredes og defineres ut fra omfanget av kriminalitet, SSBs kriminalstatistikk og hva slags kriminalitet som begås. ", "Typiske handlinger som Frp vil gi dobbel straff, er trusler, hærverk (bilbrann), tagging, vold, bæring av kniv og andre våpen, ran, tyveri, narkotikaomsetning, sier hun.", "\n\n– Hvordan skal dere definere gjengmedlemmer?", "\n\n– Det er politiets oppgave. ", "Politiet må sannsynliggjøre overfor domstolen at vedkommende er gjengmedlem, sier innvandringspolitisk talsmann Jon Engen-Helgheim.", "\n\n– Det er på høy tid å få mer grep om det som skjer i Oslo Øst. ", "Det er en skremmende utvikling. ", "Vi må slutte med bortforklaringer. ", "Mange har utfordringer, ja, men alle må likevel følge samfunnets lover og regler, legger Listhaug til.", "\n\nLes også LES OGSÅ: Dette er en getto, mener danske myndigheter. ", "Nå skal den bort.", "\n\nHar hatt justisministeren siden 2013\n\nUtvalget har vært på studietur til København og Malmö for å lære av kampen mot tung gjengkriminalitet. ", "Malmö hadde nesten dobbelt så mange drap pr. ", "innbygger som New York i 2018, ifølge rapporten.", "\n\n– Det dreier seg om å være føre var, og ikke havne i samme problemene som våre naboland sliter med, sier Engen-Helgheim.", "\n\n– Frp har hatt justisministeren siden 2013. ", "Har ikke dere et stort ansvar for at det er blitt slik?", "\n\n– Utviklingen har gått i gal retning over tid og før vi kom i regjering. ", "Vi har styrket politiet kraftig og gjort mye for å rette opp. ", "Det er behov for skarpere virkemidler enn det er politisk flertall for, sier Helgheim.", "\n\n– Tror dere at Høyre, KrF og Venstre aksepterer dobbel straff?", "\n\n– Vi ønsker å føre en tøffere politikk enn de andre partiene. ", "Vi synes ikke Granavolden-erklæringen går langt nok. ", "Vi vil gi politiet flere virkemidler. ", "Vi er nødt til å ta kraftigere grep for å stoppe dette, sier Listhaug.", "\n\nAdvarer mot klassejustis og diskriminering\n\nProfessor Bård Anders Andreassen ved Juridisk fakultet, Universitetet i Oslo, uttalte seg i en tidligere versjon av saken som om Frp foreslo «dobbeltstraff» i juridisk forstand.", "\n\nHan presiserer:\n\n– Frp er upresise i bruken av begrepet. ", "Det de snakker om er straffeskjerpelse, ikke en dobbeltstraff eller gjentagende straffeutmåling, i juridisk forstand.", "\n\n– Det er problematisk ut fra likhet for loven-prinsippet. ", "Dette er et kompleks problem som ikke løses med bare straff. ", "Denne kriminalteten må bekjempes gjennom ulike tiltak som skolegang, utdanning, forebygging og arbeid blant annet.", "\n\nAnine Kierulf, fagdirektør ved Norges institusjon for menneskerettigheter, sier at det ligger innenfor statenes suverenitet å bestemme hvordan straffesystemet skal innrettes.", "\n\n– Et samlet storting er enig om at vi ikke straffer for å ta hevn. ", "Straff skal avskrekke fra og forebygge straffbare handlinger, sier hun.", "\n\n– Dobbel straff kan høres ut som en god idé. ", "Det blir verre hvis det bare bor en klasse mennesker eller grupper med minoritetskjennetegn, som pinsevenner, eller bare muslimer i disse områdene. ", "Da vil skjerpelsen i realiteten ramme på en måte som diskriminerer enkelte grupper. ", "Det er også et spørsmål om det virker. ", "Det er ikke noen forskning som tilsier det, sier hun også.", "\n\nFrp avfeier problemstillingene\n\nKierulf mener det er et problem hvis all kriminalitet skal gi dobbel straff i enkelte bydeler.", "\n\n– Hvis fyllekjøring i Holmenkollåsen bare gir bøter, mens fyllekjøring på Grønland gir fengsel for ellers fredelige folk som ikke har råd til å bo noe annet sted, så blir det klassebetinget og kan også virke diskriminerende, sier Kierulf.", "\n\n– Det er svært lite sannsynlig at dette skal gjelde lovbrudd som trygdesvindel og den type ting. ", "Der er kriminalitet som ran, vold, hærverk og den slags som det er ment å slå ned på, sier Helgheim.", "\n\nListhaug avfeier innvendingene fra fagfolkene.", "\n\n– Det sier den gjengen om alt. ", "Vi velger å se på det faktum at Danmark har innført det og at innbyggerne ser positivt på det. ", "Lokalbefolkningen skal føle seg trygge, sier hun.", "\n\n– Det er ikke lik straff for like handlinger i dag, heller. ", "Jusprofessorene tar ikke hensyn til at vi allerede har skjerpende og formildende omstendigheter. ", "Hvis du råkjører forbi en skole, kan du få strengere straff enn om du kjører forbi en bensinstasjon, sier Helgheim.", "\n\nHan legger til:\n\n– De drar alltid frem en eller annen konvensjon, og så viser det seg hver gang at de har feil likevel, avslutter han." ]

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[ "Russ and Elke's European Travel is a small company run by husband and wife team Russ and Elke Beck, a professional travel agent.", "\n\nOver the years we have experienced some fantastic places, people, food and wine. ", "Out of our love for travel developed the idea to create very exclusive, intimate and interesting itineraries and let our clients experience, taste, smell, touch and hear what has given us so much joy in our travels.", "\n\nDay 2 - Volterra\n\nMost people know Volterra from the wildly successful \"Twilight\" movies (actually filmed in Montepulciano), but besides the Volturi hiding out in the basement of the clock tower there are many other secrets hidden away in this tiny Tuscan hill town.", "\n\nVolterra's origins are entrenched in the ancient history of the Etruscans, a little known or understood civilization that controlled much of central Italy for about 500 years beginning in 800 BC until approximately the 3rd century BC when Rome began to annex and conquer much of Etruria.", "\n\nVolterra passed from the Romans to the Florentines, then on to the powerful Medici dynasties and eventually found its way into the modern world, trailing artifacts of all of these influences. ", "Wandering the narrow streets of the old city will bring you to buildings, whose foundations are older than Rome itself.", "\n\nYou will find an ancient Roman theater as well as the famous Baptistery, an octagonal 13th century religious building in front of the Duomo of Volterra, in the center of the city. ", "It was set up in the seventh century at the site of a Roman Temple to the Sun. ", "The holy water receptacle inside of the building is actually an ancient Roman sarcophagus.", "\n\nFor us, one of the most fascinating hidden secrets in Volterra is the Church of San Francesco. ", "Elke had read about this church, but we couldn't remember it's name or location, so we had to hunt for it. ", "Leaving the main Piazza behind we wandered through the narrow, winding streets popping our head into every doorway that seemed to be a house of worship. ", "And there are more than a few of those:) Eventually, just as we were wearing down from the heat of the day, we reached the edge of town, and a ramshackle old church rose up to our right.", "\n\nWandering in we were prepared to be disappointed again, and I was... The church interior, as opposed to the exterior, was just a modern looking church with 20th century paintings and a rather bland air about it.", "\n\nElke, however, started to get excited, the name of the church had rung a bell for her, and she began to wander down the aisles, poking her head into every doorway. ", "I followed, hissing at her that this was another dead end. ", "Boy was I wrong!!!", "\n\nBeside the alter, off to the right, there stands a humble wooden door. ", "Elke passed through the door and let it swing shut in my face. ", "A moment later she poked her head out and, very excitedly, told me to look for a light switch. ", "Now, I'm not sure about you, but I'm not into pushing buttons and turning on switches in places where I don't know what they will do, but, rather than risk the wrath of Elke, I did as instructed.", "\n\nA weak light escaped from around Elke's head as she poked out of the portal once more. ", "She stepped back and swung the door open. ", "My eyes adjusted to the spectacular sight that awaited me. ", "I stepped down 2 small steps and walked to the center of the small chapel. ", "What we had \"found\", is what I later understood to be the Chapel of the Daily Cross, with frescoes by Cenni di Francesco and Jacopo da Firenze depicting scenes from the Legends of the True Cross. ", "These frescoes date to the early 15th century and were lit by a lonely incandescent bulb crudely wired to the ceiling.", "\n\nWe spent nearly an hour in the small room, never interrupted. ", "No other tourists made the search for this magnificent hidden chapel. ", "We searched for the meanings and tried to understand the scenes played out in the magnificent frescos, some of which seemed as if the paint had yet to dry and others were damaged by years of water and neglect.", "\n\nReluctantly we took our leave and re-entered the modern church, that had been built around the chapel, and then out into the blazing Italian sun where we chatted about our \"find\" as if we were Indiana Jones himself.", "\n\nWhenever we find ourselves in Volterra, we always make the trip to this little chapel and sit quietly to enjoy what God inspired and Man executed so wonderfully." ]

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[ "Consumer Banking and Payment\n\nFinancial institutions are also increasingly reaching out to individuals who have been outside of or underserved by the banking industry by offering nontraditional services and new products. ", "The bewildering array of new payment systems and electronic commerce can create great confusion and the potential for abuse of consumers. ", "Some of these new systems are also developing outside of the framework of older consumer protection laws or are designed to skirt stronger protections.", "\n\nNCLC monitors these developments and works for protections for lower income consumers in the banking and payment systems." ]

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[ "Visualization of the living cytoskeleton by video-enhanced microscopy and digital image processing.", "\nTwo steps led to our present-day view of the cytoskeleton as a highly dynamic structure that is actively involved in force generation for various kinds of cell motility and, as a result, is itself often actively moving. ", "The first step was the introduction of video microscopy, especially of the Allen Video Enhanced Contrast-Differential Interference Contrast Microscopy (AVEC-DIC), which allows the visualization of cellular structures in the light microscope that are up to 10 times smaller than the limit of resolution. ", "This enables one to see images of unfixed, unstained, native or purified microtubules and actin bundles, and their interaction with membrane-bound organelles. ", "The second step was the discovery of a system exceptionally well-suited to study microtubule and organelle movements, namely, the extruded axoplasm of the squid giant axon. ", "From this axon the cytoplasm can be extruded free from surrounding plasma membrane, and individual microtubules and organelles can be separated from the bulk axoplasm. ", "The study of these native microtubules by AVEC-DIC microscopy yielded a great number of quite unexpected details of the dynamic behaviour of both the microtubules themselves and the motility associated with them." ]

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[ "Intracerebral aspergillus abscess: case report.", "\nIntracranial aspergillosis is rare and often fatal. ", "The authors report the successful treatment of a right temporal intracerebral aspergillus abscess." ]

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[ "Many adults believe they are unable to hula-hoop. ", "If your most recent attempts have been in the aisle at the local box store, it would be impressive if you could! ", "Most are surprised at how easy it actually is when they try using an adult sized hoop. ", "Join the fun new fitness trend that feels more like recess than cardio. ", "Rabbit Wheel Studio makes adult size beginner, intermediate and dance hoops. ", "Please email for assistance determining the best size/style hoop for your needs.", "\n\n***Shipping of hoops is unavailable at this time, but a small selection of hoops is available for purchase in person at http://www.silksnpole.com/. Sorry for any inconvenience.***", "\n\n***Each piece is individually hammered one character at a time and everything is freehand. ", "Because of this, no two pieces will be exactly alike and you should expect variations in the spacing, depth of the designs and placement. ", "This is not to be considered a defect but to a part of the beauty and charm of a hand made piece.***", "\n\nFrom time to time, there will be original painted mandalas available here on this website for purchase. ", "All paintings are also available as prints or on products (pillows, phone cases, clothing, office supplies, etc.) ", "that feature the images at www.fineartamerica.com and/or www.redbubble.com.", "\n\nPillows from Red Bubble\n\nAbout RWS\n\nRabbit Wheel Studio is the collection of original works and pieces created by Amber Bradshaw. ", "What began as the desire to create her own dance hoop after taking a hula-hooping fitness class, soon turned into several requests to make more hoops for classmates and friends. ", "The joy of hooping and making hoops as a hobby eventually became a job leading the hoop class! ", "It was inside those hoops that Amber began to feel the creative flow that inspired her to step outside her comfort zone and take a mandala painting class taught by a childhood friend. ", "That afternoon, painting and reminiscing with her friend, the ember of creativity that began with a hoop, ignited like a wildfire and has consumed Amber's brain with ideas, patterns, designs and colors. ", "She expresses her creativity across many mediums, including, but not limited to; mandala paintings, painted coasters, beaded bracelets, necklaces, hand-stamped metal jewelry and keepsakes and of course, hula-hoops. ", "Amber says, \"I really just enjoy making things that make other people happy!\"", "\n\nThe story behind the name Rabbit Wheel Studio... \"As many of my friends and family know, I've collected rabbits for many years so that part of the name was kind of a no-brainer. ", "The wheel reference is two-fold. ", "As I began looking at my work as a whole, everything had a similar circular theme; hoops, mandalas, bracelets, necklaces. ", "Round and round...like the ideas that spin through my brain...like a wheel! ", "And so, as a little business began to grow from these things I created, Rabbit Wheel Studio was born.\"", "\n\nAmber currently resides in Kansas City, Missouri and is the proud mother of a teenage daughter and dog mom to three fur babies.", "\n\n“Each person’s life is like a mandala – a vast, limitless circle. ", "We stand in the center of our own circle, and everything we see, hear and think forms the mandala of our life.”" ]

