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0.18816383183002472, "25409": 0.6553317308425903, "25458": 0.20739519596099854, "25531": 0.0038986403960734606, "25714": 0.0019512200960889459, "25876": 0.13499516248703003, "26296": 0.7827593088150024, "26305": 0.1229778528213501, "26745": 0.8845420479774475, "26874": 0.07159364968538284, "27018": 0.11081436276435852, "28227": 0.8500841856002808, "28436": 0.0038986403960734606, "28466": 0.03831886500120163, "28616": 0.9635916948318481, "28689": 0.1401015669107437, "28828": 0.06520967930555344, "28829": 0.23092569410800934, "28873": 0.022212404757738113, "28927": 0.1602703034877777, "28947": 0.10906458646059036, "29125": 0.41195443272590637, "29172": 1.0123108625411987, "29458": 0.13925230503082275} | 21502234 | BACKGROUND The association between the deficiency in mismatch repair (MMR) genes and prognosis in women with endometrial cancer is unclear. Here we report a systematic review and meta-analysis exploring this association. METHODS We searched literature databases (MEDLINE, EMBASE, and Cochrane) from 1980 until December 2011 to identify studies evaluating the association between MMR status and clinical outcome in endometrial cancer. The main outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS Twenty-three studies met the inclusion criteria. The median sample size of studies was 112, 74% were retrospective case-series and 70% performed microsatellite instability (MSI) analysis to evaluate the status of MMR. Only 22% of studies used the panel of five microsatellite markers recommended by the National Cancer Institute. Seven studies used immunohistochemistry to define MMR deficiency, but only two of them determined the expression of all four MMR proteins. Overall, significant associations between MMR and outcome were observed in 32% of studies. There was marked inter-study heterogeneity for estimates of OS and DFS. Pooled analysis did not show any significant association between deficiency in MMR and worse OS (6 studies, hazard ratio [HR] 2.0, p=0.11) or DFS (4 studies, HR ratio 1.31, p=0.66). CONCLUSION There is no definitive evidence of a significant association between MMR status and detrimental survival in endometrial cancer. | Mismatch repair status and clinical outcome in endometrial cancer: a systematic review and meta-analysis. |
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"25194": 0.8013357520103455, "25409": 0.7647408246994019, "25456": 0.8400169610977173, "25468": 0.26146242022514343, "25746": 0.42990362644195557, "25761": 0.8893690705299377, "26224": 0.014542185701429844, "26243": 0.014542185701429844, "26402": 0.4752389192581177, "26435": 0.05694137513637543, "26512": 0.08064348995685577, "26520": 0.0752234235405922, "26651": 0.04860413447022438, "26963": 0.23787821829319, "27009": 0.5607312321662903, "27144": 1.0960047245025635, "27287": 0.14602625370025635, "27292": 0.6054253578186035, "27295": 0.5104349255561829, "27531": 0.2026219218969345, "27814": 0.09495500475168228, "27854": 0.16359257698059082, "27881": 0.1510767638683319, "28024": 0.1332872211933136, "28027": 0.07068414986133575, "28032": 0.4067663550376892, "28154": 0.052318159490823746, "28156": 0.2531573474407196, "28848": 0.43875885009765625, "28987": 0.05046287178993225, "29206": 1.070887804031372, "29290": 0.6603899002075195, "29369": 0.47463157773017883} | 21521236 | In a search for mediators of the p53 tumor suppressor pathway, which induces pleiotropic and often antagonistic cellular responses, we identified the long noncoding RNA (lncRNA) NEAT1. NEAT1 is an essential architectural component of paraspeckle nuclear bodies, whose pathophysiological relevance remains unclear. Activation of p53, pharmacologically or by oncogene-induced replication stress, stimulated the formation of paraspeckles in mouse and human cells. Silencing Neat1 expression in mice, which prevents paraspeckle formation, sensitized preneoplastic cells to DNA-damage-induced cell death and impaired skin tumorigenesis. We provide mechanistic evidence that NEAT1 promotes ATR signaling in response to replication stress and is thereby engaged in a negative feedback loop that attenuates oncogene-dependent activation of p53. NEAT1 targeting in established human cancer cell lines induced synthetic lethality with genotoxic chemotherapeutics, including PARP inhibitors, and nongenotoxic activation of p53. This study establishes a key genetic link between NEAT1 paraspeckles, p53 biology and tumorigenesis and identifies NEAT1 as a promising target to enhance sensitivity of cancer cells to both chemotherapy and p53 reactivation therapy. | p53 induces formation of NEAT1 lncRNA-containing paraspeckles that modulate replication stress response and chemosensitivity |
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Activated in nature by microbes and microbial-derived products, the phagocyte NADPH oxidase is rapidly assembled, and generates reactive oxidant intermediates (ROIs) in response to infectious threat. Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase characterized by recurrent and severe bacterial and fungal infections, and pathology related to excessive inflammation. Studies in CGD patients and CGD mouse models indicate that NADPH oxidase plays a key role in modulating inflammation and injury that is distinct from its antimicrobial function. The mechanisms by which NADPH oxidase mediates killing of pathogens and regulation of inflammation have broad relevance to our understanding of normal physiological immune responses and pathological states, such as acute lung injury and bacterial or fungal infections. | Regulation of innate immunity by NADPH oxidase. |
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"25714": 0.11343330889940262, "25750": 0.06795065850019455, "25775": 0.35950297117233276, "26305": 0.006812678650021553, "26402": 0.75193190574646, "26591": 0.0058422754518687725, "27133": 0.9827804565429688, "27144": 0.4093637466430664, "27651": 0.1384023278951645, "27753": 0.3622259199619293, "27833": 0.1946154683828354, "27944": 0.8281423449516296, "28156": 0.6764062643051147, "28194": 0.6451379656791687, "28268": 0.09406650811433792, "28311": 0.846739649772644, "28483": 0.7389566898345947, "28696": 1.057410478591919, "29111": 0.3547199070453644, "29167": 0.02792670577764511, "29290": 0.0797421783208847} | 21547032 | Objective:In mice and in humans, treatment with the second-generation antipsychotic drug olanzapine (OLZ) produces excessive weight gain, adiposity and secondary metabolic complications, including loss of glucose and insulin homeostasis. In mice consuming a high-fat (HF) diet, a similar phenotype develops, which is inhibited by the analgesic acetaminophen (APAP) and by the antioxidant tetrahydroindenoindole (THII). Therefore, we examined the ability of APAP and THII to prevent metabolic changes in mice receiving OLZ.Design and Measurement:C57BL/6J mice received either a normal diet or a HF diet, and were administered daily dosages of OLZ (3 mg kg−1 body weight), alone or with APAP (30 mg kg−1 body weight) or THII (4.5 mg kg−1 body weight), for 10 weeks. Parameters of body composition and metabolism, including glucose and insulin homeostasis and oxidative stress, were examined. Results:OLZ treatment doubled the HF diet-induced increases in body weight and percent body fat. These increases were partially prevented by both APAP and THII, although food consumption was constant in all groups. The THII protection was associated with an increase in whole body and mitochondrial respiration. OLZ also exacerbated, and both APAP and THII prevented, HF diet-induced loss of glucose tolerance and insulin resistance. As increased body fat promotes insulin resistance by a pathway involving oxidative stress, we evaluated production of reactive oxygen and lipid peroxidation in white adipose tissue (WAT). HF diet caused an increase in lipid peroxidation, NADPH-dependent O2 uptake and H2O2 production, which were further exacerbated by OLZ. APAP, THII and the NADPH oxidase inhibitor, diphenyleneiodonium chloride, each abolished oxidative stress in WAT.Conclusions:We conclude that both APAP and THII intervene in the development of obesity and metabolic complications associated with OLZ treatment. | Protection from olanzapine-induced metabolic toxicity in mice by acetaminophen and tetrahydroindenoindole |
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"25714": 0.034552380442619324, "25952": 0.49923527240753174, "25969": 0.10731173306703568, "25971": 0.28890204429626465, "26013": 0.06612417846918106, "26244": 0.00875066313892603, "26563": 0.176772341132164, "26745": 0.6048921346664429, "26835": 0.562402069568634, "26927": 1.5630667209625244, "26986": 0.5887627601623535, "27605": 0.5104349255561829, "27781": 0.33675122261047363, "28293": 0.034552380442619324, "28389": 0.5584990978240967, "28406": 0.09050461649894714, "28616": 0.9363996982574463, "28633": 0.15023678541183472, "28873": 0.5640701055526733, "28927": 0.2539152204990387, "28947": 0.026025565341114998, "29090": 0.11865071207284927, "29301": 0.4879087805747986, "29490": 0.4855078160762787} | 21550246 | Prion diseases are caused by an unconventional infectious agent termed prion, composed mainly of the misfolded prion protein (PrPSc). The development of highly sensitive assays for biochemical detection of PrPSc in blood is a top priority for minimizing the spread of the disease. Here we show that the protein misfolding cyclic amplification (PMCA) technology can be automated and optimized for high-efficiency amplification of PrPSc. We show that 140 PMCA cycles leads to a 6,600-fold increase in sensitivity over standard detection methods. Two successive rounds of PMCA cycles resulted in a 10 million–fold increase in sensitivity and a capability to detect as little as 8,000 equivalent molecules of PrPSc. Notably, serial PMCA enables detection of PrPSc in blood samples of scrapie-afflicted hamsters with 89% sensitivity and 100% specificity. These findings represent the first time that PrPSc has been detected biochemically in blood, offering promise for developing a noninvasive method for early diagnosis of prion diseases. | Detection of prions in blood |
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1.0229004621505737, "26520": 0.20421554148197174, "26601": 0.006812678650021553, "26702": 0.06520967930555344, "26927": 0.05786345899105072, "27144": 0.13925230503082275, "27247": 0.034552380442619324, "27263": 0.0354953333735466, "27598": 0.6522845029830933, "27673": 0.10993985831737518, "27881": 0.05139094591140747, "27896": 0.08064348995685577, "28032": 0.9455460906028748, "28155": 0.09850110858678818, "28309": 0.006812678650021553, "28327": 0.8357921838760376, "28378": 0.6527929902076721, "28828": 0.2409527748823166, "29206": 0.8941729068756104, "29610": 1.4918501377105713} | 21551568 | PURPOSE To investigate the overall occurrence and relationship of genetic alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in thyroid tumors and explore the scope of this pathway as a therapeutic target for thyroid cancer. EXPERIMENTAL DESIGN We examined collectively the major genetic alterations and their relationship in this pathway, including PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation, in a large series of primary thyroid tumors. RESULTS Occurrence of any of these genetic alterations was found in 25 of 81 (31%) benign thyroid adenoma (BTA), 47 of 86 (55%) follicular thyroid cancer (FTC), 21 of 86 (24%) papillary thyroid cancer (PTC), and 29 of 50 (58%) anaplastic thyroid cancer (ATC), with FTC and ATC most frequently harboring these genetic alterations. PIK3CA copy gain was associated with increased PIK3CA protein expression. A mutual exclusivity among these genetic alterations was seen in BTA, FTC, and PTC, suggesting an independent role of each of them through the PI3K/Akt pathway in the tumorigenesis of the differentiated thyroid tumors. However, coexistence of these genetic alterations was increasingly seen with progression from differentiated tumor to undifferentiated ATC. Their coexistence with BRAF mutation was also frequent in PTC and ATC. CONCLUSIONS The data provide strong genetic implication that aberrant activation of PI3K/Akt pathway plays an extensive role in thyroid tumorigenesis, particularly in FTC and ATC, and promotes progression of BTA to FTC and to ATC as the genetic alterations of this pathway accumulate. Progression of PTC to ATC may be facilitated by coexistence of PI3K/Akt pathway-related genetic alterations and BRAF mutation. The PI3K/Akt pathway may thus be a major therapeutic target in thyroid cancers. | Genetic alterations and their relationship in the phosphatidylinositol 3-kinase/Akt pathway in thyroid cancer. |
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0.09228714555501938, "26780": 0.4093637466430664, "26886": 0.26146242022514343, "27133": 0.9440274834632874, "28227": 0.6739205718040466, "28268": 0.2478361576795578, "28403": 0.9108069539070129, "28591": 0.0606246218085289, "28828": 0.04487626627087593, "29125": 0.2034190446138382, "29172": 0.2034190446138382, "29454": 0.5080875158309937} | 21553394 | In recent years, new functional roles of vitamin D beyond its traditional role in calcium homoeostasis and bone metabolism have emerged linking the fat-soluble vitamin to various non-communicable diseases. Vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25-30 nmol/l) and sub-optimal status (25(OH)D < 50-100 nmol/l) are increasingly associated with unfavourable metabolic phenotypes, including insulin resistance, type 2 diabetes and CVD; conditions also commonly linked with overweight and obesity. Early studies reported poor vitamin D status in the morbidly obese. More recently, it has been observed that a graded relationship between vitamin D status and BMI, or specifically adiposity, exists in the general population. A number of hypotheses have been proposed to explain the potential mechanisms whereby alterations in the vitamin D endocrine system occur in the obese state. Plausible explanations include sequestration in adipose tissue, volumetric dilution or negative feedback mechanisms from increased circulating 1,25-dihydroxyvitamin D3. Others hypothesise that heavier individuals may partake in less outdoor activity, may also cover-up and wear more clothing than leaner individuals, thus decreasing sun exposure and limiting endogenous production of cholecalciferol in the skin. Moreover, in some but not all studies, BMI and adiposity have been negatively associated with the change in vitamin D status following vitamin D supplementation. It therefore remains unclear if body size and/or adiposity should be taken into account when determining the dietary requirements for vitamin D. This review will evaluate the current evidence linking vitamin D status and supplementation to overweight and obesity, and discuss the implications for setting dietary requirements. | Vitamin D and obesity: current perspectives and future directions. |