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[ "Q:\n\nExtension of Completions of Number Fields\n\nOn p. 116 of Milne's notes on Algebraic Number Theory, he gives the following construction.", "\nLet $K$ be a field with a valuation $|\\cdot|$ (archimedean or discrete\nnonarchimedean), and let $L$ be a finite separable extension of $K.$\nWrite $L = K[\\alpha]$, and let $f(X)$ be the minimum polynomial of $\\alpha$ over $K.$ Let $|\\cdot|'$ be an extension of $|\\cdot|$ to L. Then we can form the completion $\\hat{L}$ of $L$ with respect to $|\\cdot|'$. Then $\\hat{L} = \\hat{K}[\\alpha].$ In particular, $\\hat{L}$ does not depend seem to depend on which extension $|\\cdot|'$ of $|\\cdot|$ we choose. ", "\nFor example, if $L/K$ is a separable extension of number fields, $\\mathfrak{p}$ is a prime ideal of $K$ and $\\mathcal{P}_1,\\dotsc,\\mathcal{P}_n$ are primes of $L$ dividing $\\mathfrak{p}$ then this seems to show that all completions $L_{\\mathcal{P}_i}$ of $L$ with respect to $|\\cdot|_{\\mathcal{P}_i}$ are equal.", "\nMy question is: is this reasoning correct? ", "Are all such completions indeed equal? ", "This seems strange to me, but possibly I just don't have the correct intuition here.", "\n\nA:\n\nAfter an enlightening talk with my friend Ben today, I think I can answer my own question now. ", "Thanks to Ben for pointing out this solution!", "\nAs was pointed out by Lubin in his answer to this question, the completions may not be equal or even isomorphic. ", "So the question is now: where is the flaw in my reasoning? ", "Still $\\hat{K}[\\alpha]$ does not seem to depend on which completion $\\hat{L}$ of $L$ we took?", "\nThis is where I am wrong. ", "At the start we have $\\alpha\\in L$. However, when we consider $\\hat{K}[\\alpha]$, we are taking $\\alpha\\in \\hat{L}$. Hence, quietly, we are not really considering $\\alpha$ but rather the image of $\\alpha$ under the embedding $L\\hookrightarrow\\hat{L}$. Let's call the distinct completions $L_i$ for a moment and let's refer to the image of $\\alpha$ in $L_i$ as $\\alpha_i$ to clearly emphasise its dependence on $L_i$. It is not so hard to see that the $\\alpha_i$ can now be very distinct elements of the algebraic closure of $\\hat{K}$ and hence the $\\hat{K}[\\alpha_i]$ - this is what we called $\\hat{K}[\\alpha]$ before - can be different fields depending on the completion $L_i$.\n\n" ]

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[ "Sylvania Waters (TV series)\n\nSylvania Waters was an Australian reality television series that followed the lives of an Australian family – one of the first such programs in Australia. ", "It premiered on Australian television in 1992 and was co-produced by the Australian Broadcasting Corporation (ABC) and the British Broadcasting Corporation (BBC). ", "The show documented the lives of Noeline Baker and Laurie Donaher of 48 Macintyre Crescent in the Sydney waterside suburb of Sylvania Waters over a six-month period, emphasising the couple's newfound wealth and luxurious lifestyle as well as interpersonal conflicts.", "\n\nReferences\n\nExternal links\nEncyclopedia of Television\nSylvania Waters at the National Film and Sound Archive\n\nCategory:1992 Australian television series debuts\nCategory:1992 Australian television series endings\nCategory:Australian reality television series\nCategory:Australian Broadcasting Corporation shows\nCategory:Television shows set in Sydney\nCategory:1990s Australian television series" ]

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[ "\n979 S.W.2d 127 (1998)\nBuddy James SMITH, Appellant,\nv.\nGENERAL MOTORS CORPORATION, and Royal Oaks Chevrolet-Cadillac, Inc., Appellees.", "\nNo. ", "1997-CA-002295-MR.", "\nCourt of Appeals of Kentucky.", "\nOctober 16, 1998.", "\n*128 Thomas L. Osborne, C. Thomas Miller, Paducah, for Appellant.", "\nDonald Craig York, Louisville, for Appellee/GM.", "\nJohn C. Whitfield, Madisonville, for Appellee/Royal Oaks Chevrolet.", "\nBefore HUDDLESTON, KNOPF, and MILLER, JJ.", "\n\nOPINION\nMILLER, Judge.", "\nBuddy James Smith brings this appeal from a summary judgment (Ky. R. Civ.", "Proc. (", "CR) 56) of the McCracken Circuit Court entered April 24, 1997. ", "We reverse and remand.", "\nOn or about December 15, 1994, Buddy James Smith (Smith) purchased a new GMC van from co-appellee, Royal Oaks Chevrolet-Cadillac, Inc. (Royal Oaks), in Paducah, Kentucky. ", "His employer paid for the vehicle as a retirement gift. ", "During the first 4,800 miles, the van \"stalled\" three times on interstate roads while traveling at highway speed. ", "In June, 1995, Smith took the van to Royal Oaks complaining of the stalling incidents. ", "Royal Oaks examined the vehicle and was unable to find a defect. ", "Smith was advised to keep driving the van. ", "About one month later, he complained to co-appellee, General *129 Motors Corporation (General Motors). ", "He requested both Royal Oaks and General Motors to sign statements that the vehicle was safe for use. ", "Each declined. ", "Being unsatisfied with these responses, Smith returned the van to Royal Oaks.", "\nOn November 7, 1995, Smith filed suit against Royal Oaks and General Motors, alleging breach of warranty under the sales provision of our Uniform Commercial Code (UCC)(codified in Ky.Rev.Stat. (", "KRS) 355.2-101—355.2-725) and violation of our Consumer Protection Act (codified in KRS 367.110 - 367.360). ", "In the course of discovery, Smith learned that Royal Oaks had made pre-sale repairs to the van. ", "In March 1994, some nine months before Smith acquired the van, repairs were made to the radiator. ", "At the time, the odometer reading was eight miles. ", "In August of the same year, the van was serviced for engine performance problems, which included \"[dying] at highway speeds.", "\"[1] At this time, the odometer reading was forty-five miles. ", "These repairs totaled $323.33. ", "Royal Oaks did not advise Smith of the vehicle's service history prior to his taking possession of same. ", "Upon learning said history, Smith amended his complaint to allege fraud. ", "On April 24, 1997, the McCracken Circuit Court entered summary judgment dismissing Smith's complaint in its entirety. ", "This appeal followed.", "\nCertain facts are not in dispute. ", "The van was sold as a new vehicle by Royal Oaks, GM's franchised dealer. ", "As such, it was accompanied by the General Motors' new vehicle warranty and, likewise, afforded all protection of the law relative to the sale of new vehicles.", "\n\nFRAUD CLAIM AGAINST ROYAL OAKS\nSmith contends that the circuit court committed reversible error by entering summary judgment upon his claim of fraud. ", "We agree. ", "On this claim, we are of the opinion that Smith established sufficient facts to preclude summary judgment as to Royal Oaks' failure to disclose the van's pre-sale history.[2]\nSummary judgment is proper only when there exists no material issue of fact and movant is entitled to judgment as a matter of law. ", "Steelvest, Inc. v. Scansteel Service Center, Inc., Ky., 807 S.W.2d 476 (1991). ", "To establish an actionable case of fraud based upon suppression of a fact, Smith must demonstrate (1) that Royal Oaks had a duty to disclose a material fact, (2) that Royal Oaks failed to disclose same, (3) that Royal Oaks' failure to disclose the material fact induced him to act, and (4) that he suffered actual damages therefrom. ", "See Faulkner Drilling Company, Inc. v. Gross, Ky.App., ", "943 S.W.2d 634 (1997), and Wahba v. Don Corlett Motors, Inc., Ky.App., ", "573 S.W.2d 357 (1978). ", "Royal Oaks asserts, however, there existed no duty upon it to disclose the pre-sale history of the van.", "\nIt is, of course, well established that mere silence is not fraudulent absent a duty to disclose. ", "Hall v. Carter, Ky., 324 S.W.2d 410 (1959). ", "A duty to disclose may arise from a fiduciary relationship, from a partial disclosure of information, or from particular circumstances such as where one party to a contract has superior knowledge and is relied upon to disclose same. ", "See Bryant v. Troutman, Ky., 287 S.W.2d 918 (1956); Dennis v. Thomson, 240 Ky. 727, 43 S.W.2d 18 (1931); and Faulkner, 943 S.W.2d at 634. ", "Considering Royal Oaks' superior knowledge and Smith's reliance thereupon, we are of the opinion there arose, as a matter of law, a duty upon Royal Oaks to disclose material defects and repairs known to it. ", "We believe issues of fact exist as to whether the van's pre-sale history of repairs and defects would be considered material to a reasonable person. ", "See Faulkner, 943 S.W.2d at 634. ", "We therefore conclude that material issues of fact exist as to Smith's common law fraud claim, thus precluding summary judgment.", "\nWe additionally think statutory provisions exist that imposed upon Royal Oaks a duty to disclose the van's pre-sale history. ", "One such statute is KRS 190.071(1)(e), set *130 forth in KRS Chapter 190, \"Motor Vehicle Sales.\" ", "KRS 190.071(1)(e) reads as follows:\n(1) It shall be a violation of this section for any new motor vehicle dealer:\n. . .", "\n(e) To use false or fraudulent representations in connection with the operation of the new motor vehicle dealership. (", "Emphasis added.)", "\n\"Fraud,\" in the above context, is defined in KRS 190.010(23) as\n\"a misrepresentation in any manner, whether intentionally false or due to gross negligence, of a material fact; a promise or representation not made in good faith; or an intentional failure to disclose material fact.\" (", "Emphases added.)", "\nConsidering this definition of fraud, we believe KRS 190.071(1)(e) imposes an affirmative duty upon new motor vehicle dealers to disclose material facts to customers while in the course of conducting business. ", "We further believe that failure to so inform the customers may constitute fraud. ", "We are buttressed in our interpretation of same by KRS 190.015 wherein the Legislature declared its public policy underlying Chapter 190:\n190.015. ", "Public policy declared.", "\nThe Legislature finds and declares that the distribution and sale of vehicles within this state vitally affects the general economy of the state and the public interest and the public welfare, and that in order to promote the public interest and public welfare, . . . ", "it is necessary to regulate and license vehicle manufacturers, distributors . . . ", "distributor representatives, and to regulate and license dealers of vehicles doing business in this state, in order to prevent frauds, impositions, and other abuses upon its citizens.. . . (", "Emphasis added.)", "\nUpon the forgoing, we are of the opinion that KRS 190.071(1)(e) imposed upon Royal Oaks a duty to disclose such material pre-sale repairs and defects known to it and that issues of fact exist as to whether the van's pre-sale repairs and defects were material. ", "See Faulkner, 943 S.W.2d at 634.", "\nWe are also persuaded by Smith's argument that KRS 186A.540 imposed an affirmative duty upon Royal Oaks to disclose repairs exceeding $300.00. ", "That statute is found in the \"Damaged Motor Vehicles\" Act (KRS 186A.500-550) and states as follows:\nAn individual or a dealer required to be licensed pursuant to KRS Chapter 190 shall disclose all damages to a motor vehicle which result in repairs or repair estimates that exceed three hundred dollars ($300) and that occur while the motor vehicle is in his possession and prior to delivery to a purchaser. ", "Disclosure shall be in writing and shall require the purchaser's signature acknowledging the disclosure of damages. (", "Emphasis added.)", "\nRoyal Oaks urges this Court to adopt a narrow interpretation of the above statute so that it includes only \"body\" damage to motor vehicles. ", "We decline to do so. ", "We believe said statute should be broadly interpreted to include any motor vehicle repairs over $300.00, be they mechanical, body, or otherwise. ", "We view such broad interpretation as mandated by the legislative purpose of the \"Damaged Motor Vehicles\" Act:\n186A.500. ", "Legislative finding.", "\nThe General Assembly finds that purchasers when buying vehicles are entitled to know if the vehicle has sustained prior severe damage.. . . (", "Emphasis added.)", "\nAs the van's cumulative repair work exceeded $300.00, we think KRS 186A.540 imposed a duty upon Royal Oaks to disclose the repairs.", "\nIn sum, we are persuaded there existed both a common law and statutory basis for imposition of a duty upon Royal Oaks to disclose material pre-sale repairs and defects of the van and that issues of fact exist to preclude summary judgment thereupon.", "\n\nCONSUMER PROTECTION CLAIM AGAINST ROYAL OAKS AND GENERAL MOTORS\nUpon the aforementioned grounds, we likewise perceive that Smith should not have suffered summary judgment upon his claim that failure to disclose the van's pre-sale history constituted a false, misleading and/or deceptive trade practice under the Consumer Protection Act. ", "KRS 367.170. ", "Cf. *", "131 Ford Motor Company v. Mayes, Ky.App., ", "575 S.W.2d 480 (1978)(holding that Ford Motor Company's failure to repair or replace a defective vehicle constituted an unfair trade practice under the Consumer Protection Act). ", "We believe this claim should proceed against both Royal Oaks and General Motors. ", "We note that \"false\", \"misleading\", and \"deceptive\" are defined in terms generally understood and perceived by the public. ", "Cf. ", "Dare To Be Great, Inc. v. Commonwealth, Ky., 511 S.W.2d 224 (1974). ", "Certainly, a fact-finder might reasonably conclude that the sale of the van as \"new\" without disclosure of its pre-sale history constituted a false, misleading or deceptive act. ", "Thus, we believe summary judgment upon this issue was improper.", "\n\nBREACH OF WARRANTY CLAIM AGAINST ROYAL OAKS AND GENERAL MOTORS\nWe now turn to the consideration of Smith's breach of warranty claim against Royal Oaks and General Motors. ", "KRS 355.2-314(1), a provision of our UCC, implies a warranty of merchantability in all contracts of sale. ", "If goods are defective, they may, of course, be rejected. ", "KRS 355.2-602. ", "If a defect is not discovered until after acceptance, however, a revocation of the acceptance may be effected, and the buyer may have \"the same rights and duties with regard to the goods . . . ", "as if he had rejected them.\" ", "KRS 355.2-608(3). ", "In the case at hand, Smith accepted the van, together with all the rights afforded him under the UCC. ", "When he experienced stalling at highway speeds, he gave appellees prompt and ample opportunity to correct same. ", "KRS 355.2-608. ", "They gave him no assurance, but suggested that he continue utilizing the vehicle under what he perceived to be extraordinary risk. ", "Unsatisfied with the proffered remedy, Smith revoked his acceptance by delivering the van to the dealer. ", "See Mayes, 575 S.W.2d at 480.", "\nThe appellees, as did the circuit court, believe it incumbent upon Smith to prove by direct evidence a specific defect. ", "In their briefs and at oral argument, the appellees relied upon Briner v. General Motors Corporation, Ky., 461 S.W.2d 99 (1971), for this proposition. ", "In Briner, the appellant was injured in an automobile accident. ", "She instituted an action against the manufacturer of the automobile, General Motors Corporation, and the dealer/seller, Universal. ", "The bases of the action were \"manufacturer's liability and negligent repair.\" ", "Id. at 100. ", "Essentially, the appellant claimed that a defect existed in the steering system of the vehicle causing her to veer across the centerline and strike another automobile and that such defect was the proximate cause of the accident. ", "It is crucial to note that the appellant in Briner had the burden of proving not only the existence of a defect but, more importantly, that such defect caused the accident. ", "Indeed, the Briner Court pointed out that \"[t]here was no direct proof of the existence of a defective mechanical condition existing at the time of the accident which could have caused it.\" (", "Emphasis added.) ", "Id. at 101. ", "The Court recognized that such \"causal relationship\" may be proved by circumstantial evidence but thereafter invoked the well-founded rule of law that such relationship may not be proved by an inference which is itself based upon an inference. ", "The following is the Court's ratiocination:\nTo justify a finding of liability on Universal's part would require a jury first to infer a breakdown in the steering mechanism attributable to a defect. ", "Secondly, it would be required to further infer that, had Universal made different inspections and tests it would have discovered and corrected the condition which ultimately caused plaintiff's car to veer to the left. ", "This is piling inference upon inference, which leads to speculation. . . .", "\n[10] . . .", "\nAs said in Le Sage v. Pitts, 311 Ky. 155, 223 S.W.2d 347, 352 (1949):\n\"An inference may be drawn from a clearly established fact, but, if the conclusion is drawn upon a fact dependent for proof of its existence upon a prior inference, the evidentiary fact is too remote to support the conclusion.\"", "\nId. at 101-102. ", "The Briner Court simply held that inference of a \"causal relationship\" was impermissible as it was based upon inference of a defective condition. ", "Such are *132 not the circumstances in the case at hand. ", "As no accident occurred, Smith need not prove a \"causal relationship.\" ", "The reasoning of Briner is inapposite to the case at hand. ", "Smith invokes but a single inference in his attempt to prove a defective condition. ", "We view such as clearly permissible. ", "We think it only necessary for Smith to prove that the van stalled. ", "Such is evidence of a defective condition. ", "A defect may be proved by a sufficient quantum of circumstantial evidence. ", "Indeed, it has been observed that \"[i]t matters not that the evidence be circumstantial for as Thoreau put it `Some circumstantial evidence is very strong, as when you find a trout in the milk.'\" ", "Embs v. Pepsi-Cola Bottling Company of Lexington, Kentucky, Inc., Ky., 528 S.W.2d 703, 706 (1975). ", "Considering the van's uncontroverted prior history of stalling, the witnessing of said stalling by several others besides Smith, and the documented stalling of other General Motors' vans, we liken the weight of circumstantial evidence herein to that of the proverbial \"trout in the milk.\"", "\nIn sum, we are convinced that the record presents a material issue of fact as to whether the van's stalling was a material defect rendering the vehicle unmerchantable. ", "Under the doctrine announced in Steelvest, 807 S.W.2d at 476, we are therefore of the opinion that the summary judgment upon the breach of warranty claim was inappropriate.", "\n\nConclusion\nWe think summary judgment was improperly granted on Smith's claims of fraud, violation of the Consumer Protection Act, and breach of warranty.", "\nFor the foregoing reasons, the judgment of the McCracken Circuit Court is reversed, and this cause is remanded for proceedings consistent with this opinion.", "\nALL CONCUR.", "\nNOTES\n[1] During discovery, it was learned that other General Motor's vans had experienced stalling problems.", "\n[2] At oral argument, Smith informed the Court that the fraud claim would be directed only against Royal Oaks.", "\n" ]

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[ "Q:\n\nAndroid:Failed to resolve dependency in android studio\n\nI am using the Android Studio 1.4 and i am developing application\n where i need to store data into Couchbase Lite.", "\n I am adding dependency as follows in app level build.gradle\n compile 'com.couchbase.lite:couchbase-lite-android:1.0.2'\napply plugin: 'com.android.application'\n\nandroid {\n compileSdkVersion 23\n buildToolsVersion \"23.0.1\"\n\n packagingOptions {\n exclude 'META-INF/ASL2.0'\n exclude 'META-INF/LICENSE'\n exclude 'META-INF/NOTICE'\n }\n\n defaultConfig {\n applicationId \"com.couchbase.examples.couchdb\"\n minSdkVersion 15\n targetSdkVersion 23\n versionCode 1\n versionName \"1.0\"\n }\n buildTypes {\n release {\n minifyEnabled false\n proguardFiles getDefaultProguardFile('proguard-android.txt'), 'proguard-rules.pro'\n }\n }\n}\n\ndependencies {\n compile fileTree(dir: 'libs', include: ['*.jar'])\n testCompile 'junit:junit:4.12'\n compile 'com.android.support:appcompat-v7:23.0.1'\n compile 'com.android.support:design:23.0.1'\n compile 'com.couchbase.lite:couchbase-lite-android:1.0.2'\n}\n\nand the code bellow is of another build.grade where i have added the following code:\n repositories {\n jcenter()\n maven {\n url \"http://files.couchbase.com/maven2/\"\n }\n\nBut the problem is that i am getting error when i clicked on \"Sync project with gradle file option\" in android studio. ", "The error is:\nFailed to resolve:com.couchbase.lite:couchbase-lite-android:1.0.2\n\nA:\n\nFailed to resolve:com.couchbase.lite:couchbase-lite-android:1.0.2\n\nThis issue happens because\ncompile 'com.couchbase.lite:couchbase-lite-android:1.0.2'\n\ndoesn't exist on jcenter repo.", "\nYou can check this link.", "\nCurrently the only version is 1.1.0.", "\nJust use:\ncompile 'com.couchbase.lite:couchbase-lite-android:1.1.0'\n\n" ]

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[ "Brief report: perception of body posture--what individuals with autism spectrum disorder might be missing.", "\nAutism has been associated with atypical face and configural processing, as indicated by the lack of a face inversion effect (better recognition of upright than inverted faces). ", "We investigated whether such atypical processing was restricted to the face or extended to social information found in body postures. ", "An inversion paradigm compared recognition of upright and inverted faces, body postures, and houses. ", "Typical adults demonstrated inversion effects for both faces and body postures, but adults with autism demonstrated only a face inversion effect. ", "Adults with autism may not have a configural processing deficit per se, but instead may have strategies for recognizing faces not used for body postures. ", "Results have implications for therapies employing training in imitation and body posture perception." ]

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[ "import React, { useMemo } from 'react'\nimport NavigatorItem from '../atoms/NavigatorItem'\nimport { NoteStorage } from '../../../lib/db/types'\nimport { useGeneralStatus } from '../../lib/generalStatus'\nimport { getTagListItemId } from '../../../lib/nav'\nimport { useRouter, usePathnameWithoutNoteId } from '../../lib/router'\nimport { useContextMenu, MenuTypes } from '../../../lib/contextMenu'\nimport { useDialog, DialogIconTypes } from '../../../lib/dialog'\nimport { useDb } from '../../lib/db'\nimport { useTranslation } from 'react-i18next'\nimport { mdiTagMultiple, mdiPound } from '@mdi/js'\n\ninterface TagListFragmentProps {\n storage: NoteStorage\n}\n\nconst TagListFragment = ({ storage }: TagListFragmentProps) => {\n const { toggleSideNavOpenedItem, sideNavOpenedItemSet } = useGeneralStatus()\n const { id: storageId, tagMap } = storage\n const { push } = useRouter()\n const { popup } = useContextMenu()\n const { messageBox } = useDialog()\n const { removeTag } = useDb()\n const { t } = useTranslation()\n const currentPathname = usePathnameWithoutNoteId()\n\n const tagListNavItemId = getTagListItemId(storage.id)\n const tagListIsFolded = !", "sideNavOpenedItemSet.has(tagListNavItemId)\n\n const { toggleNav } = useGeneralStatus()\n\n const tagList = useMemo(() => {\n return Object.keys(tagMap).map((tagName) => {\n const tagPathname = `/m/storages/${storageId}/tags/${tagName}`\n const tagIsActive = currentPathname === tagPathname\n return (\n <NavigatorItem\n key={`storage:${storageId}/tags:${tagName}`}\n depth={2}\n iconPath={mdiPound}\n label={tagName}\n onClick={() => {\n push(tagPathname)\n toggleNav()\n }}\n active={tagIsActive}\n onContextMenu={(event) => {\n event.preventDefault()\n popup(event, [\n {\n type: MenuTypes.", "Normal,\n label: t('tag.remove'),\n onClick: () => {\n messageBox({\n title: `Remove \"${tagName}\" tag`,\n message: t('tag.removeMessage'),\n iconType: DialogIconTypes.", "Warning,\n buttons: [t('tag.remove'), t('general.cancel')],\n defaultButtonIndex: 0,\n cancelButtonIndex: 1,\n onClose: (value: number | null) => {\n if (value === 0) {\n removeTag(storageId, tagName)\n }\n },\n })\n },\n },\n ])\n }}\n />\n )\n })\n }, [\n storageId,\n tagMap,\n push,\n currentPathname,\n popup,\n messageBox,\n removeTag,\n t,\n toggleNav,\n ])\n\n if (tagList.length === 0) {\n return null\n }\n\n return (\n <>\n <NavigatorItem\n depth={1}\n iconPath={mdiTagMultiple}\n label={t('tag.tags')}\n folded={tagList.length > 0 ? ", "tagListIsFolded : undefined}\n onFoldButtonClick={() => {\n toggleSideNavOpenedItem(tagListNavItemId)\n }}\n onClick={() => {\n toggleSideNavOpenedItem(tagListNavItemId)\n }}\n onContextMenu={(event) => {\n event.preventDefault()\n }}\n />\n {!", "tagListIsFolded && tagList}\n </>\n )\n}\n\nexport default TagListFragment\n" ]

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[ "Tick infestation in soldiers who were bivouacked in the Perth region.", "\nWe report observations on infestations with the tick, Amblyomma triguttatum, in soldiers who were bivouacked in two areas near Perth; 34% of 175 persons were infested with varying stages of the ectoparasite. ", "Most persons were infested with only one tick but some troops had multiple infestations. ", "Local skin reactions to tick-bites were frequent; they usually developed 24-48 h after removal of the tick and may indicate delayed hypersensitivity reactions. ", "A small number of persons developed secondary bacterial infections. ", "Management and prevention of these infestations is reviewed briefly." ]

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[ "Surprise, surprise. ", "Yet another Democrat telling yet another lie to oppose a gun rights bill that doesn’t do what they claim it does.", "\n\nThis time it was Rep. Jamie Raskin, a Democrat representing Maryland’s 8th District, who took to the House floor while opposing the Concealed Carry Reciprocity Act to claim that there have been more than 378 mass shootings this year.", "\n\nAs Washington Free Beacon writer Stephen Gutowski noted, this 378 number was nonsense, even using Raskin’s own definition of “mass shooting” as four or more people killed, and looking at statistics compiled by a gun control advocacy group.", "\n\nAs Gutowski observed, this group has a far broader definition than the FBI for mass shooting, but even by this standard, Raskin was off by more than 300.", "\n\nRaskin posted several tweets calling the bill “dangerous” and bemoaning how it would trample on “states’ rights.” (", "Democrats always love states’ rights when it’s a right that conservatives support expanding, as we all know).", "\n\nIn another clip from Raskin’s remarks, he cites statistics about deaths caused by guns owned by concealed carry permit holders, but inflates the statistics again, most notably by including suicides.", "\n\nSuicide is of course a tragedy, but Raskin is trying to argue that the general public is at risk of being murdered by concealed carry permit holders, and someone making the awful decision to end their own life doesn’t do that.", "\n\nThe reality that Democrats don’t want to admit is that concealed carry permit holders commit crimes far less frequently than the general population, including gun crimes and other crimes involving violence.", "\n\nThe Texas Department of Public Safety has been compiling statistics on crimes committed by Texans with handgun licenses (since Texas passed open carry, just one general license is required) since 1996, and has published reports comparing license holders with the general population.", "\n\nThe reports are available on the DPS website for every year from 1996 through 2016, and covers all convictions by Texas residents who are at least 21 years old (to match the minimum age for a gun license) and waits for one year after the conviction to allow time for appeals.", "\n\nEvery single year of the DPS reports, the percentage of all convictions committed by gun license holders never reaches even one-half of one percent.", "\n\nFor 2016, the most recent report available, there were 42,797 convictions in Texas, 148 of which were by gun license holders, for a percentage of 0.3458%.", "\n\nThis rarity of crimes committed by gun license holders extends throughout the various categories, including sexual assaults and murders. ", "And it’s important to note that being included on the list as convicted of one of these crimes does not necessary mean a gun was used in the crime.", "\n\nThese kind of facts are uninteresting to Democrats like Raskin, who resort to fear-mongering to argue against law-abiding citizens exercising their rights. ", "Never mind that when a concealed carry permit holder did make news in a recent mass shooting, it’s because he helped defend innocent lives, like Stephen Willeford did during the Sutherland Springs church shooting.", "\n\nWilleford was a certified NRA instructor too, armed with an AR-15, so don’t expect Raskin and his fellow gun control advocates to want to talk about him.", "\n\nhttps://www.redstate.com/sarah-rumpf/2017/12/06/shocker-democrat-congressman-lies-mass-shootings-oppose-concealed-carry-bill/" ]

{ "pile_set_name": "OpenWebText2" }

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[ "HD 222399\n\nHD 222399 is a double star in the northern constellation of Andromeda. ", "The magnitude 6.57 primary is an F-type subgiant star with a stellar classification of F2IV. ", "It has a magnitude 10.57 companion at an angular separation of 14.7″ along a position angle of 162° (as of 2002).", "\n\nReferences\n\nExternal links\n Image HD 222399\n\nCategory:Andromeda (constellation)\n222399\nCategory:Double stars\nCategory:F-type subgiants\n8973\nCategory:Durchmusterung objects\n116781" ]

{ "pile_set_name": "Wikipedia (en)" }

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[ "Correlation of aryl hydrocarbon hydroxylase activity of human lymphocyte cultures and plasma elimination rates for antipyrine and phenylbutazone.", "\nA high correlation was observed between the aryl hydrocarbon hydroxylase activities in short-term lymphocyte cultures of 23 individuals and their plasma half-lives of antipyrine and phenylbutazone. ", "Individuals with low inducibility of aryl hydrocarbon hydroxylase activities had very long plasma half-lives of antipyrine and phenylbutazone, whereas subjects with high inducibility of aryl hydrocarbon hydroxylase activites had relatively short plasma half-lives. ", "Individuals with intermediate aryl hydrocarbon hydroxylase activities displayed intermediate half-lives for both drugs. ", "The observed correlation indicates determinants which are common to the elimination of antipyrine or phenylbutazone, and aryl hydrocarbon hydroxylase metabolism of hydrocarbons. ", "The differences in rates of drug elimination are probably due to genetic differences and may have pharmacological and therapeutic significance." ]