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We show that unmodified p53 actively binds to two sites at -1.4 and -2.3 kb within the chromatin-assembled p21 promoter and requires the C terminus and the histone acetyltransferase, p300, for transcription. Acetylation of the C terminus by p300 is not necessary for binding or promoter activation. Instead, p300 acetylates p53-bound nucleosomes in the p21 promoter with spreading to the TATA box. Thus, p53 is an active DNA and chromatin binding protein that may selectively regulate its target genes by recruitment of specific cofactors to structurally distinct binding sites. | Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment. |
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"26435": 0.05046287178993225, "26721": 0.6430866718292236, "27166": 0.6921701431274414, "27790": 0.1677299439907074, "27833": 1.4450790882110596, "28093": 1.651509165763855, "28139": 0.857568621635437, "28487": 0.8666408061981201, "28715": 0.055094651877880096, "29166": 0.11430477350950241, "29336": 0.6075552701950073, "29489": 0.11691460013389587} | 21557614 | Statins are potent inhibitors of cholesterol biosynthesis. In clinical trials, statins are beneficial in the primary and secondary prevention of coronary heart disease. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering. Indeed, recent studies indicate that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting the thrombogenic response. Furthermore, statins have beneficial extrahepatic effects on the immune system, CNS, and bone. Many of these pleiotropic effects are mediated by inhibition of isoprenoids, which serve as lipid attachments for intracellular signaling molecules. In particular, inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the pleiotropic effects of statins. | Pleiotropic effects of statins. |
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The efficiency of these methods is limited by nonhomologous end joining (NHEJ), an alternative DNA repair pathway that competes with homology-directed repair (HDR). To promote HDR at the expense of NHEJ, we targeted DNA ligase IV, a key enzyme in the NHEJ pathway, using the inhibitor Scr7. Scr7 treatment increased the efficiency of HDR-mediated genome editing, using Cas9 in mammalian cell lines and in mice for all four genes examined, up to 19-fold. This approach should be applicable to other customizable endonucleases, such as zinc finger nucleases and transcription activator–like effector nucleases, and to nonmammalian cells with sufficiently conserved mechanisms of NHEJ and HDR. | Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining |
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"25969": 0.18004031479358673, "26000": 0.6043586730957031, "26013": 0.503966212272644, "26131": 0.46302130818367004, "26236": 0.14939609169960022, "26244": 0.03360854089260101, "26394": 0.011650617234408855, "26399": 0.10203468054533005, "26402": 0.47766464948654175, "26520": 0.04767346754670143, "26601": 0.030771657824516296, "26646": 0.1384023278951645, "26721": 0.7629209756851196, "26835": 0.5640701055526733, "27058": 1.0423725843429565, "27363": 0.12038381397724152, "27781": 0.2976420819759369, "27854": 0.19381128251552582, "28032": 0.7683706283569336, "28389": 0.15023678541183472, "28691": 0.4203280806541443, "28848": 0.04113444685935974, "28873": 0.9155091643333435, "28940": 0.07159364968538284, "29125": 0.34023189544677734, "29535": 1.2238903045654297} | 21562657 | K3/MIR1 and K5/MIR2 of Kaposi's sarcoma-associated herpesvirus (KSHV) are viral members of the membrane-associated RING-CH (MARCH) ubiquitin ligase family and contribute to viral immune evasion by directing the conjugation of ubiquitin to immunostimulatory transmembrane proteins. In a quantitative proteomic screen for novel host cell proteins downregulated by viral immunomodulators, we previously observed that K5, as well as the human immunodeficiency virus type 1 (HIV-1) immunomodulator VPU, reduced steady-state levels of bone marrow stromal cell antigen 2 (BST2; also called CD317 or tetherin), suggesting that BST2 might be a novel substrate of K5 and VPU. Recent work revealed that in the absence of VPU, HIV-1 virions are tethered to the plasma membrane in BST2-expressing HeLa cells. By targeting BST2, K5 might thus similarly overcome an innate antiviral host defense mechanism. Here we establish that despite its type II transmembrane topology and carboxy-terminal glycosylphosphatidylinositol (GPI) anchor, BST2 represents a bona fide target of K5 that is downregulated during primary infection by and reactivation of KSHV. Upon exit of the protein from the endoplasmic reticulum, lysines in the short amino-terminal domain of BST2 are ubiquitinated by K5, resulting in rapid degradation of BST2. Ubiquitination of BST2 is required for degradation, since BST2 lacking cytosolic lysines was K5 resistant and ubiquitin depletion by proteasome inhibitors restored BST2 surface expression. Thus, BST2 represents the first type II transmembrane protein targeted by K5 and the first example of a protein that is both ubiquitinated and GPI linked. We further demonstrate that KSHV release is decreased in the absence of K5 in a BST2-dependent manner, suggesting that K5 contributes to the evasion of intracellular antiviral defense programs. | Molecular mechanism of BST2/tetherin downregulation by K5/MIR2 of Kaposi's sarcoma-associated herpesvirus. |
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"25714": 0.7969439625740051, "25937": 0.15943801403045654, "25950": 0.8997484445571899, "26243": 0.011650617234408855, "26258": 0.07431721687316895, "26402": 0.987156867980957, "26572": 0.3027053773403168, "26651": 0.05417001247406006, "26773": 0.28155985474586487, "26927": 0.03925827145576477, "27058": 0.757441520690918, "27295": 0.5718178153038025, "27360": 0.06154331564903259, "27491": 0.7067264318466187, "27698": 0.1602703034877777, "27781": 0.7352184057235718, "27846": 0.4318077862262726, "27854": 0.22001366317272186, "28156": 0.36426326632499695, "28228": 0.48430517315864563, "28667": 0.6563454270362854, "28691": 0.18167030811309814, "28723": 0.7445381283760071, "28774": 0.15359249711036682, "28788": 0.46117570996284485, "29299": 0.5370414853096008, "29610": 0.5596157908439636, "29720": 0.35128939151763916} | 21564598 | Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH. Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn(-/-) mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation. | Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin. |
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"25613": 0.01934296265244484, "25643": 0.21135559678077698, "25937": 0.09672962874174118, "26163": 0.8829278349876404, "26226": 0.3019835948944092, "26237": 1.1935672760009766, "26266": 0.7710843086242676, "26319": 0.12642613053321838, "26404": 0.02792670577764511, "26462": 0.1685553640127182, "26534": 0.14433705806732178, "26563": 0.04394211992621422, "26786": 0.28155985474586487, "26906": 0.04767346754670143, "27339": 0.4437839686870575, "27572": 0.01934296265244484, "27753": 0.8893690705299377, "27794": 0.9302552938461304, "27833": 0.8264343738555908, "27908": 0.20580662786960602, "28093": 0.38041436672210693, "28155": 0.056018441915512085, "28196": 0.24248650670051575, "28353": 0.43244171142578125, "28436": 0.5784112811088562, "28696": 0.0009760859538801014, "28915": 0.2145126610994339, "29166": 0.3656192123889923, "29215": 0.3084607720375061, "29299": 0.04113444685935974, "29458": 0.05417001247406006, "29464": 0.5557019114494324} | 21571708 | CONTEXT Circulating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke. OBJECTIVE To assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes. STUDY SELECTION Long-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators. DATA EXTRACTION Individual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline. DATA SYNTHESIS Lipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer. CONCLUSION Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes. | Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. |
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It has been thought that the incoherent FFL is designed simply to induce a transient response shaped by a 'fast activation and delayed inhibition'. We find that the dynamics of various incoherent FFLs can be further classified into two types: time-dependent biphasic responses and dose-dependent biphasic responses. Why do the structurally identical incoherent FFLs play such different dynamical roles? Through computational studies, we show that the dynamics of the two types of incoherent FFLs are mutually exclusive. Following from further computational results and experimental observations, we hypothesize that incoherent FFLs have been optimally designed to achieve distinct biological function arising from different cellular contexts. Additional Supporting Information may be found in the online version of the article. | The biphasic behavior of incoherent feed-forward loops in biomolecular regulatory networks. |
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"27615": 0.3519764244556427, "27756": 0.1808556467294693, "28093": 0.36086538434028625, "28393": 0.02792670577764511, "28804": 0.2516399025917053, "29234": 0.8682814836502075} | 21590125 | Data of prescribing practices for antipsychotics are of great interest with respect to quality of care. Consequently, we analysed all prescriptions under the statutory health insurance redeemed at pharmacies in Southern Germany between July 1999 and December 2001. The database covers prescriptions for approximately 25 million people. Up to 6% of the population were prescribed an antipsychotic at least once during the study period. Most prescriptions were for conventional antipsychotics and written by non-specialists. Patients receiving second generation antipsychotics were more likely to receive continuous antipsychotic therapy. For a large proportion of patients, antipsychotic polypharmacy, as well as comedication for somatic illnesses, were observed. In particular, drugs for the treatment of cardiovascular and metabolic disorders were frequently co-prescribed. Physicians should consider patients' cardiovascular and metabolic risk profile when making treatment choices. The data suggest that the majority of antipsychotics are used for the treatment of disorders other than schizophrenia. It is important to raise awareness among non-specialists about the indications, efficacy and side-effects of the antipsychotics because these physicians account for the majority of antipsychotic prescriptions. | Antipsychotic prescribing patterns in Germany: a retrospective analysis using a large outpatient prescription database. |
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0.9987343549728394, "26825": 0.18978065252304077, "26910": 0.7124901413917542, "27080": 0.8366385698318481, "27211": 1.207676887512207, "27216": 0.48430517315864563, "27287": 0.011650617234408855, "27633": 0.07068414986133575, "27697": 0.9842413663864136, "27790": 1.2566616535186768, "27854": 0.46608972549438477, "28251": 1.4386125802993774, "28691": 0.2184450328350067, "28696": 0.09672962874174118, "28715": 0.8161250352859497, "28991": 0.009718249551951885, "29060": 0.08064348995685577, "29146": 0.4248080551624298} | 21598000 | Plus-end tracking proteins, such as EB1 and the dynein/dynactin complex, regulate microtubule dynamics. These proteins are thought to stabilize microtubules by forming a plus-end complex at microtubule growing ends with ill-defined mechanisms. Here we report the crystal structure of two plus-end complex components, the carboxy-terminal dimerization domain of EB1 and the microtubule binding (CAP-Gly) domain of the dynactin subunit p150Glued. Each molecule of the EB1 dimer contains two helices forming a conserved four-helix bundle, while also providing p150Glued binding sites in its flexible tail region. Combining crystallography, NMR, and mutational analyses, our studies reveal the critical interacting elements of both EB1 and p150Glued, whose mutation alters microtubule polymerization activity. Moreover, removal of the key flexible tail from EB1 activates microtubule assembly by EB1 alone, suggesting that the flexible tail negatively regulates EB1 activity. We, therefore, propose that EB1 possesses an auto-inhibited conformation, which is relieved by p150Glued as an allosteric activator. | Structural basis for the activation of microtubule assembly by the EB1 and p150Glued complex. |