{ "pile_set_name": "PubMed Abstracts" }

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[ "5 F.3d 1499\nU.S.v.", "Leach***\nNO. ", "92-8947\nUnited States Court of Appeals,Eleventh Circuit.", "\nSept 30, 1993\n\n1\nAppeal From: N.D.Ga.", "\n\n\n2\nAFFIRMED.", "\n\n\n\n*\n Fed.", "R.App.", "P. 34(a); 11th Cir.", "R. 34-3\n\n\n**\n Local Rule 36 case\n\n\n" ]

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[ "Betfair Promotion Code for a Free Bet Bonus\nA Promotion Code for Betfair is not needed for the present SPORTSBOOK sign up bonus offer,so there is no need to use apromo code to get a £50 free bet from Betfair.", "You will need to click on the banner if you want to claim their current EXCHANGE offer of a £20 free bet + £1000 cashback.", "Betfair are the biggest and best betting exchange in the world and any punter who takes his betting seriously really must have an account with them as part of a betting portfolio as you can achieve on average 20% better odds betting with them rather than using a traditional bookmaker to place your bets and it is very easy to claim the present £50 bonus offer.", "\n\nWhat is the £1000 + £20 Betfair promo code?", "\n\nTo claim the £1000 cashback bonus+£20 free bet, you will need to use the \"Betfair promo code\" BOB201 by clicking on the banner on the left.", "This bonus code will entitle you to receive up to £1000 cashback after your first 30 days of betting with them,and what is great about this promotional offer is that it does not matter if your bets win or lose in your first 30 days of betting with them as you still accumulate points towards your cashback amount which could be as much as £1000 depending on how many bets you place during your first 30 days of opening an account.", "You do not have to worry about remembering the BOB201 as on our site theit is automatically entered for you when you click on the banner to open an account with them,and as an added bonus for a limited time you also get a £20 free bet if you stake £20 or greater (any odds,any sports event) on your first bet and it loses.", "\n\nUse a Betfair Promotion Code Today!", "\n\nSign up code - \"BOB201\"\n\nGet the best of both worlds by clicking on the banner above!", "\nRegister using promo code\nBOB201 and deposit a min of £20\nStake at least £20 on your first sports bet,and if it loses they’ll refund you £20.Plus,earn up to £1000 cashback the more you bet in your first 30 days!....Plus...\nDeposit or transfer at least £25 into the Betfair Casino,and you could earn up to £200 in bonuses." ]

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[ "Q:\n\nBorrowing changes type of Vector\n\nOriginally I wrote this:\nfn split_line(line: &String) -> Vec<String> {\n let mut chars = line.chars();\n let mut vec = Vec::new();\n let mut s = String::from(\"\");\n while let Some(x) = chars.next() {\n match x {\n '<' => {},\n '/' => {\n vec.push(s);\n break;\n }\n ' ' => {\n vec.push(s);\n s.clear();\n }\n _ => s.push(x),\n }\n }\n vec\n}\n\nand received this error:\nuse of moved value: 's'\nso I changed vec.push(s) to vec.push(&s), which removed my original error, but changed vec from std::vec::Vec<std::string::String> to std::vec::Vec<&std::string::String>.", "\nWhy? ", "How can I borrow s without changing vec?", "\n\nA:\n\nWhen you do vec.push(s), s is moved into the vector, which means s no longer holds a meaningful value. ", "All you need to do is reset s to a new String.", "\nfn split_line(line: &str) -> Vec<String> {\n let mut chars = line.chars();\n let mut vec = Vec::new();\n let mut s = String::new();\n while let Some(x) = chars.next() {\n match x {\n '<' => {},\n '/' => {\n vec.push(s);\n break;\n }\n ' ' => {\n vec.push(s);\n s = String::new();\n }\n _ => s.push(x),\n }\n }\n vec\n}\n\n" ]

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[ "Looking for Comedy Central full episodes? ", "Hi there. ", "Get the latest episodes of The Daily Show with Jon Stewart, The Colbert Report, South Park and @midnight, plus other shows. ", "Seriously, there's hours and hours of stuff to watch: sign in with your TV provider to access everything, including Tosh.0, Key & Peele, Workaholics and more. ", "You can also kick back with great stand-up specials, archive shows (including Chappelle's Show) and full seasons of returning series. ", "Full episodes available now: The Daily Show with Jon Stewart* The Colbert Report* South Park* @midnight* Tosh.0 Workaholics Key & Peele Broad City Kroll Show Review Inside Amy Schumer Futurama Chappelle's Show Original digital shorts* Plus more shows added all the time *No TV provider sign-in required to watch the latest episodes For help, contact [email protected]" ]

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[ "Anna Glasier\n\nAnnabelle \"Anna\" Frances Glasier OBE, FFSRH, FRCOG FRSE is an English physician in the field of reproductive medicine. ", "Glasier is a world expert on emergency contraception, and her work has been instrumental in making it available in the UK and other countries without medical prescription\n\nEducation\nIn 1973 Glasier graduated from the University of Bristol with a BSc. ", "She then attended the University of Edinburgh graduating with a MBChB in 1976. ", "She specialised in obstetrics and gynaecology, working under the supervision of Allan Templeton. ", "She passed her MD in 1983, qualifying as a doctor. ", "Her thesis was on the hormonal mechanisms underlying lactational infertility.", "\n\nCareer \nIn 1989 Glasier became a clinical scientist at the Medical Research Council Unit of Reproductive Biology. ", "She held the position of Director of Family Planning and Well Woman Services at NHS Lothian from 1990-2010, and was Lead Clinician for Sexual Health. ", "Her research specialities are reproductive health, and she is globally recognised in the field of emergency contraception, with her work playing an instrumental role in its deregulation.", "\n\nShe has worked with international organisations, including the Population Council in New York, and the World Health Organization, where she chaired the Human Reproduction Programme’s Scientific and Technical Advisory Group from 2004 to 2008.", "\n\nShe is an honorary professor at the London School of Hygiene and Tropical Medicine (Department of Public Health and Policy) and the Emeritus Professor in the Centre for Reproductive Health at the University of Edinburgh.", "\n\nAwards and honours \n OBE for services to women's health, 2005\n Honorary Doctor of Laws from the University of Dundee, 2006\n Lifetime achievement award, Society of Family Planning, 2012\n Honorary graduate of the University of Aberdeen, 2014\n Fellow of the Royal Society of Edinburgh, 2015\n Fellow of the Royal College of Obstetricians and Gynaecologists\n\nPersonal life\nGlasier is the daughter of Phillip Glasier and sister of Jemima Parry-Jones, both noted for their work with birds of prey.", "\n\nReferences\n\nExternal links \n\n \n\nCategory:Living people\nCategory:20th-century English medical doctors\nCategory:English obstetricians\nCategory:British gynaecologists\nCategory:British medical researchers\nCategory:Officers of the Order of the British Empire\nCategory:Alumni of the University of Edinburgh\nCategory:Fellows of the Royal Society of Edinburgh\nCategory:Alumni of the University of Bristol\nCategory:Family planning\nCategory:Fellows of the Royal College of Obstetricians and Gynaecologists\nCategory:Year of birth missing (living people)" ]

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[ "Q:\n\nHow to properly list all elasticsearch indices from node.js\n\nIn my node.js app, I'm trying to build a list of all elasticsearch indices and send this list as JSON to my Angular app.", "\nI'm using elasticsearch.js module:\nnpm install elasticsearch\n\nconst elasticsearch = require('elasticsearch');\nconst client = new elasticsearch.", "Client({\n host: 'localhost:9200',\n log: 'trace'\n});\n\nThen, in my REST API route handler, I'm pinging elasticsearch, and running a query, which suppose to return all indices:\nindexRoutes.route('/').get(function (req, res) {\n client.ping({\n requestTimeout: 30000,\n }, function (error) {\n if (error) {\n console.error('elasticsearch cluster is down!');", "\n } else {\n console.log('All is well');\n client.cat.indices({format: 'json'})\n .then(console.log(index));\n }\n });\n});\n\nI assume, that once the promise is resolved, there would be an object returned from it, so I'm referencing that object as \"index\", but only getting the error \"index is not defined\".", "\nWhat is the proper way to obtain such listing and assign the result to a String?", "\n\nA:\n\nclient.cat.indices({format: 'json'})\n.then(console.log(index));\n\nshould be\nclient.cat.indices({format: 'json'})\n.then((yourResponse) => {\n console.log(yourResponse);\n});\n\nor more directly\nclient.cat.indices({format: 'json'})\n.then(console.log); // notice I pass the function itself, I don't call it\n\nPromise.prototype.then takes a callback as an argument - i.e. a function to be called when the promise eventually fulfills. ", "What your code says is \"call console.log and pass its returned value to Promise.prototype.then\".", "\nIt crashes because you're not referencing an object as index, you're accessing an index variable that was (apparently) never declared.", "\nIn the version I show, yourResponse is declared as the first (and only) parameter of an anonymous arrow function (shaped as (...) => {...}) that is passed to Promise.prototype.then. ", "So yourResponse is here populated with the result of the call by .then when its promise fulfills.", "\n\n" ]