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"28848": 0.7881022095680237, "28991": 1.200058937072754, "29129": 0.46424978971481323, "29206": 0.8450632095336914, "29290": 0.4794800877571106} | 21601459 | While most somatic cells undergoing induced pluripotent stem (iPS) cell reprogramming with Yamanaka factors accumulate at stable partially reprogrammed stages, the molecular mechanisms required to achieve full reprogramming are unknown. MicroRNAs (miRNAs) fine-tune mRNA translation and are implicated in reprogramming, but miRNA functional targets critical for complete iPS cell reprogramming remain elusive. We identified methyl-DNA binding domain protein 2 (MBD2) as an epigenetic suppressor, blocking full reprogramming of somatic to iPS cells through direct binding to NANOG promoter elements preventing transcriptional activation. When we overexpressed miR-302 cluster we observed a significant increase in conversion of partial to fully reprogrammed iPS cells by suppressing MBD2 expression, thereby increasing NANOG expression. Thus, expression of exogenous miR-302 cluster (without miR-367) is efficient in attaining a fully reprogrammed iPS state in partially reprogrammed cells by relieving MBD2-mediated inhibition of NANOG expression. Our studies provide a direct molecular mechanism involved in generating complete human iPS cell reprogramming to study disease pathogenesis, drug screening, and for potential cell-based therapies. | Epigenetic regulation of NANOG by miR-302 cluster-MBD2 completes induced pluripotent stem cell reprogramming. |
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"28613": 1.1325355768203735, "28731": 0.7500885725021362, "29090": 0.49982786178588867, "29109": 0.820433497428894, "29129": 0.1358480453491211} | 21602220 | The physiology of ethanologenic Escherichia coli grown anaerobically in alkali-pretreated plant hydrolysates is complex and not well studied. To gain insight into how E. coli responds to such hydrolysates, we studied an E. coli K-12 ethanologen fermenting a hydrolysate prepared from corn stover pretreated by ammonia fiber expansion. Despite the high sugar content (∼6% glucose, 3% xylose) and relatively low toxicity of this hydrolysate, E. coli ceased growth long before glucose was depleted. Nevertheless, the cells remained metabolically active and continued conversion of glucose to ethanol until all glucose was consumed. Gene expression profiling revealed complex and changing patterns of metabolic physiology and cellular stress responses during an exponential growth phase, a transition phase, and the glycolytically active stationary phase. During the exponential and transition phases, high cell maintenance and stress response costs were mitigated, in part, by free amino acids available in the hydrolysate. However, after the majority of amino acids were depleted, the cells entered stationary phase, and ATP derived from glucose fermentation was consumed entirely by the demands of cell maintenance in the hydrolysate. Comparative gene expression profiling and metabolic modeling of the ethanologen suggested that the high energetic cost of mitigating osmotic, lignotoxin, and ethanol stress collectively limits growth, sugar utilization rates, and ethanol yields in alkali-pretreated lignocellulosic hydrolysates. | Complex physiology and compound stress responses during fermentation of alkali-pretreated corn stover hydrolysate by an Escherichia coli ethanologen. |
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0.08871890604496002, "25808": 1.013020396232605, "26163": 0.5729197263717651, "26189": 0.23402166366577148, "26404": 0.12556517124176025, "26462": 0.23633737862110138, "26906": 0.1677299439907074, "27144": 0.2749055027961731, "27159": 0.6548244953155518, "27480": 0.15693697333335876, "27528": 0.8861536383628845, "27678": 0.12814582884311676, "28086": 0.27934664487838745, "28093": 0.026976587250828743, "28436": 0.5244048833847046, "28591": 0.2983669638633728, "28739": 0.18248429894447327, "29048": 1.1786550283432007} | 21616324 | BACKGROUND Control of blood pressure (BP) following renal transplantation may improve allograft and patient survival. Our aims were (i) to describe the distribution of BP and the prevalence of systolic and/or diastolic hypertension in children over the first 5 years following renal transplantation and (ii) to evaluate clinical risk factors and centre-specific factors associated with hypertension in this population. METHODS We conducted a retrospective case note review of all current paediatric kidney transplant patients in the UK, with data collected at 6 months, 1, 2 and 5 years following transplantation in subjects with hypertension (systolic and/or diastolic BP > 95th > ) and non-hypertensive subjects BP ≤ 95th > . RESULTS In total, 27.3% (117/428), 27.6% (118/428), 26.0% (95/365) and 25.6% (50/195) of the patients were hypertensive (systolic and/or diastolic BP > 95th > ) at 6 months, 1, 2 and 5 years following transplantation, respectively. A total of 58.4% of the patients at 6 months, 52.8% at 1 year, 48.2% at 2 years and 48.2% at 5 years were receiving anti-hypertensive therapy, of whom 31.6-36.6% remained hypertensive. When subjects were identified as being hypertensive, on anti-hypertensive medication or had untreated hypertension (systolic and/or diastolic BP > 95th > ), 66.4, 61.0, 56.4 and 55.9% of patients were hypertensive at 6 months, 1, 2 and 5 years, respectively. In a multivariate model, odds ratios for systolic hypertension were 4.16 (deceased versus living donor), 2.65 (lowest versus highest quartile of height z-score) and 2.07 (if on anti-hypertensive; yes versus no). There was significant variation in prevalent rates of hypertension between centres (P < 0.0001) that remained significant (P = 0.003) after adjustment for all the factors in the multivariate model. CONCLUSIONS Control of BP after kidney transplantation remains sub-optimal in paediatric centres in the UK. Just over 25% of patients remain hypertensive 5 years following transplantation. Significant differences between centres remain unexplained and may reflect differences in assessment and management of hypertension. | Systemic arterial hypertension in children following renal transplantation: prevalence and risk factors. |
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"27427": 0.6471850275993347, "27854": 0.07612881064414978, "28227": 0.23556606471538544, "28248": 0.40220460295677185, "28516": 0.0354953333735466, "28517": 0.04674193635582924, "29290": 0.6911921501159668, "29391": 0.03266380727291107} | 21622715 | Transcriptional factors binding to cAMP-responsive elements (CREs) in the promoters of various genes belong to the basic domain-leucine zipper superfamily and are composed of three genes in mammals, CREB, CREM, and ATF-1. A large number of CREB, CREM, and ATF-1 proteins are generated by posttranscriptional events, mostly alternative splicing, and regulate gene expression by acting as activators or repressors. Activation is classically brought about by signaling-dependent phosphorylation of a key acceptor site (Ser133 in CREB) by a number of possible kinases, including PKA, CamKIV, and Rsk-2. Phosphorylation is the prerequisite for the interaction of CBP (CREB-binding protein), a co-activator that has also histone acetyltransferase activity. Repression may involve dynamic dephosphorylation of the activators and thus decreased association with CBP. Another pathway of transcriptional repression on CRE sites implicates the inducible repressor ICER (inducible cAMP early repressor), a product of the CREM gene. Being an inducible repressor, ICER is involved in autoregulatory feedback loops of transcription that govern the down-regulation of early response genes, such as the proto-oncogene c-fos. The liver represents a remarkable physiological setting where cAMP-responsive signaling plays a major role. Indeed, a finely tuned program of gene expression is triggered by partial hepatectomy, so that through specific checkpoints a coordinated regeneration of the tissue is obtained. Temporal kinetics of transcriptional activation after hepatectomy reveals a pattern of early induction for several genes, some of them controlled by the CREB/CREM transcription factors. An important role of CREM in liver physiology was suggested by the robust induction of ICER after partial hepatectomy. The delay in tissue regeneration in CREM-deficient mice confirmed the important function of this factor in regulating hepatocyte proliferation. As gene induction is accompanied by critical changes in chromatin organization, the deciphering of the specific modification codes that histones display during liver regeneration and physiology will provide exciting new insights into the dynamics of chromatin architecture. | Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM. |
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0.13414156436920166, "26886": 0.1358480453491211, "27354": 0.9194108247756958, "27453": 0.03360854089260101, "28155": 0.11343330889940262, "28268": 0.6980181336402893, "28321": 0.24401791393756866, "28329": 0.18492233753204346, "28403": 0.08513788133859634, "28436": 0.05046287178993225, "28616": 0.9084475636482239, "28648": 0.18654440343379974, "28800": 0.10291612148284912, "28993": 0.7210738658905029, "29365": 0.03360854089260101} | 21623140 | Objective: The main objective of the study was to develop appropriate dietary assessment instruments for the French Mediterranean region and to validate the measurements they provide. Subjects and Methods: Three different assessment methods were submitted to a sample of 150 male and female volunteers. 98 completed the protocol, which consisted of a 4 d weighed dietary record (PETRA) and a 7 d estimated-diet record (S7) based on a check list and a set of photographs, both these records being completed once in each season of the year, and a semi-quantitative (standard portion) food-frequency questionnaire (FFQ) including questions eliciting socio-demographic and anthropometric data, which was completed once only. The days when PETRA was used to evaluate food consumption coincided with the first 4 d of S7 (S4).Results: Validation was based on nutrients and foods. Energy-adjusted Pearson correlation coefficients between S4 and PETRA ranged from 0.32 for vitamin E to 0.81 for vitamin C (mean: 0.65 for 21 nutrients). There was practically no misclassification in opposite extreme quartiles. Spearman correlation coefficients ranged from 0.63 for fish and sea-food to 0.90 for wine (mean: 0.76 for 16 food groups). There was practically no misclassification in opposite extreme quartiles. De-attenuated energy-adjusted Pearson correlation coefficients between FFQ and S7 ranged from 0.22 for proteins and monounsaturated fatty acids to 0.80 for iron (mean: 0.45). 10% or less of subjects were misclassified in opposite extreme quartiles (except for vitamin C, 12%). Spearman correlation coefficients ranged from 0.25 for green-yellow-red raw vegetables to 0.76 for wine (mean: 0.42). 8% or less of subjects were misclassified in opposite extreme quartiles (except for citrus fruit, 11%).Conclusions: Portion estimation using the set of photographs was validated by the correlation between S4 and PETRA for both nutrients and foods. The FFQ provides a reasonably reliable measure of macronutrient intake and a good measure of micronutrient intake when compared with the data in the literature. It performs less well for food intake. Better results can be achieved for FFQ: (i) by using the set of photographs instead of standard portions and (ii) by adding further questions on foods which are insufficiently covered. Sponsorship: This work has been financially supported by INSERM contract 91-1006 and the Ardèche and Hérault Committees of the ‘Ligue contre le cancer’. | Comparison of dietary assessment methods in a Southern French population: use of weighed records, estimated-diet records and a food-frequency questionnaire |
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"24316": 1.3794349431991577, "24382": 0.7201237678527832, "24556": 0.6517757177352905, "24848": 0.00875066313892603, "25095": 0.07250232994556427, "25194": 0.969535231590271, "25524": 0.4891071021556854, "25605": 1.245482087135315, "25644": 0.010684899985790253, "25714": 0.083342544734478, "25761": 0.38174858689308167, "25778": 0.9710156321525574, "25950": 0.10379679501056671, "26243": 0.28450319170951843, "26244": 0.07884006202220917, "26402": 0.4500300884246826, "26632": 1.4037197828292847, "26773": 0.7408206462860107, "27152": 0.1221139207482338, "27295": 0.6389714479446411, "27321": 0.3163207769393921, "27325": 0.040196798741817474, "27781": 0.10203468054533005, "27854": 0.07068414986133575, "28498": 1.1394343376159668, "28696": 0.006812678650021553, "28788": 0.2918238639831543, "28835": 0.24171993136405945, "29290": 0.055094651877880096, "29441": 0.0019512200960889459} | 21626639 | Macrophages play a relevant role in innate and adaptive immunity depending on the balance of the stimuli received. From an analytical and functional point of view, macrophage stimulation can be segregated into three main modes, as follows: innate, classic, and alternative pathways. These differential activations result in the expression of specific sets of genes involved in the release of pro- or anti-inflammatory stimuli. In the present work, we have analyzed whether specific metabolic patterns depend on the signaling pathway activated. A [1,2-(13)C(2)]glucose tracer-based metabolomics approach has been used to characterize the metabolic flux distributions in macrophages stimulated through the classic, innate, and alternative pathways. Using this methodology combined with mass isotopomer distribution analysis of the new formed metabolites, the data show that activated macrophages are essentially glycolytic cells, and a clear cutoff between the classic/innate activation and the alternative pathway exists. Interestingly, macrophage activation through LPS/IFN-gamma or TLR-2, -3, -4, and -9 results in similar flux distribution patterns regardless of the pathway activated. However, stimulation through the alternative pathway has minor metabolic effects. The molecular basis of the differences between these two types of behavior involves a switch in the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2) from the liver type-PFK2 to the more active ubiquitous PFK2 isoenzyme, which responds to Hif-1alpha activation and increases fructose-2,6-bisphosphate concentration and the glycolytic flux. However, using macrophages targeted for Hif-1alpha, the switch of PFK2 isoenzymes still occurs in LPS/IFN-gamma-activated macrophages, suggesting that this pathway regulates ubiquitous PFK2 expression through Hif-1alpha-independent mechanisms. | Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. |
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"27321": 0.13670019805431366, "27615": 0.029824240133166313, "28093": 0.06886265426874161, "28227": 0.2409527748823166, "28403": 0.23710809648036957, "28767": 0.37640097737312317, "28915": 0.5415972471237183, "29336": 0.2954642176628113, "29537": 0.06703783571720123} | 21636085 | BACKGROUND Increased plasma homocysteine is associated with coronary artery disease, peripheral vascular disease and venous thrombosis. Folic acid is the most effective therapy for reducing homocysteine levels. The lowest effective supplement of folic acid is not known, particularly for the elderly who have the highest prevalence of these conditions. AIM To explore the effects of daily supplements of 0, 50, 100, 200, 400 and 600 microg folic acid on plasma homocysteine in an elderly population. DESIGN Randomized double-blind placebo-controlled trial. METHODS Participants (n=368) aged 65-75 years were randomly allocated to receive one of the treatments for 6 weeks. Plasma homocysteine was recorded after 3 weeks and 6 weeks of supplementation. RESULTS Only the 400 microg and 600 microg groups had significantly lower homocysteine levels compared to placebo (p=0.038 and p<0.001, respectively). Using multiple linear regression and each individual's total folic acid intake (diet plus supplement), a total daily folic acid intake of 926 microg per day would be required to ensure that 95% of the elderly population would be without cardiovascular risk from folate deficiency. DISCUSSION A daily folic acid intake of 926 microg is unlikely to be achieved by diet alone. Individual supplementation or fortification of food with folic acid will be required to reach this target. | The effect of folic acid supplementation on plasma homocysteine in an elderly population. |
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"27166": 0.40220460295677185, "27295": 0.27342069149017334, "27753": 0.28963330388069153, "27811": 0.08064348995685577, "28290": 0.2990913391113281, "28424": 0.4400174915790558, "28637": 0.10203468054533005, "28696": 0.9886114001274109, "28739": 0.15693697333335876, "28993": 0.7220231294631958, "29048": 0.6086184978485107, "29166": 0.7067264318466187, "29206": 0.16276304423809052, "29299": 0.6343214511871338} | 21641088 | Obesity is a multifactorial disease with a marked genetic component. The situation is further complicated by the heterogeneity of obesity demonstrated by the topographical distribution of body fat, e.g. upper body (central) and lower body (gluteal) obesity. Furthermore, the distribution of fat shows a stronger heritable tendency compared with total body fat. Central obesity is characterized by hyperinsulinaemia and insulin resistance, a feature in common with non-insulin dependent diabetes mellitus, hypertension and atherosclerosis. In order to study the molecular genetics of central obesity we have examined 56 severely obese (mean body mass index 40), unrelated British Caucasoid young non-diabetic women for associations of restriction fragment length polymorphism of candidate genes with anthropometric measurements and indices of insulin secretion and resistance. The candidate genes examined were insulin receptor, insulin sensitive glucose transporter and insulin. An association of the class 3 allele of the hypervariable region in the 5' flanking region of the insulin gene was found with upper segment obesity (P = 0.005). Furthermore, the class 3 allele was also associated with fasting hyperinsulinaemia (P = 0.01), stimulated insulin secretion (P = 0.01) and insulin resistance as calculated from the homeostatic model of assessment (HOMA; P = 0.008). No such associations were found with the other candidate genes studied. This data suggests that polymorphisms in the 5' flanking region of the insulin gene may affect expression of the gene and thereby modulate insulin production in severely obese female subjects. | Central obesity and hyperinsulinaemia in women are associated with polymorphism in the 5' flanking region of the human insulin gene. |
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0.12986256182193756, "28896": 1.1834511756896973, "28911": 0.11517547070980072, "29207": 0.16110190749168396, "29237": 0.026976587250828743, "29458": 0.7537717819213867, "29490": 0.46853771805763245, "29598": 0.5540198087692261} | 21644993 | Bacterial vaccines can reduce carriage rates. Colonization is usually a binary endpoint. Real time quantitative PCR (qPCR) can quantify bacterial DNA in mucosal samples over a wide range. Using culture and single-gene species-specific qPCRs for Streptococcus pneumoniae (lytA), Streptococcus pyogenes (ntpC), Moraxella catarrhalis (ompJ), Haemophilus influenzae (hdp) and Staphylococcus aureus (nuc) and standard curves against log-phase reference strain broth cultures we described frequency and peak density distributions of carriage in nasopharyngeal swabs from 161 healthy 2-4 y old children collected into STGG broth. In general, detection by qPCR and culture was consistent. Discordance mostly occurred at lower detection thresholds of both methods, although PCR assays for S. pyogenes and S. aureus were less sensitive. Density varied across 5-7 orders of magnitude for the 5 species with the abundant species skewed toward high values (modes: S. pneumoniae log3-4, M. catarrhalis & H. influenzae log4-5 CFU/ml broth). Wide ranges of bacterial DNA concentrations in healthy children carrying these bacteria could mean that different individuals at different times vary greatly in infectiousness. Understanding the host, microbial and environmental determinants of colonization density will permit more accurate prediction of vaccine effectiveness. | Population density profiles of nasopharyngeal carriage of 5 bacterial species in pre-school children measured using quantitative PCR offer potential insights into the dynamics of transmission. |
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"26837": 0.026025565341114998, "27133": 0.7737906575202942, "27184": 0.10379679501056671, "27354": 0.10291612148284912, "27854": 0.03831886500120163, "28177": 0.8764448165893555, "28696": 0.1905880719423294, "28848": 0.6456501483917236} | 21645205 | A core group of regulatory factors control circadian rhythms in mammalian cells. While the suprachiasmatic nucleus in the brain serves as the central core circadian oscillator, circadian clocks also exist within peripheral tissues and cells. A growing body of evidence has demonstrated that >20% of expressed mRNAs in bone and adipose tissues oscillate in a circadian manner. The current manuscript reports evidence of the core circadian transcriptional apparatus within primary cultures of murine and human bone marrow-derived mesenchymal stem cells (BMSCs). Exposure of confluent, quiescent BMSCs to dexamethasone synchronized the oscillating expression of the mRNAs encoding the albumin D binding protein (dbp), brain-muscle arnt-like 1 (bmal1), period 3 (per3), rev-erb alpha (Rev A), and rev-erb beta (Rev B). The genes displayed a mean oscillatory period of 22.2 to 24.3 h. The acrophase or peak expression of mRNAs encoding "positive" (bmal1) and "negative" (per3) components of the circadian regulatory apparatus were out of phase with each other by approximately 8-12 h, consistent with in vivo observations. In vivo, phosphyrylation by glycogen synthase kinase 3beta (GSK3beta) is known to regulate the turnover of per3 and components of the core circadian regulatory apparatus. In vitro addition of lithium chloride, a GSK3beta inhibitor, significantly shifted the acrophase of all genes by 4.2-4.7 h oscillation in BMSCs; however, only the male murine BMSCs displayed a significant increase in the length of the period of oscillation. We conclude that human and murine BMSCs represent a valid in vitro model for the analysis of circadian mechanisms in bone metabolism and stem cell biology. | Circadian mechanisms in murine and human bone marrow mesenchymal stem cells following dexamethasone exposure. |
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21651116 | Herpesviruses encode membrane-associated G protein-coupled receptors (GPCRs) in their viral genomes that are structurally similar to chemokine receptors. These GPCRs hijack GPCR-mediated cellular signalling networks of the host for survival, replication and pathogenesis. In particular the herpesvirus-encoded chemokine receptors ORF74, BILF1 and US28, which are present at inflammatory sites and tumour cells, provide important virus-specific targets for directed therapies. Given the high druggability of GPCRs in general, these viral GPCRs can be considered promising antiviral drug targets. | Herpesvirus-encoded GPCRs: neglected players in inflammatory and proliferative diseases? |
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"28086": 0.6038249135017395, "28297": 0.3750596046447754, "28405": 0.11517547070980072, "28424": 0.10555581003427505, "28691": 0.09672962874174118, "28775": 0.823009729385376, "28788": 0.14939609169960022, "28935": 0.018384648486971855, "29109": 0.1011524572968483, "29129": 0.0009760859538801014, "29206": 0.9621002674102783, "29290": 0.4450363218784332, "29292": 0.176772341132164, "29486": 0.5838727951049805, "29516": 0.036437395960092545} | 21676556 | The midbody is a singular organelle formed between daughter cells during cytokinesis and required for their final separation. Midbodies persist in cells long after division as midbody derivatives (MBds), but their fate is unclear. Here we show that MBds are inherited asymmetrically by the daughter cell with the older centrosome. They selectively accumulate in stem cells, induced pluripotent stem cells and potential cancer ‘stem cells’ in vivo and in vitro. MBd loss accompanies stem-cell differentiation, and involves autophagic degradation mediated by binding of the autophagic receptor NBR1 to the midbody protein CEP55. Differentiating cells and normal dividing cells do not accumulate MBds and possess high autophagic activity. Stem cells and cancer cells accumulate MBds by evading autophagosome encapsulation and exhibit low autophagic activity. MBd enrichment enhances reprogramming to induced pluripotent stem cells and increases the in vitro tumorigenicity of cancer cells. These results indicate unexpected roles for MBds in stem cells and cancer ‘stem cells’. | Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity |
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We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies. | Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. |
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0.036437395960092545, "26557": 0.6451379656791687, "26591": 0.036437395960092545, "26646": 0.3241194784641266, "26721": 0.043007105588912964, "26835": 0.1011524572968483, "27144": 0.3622259199619293, "27484": 0.03360854089260101, "27673": 0.2763880789279938, "27794": 0.6338034868240356, "28024": 0.19782574474811554, "28282": 0.04113444685935974, "28389": 1.4971086978912354, "28483": 0.952351450920105, "28793": 1.0437490940093994, "28873": 0.8272887468338013, "29361": 0.17267228662967682} | 21700295 | Importance More than 240 million individuals worldwide are infected with chronic hepatitis B virus (HBV). Among individuals with chronic HBV infection who are untreated, 15% to 40% progress to cirrhosis, which may lead to liver failure and liver cancer. Observations Pegylated interferon and nucleos(t)ide analogues (lamivudine, adefovir, entecavir, tenofovir disoproxil, and tenofovir alafenamide) suppress HBV DNA replication and improve liver inflammation and fibrosis. Long-term viral suppression is associated with regression of liver fibrosis and reduced risk of hepatocellular carcinoma in cohort studies. The cure (defined as hepatitis B surface antigen loss with undetectable HBV DNA) rates after treatment remain low (3%-7% with pegylated interferon and 1%-12% with nucleos[t]ide analogue therapy). Pegylated interferon therapy can be completed in 48 weeks and is not associated with the development of resistance; however, its use is limited by poor tolerability and adverse effects such as bone marrow suppression and exacerbation of existing neuropsychiatric symptoms such as depression. Newer agents (entecavir, tenofovir disoproxil, and tenofovir alafenamide) may be associated with a significantly reduced risk of drug resistance compared with older agents (lamivudine and adefovir) and should be considered as the first-line treatment. Conclusions and Relevance Antiviral treatment with either pegylated interferon or a nucleos(t)ide analogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or tenofovir alafenamide) should be offered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression of liver disease. Nucleos(t)ide analogues should be considered as first-line therapy. Because cure rates are low, most patients will require therapy indefinitely. | Chronic Hepatitis B Infection: A Review |