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[ "Introduction {#S0001}\n============\n\nIn eukaryotic cells, nuclear-cytoplasmic shuttling of proteins is a key step in the regulation of intracellular signaling and the adaptation of cell homeostasis to the environment. ", "Proteins are translated in the cytoplasm, but many proteins, especially transcription factors, need to be localized to the nucleus to exert their specific function.[@CIT0001] The nuclear envelope separates the nucleus and the cytoplasm and defines two specialized compartments. ", "Nuclear pore complexes (NPCs) enable passive passage of proteins with a molecular mass up to a size of \\~40 kDa, whereas the nuclear-cytoplasmic transport of larger macromolecules is energy-dependent and requires nuclear transport receptors called karyopherins or importins/exportins.[@CIT0002] Importins recognize their cargo proteins in the cytoplasm via nuclear localization signals (NLS) and mediate nuclear import through the NPC. ", "Inside the nuclear compartment, disassembly of the import complex is achieved by binding of RanGTP.[@CIT0003] In contrast, exportins bind their cargo proteins in the nucleus via nuclear export signals (NES) together with RanGTP. ", "In the cytoplasm, the trimeric export complex disassembles upon GTP hydrolysis of RanGTP.[@CIT0004] The main mediator of nuclear export is Exportin 1 (XPO1).[@CIT0005] XPO1 binds a short leucine-rich or hydrophobic nuclear export signal of the cargo protein and directly interacts with nucleoporins in the NPC.[@CIT0006]\n\nIn recent years, XPO1 turned out to be responsible for the nuclear export of more than 200 cargo proteins including many of the major (proto-) oncoproteins and tumor suppressors such as BRCA1,[@CIT0007] p53,[@CIT0008] cyclin D1[@CIT0009] and the FoxO subfamily of Forkhead transcription factors.[@CIT0010] Deregulation of nuclear export processes causes mislocalization, inactivation or aberrant activation of cancer-related proteins and has been implicated in uncontrolled cancer cell growth and radio- and drug resistance.[@CIT0011],[@CIT0012] For example, inactivation of p53 during tumor development is caused by cytoplasmic accumulation of p53 and depends on MDM2-mediated ubiquitination efficient nuclear export of nuclear p53.[@CIT0013] Moreover, in esophageal cancer samples, several mutations were identified that disrupt phosphorylation-dependent nuclear export of cyclin D1 suggesting that nuclear accumulation of cyclin D1 contributes to the genesis and progression of neoplastic growth.[@CIT0014] The promising potential of XPO1 as a valid target for therapeutic intervention is further underlined by the fact that XPO1 protein expression is increased in various solid tumors such as ovarian,[@CIT0015] osteosarcoma,[@CIT0016] pancreatic,[@CIT0017] cervical[@CIT0018] and gastric[@CIT0019] cancers and hematological malignancies.[@CIT0020],[@CIT0021] In addition, poor clinical outcome, increased metastasis, increased tumor size and decreased progression-free and overall survival is associated with XPO1 overexpression.", "\n\nAlthough XPO1 inhibition affects all XPO1 cargo proteins bearing an NES, malignant cells are more affected by nuclear export inhibition. ", "Tumor cells have to adapt to their surrounding microenvironment which may result in a higher dependence on nuclear-cytoplasmic transport.[@CIT0022] This makes nuclear transport receptors promising targets for therapeutic intervention for several disease states and especially in cancer.", "\n\nPreviously, the anti-fungal antibiotic leptomycin B (LMB) has been reported to be a potent compound for the inhibition of XPO1-dependent nuclear export.[@CIT0023] However, LMB showed systemic toxicity in both animals and humans in phase I clinical studies resulting in discontinuation of clinical development.[@CIT0024] More recently, novel, orally bioavailable, small-molecule selective inhibitor of nuclear export (SINE) compounds such as selinexor have been described. ", "These compounds form covalent bonds with cysteine-528 of the XPO1 cargo-binding pocket, thereby inhibiting interaction between XPO1 and its cargo proteins.[@CIT0025] Selinexor is currently under evaluation in phase II and III clinical trials. ", "Thereby, promising antitumor activity in both solid and hematological cancer types was demonstrated.[@CIT0026]--[@CIT0028] In July 2019, the U.S. Food and Drug Administration (FDA) has approved selinexor (XPOVIO^TM^) in combination with dexamethasone for the treatment of adult patients with relapsed or refractory multiple myeloma (NCT02336815).", "\n\nHypoxia is a characteristic feature of solid tumors evolving due to an imbalance between oxygen availability and consumption. ", "Cancer cells induce metabolic changes and develop a metabolic flexibility to survive and proliferate in low oxygen tension conditions. ", "The transcription factor hypoxia-inducible factor (HIF) is a master regulator in the adaptation to hypoxia and the regulation of cancer cell metabolism since HIF specific target genes are involved in the activation of numerous cellular processes including cell survival, glycolytic energy metabolism, erythropoiesis, vascular remodeling and angiogenesis.[@CIT0029] Accordingly, a strong correlation between the nuclear accumulation of HIF and malignant cancer phenotype, poor patient prognosis and tumor resistance has been described.[@CIT0030],[@CIT0031] Since the activity of HIF depends on its correct spatial arrangement, intracellular localization of HIF plays a major role for the broad metabolic reprogramming of cancer cells and involves nuclear export by XPO1.[@CIT0032],[@CIT0033]\n\nThe heterodimeric transcription factor HIF consists of one of the three different oxygen-labile α-subunits (primarily HIF-1α) and a constitutive β-subunit. ", "In contrast, protein expression of HIF-1α is tightly regulated by oxygen-dependent post-translational modifications.[@CIT0034] In normoxia, HIF-1α is hydroxylated by one of the three cellular oxygen sensors prolyl hydroxylase domain (PHD) proteins PHD1, PHD2 or PHD3 resulting in recognition by von Hippel--Lindau protein followed by ubiquitination and proteasomal degradation.[@CIT0035] Under hypoxic conditions, lack of oxygen inhibits PHD activity and results in HIF-1α stabilization and subsequent translocation to the nucleus. ", "The knowledge about the pattern of regulation of HIF was extended by a recent publication showing that the scaffold protein LIM Domain-Containing Protein 1 (LIMD1) is also involved in HIF-1 regulation in normoxia as well as in hypoxia.[@CIT0036] *LIMD1* was identified to be a HIF-1 target gene acting via a so far unknown negative feedback mechanism involving PHD2‐LIMD1‐VHL complex formation.", "\n\nWe set out to address the biological and physiological activity of the XPO1-inhibitor selinexor on the HIF-signaling pathway in 2D monolayer and 3D tumor spheroid culture models. ", "Upon selinexor treatment, 2D monolayer-cultured cells show a decrease in HIF-1α protein expression, HIF transcriptional activity and HIF-1 target gene expression in hypoxic conditions. ", "Moreover, we investigated the basic mechanism underlying selinexor-dependent HIF-inhibition in the same model demonstrating that it does not depend on the HIF-LIMD1 negative feedback mechanism. ", "Utilizing 3D tumor spheroid culture models, we determined that selinexor decreases cell viability, 3D tumor spheroid growth and HIF-1α protein expression in a model representing in vivo physiological conditions. ", "We demonstrate the molecular mechanistic effect of the XPO1-inhibitor selinexor on the HIF-dependent signaling pathway in 2D and 3D culture models of MCF-7 breast cancer cells.", "\n\nMaterials And Methods {#S0002}\n=====================\n\nCell Culture, DNA Transfection And Selinexor Treatment {#S0002-S2001}\n------------------------------------------------------\n\nHuman cell lines were purchased from the ATCC or the DSMZ. ", "All cell lines used were regularly tested for contaminations by mycoplasma (Mycoplasma Detection Kit, Southern Biotech, Birmingham, USA). ", "MCF-7 (human breast adenocarcinoma), Hep3B (hepatocellular carcinoma) and U2OS (human osteosarcoma) cells were grown in DMEM (Gibco, Darmstadt, Germany) culture medium. ", "Ten percent fetal calf serum (Gibco), 100 IU/mL penicillin and 100 mg/mL streptomycin (PAA Laboratories, Coelbe, Germany) were added to the culture medium. ", "Cells were grown in an incubator at 37°C and 5% CO~2~. For hypoxic culture conditions, a hypoxia workstation (InvivO~2~ 400, Baker Ruskinn, I&L Biosystems, Königswinter, Germany) was used containing 1% O~2~, 94% N~2~ and 5% CO~2~ for 24 hrs. ", "Normoxic control cells were placed in an incubator (5% CO~2~, 21% O~2~, and 74% N~2~) for the same period of time. ", "Semi-confluent cell cultures were transiently transfected using GeneJuice transfection reagent (Merck, Darmstadt, Germany) for 24 hrs as described by the manufacturer. ", "Where indicated, cells were pre-treated with selinexor (Karyopharm Therapeutics Inc., Newton, MA, USA) dissolved in dimethyl-sulfoxide (DMSO) at the concentrations between 0.01 and 2.0 μm for 1 hr before starting the experiment. ", "Selinexor was obtained from Karyopharm Therapeutics. ", "After addition of selinexor, culture medium was not changed until normoxic or hypoxic incubation was started. ", "As control, DMSO was added to the culture medium.", "\n\n3D Tumor Spheroid Cell Culture On Polydimethylsiloxane (PDMS) {#S0002-S2002}\n-------------------------------------------------------------\n\nDow Corning's Sylgard 184 silicone elastomer kit (VWR, Darmstadt, Germany) was used in a 10 to 1 ratio of base to curing agent (w/w) to cast PDMS in flat-bottom, tissue culture-treated multiwell cell culture plates (Sarstedt, Nümbrecht, Germany). ", "The PDMS pre-polymer components were manually mixed with a pipette tip in a 50 mL tube for 30 s. Of the pre-polymer, 300 μL or 60 µL was pipetted into each well of a 24-well or 96-well plate, respectively. ", "After settling of the pre-polymer at room temperature (20°C--25°C) for 30 mins, the plates were cured at 40°C for 4 hrs. ", "The PDMS-cured plates were used for 3D tumor spheroid cell culture. ", "Monolayer cultured MCF-7 cells were dislodged from cell culture T75-flasks (Sarstedt) by 0.05% Trypsin-EDTA (Gibco). ", "Cells were centrifuged at 1100 rpm for 5 mins and resuspended in DMEM culture medium. ", "For a single well of a 24-well or 96-well plate cured with PDMS, 50,000 or 10,000 cells were used, respectively. ", "Culture medium was changed twice, at day 4 and day 8 after seeding. ", "Before used for any of the assays/treatment conditions, 3D tumor spheroids were allowed to grow for at least 3 days. ", "3D tumor spheroids were treated with selinexor at day 4 or day 8 after seeding. ", "Eleven days after seeding cell viability and cytotoxic effects were assessed in 3D tumor spheroids having a size of \\~350μm. ", "The size and morphology of tumor spheroids were analyzed with an inverted tissue culture microscope (Axiovert 25, Zeiss, Zaventem, Belgium) with a 10x objective lens. ", "Pictures were taken using a digital camera and an appropriate photo adapter (Olympus Camedia C-3040, Olympus, Hamburg, Germany).", "\n\n3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) Cytotoxicity Assay {#S0002-S2003}\n-------------------------------------------------------------------------------------\n\nCytotoxicity of selinexor on MCF-7, Hep3B and U2OS cells was analyzed using the colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT, Sigma-Aldrich, München, Germany) assay. ", "Cells were seeded in 96-well plates and treated with selinexor in the range of 0.01--2.0 μM or DMSO. ", "After 24 hrs, cells were incubated with MTT solution (5 g/l) for 24 hrs and then lysed with DMSO. ", "The optical density represents the cellular metabolic activity and was detected with a microplate reader (Thermo Fisher Scientific, Bonn, Germany) at 570 nm. ", "Four technical replicates were measured.", "\n\nFluorescent Microscopy {#S0002-S2004}\n----------------------\n\nU2OS cells were grown in 24-well plates to semi-confluency. ", "Cells were pre-treated for 1 hr with 1.0 μm selinexor or DMSO in normoxic conditions (20% O~2~). ", "Activity of PHD proteins was inhibited by addition of 1 mM Dimethyloxaloylglycine (DMOG) for 4 hrs stabilizing HIF-1α. ", "Selinexor/DMSO treatment was continued during incubation with DMOG. ", "Afterwards, cells were washed with PBS and fixed with 250 µL of 3.7% formaldehyde in PBS for 15 mins. ", "Permeabilization was achieved by treatment with 0.1% Triton-X 100 and non-specific staining was blocked with 0.2% gelatin from cold water fish skin in PBS overnight. ", "Cells were incubated with mouse anti-HIF-1α antibody diluted 1:100 in 0.2% gelatin from cold water fish skin in PBS overnight (Cat No 610959, BD Transduction Laboratories, Heidelberg, Germany). ", "After washing with PBS, cells were incubated with an Alexa 488-labelled goat anti-mouse secondary antibody diluted 1:500 in 0.2% gelatin from cold water fish skin in PBS (Cat No A-11017, Thermo Fisher Scientific). ", "For mounting, cells were treated with ProLong Gold antifade reagent with DAPI on glass slides (Invitrogen, Darmstadt, Germany). ", "Samples were allowed to dry for 1 day before they were observed under an all-in-one Type Fluorescence Microscope (BZ-8000, Keyence, Osaka, Japan) with a 20x objective lens using the BZ Analyzer Software (Keyence). ", "Two technical replicates were analyzed.", "\n\nRNA Isolation And Quantitative Real-Time PCR {#S0002-S2005}\n--------------------------------------------\n\nMCF-7, Hep3B and U2OS cells were grown in 24-well plates and pre-treated with 0.1 or 1.0 µM selinexor 1 hr before normoxic (20% O~2~) or hypoxic (1% O~2~) incubation. ", "After 4 hrs of incubation, total RNA was extracted using the total RNA Purification Kit (Jena Bioscience, Jena, Germany) according to the manufacturer's protocol. ", "cDNA of total RNA (100--300 ng) was synthesized with the M-MuLV reverse transcriptase (New England Biolabs, Frankfurt, Germany) and random hexamer primers (Thermo Fisher Scientific) following the instructions of the manufacturer. ", "Quantitative RT-PCR was performed in the Eco48 qPCR System (PCRmax Limited Beacon Road, Staffordshire, United Kingdom) with 1 μL cDNA and the SensiMix SYBR Kit (Bioline, Luckenwalde, Germany) in a total volume of 12.5 μL. PCR primer sequences can be provided upon request by the authors. ", "Expression values were normalized to relative expression of ribosomal protein L28*(RPL28)* and four technical replicates were measured.", "\n\nLuciferase Reporter Gene Assay {#S0002-S2006}\n------------------------------\n\nMCF-7, Hep3B and U2OS cells were used to measure HIF-1 activity in reporter gene studies. ", "Cells were allowed to grow on 24-well plates before they were transiently transfected with a hypoxia-responsive luciferase plasmid which contains six HIF-1 binding sites from the transferrin 3′ enhancer.[@CIT0037] Empty control vector (pGL4 vector, Promega, Mannheim, Germany) served as transfection control. ", "Medium was renewed 24 hrs after transient transfection. ", "Cells were pre-treated with 0.1 or 1.0 µM selinexor or DMSO for 1 hr before incubation in normoxia (20% O~2~) or hypoxia (1% O~2~) for 24 hrs. ", "After incubation, lysis was performed using Reporter Lysis 5X Buffer (Promega). ", "Luminescent signal intensities were analyzed with the Luciferase Assay System (Promega) using a MicroLumat LB 96P Plate Reader (Berthold Technologies, Bad Wildbad, Germany). ", "Bio-Rad DC Protein Assay (Bio-Rad, München, Germany) was used for determination of protein concentrations. ", "Firefly luciferase (FL) activities were normalized to protein concentrations. ", "Three technical replicates were analyzed.", "\n\nProtein Extraction And Immunoblot Analysis {#S0002-S2007}\n------------------------------------------\n\n3D tumor spheroids were extracted from their 3D culture environment for protein extraction. ", "Therefore, culture medium was carefully resuspended and pooled in a single falcon tube per sample. ", "PDMS-cured plates were rinsed with 1 medium-volume of ice-cold PBS. ", "The rinse was transferred to the same tube. ", "The solution was centrifuged at 170 × g for 10 mins so that the tumor spheroids collected at the bottom without forming a tight pellet. ", "The supernatant was removed and the tumor spheroids were gently washed with 1 mL ice-cold PBS and transferred to a new reaction tube. ", "Again, tumor spheroids were centrifuged at 170 × g for 5 mins. ", "Supernatant was removed and tumor spheroids were extracted with UREA lysis buffer containing 10 mM Tris-HCl (pH 6.8), 6.7 M Urea, 10 M Glycerin, 1% SDS and 5 mM DTT. ", "Protein extracts were supplemented with protease inhibitor cocktail (Roche, Mannheim, Germany). ", "Protein concentrations were analyzed with the Bio-Rad DC Protein Assay (Bio-Rad, Munich, Germany). ", "A total of 100 µg protein lysate were subjected to 7.5% SDS-PAGE and transferred by semidry blotting onto nitrocellulose membrane (Amersham Hybond-ECL, GE Healthcare). ", "Membranes were blocked by incubation in 5% nonfat dry milk powder in PBS for at least 2 hrs at 4°C. ", "Membranes were treated with a monoclonal mouse anti-HIF-1α antibody (Cat. ", "No. ", "610959, BD Biosciences, Heidelberg, Germany) diluted 1:1000 in 3% nonfat dry milk powder in PBS with cautious shaking overnight at 4°C and a polyclonal goat anti-mouse peroxidase (HRP)-conjugated secondary antibody diluted 1:2000 in 3% nonfat dry milk powder in PBS (Cat. ", "No. ", "P0447, Dako, Hamburg, Germany). ", "Incubation with a monoclonal rabbit anti-β-Actin antibody (Cat. ", "No. ", "4970, Cell Signaling) diluted 1:1000 in 3% nonfat dry milk powder in PBS for 1 hr followed by incubation with a polyclonal goat anti-rabbit antibody diluted 1:2000 in 3% nonfat dry milk powder in PBS (Cat. ", "No. ", "P0448, Dako, Hamburg, Germany) was performed to ensure equal protein loading and transfer. ", "Immunoreactive proteins were detected using ECL detection reagents (Amersham ECL Western Blotting Detection Reagents, GE Healthcare, Freiburg, Germany) for 1 min followed by exposure to X-ray films (Amersham Hyperfilm MP, GE Healthcare, Freiburg, Germany).", "\n\n3D Tumor Spheroid Cell Viability And Cytotoxicity Assays {#S0002-S2008}\n--------------------------------------------------------\n\nAfter 11 days, cytotoxic effects of selinexor treatment and 3D tumor spheroid cell viability were determined using the CellTox Green fluorescent cytotoxicity and CellTiter-Glo 3D luminescent cell viability assay kits (Promega) according to the manufacturer's instructions. ", "Due to their spectrally distinct measures, these assays can be multiplexed. ", "Defined numbers of cells were seeded for 3D tumor spheroid culture. ", "However, medium change and the removal of dead cells could result in different cell numbers and misinterpreting results. ", "CellTox Green Dye binds DNA in compromised cells and enhances fluorescent properties and was used to assess membrane integrity and cytotoxicity of selinexor treatment. ", "After 15 mins of incubation, supernatant was transferred to an opaque-walled multiwell plate and fluorescence was measured at 485nm~Ex~/535nm~Em~ before cell lysis (RLU BL). ", "Supernatant was transferred back to the PDMS-cured plate and CellTiter-Glo cell viability assay was performed including cell lysis of 3D tumor spheroidal cells. ", "CellTiter-Glo reagent was added, mixed by shaking for 5 mins and incubated for 25 mins at room temperature. ", "Again, supernatant was transferred to an opaque-walled multiwell plate. ", "Luminescence which associated with ATP levels and viability of the 3D tumor spheroids was recorded (RLU). ", "Finally, fluorescence was measured as described above for overall cell number determination after cell lysis (RFU AL). ", "Relative ATP levels were determined according to the following formula. ", "Numbers of disintegrated cells before starting ATP level measurement were subtracted from the overall cell numbers after total cell lysis. ", "Then, luminescence (RLU) was normalized to fluorescence (RFU) for each of the four technical replicates. ", "$$\\documentclass[12pt]{minimal}\n\\usepackage{wasysym}\n\\usepackage[substack]{amsmath}\n\\usepackage{amsfonts}\n\\usepackage{amssymb}\n\\usepackage{amsbsy}\n\\usepackage[mathscr]{eucal}\n\\usepackage{mathrsfs}\n\\DeclareFontFamily{T1}{linotext}{}\n\\DeclareFontShape{T1}{linotext}{m}{n} {linotext }{}\n\\DeclareSymbolFont{linotext}{T1}{linotext}{m}{n}\n\\DeclareSymbolFontAlphabet{\\mathLINOTEXT}{linotext}\n\\begin{document}\n$${\\rm{ATP\\ levels = }}\\,\\,{{{\\rm{RLU }}} \\over {{\\rm{RFU\\ AL - RFU\\ BL}}}}$$\n\\end{document}$$\n\nStatistical Analysis {#S0002-S2009}\n--------------------\n\nExperiments were conducted by a mixture of technical and biological replicates. ", "Due to differences in the experimental setting, the numbers of technical replicates differ and are mentioned in the corresponding sections. ", "Results are shown as mean ± standard deviation of the mean of at least n=3 independent biological replicates. ", "The number of biological replicates varied according to experimental efforts and study design. ", "One-way analysis of variance and Bonferroni's post-test was used to calculate statistical differences of means between treated and control groups. ", "Significance was accepted at p \\< 0.05\\* (\\*p \\<0.05; \\*\\*p\\<0.01; \\*\\*\\*p\\<0.001). ", "For statistical calculations, GraphPad Prism 5 software (GraphPad Software, La Jolla, CA, USA) was used.", "\n\nResults {#S0003}\n=======\n\nNo Cytotoxic Effects Of Selinexor At Concentrations Up To 1.0 μm {#S0003-S2001}\n----------------------------------------------------------------\n\nUsing the MTT cytotoxicity assay, cell viability of MCF-7, Hep3B and U2OS cells was tested after 24 hrs of selinexor treatment at the indicated concentrations in normoxia and hypoxia. ", "Cellular metabolic activity upon selinexor treatment for 24 hrs at concentrations up to 2.0 μm did not decrease by more than 24% compared to DMSO-treated control cells in MCF-7 cells ([Figure 1](#F0001){ref-type=\"fig\"}). ", "In Hep3B and U2OS cells, selinexor treatment resulted in a reduction of cellular metabolic