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"28230": 0.7201237678527832, "28424": 0.04394211992621422, "28636": 0.9980146884918213, "28756": 0.4518963396549225, "28788": 0.3526630103588104, "28873": 0.46914875507354736, "28896": 1.1400591135025024, "28965": 0.11081436276435852, "29290": 0.6764062643051147, "29721": 0.4794800877571106} | 21719289 | Although most vaccines are administered i.m., little is known about the dendritic cells (DCs) that are present within skeletal muscles. In this article, we show that expression of CD64, the high-affinity IgG receptor FcγRI, distinguishes conventional DCs from monocyte-derived DCs (Mo-DCs). By using such a discriminatory marker, we defined the distinct DC subsets that reside in skeletal muscles and identified their migratory counterparts in draining lymph nodes (LNs). We further used this capability to analyze the functional specialization that exists among muscle DCs. After i.m. administration of Ag adsorbed to alum, we showed that alum-injected muscles contained large numbers of conventional DCs that belong to the CD8α(+)- and CD11b(+)-type DCs. Both conventional DC types were capable of capturing Ag and of migrating to draining LNs, where they efficiently activated naive T cells. In alum-injected muscles, Mo-DCs were as numerous as conventional DCs, but only a small fraction migrated to draining LNs. Therefore, alum by itself poorly induces Mo-DCs to migrate to draining LNs. We showed that addition of small amounts of LPS to alum enhanced Mo-DC migration. Considering that migratory Mo-DCs had, on a per cell basis, a higher capacity to induce IFN-γ-producing T cells than conventional DCs, the addition of LPS to alum enhanced the overall immunogenicity of Ags presented by muscle-derived DCs. Therefore, a full understanding of the role of adjuvants during i.m. vaccination needs to take into account the heterogeneous migratory and functional behavior of muscle DCs and Mo-DCs revealed in this study. | CD64 expression distinguishes monocyte-derived and conventional dendritic cells and reveals their distinct role during intramuscular immunization. |
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"27011": 0.5762182474136353, "27169": 0.03360854089260101, "27404": 0.31845372915267944, "27781": 0.8332487344741821, "28282": 0.04207121208310127, "28788": 0.34715715050697327, "28873": 1.468738079071045, "28896": 0.24631060659885406, "29060": 0.022212404757738113, "29490": 0.34300774335861206, "29494": 0.043007105588912964} | 21746539 | Much excitement of the past five years in the area of T-cell-antigen recognition has centred around the immunological synapse — a complex cellular structure that forms at the interface of a T cell and a cell that expresses the appropriate peptide–MHC complexes. Thanks to new imaging technologies, we are now beginning to understand the role of cell-surface molecules and some of their attendant signalling modules in the context of cell-to-cell communication. Progress has been so rapid that T-cell-antigen recognition might be the first system in which the molecular basis of cell–cell recognition is understood. | T-cell-antigen recognition and the immunological synapse |
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0.05417001247406006, "26244": 0.21372433006763458, "26266": 0.38574060797691345, "26402": 0.24401791393756866, "26524": 0.02412080205976963, "26601": 0.10993985831737518, "26651": 0.13414156436920166, "26702": 0.9225212931632996, "26775": 1.258327841758728, "26942": 0.0752234235405922, "26963": 0.06977381557226181, "27009": 0.012615402229130268, "27292": 0.6312094330787659, "27295": 0.3027053773403168, "27697": 0.2674594223499298, "27790": 0.5651806592941284, "27854": 1.147526502609253, "27965": 0.06520967930555344, "28113": 0.6358738541603088, "28177": 0.1064341589808464, "28203": 1.0881409645080566, "28715": 0.055094651877880096, "29458": 0.5267143249511719} | 21754541 | Class B GPCRs can activate multiple signalling effectors with the potential to exhibit biased agonism in response to ligand stimulation. Previously, we highlighted key TM domain polar amino acids that were crucial for the function of the GLP-1 receptor, a key therapeutic target for diabetes and obesity. Using a combination of mutagenesis, pharmacological characterisation, mathematical and computational molecular modelling, this study identifies additional highly conserved polar residues located towards the TM helical boundaries of Class B GPCRs that are important for GLP-1 receptor stability and/or controlling signalling specificity and biased agonism. This includes (i) three positively charged residues (R3.30227, K4.64288, R5.40310) located at the extracellular boundaries of TMs 3, 4 and 5 that are predicted in molecular models to stabilise extracellular loop 2, a crucial domain for ligand affinity and receptor activation; (ii) a predicted hydrogen bond network between residues located in TMs 2 (R2.46176), 6 (R6.37348) and 7 (N7.61406 and E7.63408) at the cytoplasmic face of the receptor that is important for stabilising the inactive receptor and directing signalling specificity, (iii) residues at the bottom of TM 5 (R5.56326) and TM6 (K6.35346 and K6.40351) that are crucial for receptor activation and downstream signalling; (iv) residues predicted to be involved in stabilisation of TM4 (N2.52182 and Y3.52250) that also influence cell signalling. Collectively, this work expands our understanding of peptide-mediated signalling by the GLP-1 receptor. | Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor. |
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0.4679262638092041, "29361": 0.21687394380569458} | 21767325 | Arterial stiffness and wave reflections exert a number of adverse effects on cardiovascular function and disease risk and are associated with a greater rate of mortality in patients with end-stage renal failure and essential hypertension. Accordingly, the prevention and treatment of arterial stiffness are of paramount importance. Because arterial stiffening is being recognized as a critical precursor of cardiovascular disease (CVD), it is essential to understand the role of lifestyle modifications on preventing and reversing arterial stiffening. Available evidence indicates that lifestyle modifications, in particular aerobic exercise and sodium restriction, appear to be clinically efficacious therapeutic interventions for preventing and treating arterial stiffening. Thus, sufficient evidence is available to recommend lifestyle modifications as part of a first-line therapeutic approach for arterial stiffening. However, more information is needed for a full understanding and optimal use of lifestyle modifications in the management of arterial stiffening. | Influence of lifestyle modification on arterial stiffness and wave reflections. |
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0.037378571927547455, "29295": 0.7969439625740051, "29398": 0.015504186972975731} | 21789744 | An increased spatial dispersion of ventricular repolarization duration (QT dispersion) is associated with an increased vulnerability to arrhythmias. This study was designed to examine the effect of exercise on QT dispersion in ischemic heart disease (IHD). QT dispersion, corrected QT dispersion, and percentage change in uncorrected and corrected QT dispersion between rest and peak exercise were examined in 14 members of a control group, 17 patients with IHD, and 14 patients with IHD who were receiving beta-blockers (IHD-B). All subjects had undergone a standard Bruce protocol exercise test, and QT intervals were measured at rest and peak exercise with a digitizing tablet interfaced to a personal computer. QT dispersion at rest was markedly increased in the IHD group compared with that in the control and IHD-B groups, respectively (corrected QT dispersion in milliseconds), 74 +/- 7, 40 +/- 4, 49 +/- 5, p < 0.03). The corrected QT dispersion at peak exercise was greater in the IHD group compared with that in the control group (57 +/- 5 vs 26 +/- 3 msec, p < 0.03). The percentage change in QT dispersion with exercise was significantly higher in the IHD group (52% +/- 5%) compared with that in both the control group (28% +/- 4%, p < 0.002) and the IHD-B group (30% +/- 3%, p < 0.01). A larger mean QT dispersion at peak exercise and an increased percentage change in QT dispersion with exercise may help explain the increased susceptibility of the IHD group for arrhythmias. The cardioprotective action of beta-blockers may be explained by their blunting effect on exercise-related changes in QT dispersion. | Effect of exercise-induced ischemia on QT interval dispersion. |
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"29003": 0.2409527748823166} | 21790313 | This study reports the effects of powered mobility on the self-initiated behavior of six children with various disabilities who, between 23 and 38 months of age, learnt to use motorized wheelchairs in less than three weeks. Using a multiple baseline design, two-hour observation periods were video-recorded at 10-day intervals before and after they achieved independent mobility. Frequency of self-initiated interaction with objects, spatial exploration and communication with care-giver were analyzed. Three children increased all three types of behavior; one increased in two types but decreased in interaction with objects; and two increased in spatial exploration only. | Effects of powered mobility on self-initiated behaviors of very young children with locomotor disability. |
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We find that after gamma-irradiation BCR/ABL-positive leukemia cells accumulate more DSBs in comparison to normal cells. These lesions are efficiently repaired in a time-dependent fashion by BCR/ABL-stimulated non-homologous end-joining (NHEJ) followed by homologous recombination repair (HRR) mechanisms. However, mutations and large deletions were detected in HRR and NHEJ products, respectively, in BCR/ABL-positive leukemia cells. We propose that unfaithful repair of DSBs may contribute to genomic instability in the Philadelphia chromosome-positive leukemias. | BCR/ABL modifies the kinetics and fidelity of DNA double-strand breaks repair in hematopoietic cells. |
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BMP treatment is also an essential component of protocols for differentiation of nephron progenitors from pluripotent stem cells. This review discusses the role of BMP signaling to nephron progenitor cells in each of these contexts. | Bone morphogenetic protein signaling in nephron progenitor cells |
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"26775": 0.3963087201118469, "26838": 0.3269403576850891, "26986": 0.025073638185858727, "26994": 0.16359257698059082, "27642": 0.04113444685935974, "28156": 0.5278670787811279, "28436": 0.27342069149017334, "28848": 1.2192846536636353, "29146": 0.10993985831737518, "29217": 0.0797421783208847} | 21853444 | Alternative initiation, splicing, and polyadenylation are key mechanisms used by many organisms to generate diversity among mature mRNA transcripts originating from the same transcription unit. While previous computational analyses of alternative polyadenylation have focused on polyadenylation activities within or downstream of the normal 3'-terminal exons, we present the results of the first genome-wide analysis of patterns of alternative polyadenylation in the human, mouse, and rat genomes occurring over the entire transcribed regions of mRNAs using 3'-ESTs with poly(A) tails aligned to genomic sequences. Four distinct classes of patterns of alternative polyadenylation result from this analysis: tandem poly(A) sites, composite exons, hidden exons, and truncated exons. We estimate that at least 49% (human), 31% (mouse), and 28% (rat) of polyadenylated transcription units have alternative polyadenylation. A portion of these alternative polyadenylation events result in new protein isoforms. | Computational analysis of 3'-ends of ESTs shows four classes of alternative polyadenylation in human, mouse, and rat. |
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clones die before birth and survivors often display growth abnormalities. In an effort to correlate gene expression with survival and fetal overgrowth, we have examined imprinted gene expression in both mice cloned by nuclear transfer and in the embryonic stem (ES) cell donor populations from which they were derived. The epigenetic state of the ES cell genome was found to be extremely unstable. Similarly, variation in imprinted gene expression was observed in most cloned mice, even in those derived from ES cells of the same subclone. Many of the animals survived to adulthood despite widespread gene dysregulation, indicating that mammalian development may be rather tolerant to epigenetic aberrations of the genome. These data imply that even apparently normal cloned animals may have subtle abnormalities in gene expression. | Epigenetic instability in ES cells and cloned mice. |
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0.3870677351951599, "27398": 0.09495500475168228, "27556": 0.06429435312747955, "27615": 0.1229778528213501, "27894": 0.17840765416622162, "28032": 0.8600510358810425, "28309": 0.03925827145576477, "28400": 0.1677299439907074, "28873": 0.19862671196460724, "29439": 0.11343330889940262} | 21859699 | Providing transplantation opportunities for patients with incompatible live donors through kidney paired donation (KPD) is seen as one of the important strategies for easing the crisis in organ availability. It has been estimated that an additional 1000-2000 transplants per year could be accomplished if a national KPD program were implemented in the United States. While most of these transplants could be arranged within the participants' local or regional area, patients with hard-to-match blood types or broad HLA sensitization would benefit from matching across larger geographic areas. In this case, either patients or organs would need to travel in order to obtain maximum benefit from a national program. In this study, we describe how a triple KPD enabled a highly sensitized patient (PRA 96%) to receive a well-matched kidney from a live donor on the opposite coast. The kidney was removed in San Francisco and transported to Baltimore where it was reperfused 8 h later. The patient had prompt function and 1 year later has a serum creatinine of 1.1 mg/dl. This case provides a blueprint for solving some of the complexities that are inherent in the implementation of a national KPD program in a large country like the United States. | Successful three-way kidney paired donation with cross-country live donor allograft transport. |