activity by up to 22%. ", "Based on these results, we decided to treat cells with 0.1 µM and 1.0 µM selinexor in our experiments. ", "No differences in cytotoxicity regarding treatment with medium versus medium supplemented with low concentrations of DMSO could be detected (data not shown).Figure 1Cytotoxic effects of selinexor in 2D-cultured MCF-7 cells. ", "Defined numbers of MCF-7 (**A**), Hep3B (**B**), and U2OS (**C**) cells were incubated in normoxia (light gray) and hypoxia (gray) for 24 hrs and treated with selinexor (Sel) at the indicated concentrations in the range of 0.05 µM to 2.0 µM. DMSO treatment served as control. ", "Cytotoxicity was analyzed by MTT cytotoxicity assay. ", "Cellular metabolic activity of selinexor-treated cells is represented by relative absorbance normalized to the control. ", "For all three cell lines tested, cytotoxic effects of selinexor treatment that inhibit cellular metabolic activity are represented by a decrease in relative absorbance. ", "Cytotoxicity does not increase significantly at all selinexor concentrations tested. ", "Data are mean±SD; n = 3.", "\n\nEffects Of Selinexor Treatment On The HIF-Dependent Hypoxia Response Pathway {#S0003-S2002}\n----------------------------------------------------------------------------\n\nWe investigated whether selinexor affects stabilized HIF-1α nuclear localization after PHD inhibition by DMOG treatment. ", "Immunofluorescence staining of HIF-1α in U2OS cells was performed. ", "The subcellular distribution of HIF-1α was analyzed by fluorescence microscopy and quantified. ", "DAPI fluorescence was used for single-cell discrimination. ", "DMOG treatment resulted in nuclear accumulation of HIF-1α. ", "The presence of DMSO in the culture media had no effect on the response to DMOG. ", "HIF-1α accumulated in the nucleus with or without the presence of 0.1 µM and 1.0 µM selinexor ([Figure 2A](#F0002){ref-type=\"fig\"}).Figure 2Selinexor treatment inhibits HIF-signaling. (**", "A**) For localization studies, U2OS cells were grown in 24-well plates to 50% confluence. ", "Cells were pre-treated with 1.0 µM selinexor (Sel) or DMSO for 1 hr. ", "PHD activity was inhibited by addition of 1 mm DMOG for 4 hrs and resulted in HIF-1α stabilization. ", "HIF-1α was detected with a monoclonal anti-HIF-1α antibody by immunofluorescence analysis. ", "Samples were observed under an all-in-one Type Fluorescence Microscope with a 20 x objective lens. ", "Representative microscopic images are shown. ", "Scale bar: 20 µm. (**", "B**) Defined numbers of MCF-7, Hep3B and U2OS cells were seeded in 24-well plates. ", "A HIF-dependent firefly luciferase gene was transiently transfected. ", "Cells were pre-treated for 1 hr with selinexor at 0.1 µM and 1.0 µM or DMSO and then exposed to hypoxia (1% O~2~) for 24 hrs. ", "A normoxic (20% O~2~) control was conducted to analyze hypoxic induction. ", "The transcriptional HIF-activity is represented by the firefly reporter activity. ", "Firefly luciferase (FL) activities were normalized to protein concentrations. (**", "C**) Defined numbers of MCF-7, Hep3B and U2OS cells were treated with DMSO, 0.1 µM or 1.0 µM selinexor for 1 hr, before incubation in normoxia (20% O~2~) or hypoxia (1% O~2~) for 4 hrs. ", "Afterwards, total mRNA was reverse-transcribed and analyzed by qRT-PCR for *SLC2A1* expression. ", "Normalized ratios for mRNA encoding *SLC2A1* to that of mRNA encoding *RPL28* are shown. ", "Differences of means between treated and control groups were assessed using repeated-measures ANOVA and Bonferroni's post-test. ", "Data are mean±SD; n = 3--4; \\*p\\<0.05, \\*\\*p \\< 0.01, \\*\\*\\*p\\<0.001, ns=not significant.", "\n\nNext, we investigated the effect of selinexor treatment on HIF-transactivation playing a pivotal role for its functional in vivo relevance since hypoxia is a hallmark of solid tumor formation. ", "HIF-dependent reporter gene assays were performed in MCF-7, Hep3B and U2OS cells. ", "Cells were transiently transfected with a HIF-dependent reporter gene construct. ", "In hypoxia, HIF-dependent transcriptional activity was 2.5-50-fold higher than in normoxic conditions. ", "Treatment with selinexor (0.1 and 1.0 µM, 25 hrs) significantly reduced the hypoxic luciferase activity in a dose-dependent manner to 25.6% and 8.6% (Hep3B), 83.8% and 52.9% (U2OS) and 28.9% and 12.7% (MCF-7) ([Figure 2B](#F0002){ref-type=\"fig\"}). ", "DMSO-treated cells served as controls. ", "These findings indicate that the blockage of nuclear export via XPO1 has a major influence on HIF-transactivation.", "\n\nTo further analyze the role of selinexor in the HIF-dependent transcriptional regulation, total RNA was isolated from MCF-7, Hep3B and U2OS cells treated with or without selinexor. ", "mRNA levels of the specific HIF-1 target gene *SLC2A1* were analyzed by qRT-PCR. ", "Hypoxia significantly induced expression of the HIF-1 target gene *SLC2A1*. ", "DMSO in the culture media did not alter the expression of the HIF-1 target gene (data not shown). ", "In comparison to control cells treated with DMSO, treatment with selinexor significantly reduced mRNA expression of *SLC2A1* in a dose-dependent manner in MCF-7 and U2OS cells ([Figure 2C](#F0002){ref-type=\"fig\"}). ", "These results indicate that nuclear export inhibition by selinexor inhibits HIF-1 target gene expression.", "\n\nSince HIF-α-degradation in hypoxia is mediated by a negative feedback mechanism involving PHD2-LIMD1-VHL complex formation (24). ", "In order to investigate a possible involvement of LIMD1 in the inhibition of HIF-signaling upon selinexor treatment, we analyzed *LIMD1* expression in MCF-7 cells. ", "To test this, MCF-7 cells were treated with 0.1 µM and 1.0 µM selinexor and cultured in hypoxic conditions. ", "The expression of *LIMD1* mRNA was analyzed by qRT-PCR and showed that relative *LIMD1* mRNA levels are not affected by inhibition of nuclear export using selinexor in different concentrations (data not shown).", "\n\nSelinexor Treatment At A Concentration Of 1.0 µm Is Cytotoxic For MCF-7 3D Tumor Spheroids And Affects ATP Levels {#S0003-S2003}\n-----------------------------------------------------------------------------------------------------------------\n\nMembrane integrity of 3D tumor spheroid cells treated with selinexor was measured using the CellTox Green fluorescent cytotoxicity assay. ", "Therefore, fluorescent signal intensities were measured before cell lysis at 485nm~Ex~/535nm~Em~. High signal intensities correlated with a high number of cells that had been damaged by selinexor treatment. ", "Treatment with 0.01, 0.05 µM and 0.1 µM selinexor had no significant cytotoxic effects in 3D conditions during the course of 4 and 8 days of treatment. ", "However, treatment with 1.0 µM selinexor significantly increased fluorescent signal intensities in the CellTox Green fluorescent cytotoxicity assay ([Figure 3A](#F0003){ref-type=\"fig\"}). ", "These results indicate that selinexor at a concentration of 1.0 µM may damage membrane integrity in MCF-7 3D tumor spheroids.", "Figure 3Membrane integrity and ATP levels are decreased in selinexor-treated 3D tumor spheroids. ", "Defined numbers of MCF-7 cells were seeded on PDMS cured 96-well plates. ", "3D tumor spheroids were allowed to grow for 3 days before they were treated with selinexor (Sel) at concentrations of 0.1 µM and 1.0 µM at day 4 or day 8 after seeding. ", "At day 11, cytotoxic effects and 3D tumor spheroid cell viability after selinexor treatment were determined. (**", "A**) CellTox green dye was combined with appropriate assay buffer and added. ", "After 15 mins, fluorescence was measured. (**", "B**) CellTiter-Glo substrate was mixed with appropriate buffer and added to experimental wells by which cell lysis was induced. ", "Luminescence was recorded to measure intracellular ATP levels. ", "Fluorescence was recorded and represents the number of cells. ", "ATP levels are normalized to the amount of cells after lysis. ", "Differences of means between treated and control groups were assessed using repeated-measures ANOVA and Bonferroni's post-test. ", "Data are mean±SD; n = 4; \\*\\*p \\< 0.01, \\*\\*\\*p\\<0.001.", "\n\nWe furthermore analyzed the effect of selinexor treatment on ATP levels in MCF-7 3D spheroids. ", "CellTiter-Glo 3D luminescent cell viability assays were performed. ", "Luminescence was measured representing ATP levels in 3D tumor spheroids. ", "The CellTiter-Glo 3D cell viability assay was multiplexed with the CellTox Green fluorescent cytotoxicity assay to calculate ATP levels in 3D tumor spheroidal cells. ", "Treatment with 1.0 µM selinexor resulted in lower luminescent signal intensities after 4 and 8 days of treatment indicating that selinexor decreased ATP levels in 3D tumor spheroids at a concentration of 1.0 µM ([Figure 3B](#F0003){ref-type=\"fig\"}).", "\n\n3D Tumor Spheroid Formation And Growth Is Inhibited By Selinexor {#S0003-S2004}\n----------------------------------------------------------------\n\nIn order to assess the capacity of MCF-7 cells to form and maintain 3D tumor spheroids after XPO1-blockage, the morphology of 3D tumor spheroids was investigated after selinexor treatment. ", "Morphologically, 3D tumor spheroids changed at 8 days of selinexor treatment at 0.1 µM and 1.0 µM. The size of the selinexor-treated 3D tumor spheroids was reduced resulting in very small spheroids ([Figure 4A](#F0004){ref-type=\"fig\"}). ", "Moreover, morphology of 3D tumor spheroids changed from round and spherical to irregular formed small spheroids and single-cell morphology.", "Figure 4Selinexor induces disaggregation of 3D tumor spheroids. ", "Defined numbers of MCF-7 cells were grown on PMDS cured plates to form 3D tumor spheroids. ", "On day 4, 3D tumor spheroids were treated with DMSO or 0.1 µM or 1.0 µM selinexor (Sel). (**", "A**) Pictures were taken using an inverted tissue culture microscope with a 10X objective lens with a digital camera and an appropriate photo adapter. ", "Black arrows indicate examples of 3D tumor spheroid disaggregation. ", "Scale bar: 100 µm. (**", "B**) MCF-7 3D tumor spheroids were analyzed for HIF-1α protein expression on day 11. ", "Immunoblot analysis was performed using a monoclonal anti-HIF-1α antibody. ", "The anti-actin antibody served as control for equal protein loading and transfer. ", "The immunoblots shown are representative for three independent experiments. ", "Analysis of densitometry was performed using Image J software. ", "Relative HIF-1α protein expression was calculated after normalization to actin protein levels. ", "Data are mean±SD; n=3; \\*p\\<0.05, \\*\\*p \\< 0.01.", "\n\nSelinexor Inhibits HIF-1α Protein Levels In 3D Tumor Spheroids {#S0003-S2005}\n--------------------------------------------------------------\n\nIschemic hypoxia occurs frequently in solid tumors and is associated with HIF-1 activation, thereby modulating gene expression, tumor angiogenesis, and growth.[@CIT0038] We therefore aimed to investigate HIF-1α protein expression in MCF-7 3D tumor spheroids cultured in normoxic conditions. ", "HIF-1α protein could be detected in MCF-7 3D tumor spheroids cultured for 11 days. ", "Next, we analyzed the effect of XPO1 inhibition on HIF-1α protein expression in 3D tumor spheroids. ", "Therefore, 3D tumor spheroids were treated with 0.1 µM and 1.0 µM selinexor for 8 days. ", "HIF-1α protein expression decreased dose-dependently in comparison to DMSO-treated control tumor spheroids ([Figure 4B](#F0004){ref-type=\"fig\"}).", "\n\nDiscussion {#S0004}\n==========\n\nThe increased expression of nuclear transport receptors in cancer cells causes a deregulation in nucleo-cytoplasmic transport and has been linked to poor patient prognosis, cancer proliferation, tumor size and chemoresistance. ", "For example, high expression of the import receptor importin-β promotes non-small cell lung cancer proliferation and chemoresistance.[@CIT0039] Moreover, high XPO1 expression associates with poor patient outcome in various cancers such as acute myeloid leukemia and ovarian cancer.[@CIT0015],[@CIT0020] Such data suggest that the targeted mislocalization of proteins may be a global, but promising strategy in cancer therapy. ", "Progress in the development of drugs altering transport processes has been made.[@CIT0040] Accordingly, in July 2019, the first and only nuclear export inhibitor has been approved by the FDA. ", "The accelerated FDA approval of Selinexor (XPOVIO^TM^) is based on a 25.3% response rate seen in the Phase 2b Selinexor Treatment of Refractory Myeloma (STORM) trial (NCT02336815). ", "In combination with dexamethasone, Selinexor (XPOVIO^TM^) is now commercially available in the US for the treatment of adult patients with multiple myeloma whose disease is refractory to proteasome inhibitors, immunomodulatory agents, and an anti-CD38 monoclonal antibody.", "\n\nOur results indicate the importance of active nuclear transport in the regulation of hypoxia-related pathways. ", "Many XPO1 cargo proteins have been described so far including HIF-1α and HIF-2α.[@CIT0041],[@CIT0042] However, continuous active transport might be less important for the maintenance of nuclear and cytoplasmic proteome than expected, given that in frog oocytes only \\~3% of the proteome responds significantly to XPO1 inhibition.[@CIT0043] Thus, our findings clearly indicate that HIF-dependent signaling belongs to a small group of signaling pathways that depend on continuous nuclear protein import and export.", "\n\nDifferent studies underline that appropriate subcellular localization of the proteins involved in the hypoxia-related pathways is crucial for the regulation of HIF-dependent transcription. ", "Localization studies revealed that the major proteins involved in hypoxia-related pathways show distinct intracellular localization patterns. ", "HIF-α can be detected in the nucleus in hypoxia and nuclear import depends on classical NLS sequence motifs involving several importins.[@CIT0044],[@CIT0045] HIF-1β is permanently located in the nucleus. ", "Furthermore, PHD1 is located almost exclusively in the nucleus, the vast majority of PHD2 is restricted to the cytoplasm and PHD3 can be detected in both compartments.[@CIT0046],[@CIT0047] However, HIF-1α as well as the three PHD isoforms shuttle between nucleus and cytoplasm and belong to the cargo proteins of exportin XPO1. ", "Herein, we inhibited XPO1-dependent nuclear protein export by the SINE compound selinexor. ", "We further investigated the effect of XPO1-inhibition on the HIF-dependent hypoxia response pathway. ", "We show, that HIF-1α protein expression, HIF-transcriptional activity as well as HIF-dependent target gene expression is inhibited by selinexor treatment. ", "Since HIF is a transcription factor, one could expect that inhibition of nuclear HIF export results in amplified activation of the HIF pathway. ", "However, previous studies underlined the importance of the tightly regulated nuclear transport of the oxygen sensor proteins and the dependence of HIF-1α hydroxylation and ubiquitination on the nuclear translocation. ", "Wotzlaw et al presented data obtained from FRET measurements demonstrating that PHD1 and HIF-1α exclusively interact in the nucleus.[@CIT0048] Activity of PHD2, the key regulator of HIF-1α stability, depends on the intranuclear localization and thus the subcellular microenvironment of the nucleus.[@CIT0047] Moreover, Groulx and Lee detected ubiquitinated forms of HIF-α, as well as VHL/ubiquitinated HIF-α complexes, solely in the nuclear compartment.[@CIT0049] These findings are in line with our data and contribute to a model in which nuclear accumulation of HIF-1α and the PHDs caused by XPO1-inhibition results in higher PHD hydroxylation activity and increased rates of ubiquitination and degradation of HIF-1α in the nucleus.", "\n\nRecently, Foxler et al detected a so far unknown role of the scaffold protein LIMD1 in the regulation of the HIF-pathway. ", "LIMD1 simultaneously binds the PHDs and VHL and enables efficient degradation of HIF-1α.[@CIT0050] Moreover, *LIMD1* itself could be identified as a HIF-1 target gene mediating a negative regulatory feedback mechanism for hypoxic HIF-1α degradation.[@CIT0036] Since LIMD1 is an XPO1 cargo substrate that accumulates in the nucleus upon LMB treatment and shuttles between both compartments, nuclear export inhibition could result in nuclear accumulation of LIMD1 and increased activity of the HIF-LIMD1 negative feedback mechanism.[@CIT0051] Therefore, the effect of selinexor treatment on *LIMD1* mRNA was investigated. ", "As expected, LIMD1 accumulates in the nucleus after treatment with selinexor (data not shown). ", "However, our data show that *LIMD1* mRNA was not affected by treatment with 0.1 µM or 1.0 µM selinexor. ", "Thus, we can hypothesize that selinexor inhibits HIF activity in a mechanism that is independent of PHD2-LIMD1-VHL complex formation.", "\n\nThe important contributions of the HIF-pathway in key cellular processes elucidate its crucial role in the pathophysiology of cardiovascular disease, chronic lung disease and cancer, which represent the major causes of mortality among industrialized societies. ", "Strikingly, the expression patterns, as well as the subcellular localization of HIF and the PHDs, have been linked with tumorigenesis. ", "HIF-1 is activated in cancer cells as a result of intratumoral hypoxia or genetic alterations and increased nuclear HIF-1 expression promotes tumor progression, increases radioresistance of cancer cells and correlates with increased malignancy.[@CIT0052] Moreover, nuclear localization of the PHD isoforms correlates with less differentiating and strongly proliferating tumors and predicts radiation resistance.[@CIT0053],[@CIT0054] Based on these findings, the targeted mislocalization of HIF and the PHDs seems to represent a promising strategy to modulate hypoxia-dependent signaling in cancer cells. ", "Therefore, we investigated the potential of selinexor for the development of new anticancer strategies in cancer cells grown as 3D tumor spheroids. ", "3D culture models are regarded as more authentic realistic and representative models that recapitulate human solid tumor architecture and physiology more accurately than immortalized cancer cells in 2D monolayer cell cultures. ", "3D tumor spheroids possess features that mimic in vivo growth conditions of tumors such as cell--cell interaction, drug penetration, treatment response and, most important for investigating the HIF-signaling pathway, hypoxia.[@CIT0055]--[@CIT0061] Therefore, MCF-7 tumor spheroids were grown on PDMS coated cell culture plates for 4 or 8 days until they were treated with selinexor for 4 or 8 more days. ", "Treatment with 1.0 µM selinexor significantly damaged membrane integrity of 3D tumor spheroids and reduced intracellular ATP levels ([Figure 3](#F0003){ref-type=\"fig\"}). ", "In comparison, MTT assays in 2D-cultured monolayer cells showed that selinexor treatment at concentrations of up to 2.0 μm did not decrease cell viability by more than 10--25% compared to DMSO-treated control cells ([Figure 1](#F0001){ref-type=\"fig\"}). ", "Moreover, 3D tumor spheroid growth and morphology were sensitive to selinexor treatment at concentrations of 0.1 µM and 1.0 µM in our study. ", "Spheroid morphology was dramatically changed by selinexor treatment. ", "The 3D tumor spheroids changed from round and spherical to irregular formed small spheroids and single-cell morphology ([Figure 4](#F0004){ref-type=\"fig\"}). ", "In accordance with these findings, HIF-1α protein expression was affected by selinexor treatment in 3D tumor spheroids at the same concentrations. ", "As expected, strong HIF-1α protein levels were detected in DMSO-treated 3D tumor spheroids which can be explained by the development of a hypoxic core region in the spheroids. ", "Treatment with selinexor resulted in disintegration of 3D tumor spheroids which was reflected by a decrease in HIF-1α protein expression. ", "Taken together, these results indicate that 3D tumor spheroids are more sensitive towards selinexor treatment than cells cultured in 2D monolayers. ", "This observation underlines the therapeutic benefit of nuclear transport inhibition and can be explained by increased proliferative and metabolic demands of 3D tumor spheroids and an increased dependence on the nuclear transport machinery. ", "Interestingly, Kuusisto and Jans identified a so-called hypersensitivity of malignant cell types towards the inhibition of the nuclear import receptor importin β.[@CIT0062] Moreover, as mentioned earlier, the overexpression of nuclear transport receptors in cancer cells indicates an increased dependence of cancer cells on specific proteins which is referred to as tumor cell addiction.[@CIT0063] In consequence, 3D tumor spheroids show great potential for studying the HIF-dependent hypoxic response and should be considered in future research.", "\n\nConclusion {#S0005}\n==========\n\nIn conclusion, our results demonstrate the significant impact of the nuclear transport machinery for the regulation of the hypoxic response in cancer cells. ", "Nuclear export inhibition results in decreased transcriptional HIF-activity and disaggregation of 3D tumor spheroids. ", "By this, our study underlines the promising potential of nuclear transport inhibition by selinexor for therapeutic intervention in cancer.", "\n\nWe thank S. G. Schindler, B. Rudzewski, T. Svensson and P. Rouina for excellent technical work. ", "The authors also thank J. Dunst and D. Rades for their support.", "\n\nAbbreviations {#S0006}\n=============\n\nARNT, aryl hydrocarbon nuclear translocator; DMOG, dimethyloxalylglycine; DMSO, dimethylsulfoxide; HIF, hypoxia-inducible factor; IVM, ivermectin; LMB, leptomycin B; LIMD1, LIM domain-containing protein 1; NES, nuclear export signal; NLS, nuclear localization signal; PHD, prolyl hydroxylase domain protein; PMDS, polydimethylsiloxane; RPL28, ribosomal protein L28; SLC2A1, solute carrier family 2 member 1; XPO1, Exportin 1.", "\n\nDisclosure {#S0007}\n==========\n\nYosef Landesman is an employee of Karyopharm Therapeutics and holds patents, equity and stocks and has received both major and minor remunerations from Karyopharm. ", "The authors report no other conflicts of interest in this work.", "\n" ]