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0.6149744987487793, "29480": 0.02792670577764511} | 21866916 | Astrocytes represent at least 50% of the volume of the human brain. Besides their roles in various supportive functions, astrocytes are involved in the regulation of stem cell proliferation, synaptic plasticity and neuroprotection. Astrocytes also influence neuronal physiology by responding to neurotransmitters and neuropeptides and by releasing regulatory factors termed gliotransmitters. In particular, astrocytes express the PACAP-specific receptor PAC1-R and the PACAP/VIP mutual receptors VPAC1-R and VPAC2-R during development and/or in the adult. There is now clear evidence that PACAP and VIP modulate a number of astrocyte activities such as proliferation, plasticity, glycogen production, and biosynthesis of neurotrophic factors and gliotransmitters. | Role of PACAP and VIP in astroglial functions. |
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"25608": 0.029824240133166313, "25644": 0.10555581003427505, "25761": 0.25088030099868774, "26157": 0.06246116757392883, "26402": 0.8004589080810547, "26451": 0.22157983481884003, "26475": 0.9754437208175659, "26520": 0.06795065850019455, "26773": 0.7417513132095337, "26837": 0.026025565341114998, "26874": 0.1384023278951645, "27058": 1.2140778303146362, "27059": 0.6430866718292236, "27074": 0.5110208988189697, "27233": 0.7629209756851196, "27321": 0.4067663550376892, "27642": 0.006812678650021553, "27697": 0.026976587250828743, "27790": 0.15526613593101501, "28156": 0.3077431619167328, "28353": 0.2184450328350067, "28406": 0.16524957120418549, "29160": 0.8349450826644897, "29172": 0.12384103983640671, "29295": 0.026025565341114998} | 21868715 | Molecular mechanisms leading to myocardial injury during warm or cold ischemia are insufficiently understood. Although proteasomes are thought to contribute to myocardial ischemia-reperfusion injury, their roles during the ischemic period remain elusive. Because donor hearts are commonly exposed to prolonged global cold ischemia prior to cardiac transplantation, we evaluated the role and regulation of the proteasome during cold ischemic storage of rat hearts in context of the myocardial ATP content. When measured at the actual tissue ATP concentration, cardiac proteasome peptidase activity increased by 225% as ATP declined during cold ischemic storage of hearts in University of Wisconsin (UW) solution for up to 48h. Addition of the specific proteasome inhibitor epoxomicin to the UW solution inhibited proteasome activity in the cardiac extracts, significantly reduced edema formation and preserved the ultrastructural integrity of the cardiomyocyte. Utilizing purified 20S/26S proteasome enzyme preparations, we demonstrate that this activation can be attributed to a subset of 26S proteasomes which are stable at ATP concentrations far below physiological levels, that ATP negatively regulates its activity and that maximal activation occurs at ATP concentrations in the low mumol/L range. These data suggest that proteasome activation is a pathophysiologically relevant mechanism of cold ischemic myocardial injury. A subset of 26S proteasomes appears to be a cell-destructive protease that is activated as ATP levels decline. Proteasome inhibition during cold ischemia preserves the ultrastructural integrity of the cardiomyocyte. | A subset of 26S proteasomes is activated at critically low ATP concentrations and contributes to myocardial injury during cold ischemia. |
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"29516": 0.19541899859905243, "29610": 0.27342069149017334, "29611": 0.09495500475168228} | 21870716 | The ability of children to cope with a chronic medical problem requiring prolonged treatment has an effect on the quality of life of these children and of their parents and serves as an index of the quality of treatment. This study deals with coping ability and satisfaction with treatment of children whose stature was two or more SD below the average for age and gender. The study population included 96 patients, 53 of whom were male, who were on growth hormone (GH) treatment for at least 1 year. 65 patients were without any underlying disease, 15 had classical GH deficiency and 16 had Turner syndrome or renal disease. All patients were treated with daily injections at home from 12 to 66 months. Using a self-administered questionnaire, the ability to cope and the degree of satisfaction and compliance with treatment were assessed. No significant differences were found with respect to gender, the presence of an underlying disease, age at which treatment commenced or duration of treatment. Despite the fact that the outcome of GH treatment on final height has yet to be established, satisfaction and compliance were high. | Coping and satisfaction with growth hormone treatment among short-stature children. |
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breast parenchyma by mammography. Four groups of patients were isolated. The study encompassed a five-year period and was done by reviewing the mammograms of all women over the age of 30 who had been examined at Hutzel Hospital, Detroit. The average time of followup would be approximately 2 1/2 years. Four groups had an incidence of developing breast cancer of 0.1, 0.4, 1.7, and 2.2. These parenchymal patterns are described and criteria for their identification are given. | Risk for breast cancer development determined by mammographic parenchymal pattern. |
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0.17759032547473907} | 21874414 | We develop a systematic coarse-graining procedure for modeling red blood cells (RBCs) using arguments based on mean-field theory. The three-dimensional RBC membrane model takes into account the bending energy, in-plane shear energy, and constraints of fixed surface area and fixed enclosed volume. The coarse-graining procedure is general, it can be used for arbitrary level of coarse-graining and does not employ any fitting parameters. The sensitivity of the coarse-grained model is investigated and its behavior is validated against available experimental data and in dissipative particle dynamics (DPD) simulations of RBCs in capillary and shear flows. | Accurate coarse-grained modeling of red blood cells. |
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Two mouse models deficient in CD4 T cells were used to examine the mechanism by which these cells participate in protection against Mycobacterium tuberculosis challenge. Transgenic mice deficient in either MHC class II or CD4 molecules demonstrated increased susceptibility to M. tuberculosis, compared with wild-type mice. MHC class II-/- mice were more susceptible than CD4-/- mice, as measured by survival following M. tuberculosis challenge, but the relative resistance of CD4-/- mice did not appear to be due to increased numbers of CD4-8- (double-negative) T cells. Analysis of in vivo IFN-gamma production in the lungs of infected mice revealed that both mutant mouse strains were only transiently impaired in their ability to produce IFN-gamma following infection. At 2 wk postinfection, IFN-gamma production, assessed by RT-PCR and intracellular cytokine staining, in the mutant mice was reduced by >50% compared with that in wild-type mice. However, by 4 wk postinfection, both mutant and wild-type mice had similar levels of IFN-gamma mRNA and protein production. In CD4 T cell-deficient mice, IFN-gamma production was due to CD8 T cells. Thus, the importance of IFN-gamma production by CD4 T cells appears to be early in infection, lending support to the hypothesis that early events in M. tuberculosis infection are crucial determinants of the course of infection. | Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis. |
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0.1229778528213501, "24278": 0.9621002674102783, "24546": 0.0058422754518687725, "25416": 0.20660123229026794, "25468": 0.39367714524269104, "26045": 0.3012613356113434, "26261": 1.0519683361053467, "26456": 0.23556606471538544, "26745": 0.3982778787612915, "26835": 0.3134697377681732, "26846": 0.06795065850019455, "27144": 0.16442140936851501, "27159": 0.1685553640127182, "27528": 0.5104349255561829, "27605": 0.17431432008743286, "27641": 0.1808556467294693, "28082": 0.21765978634357452, "28086": 0.1384023278951645, "28177": 0.4926934838294983, "28228": 0.8917738795280457, "28296": 0.6223390698432922, "28723": 0.08961215615272522, "28804": 0.03925827145576477, "28879": 0.09406650811433792, "29125": 0.12038381397724152, "29514": 0.7746911644935608, "29598": 0.6027565002441406, "29610": 0.12384103983640671} | 21884059 | Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality following allogenic haematopoietic stem-cell transplantation and thus the focus of much ongoing research. Despite considerable advances in our understanding of the pathophysiology, diagnosis and predisposing factors for both acute and chronic forms of the disease, a standardised therapeutic strategy is still lacking. There is good evidence for initial treatment of both acute and chronic forms of the disease with corticosteroid therapy. However, the most effective approach to steroid-refractory disease remains controversial, with current practice based mainly on smaller studies and varying considerably between local institutions. Timely diagnosis, multidisciplinary working and good supportive care, including infection prophylaxis, are clearly important in optimizing response and survival in such patients. It is hoped that in the future systematic research strategies and the identification of novel therapeutic targets may improve outcome further. The following review aims to outline some of the existing options for the treatment and management of acute and chronic GVHD. | Treatment and management of graft-versus-host disease: improving response and survival. |
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"26056": 0.14349138736724854, "26180": 1.4274288415908813, "26261": 0.2969166338443756, "26319": 0.07159364968538284, "26651": 0.12470348179340363, "27196": 0.22548456490039825, "27354": 0.47463157773017883, "27395": 0.28963330388069153, "27833": 0.007782140281051397, "28093": 0.26820653676986694, "28228": 0.9432673454284668, "28329": 0.29619070887565613, "28687": 0.2105647772550583, "28732": 0.8780695199966431, "29234": 0.4093637466430664, "29235": 1.2948341369628906, "29458": 0.6400018334388733, "29514": 0.3656192123889923, "29610": 0.0842406153678894} | 21884449 | AIMS To explore the utility of self-report measures of inhaled corticosteroid (ICS) adherence, degree of rhinitis and smoking status and their association with asthma control. METHODS Patients prescribed ICS for asthma at 85 UK practices were sent validated questionnaire measures of control (Asthma Control Questionnaire; ACQ) and adherence (Medication Adherence Report Scale), a two-item measure of smoking status, and a single-item measure of rhinitis. RESULTS Complete anonymised questionnaires were available for 3916 participants. Poor asthma control (ACQ >1.5) was associated with reported rhinitis (OR = 4.62; 95% CI: 3.71-5.77), smoking (OR = 4.33; 95% CI: 3.58-5.23) and low adherence to ICS (OR = 1.35; 95% CI: 1.18-1.55). The degree of rhinitis was important, with those reporting severe rhinitis exhibiting the worst asthma control, followed by those reporting mild rhinitis and then those reporting no rhinitis symptoms (F(2, 3913)=128.7, p<.001). There was a relationship between the number of cigarettes smoked each day and asthma control (F(5,655)=6.08, p<.001). CONCLUSIONS Poor asthma control is associated with self-reported rhinitis, smoking and low medication adherence. These potentially modifiable predictors of poor asthma control can be identified through a brief self-report questionnaire, used routinely as part of an asthma review. | The value of self-report assessment of adherence, rhinitis and smoking in relation to asthma control. |
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"29060": 0.4158279001712799, "29109": 0.15359249711036682, "29290": 0.08154398202896118, "29514": 0.6181373596191406} | 21891856 | Mouse ovarian surface epithelial cells (MOSEC) were obtained from virgin, mature mice by mild trypsinization and were repeatedly passaged in vitro. Early passage cells (<20 passages) exhibited a cobblestone morphology and contact inhibition of growth. After approximately 20 passages in vitro, cobblestone morphology and contact inhibition of growth was lost. Tumor forming potential was determined by s.c. and i.p. injection of early and late passage cells into athymic and syngeneic C57BL6 mice. Subcutaneous tumors formed in approximately 4 months and were present only at the injection site. Intraperitoneal injection of late passage MOSEC into athymic and syngeneic mice resulted in growth of tumor implants throughout the abdominal cavity, and production of hemorrhagic ascitic fluid. Early passage MOSEC did not form tumors in vivo. Histopathologic analysis of tumors revealed a highly malignant neoplasm containing both carcinomatous and sarcomatous components. Late passage MOSEC expressed cytokeratin and did not produce ovarian steroids in response to gonadotropin stimulation in vitro. Ten clonal lines were established from late passage MOSEC. Each clone formed multiple peritoneal tumors and ascitic fluid after i.p. injection into C57BL6 mice. Three cell lines examined cytogenetically were polyploid with near-tetraploid modal chromosome numbers. Common clonal chromosome gains and losses included +5, +15, +19 and -X, -3, -4. One cell line had a clonal translocation between chromosomes 15 and 18 and another had a small marker chromosome; common structural abnormalities were not observed. These data describe the development of a mouse model for the study of events related to ovarian cancer in humans. The ability of the MOSEC to form extensive tumors within the peritoneal cavity, similar to those seen in women with Stage III and IV cancer, and the ability of the MOSEC to produce tumors in mice with intact immune systems, makes this model unique for investigations of molecular and immune interactions in ovarian cancer development. | Development of a syngeneic mouse model for events related to ovarian cancer. |