{ "pile_set_name": "PubMed Central" }

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[ "Please suggest what's wrong with the FC6 machine. ", "Is there any more setting to be done in the FC6 box?", "\n\nThanks and regards,\nRajat\n\njschiwal\n\n05-07-2007 04:24 AM\n\nWhen I routed my desktop through my laptop in order to have access to my wireless router, I didn't add host routes like you are doing. ", "However, I found out that I needed to modprobe ip_conntrack before it would work." ]

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[ "Hi my name is Cheryl,\nOwner and Operator of Current Expressions Facial Tone Skin Care,\n\nFor as long as I can remember, I have had passion for making women look and feel better, I think I started in my teenage years. ", "I would do my mothers hair for special occasions, and that led to all of my mothers friends wanting their hair done as well.", "\n\nMy friends were next in line, I would cut hair, and bangs, as well as apply make-up on friends that didn't know what to do. ", "This led me into the hair and cosmetology industry, where I stayed until after my children were born. ", "With my boys now in school I was once again drawn back into the beauty industry, this time as a Skin Care specialist, and Facial Tone Clinician.", "\n\nI worked for many years in spas, and anti-aging clinics gaining experience and perfecting my skills.", "\nAs time went on, and the growing demand for a more holistic approach for anti-aging, I took it upon myself to, research the latest microcurrent technology available,and after purchasing my equipment I opened Current Expressions facial tone & skin care clinic." ]

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[ "Q:\n\nSliders providing null values to complex shiny application at startup and periodically as inputs change\n\nI am currently developing a complex (multiple pages of nested navs/tabs) web application using R's Shiny package.", "\nI am currently experiencing an issue where sometimes accessing the values of these sliders from R via input$ returns NULL for no apparent reason. ", " When this happens, the various outputs dependent on these sliders cannot be produced due to errors.", "\nThis problem goes away if the user forces the application to recalculate by changing an input.", "\nThe error occurs primarily at startup, though on occasion it will occur in the middle of a session as the user plays with the inputs.", "\nI am currently working on a clean example to reproduce this, but if anyone has experienced this before or has any ideas I would certainly appreciate the help.", "\n\nA:\n\nOn the shiny google group, I was informed that this is expected behavior. ", " The inputs take time to load and you must define what inputs are required to be non-null to produce each given output.", "\nThe solution here was to use the following in the relevant outputs:\nshiny::validate(need(input$myinput, message=FALSE))\n\nIt is important to call validate this way as this name is used by other packages. ", " I spent a long time trying to use validate and getting errors because it was calling the wrong validate function from a different package.", "\n\n" ]

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[ "Comparison of alteplase versus heparin for resolution of major pulmonary embolism.", "\nComplete resolution of major pulmonary embolism (PE) treated with heparin alone can often take > 3 weeks. ", "Thrombolytic agents effectively resolve pulmonary artery thrombi within a few hours. ", "However, the effect of the 2 types of treatment on recovery of right ventricular function has not yet been followed for periods of > 24 hours. ", "We prospectively examined 40 consecutive patients with documented major PE (symptoms being present for < or = 8 weeks). ", "After diagnosis, 27 patients (68%) were treated with alteplase plus heparin and 13 (32%) with heparin alone. ", "There was no significant difference between the 2 groups with regard to baseline parameters. ", "At 12 hours, systolic pulmonary artery pressure decreased from 56 +/- 20 to 37 +/- 21 mm Hg in the alteplase group, and from 50 +/- 11 to 46 +/- 12 mm Hg in the heparin group (significantly more; p = 0.016). ", "On echocardiographic follow-up, a decrease in end-diastolic dimensions of the right ventricle and an increase in left ventricular dimensions was significantly more pronounced in the alteplase group (p <0.001 and p = 0.05, respectively). ", "The incidence of right ventricular dilation and paradoxical septal wall motion decreased significantly only in the thrombolyis group. ", "However, at 1-week follow-up, no difference was seen between the 2 groups regarding the overall change in right or left ventricular dimensions or the final values of other echocardiographic parameters. ", "Thus, echocardiography is particularly useful for hemodynamic follow-up of major PE. ", "Thrombolysis may rapidly reduce pulmonary artery pressure, but resolution of right ventricular pressure overload also occurs within 1 week in patients treated with heparin alone." ]