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0.841701865196228, "26778": 0.5341835021972656, "26785": 0.6838265657424927, "27011": 0.9702757596969604, "27094": 0.41840189695358276, "27144": 0.4437839686870575, "27354": 0.06429435312747955, "27404": 0.14179791510105133, "27673": 0.10203468054533005, "27870": 0.8997484445571899, "27881": 0.306306391954422, "28207": 0.04487626627087593, "28479": 0.3777405619621277, "28648": 0.36697331070899963, "28699": 0.757441520690918, "28711": 0.9500881433486938, "28873": 0.036437395960092545, "29166": 0.8022117614746094, "29458": 0.007782140281051397, "29610": 0.026025565341114998} | 21902400 | Hypoxia, a characteristic feature of locally advanced solid tumors, has emerged as a pivotal factor of the tumor (patho-)physiome since it can promote tumor progression and resistance to therapy. Hypoxia represents a “Janus face” in tumor biology because (a) it is associated with restrained proliferation, differentiation, necrosis or apoptosis, and (b) it can also lead to the development of an aggressive phenotype. Independent of standard prognostic factors, such as tumor stage and nodal status, hypoxia has been suggested as an adverse prognostic factor for patient outcome. Studies of tumor hypoxia involving the direct assessment of the oxygenation status have suggested worse disease-free survival for patients with hypoxic cervical cancers or soft tissue sarcomas. In head & neck cancers the studies suggest that hypoxia is prognostic for survival and local control. Technical limitations of the direct O2 sensing technique have prompted the use of surrogate markers for tumor hypoxia, such as hypoxia-related endogenous proteins (e.g., HIF-1α, GLUT-1, CA IX) or exogenous bioreductive drugs. In many—albeit not in all—studies endogenous markers showed prognostic significance for patient outcome. The prognostic relevance of exogenous markers, however, appears to be limited. Noninvasive assessment of hypoxia using imaging techniques can be achieved with PET or SPECT detection of radiolabeled tracers or with MRI techniques (e.g., BOLD). Clinical experience with these methods regarding patient prognosis is so far only limited. In the clinical studies performed up until now, the lack of standardized treatment protocols, inconsistencies of the endpoints characterizing the oxygenation status and methodological differences (e.g., different immunohistochemical staining procedures) may compromise the power of the prognostic parameter used. | Hypoxia in cancer: significance and impact on clinical outcome |
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METHODS The study was conducted on 130 interns of 2010-11 batch from a government-run medical college in Kolkata, India. All participants completed a self-administered questionnaire with items relating to basic components of standard precautions and post-exposure prophylaxis for HIV. The questionnaire also included open ended questions relating to reasons for non-adherence to the practice of standard precautions along with additional space for specific comments, if any. RESULTS Poor adherence in the use of personal protective equipment, hand washing, safe handling and disposal of needles and sharp objects were found to be among the practices for which the interns expressed correct knowledge. While the main reasons for non-adherence were found to be clumsiness in handling needles, wearing gloves, feeling uncomfortable when wearing aprons, impracticality of regular hand-washing and non-availability of equipment. Although the majority of the respondents (84.6%) expressed awareness of washing sites of injured with soap and water, approximately 32.3% did not know that antiseptics could cause more damage. Also, only 63.8% expressed awareness of reporting any incidence of occupational exposure, while knowledge on post-exposure prophylaxis regimens was generally found to be poor. CONCLUSION The considerable gap between knowledge and practice of standard precautions and inadequate knowledge of post-exposure prophylaxis emphasizes the need for continuous onsite training of interns with supportive supervision and monitoring of their activities. | Knowledge and Practice of Standard Precautions and Awareness Regarding Post-Exposure Prophylaxis for HIV among Interns of a Medical College in West Bengal, India. |
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interference and cellular microRNAs (miRNAs) has not only affected how biological research is conducted but also revealed an entirely new level of post-transcriptional gene regulation. Here, I discuss the potential functions of the virally encoded miRNAs recently identified in several pathogenic human viruses and propose that cellular miRNAs may have had a substantial effect on viral evolution and may continue to influence the in vivo tissue tropism of viruses. Our increasing knowledge of the role and importance of virally encoded miRNAs will probably offer new insights into how viruses that establish latent infections, such as herpesviruses, avoid elimination by the host innate or adaptive immune system. Research into viral miRNA function might also suggest new approaches for treating some virally induced diseases. | Viruses and microRNAs |
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0.304147332906723, "21557": 0.1873544454574585, "21652": 0.1485546976327896, "21791": 0.43938836455345154, "22171": 0.17431432008743286, "22173": 0.3353555500507355, "22254": 0.28082266449928284, "22382": 0.37371641397476196, "22667": 0.05970508232712746, "22816": 0.41647201776504517, "23035": 0.5865923762321472, "23569": 0.23864774405956268, "23576": 0.13243216276168823, "24319": 0.1734936386346817, "24710": 0.014542185701429844, "25172": 0.6275664567947388, "25613": 0.022212404757738113, "25807": 0.1212492436170578, "25971": 0.08692999184131622, "26016": 0.016465263441205025, "26163": 0.21293537318706512, "26290": 1.1400591135025024, "26462": 0.23864774405956268, "27419": 0.12038381397724152, "28943": 0.034552380442619324, "29076": 0.012615402229130268, "29224": 0.151916041970253} | 21914176 | BACKGROUND Glaucoma is the World's leading cause of irreversible blindness, and poses serious public health and economic concerns. DESIGN Review. SAMPLES Published randomized trials and population-based studies since 1985. METHODS We report the economic impact of primary open-angle glaucoma and model the effect of changes in detection rates and management strategies. MAIN OUTCOME MEASURES The cost-effectiveness of different interventions to prevent vision loss from primary open-angle glaucoma was measured in terms of financial cost (Australian dollars) and disability-adjusted life years. RESULTS The prevalence of glaucoma in Australia is expected to increase from 208 000 in 2005 to 379 000 in 2025 because of the aging population. Health system costs over the same time period are estimated to increase from $AU355 million to $AU784 million. Total costs (health system costs, indirect costs and costs of loss of well-being) will increase from $AU1.9 billion to $AU4.3 billion in Australia. CONCLUSION Primary open-angle glaucoma poses a significant economic burden, which will increase substantially by 2025. This dynamic model provides a valuable tool for ongoing policy formulation and determining the economic impact of interventions to better prevent visual impairment and blindness from glaucoma. | Economic impact of primary open-angle glaucoma in Australia. |
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0.056018441915512085} | 21922424 | A novel cysteine-rich motif, named LIM, has been identified in the homeo box genes lin-11, Isl-1, and mec-3; the mec-3 and lin-11 genes determine cell lineages in Caenorhabditis elegans. We isolated LIM class homeo box genes from Xenopus laevis that are closely related to lin-11 and mec-3 in the LIM and homeo domains. This paper deals with one of these genes, Xlim-1. Xlim-1 mRNA is found at low abundance in the unfertilized egg, has a major expression phase at the gastrula stage, decreases, and rises again during the tadpole stage. In adult tissues the brain shows the highest abundance, by far, of Xlim-1 mRNA. The maternal and late expression phases of the Xlim-1 gene suggest that it has multiple functions at different stages of the Xenopus life cycle. In the gastrula embryo, Xlim-1 mRNA is localized in the dorsal lip and the dorsal mesoderm, that is, in the region of Spemann's organizer. Explant experiments showed that Xlim-1 mRNA is induced by the mesoderm-inducer activin A and by retinoic acid, which is not a mesoderm inducer but affects patterning during Xenopus embryogenesis; application of activin A and retinoic acid together results in synergistic induction. The structure, inducibility, and localized expression in the organizer of the Xlim-1 gene suggest that it has a role in establishing body pattern during gastrulation. | The LIM domain-containing homeo box gene Xlim-1 is expressed specifically in the organizer region of Xenopus gastrula embryos. |
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"26243": 0.22157983481884003, "26402": 0.39367714524269104, "27002": 0.14602625370025635, "27295": 0.5232481360435486, "27854": 0.1889725625514984, "27946": 1.264413595199585, "28032": 0.7248653769493103, "28156": 0.5404602885246277, "28177": 0.2674594223499298, "28227": 0.47463157773017883, "28518": 1.0526502132415771, "28835": 1.0305955410003662, "28901": 0.19220098853111267, "28931": 0.7408206462860107, "29290": 0.1221139207482338} | 21931005 | Permeabilized rat kidney cells rapidly released glucose 6-phosphate dehydrogenase (G6PD) following stimulation with peptide growth factors (Stanton, R.C., Seifter, J.L., Boxer, D.C., Zimmerman, E., and Cantley, L. C. (1991) J. Biol. Chem. 266, 12442-12448). To evaluate the signal transduction pathways mediating release of G6PD, two cell lines transfected with wild type or mutant platelet-derived growth factor (PDGF) receptors (PDGFR) were studied using two permeabilization protocols. G6PD release was evaluated by enzyme activity and Western blot analysis. PDGF caused a significant increase in G6PD release in 1 min in cells transfected with wild type PDGFR. PDGF did not stimulate G6PD release in cells transfected with tyrosine kinase-deficient PDGFR. PDGF did not stimulate G6PD release in cells transfected with partially autophosphorylation-deficient PDGFR in which four known signaling proteins do not associate with the PDGFR. The PDGF-stimulated release of G6PD was partially restored in PDGFR mutants in which either phosphatidylinositol-3-kinase or phospholipase C gamma 1 could associate with the PDGFR. Lastly, there was no basal or PDGF-stimulated phosphorylation of G6PD. We conclude that release of G6PD: 1) requires intrinsic PDGFR tyrosine kinase activity; 2) requires PDGFR autophosphorylation; 3) is mediated by signaling proteins that associate with the PDGFR; 4) is not mediated by direct phosphorylation of G6PD. | Signal transduction proteins that associate with the platelet-derived growth factor (PDGF) receptor mediate the PDGF-induced release of glucose-6-phosphate dehydrogenase from permeabilized cells. |
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"23614": 0.15777134895324707, "24093": 0.2317005842924118, "24221": 0.14179791510105133, "24290": 0.04394211992621422, "25172": 0.20660123229026794, "25468": 0.19541899859905243, "25750": 0.06429435312747955, "25969": 0.4067663550376892, "26013": 1.2862366437911987, "26236": 0.2478361576795578, "26638": 0.06154331564903259, "26646": 0.09672962874174118, "26835": 0.6451379656791687, "26876": 0.06612417846918106, "27179": 0.35950297117233276, "27287": 0.7764897346496582, "27321": 0.7417513132095337, "28297": 0.5021947622299194, "28389": 0.0174254160374403, "28472": 0.3897167444229126, "28498": 1.0526502132415771, "28522": 0.7978238463401794, "28788": 0.32553088665008545, "29107": 1.2824517488479614, "29334": 1.271558403968811, "29486": 0.630689799785614} | 21932050 | Human cytomegalovirus (HCMV) is one of the largest known DNA viruses. It is ubiquitous, and following resolution of primary productive infection, it persists in the human host by establishing a lifelong latent infection in myeloid lineage cells such as monocytes and their progenitors. Most adults with HCMV infection are healthy but it can cause neurologic deficits in infants, and remains an important cause of morbidity and mortality in the immunosuppressed patient. Microarray-based studies of HCMV have provided useful information about genes that are transcriptionally active during both productive and latent phases of infection. This chapter describes how to study genes in HCMV using microarrays and two cell types (productively infected human foreskin fibroblasts, and latently infected primary human myeloid progenitor cells). | Microarrays for the study of viral gene expression during human cytomegalovirus latent infection. |