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[ "Dianthus seguieri\n\nDianthus seguieri, common name Sequier's pink, is a herbaceous perennial plant of the genus Dianthus of the family Caryophyllaceae.", "\n\nEtymology\nThe genus name Dianthus derives from the Greek words for divine (\"dios\") and flower (\"anthos\"), while the species name seguieri honors the French botanist Jean-François Séguier (1733 – 1784).", "\n\nDescription\n\nDianthus seguieri is a hemicryptophyte scapose plant reaching in height. ", "This carnation has green lanceolate leaflets and pink flowers, with purple markings in the centre. ", "The flowering period extends from June through September. ", "The fruits are capsules with several brown seeds.", "\n\nDistribution\nThis species is present in southern and central Europe, mainly in Spain, France, Germany, Italy, and Switzerland.", "\n\nHabitat\nDianthus seguieri grows in dry meadows at an altitude of above sea level.", "\n\nGallery\n\nReferences\n\nExternal links\n Biolib\n Hlasek\n Flores Alpes\n\nseguieri" ]

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[ "Intelはオーストラリアシドニーで5月3日より開催されているIEM Sydney 2019において、同社でeスポーツビジネスを統括するBrittany Willams氏がインタビューに応じ、同社が最高位スポンサーを務める2020年の東京オリンピックに合わせたeスポーツイベントについて、「まだ何も決まっていない」ことを明らかにした。", "\n\n東京オリンピックに合わせてIntelがeスポーツイベントを開催するのではないか。この期待は、2018年2月の平昌オリンピックで、IntelがIOC（国際オリンピック委員会）の支援を受ける形で「IEM PyeongChang」を開催したことで急激に高まり、あたかも「IEM Tokyo 2020」の開催が既成事実化のように捉えられている。これは2019年1月に公開された日経新聞のインタビューにより決定的となった。", "\n\nただし、ここからが重要な話となるが、日本法人であるインテルジャパンはIEMの日本での開催を一度も認めていない。IEMファンならご存じの通り、IEMの主催はESLであり、IntelはIEMのメインスポンサーに過ぎない。東京オリンピックの最高位スポンサーなのはESLではなくあくまでIntelであり、Intel自身がIEMにこだわる必要はまったくないからだ。", "\n\n【Intel Extreme Masters】\n\n地球最大規模のeスポーツビジネスを展開するIntelにとって、IEMは、同社のeスポーツビジネスの1パートに過ぎず、今回インタビューに応じたBrittany Willams氏が直接担当している「NBA2K League」や、今や米国を代表するeスポーツリーグに成長した「Overwatch League」など、IEMと同等かそれ以上にコミットしているeスポーツイベントはほかにもたくさんある。", "\n\n一方、ESLにとってIEMは、姉妹イベントのESL ONEと共に同社のフラッグシップとなるeスポーツイベントだ。ホストシティはeスポーツマーケットが十分に成熟した大都市に限られており、Intel以外に現地を代表するビッグスポンサーと複数年の契約を交わす必要がある。契約金は非公表のため正確なところはわからないが、日本のeスポーツイベントで動くお金と比較して最低でも1桁、場合によっては2桁異なる数億円単位の資金が必要となる。常識的に考えれば、いくら東京オリンピックといえどもIEM Tokyoの併催は絶望的といっていい。", "\n\n可能性があるのは、IEMではなく、Intelが主催または共催する形のeスポーツイベントだ。ここでようやく冒頭のWillams氏の発言に繋がってくるわけだが、IOCとの間でコミュニケーションが行なわれてることは認めたものの、開催の有無も含めて、まだ決まっていることは何もないことを明らかにした。", "\n\n平昌オリンピックに合わせて開催された「IEM PyeongChang」はあくまでテストケースであり、「Starcraft II」（Blizzard Entertainment）と「STEEP」（Ubisoft）の2種目で行なわれたテストそのものは極めてうまくいったものの、IntelもIOCも“次のステップ”に進むためにテストの継続が必要だと捉えており、eスポーツをスポーツの1つとして捉えていいのかどうかというレベルまで遡って慎重に検討を重ねているという。", "\n\n本インタビューでの質問の意図は、本社の担当者に日経インタビューの裏を取ることにあったが、見事に肩透かしを食らった格好になる。もっとも、オリンピックのスポンサーは、その発言、行動に厳しい規制が存在し、勝手な発言や、メディアを使った観測気球を揚げる行為も厳禁とされる。その意味では、予想通りの回答が得られたというのが正直な所であり、「IEM Tokyo」の併催という過大な期待はすべきではない一方で、eスポーツ界のジャイアントであるIntel主導によるeスポーツイベントが2020年に東京で開催される期待は十分に残されている。正式発表はギリギリのタイミングになりそうだが、eスポーツファンの1人としてほどほどに期待しながら正式発表を待ちたいところだ。" ]

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[ "Wednesday, March 08, 2017\n\nBBC identified man as “Muslim” when he was denied visa, “Indian” when he was arrested for sex abuse\n\nOf course: for the establishment propaganda media, Muslims are victims only, never perpetrators.", "\n\n“BBC Was Quick to Say ‘Kashmiri Muslim’ When Denied Visa, But After Reports of a Heinous Crime… Not So Much,” by Virginia Kruta, Independent Journal Review, March 7, 2017:\n\nA sportsman was set to compete in the world snowshoe championship at Saranac Lake, New York, and he was ready to travel all the way from India to get there. ", "That’s when Tanveer Hussain was informed that “current policy” would be preventing him from obtaining a travel visa.", "\n\nThe BBC reported on his plight, pointing out the fact that Hussain was not actually traveling from a nation that was affected by President Trump’s initial order:\n\nThe embassy in Delhi would not comment on individual visa applications for reasons of privacy, but emphasised that Indian citizens are not affected by the recent executive order.", "\n\nMr Hussain’s coach, Abid Khan, said all his documents had been in order.", "\n\n“We had local government recommendation and also the invitation and verification letter from the New York snowshoe federation. ", "But as soon as a lady visa officer at the US embassy in Delhi read our names, she went inside a cabin and came back after a few minutes. ", "She said she was sorry, but that she could not help us due to the current US policy,” he told the BBC.", "\n\nNo comments:\n\nNOTE:\n\n'ASIAN' = MUSLIM 99% OF THE TIMEThe politically correct term 'Asian' is used by the leftist UK media as a way to cast suspicion on a wider group of people and take some of the negative attention away from the group usually responsible for committing the heinous acts. ", "A perfect example would be the Muslim grooming gang epidemic which are constantly referred to by the press and authorities as 'Asian' grooming gangs. ", "It isn't people from China, Japan or any Far Eastern Asian place. ", "Nor is it Sikhs, Hindus, Buddhists,Christians Etc....They are Muslims!!!! ", "Please keep this in mind when seeing the term 'Asian' on any post" ]

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[ "Hi! ", "I'm Mavis, Chicken Coop Church's mission chicken. ", "I proudly roost in a nice and comfortable basket at the Coop.", "However, I've been feeling a little \"cooped up\" lately.​You see, I am on a very important mission of gathering donations to support the missions and ministries God has called you, me, and Chicken Coop Church to cockle doodle do!Flock with me and change lives and transform hearts by spreading your wings in faith and clicking the PayPal link below." ]

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[ "Jiayi\n\nJiayi may refer to:\n\nChinese people\n Jia Yi (; 201–169 BCE), a Chinese poet\n\ntowns\n Jiayi, Guangdong (), town in Luoding\n Jiayi, Pingjiang (), a town in Pingjiang County, Hunan province.", "\n\nas Chiayi\n Chiayi (), provincial city of Taiwan\n Chiayi County (), county in central Taiwan" ]

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[ "Effects of therapeutic formalin bath on selected indices in fish.", "\nThe aim of this study is to assess the effects of a treatment bath in a formalin solution on fish, focusing on haematological, biochemical and histopathological profiles. ", "A total of 96 common carps (Cyprinus carpio) were randomly assigned to eight groups. ", "Four experimental groups were placed in the test solution for 60 minutes. ", "The concentration of the formalin bath was 0.17 ml/l (38% formaldehyde), with the water temperature of 20°C. ", "The effects of the bath were monitored immediately (E0) and 24 hours (E24h), 48 hours (E48h) and 10 days (E10d) after the bath. ", "There was a control group (C0, C24h, C48h, C10d) for each of the experimental groups. ", "Histopathological indices were strongly affected. ", "Extensive changes were found on gill and skin immediately and also after 24 h, 48 h and 10 d of the formalin treatment bath. ", "A plurality of mucinous elements was observed on the skin. ", "Moreover, structural devastation of lamellas and numerous mucinous cells were observed on the gill. ", "Changes were also found in haematological and biochemical indices. ", "It can be concluded that after applying the treatment bath in the formalin solution, the monitored profiles were affected immediately after the bath and also after 10 days (histopathological changes of skin and gill). ", "Such significant impact of therapeutic formalin bath should be considered in treatment of fish." ]

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[ "Town Talk for Feb. 22\n\nJames Foley spotted this eagle on the Eagle River perched in a tree right at the base of Cordillera. “", "He flew off before I could get in position to set up a good shot, but I did get him in flight,” Foley said. “", "I’ve lived in the valley my entire life and have always wanted a shot of a native eagle. ", "This is as close as I’ve ever come to a good shot.”" ]

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[ "gearbox suggestions for 1uzfe V8 (VVTi) ?", "\n\nHello their guys!", "\nI wanted some suggestions regarding what gearbox and differential would be suitable for a toyota 1uzfe v8 Vvti version in a toyota mark 2 74' ?", "\nkindly let me know of some suggestions . ", "I dont want something very expensive but something that would work well at a reasonable price!", "\n\nThe most commonly used gearboxes for toyota swap is the W5X series preferably W58. ", "The W5X will handle the engines stock output with ease. ", "It will break if you abuse it too much or put a lot of torque throught it. ", "These will handle 300-350 HP\n\nFor performance oriented cars the R154 is used as it can handle 600-700 HP easily\n\nThe most commonly used gearboxes for toyota swap is the W5X series preferably W58. ", "The W5X will handle the engines stock output with ease. ", "It will break if you abuse it too much or put a lot of torque throught it. ", "These will handle 300-350 HP\n\nFor performance oriented cars the R154 is used as it can handle 600-700 HP easily\n\nyeah sir . ", "i heard about W58 . ", "How much is It for ? ", "$$$??", "\n\nSent from my iPhone using PW Forums\n\nHorsepower is how Fast you hit the wall ,\nTorque is how far you take the wall with you -" ]

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[ "Today's no-shit study says infertility can do a number on a couple's sex life. ", "Just like fertility!", "\n\n\nAccording to Slate's Sarah Elizabeth Richards, researched the Stanford have found that 40% of women dealing with infertility also suffer sexual problems, like lack of arousal and desire, compared to only 25% of women in general. ", "Hormone shots may be part of the cause, but researchers think the problems are mostly psychological. ", "Therapist Ronny Diamond says that for infertile women, \"Sex, rather than being a place where you can escape the world, becomes a reminder of what you can't do. ", "You can't make a baby.\" ", "She adds that the scheduled sex mandated by fertility treatments can be a turnoff: \"When the woman calls her husband at work and says 'I'm ovulating. ", "Come home. ", "We've got to do it now,' it ruins people's ideas of romantic conception.\"", "\n\nNone of this is a shock, unfortunately — as Richards notes, \"anyone who has had trouble getting or staying pregnant knows that infertility is hard on relationships,\" and it's not surprising that it can reduce sex drive as much as it increases conflict. ", "But it's interesting to note how many of the problems caused by infertility can also be caused by its opposite — efforts to have sex without having a baby. ", "Birth control pills, for instance, can lower libido and mess with body image and mood. ", "Anybody who's ever found a lost NuvaRing in the bed several days later knows how much fun that is, as do those who've experienced side effects from Plan B. And there's always the fear of these or other methods failing — an occasional mood-killer, I'd wager, for even the most careful contraceptor. ", "It's true that one of the perks of protected sex is relative freedom from worry — that \"place where you can escape the world\" — but just as no fertility treatment is guaranteed to generate a pregnancy, no birth control is 100% guaranteed to prevent one.", "\n\n\nAll this is not to trivialize the troubles of infertile women, who, if the Stanford study is correct, are disproportionately suffering. ", "Rather, I'd like to point out that 25% — the number of fertile women who experience sexual problems — is still really high. ", "This may be in part because women still bear the responsibility for the reproductive aspects of sex. ", "Some of this is biological — we are the ones with the wombs — but some of it is social: women are the ones judged when they don't procreate, or when they get pregnant too young or out of wedlock. ", "And the fact that all the myriad forms of hormonal birth control, with all their myriad side effects, must pass through our bodies is surely due in part to where the research money goes. ", "A male birth control pill would sure be nice, but so would a general recognition that whether the goal is preventing or creating a pregnancy, men need to be equal partners.", "\n\nWhen Sex Becomes A Chore [Slate]" ]

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[ "A business typically has many database storage areas for storing company data. ", "These database storage areas may be managed by various types of enforcement systems that ensure data accuracy. ", "Enforcement systems are typically “optimistic” enforcement system types or “pessimistic” enforcement system types. ", "An optimistic enforcement system is often enacted through data profiling and checks data when it is retrieved from a storage area. ", "Optimistic enforcement systems assume that rule violations are either rare or tolerable (at least for some time period). ", "These systems apply a data profiling tool at intervals that are also based on a set of information integrity rules. ", "The profiling tool identifies violations and allows a user to take corrective actions. ", "Pessimistic enforcement systems enforce rules before new/modified data is persisted in a data store. ", "Pessimistic enforcement systems assume that integrity constraints may be violated and, therefore, enforce rules before the changes are persisted into storage.", "\nEach of these enforcement systems may have a set of rules that govern how they control the integrity of the data. ", "Over time, one set of rules may become disjointed with another set of rules and, in turn, one enforcement system may treat data differently than another enforcement system." ]

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