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(H(2)S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H(2)S had only been known for its toxicity and environmental hazard. Physiological importance of H(2)S has been appreciated for about a decade. It started by the discovery of endogenous H(2)S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H(2)S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H(2)S. The physiological functions of H(2)S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H(2)S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma, to name a few. Many new technologies have been developed to detect endogenous H(2)S production, and novel H(2)S-delivery compounds have been invented to aid therapeutic intervention of diseases related to abnormal H(2)S metabolism. While acknowledging the challenges ahead, research on H(2)S physiology and medicine is entering an exponential exploration era. | Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. |
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0.22782009840011597, "28283": 0.7647408246994019, "28498": 1.0567318201065063, "28691": 0.09495500475168228, "28742": 0.004870930220931768, "28938": 0.23633737862110138, "29533": 0.04487626627087593} | 21943141 | The recent discovery of a ubiquitous translocation pathway, specifically required for proteins with a twin-arginine motif in their signal peptide, has focused interest on its membrane-bound components, one of which is known as TatC. Unlike most organisms of which the genome has been sequenced completely, the Gram-positive eubacterium Bacillus subtilis contains two tatC-like genes denoted tatCd and tatCy. The corresponding TatCd and TatCy proteins have the potential to be involved in the translocation of 27 proteins with putative twin-arginine signal peptides of which approximately 6-14 are likely to be secreted into the growth medium. Using a proteomic approach, we show that PhoD of B. subtilis, a phosphodiesterase belonging to a novel protein family of which all known members are synthesized with typical twin-arginine signal peptides, is secreted via the twin-arginine translocation pathway. Strikingly, TatCd is of major importance for the secretion of PhoD, whereas TatCy is not required for this process. Thus, TatC appears to be a specificity determinant for protein secretion via the Tat pathway. Based on our observations, we hypothesize that the TatC-determined pathway specificity is based on specific interactions between TatC-like proteins and other pathway components, such as TatA, of which three paralogues are present in B. subtilis. | TatC is a specificity determinant for protein secretion via the twin-arginine translocation pathway. |
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Protein desumoylation is carried out by SUMO proteases, which control cellular mechanisms ranging from transcription and cell division to ribosome biogenesis. Recent advances include the discovery of two novel classes of SUMO proteases, insights regarding SUMO protease specificity, and revelations of previously unappreciated SUMO protease functions in several key cellular pathways. These developments, together with new connections between SUMO proteases and the recently discovered SUMO-targeted ubiquitin ligases (STUbLs), make this an exciting period to study these enzymes. | Function and regulation of SUMO proteases |
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microbiota in a beneficial manner. It is therefore expected that prebiotics will improve health in a way similar to probiotics, whilst at the same time being cheaper, and carrying less risk and being easier to incorporate into the diet than probiotics. AIM To review published evidence for prebiotic effects on gut function and human health. METHODS We searched the Science Citation Index with the terms prebiotic, microbiota, gut bacteria, large intestine, mucosa, bowel habit, constipation, diarrhoea, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pouchitis, calcium and cancer, focussing principally on studies in humans and reports in the English language. Search of the Cochrane Library did not identify any clinical study or meta-analysis on this topic. RESULTS Three prebiotics, oligofructose, galacto-oligosaccharides and lactulose, clearly alter the balance of the large bowel microbiota by increasing bifidobacteria and Lactobacillus numbers. These carbohydrates are fermented and give rise to short-chain fatty acid and intestinal gas; however, effects on bowel habit are relatively small. Randomized-controlled trials of their effect in a clinical context are few, although animal studies show anti-inflammatory effects in inflammatory bowel disease, while calcium absorption is increased. CONCLUSIONS It is still early days for prebiotics, but they offer the potential to modify the gut microbial balance in such a way as to bring direct health benefits cheaply and safely. | Review article: prebiotics in the gastrointestinal tract. |
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"24759": 0.6517757177352905, "25095": 0.18004031479358673, "25167": 0.016465263441205025, "25169": 0.25995752215385437, "25221": 0.0058422754518687725, "25860": 0.29036402702331543, "26237": 0.2184450328350067, "26319": 0.2223619967699051, "26786": 0.08154398202896118, "27019": 1.256105661392212, "27354": 0.5568217039108276, "27641": 0.26446542143821716, "28024": 0.9842413663864136, "28093": 0.2145126610994339, "28102": 0.14095009863376617, "28309": 0.08603433519601822, "28321": 0.02316705882549286, "28348": 0.00875066313892603, "28436": 0.2990913391113281, "28578": 0.8740028142929077, "28817": 0.7845434546470642, "29458": 0.5618454217910767, "29477": 0.1477125883102417} | 21957231 | The aim of the present study was to examine the association between pain catastrophizing and general health status in a Dutch adult community sample, including various subgroups of people with musculoskeletal pain in the analyses. For exploratory reasons this study partly replicated previous studies of the factor structure, reliability, and validity of the Pain Catastrophizing Scale (PCS). Results demonstrated that across different pain subgroups, catastrophizing uniquely contributed variance to the prediction of the various aspects of general health status beyond the variance explained by pain intensity, age, gender, and chronicity. Across subgroups strongest associations were found between catastrophizing and mental health, general health perception, social functioning, and vitality. Furthermore, the association between catastrophizing and the various aspects of general health status was not moderated by the chronicity of the pain. Results of the confirmatory factor analysis statistically confirmed a three-factor model of the PCS, which was invariant across different subgroups of people with musculoskeletal pain. Inter-factor correlations were high, and the incremental explanatory power of the three-factor model over that of a one-factor model was only marginal. This implies that a one-factor model might be justifiable as well, at least in the general community. Across various pain subgroups the reliability of the PCS total and subscales was adequate. Additional evidence for the concurrent validity of the PCS was found as well. | Pain catastrophizing and general health status in a large Dutch community sample. |
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To compare the relative risks of serious gastrointestinal complications reported with individual non-steroidal anti-inflammatory drugs. DESIGN Systematic review of controlled epidemiological studies that found a relation between use of the drugs and admission to hospital for haemorrhage or perforation. SETTING Hospital and community based case-control and cohort studies. MAIN OUTCOME MEASURES (a) Estimated relative risks of gastrointestinal complications with use of individual drugs, exposure to ibuprofen being used as reference; (b) a ranking that best summarised the sequence of relative risks observed in the studies. RESULTS 12 studies met the inclusion criteria. 11 provided comparative data on ibuprofen and other drugs. Ibuprofen ranked lowest or equal lowest for risk in 10 of the 11 studies. Pooled relative risks calculated with exposure to ibuprofen used as reference were all significantly greater than 1.0 (interval of point estimates 1.6 to 9.2). Overall, ibuprofen was associated with the lowest relative risk, followed by diclofenac. Azapropazone, tolmetin, ketoprofen, and piroxicam ranked highest for risk and indomethacin, naproxen, sulindac, and aspirin occupied intermediate positions. Higher doses of ibuprofen were associated with relative risks similar to those with naproxen and indomethacin. CONCLUSIONS The low risk of serious gastrointestinal complications with ibuprofen seems to be attributable mainly to the low doses of the drug used in clinical practice. In higher doses ibuprofen is associated with a similar risk to other non-steroidal anti-inflammatory drugs. Use of low risk drugs in low dosage as first line treatment would substantially reduce the morbidity and mortality due to serious gastrointestinal toxicity from these drugs. | Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a collaborative meta-analysis. |
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0.9021284580230713, "25455": 0.4374985992908478, "25494": 0.15610189735889435, "25525": 0.6212902665138245, "25831": 0.06429435312747955, "26181": 0.11951763927936554, "26319": 0.2576959431171417, "26780": 0.38574060797691345, "27354": 0.11865071207284927, "28093": 0.2223619967699051, "28268": 0.846739649772644, "28329": 0.11081436276435852, "28418": 0.07250232994556427, "28436": 0.2689530849456787, "28488": 0.6754127144813538, "28782": 0.040196798741817474, "29050": 0.025073638185858727, "29180": 0.0354953333735466, "29295": 0.0606246218085289} | 21993510 | OBJECTIVE To provide an independent evaluation of seven day weighed dietary records, which are currently accepted as the most accurate technique for assessing habitual dietary intake in studies investigating the links between diet and health. DESIGN Subjects who had previously participated in the Northern Ireland diet and health study were reselected by stratified random sampling to represent the range of energy intakes in the study as assessed by the seven day weighed dietary record. SETTING Northern Ireland. SUBJECTS 31 Free living adults (16 men and 15 women). MAIN OUTCOME MEASURES Energy intake as measured by the seven day weighed dietary record and total energy expenditure estimated concurrently by the doubly labelled water technique. RESULTS Average recorded energy intakes were significantly lower than measured expenditure in the group overall (9.66 MJ/day v 12.15 MJ/day, 95% confidence interval 1.45 to 3.53 MJ/day). Among those in the upper third of energy intakes the mean (SE) ratio of intake to expenditure was close to 1.0, indicating accurate records (men 1.01 (0.11), women 0.96 (0.08]. In the middle and lower thirds the ratios for men were only 0.74 (0.05) and 0.70 (0.07) respectively and for women 0.89 (0.07) and 0.61 (0.07). CONCLUSIONS These results show a serious bias in reporting habitual energy intake. If substantiated they may have wide implications for the interpretation of many nutritional studies. | Accuracy of weighed dietary records in studies of diet and health. |
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22003328 | Clustered regularly interspaced short palindromic repeats (CRISPRs) together with the associated CAS proteins protect microbial cells from invasion by foreign genetic elements using presently unknown molecular mechanisms. All CRISPR systems contain proteins of the CAS2 family, suggesting that these uncharacterized proteins play a central role in this process. Here we show that the CAS2 proteins represent a novel family of endoribonucleases. Six purified CAS2 proteins from diverse organisms cleaved single-stranded RNAs preferentially within U-rich regions. A representative CAS2 enzyme, SSO1404 from Sulfolobus solfataricus, cleaved the phosphodiester linkage on the 3'-side and generated 5'-phosphate- and 3'-hydroxyl-terminated oligonucleotides. The crystal structure of SSO1404 was solved at 1.6A resolution revealing the first ribonuclease with a ferredoxin-like fold. Mutagenesis of SSO1404 identified six residues (Tyr-9, Asp-10, Arg-17, Arg-19, Arg-31, and Phe-37) that are important for enzymatic activity and suggested that Asp-10 might be the principal catalytic residue. Thus, CAS2 proteins are sequence-specific endoribonucleases, and we propose that their role in the CRISPR-mediated anti-phage defense might involve degradation of phage or cellular mRNAs. | A novel family of sequence-specific endoribonucleases associated with the clustered regularly interspaced short palindromic repeats. |
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0.10026945173740387, "26237": 1.1236859560012817, "26319": 0.08871890604496002, "26369": 0.8941729068756104, "26404": 0.05046287178993225, "26563": 0.9628462791442871, "26699": 0.8780695199966431, "27162": 0.25995752215385437, "27197": 0.9037119746208191, "27312": 0.07793712615966797, "27400": 0.3409265875816345, "27794": 0.8821197748184204, "28207": 0.25088030099868774, "28436": 0.17431432008743286, "28488": 0.2652147710323334, "28691": 0.06246116757392883, "28739": 0.0606246218085289, "28774": 0.7076893448829651, "29107": 0.10555581003427505, "29299": 0.29400965571403503, "29458": 0.10026945173740387, "29477": 0.24325250089168549} | 22007333 | Menstrual and reproductive factors may increase breast cancer risk through a pathway that includes increased mammographic density. We assessed whether known or suspected menstrual and reproductive breast cancer risk factors were cross-sectionally associated with mammographic density, by measuring area of radiographic density and total breast area on mammograms from 801 participants in the Study of Women’s Health Across the Nation (SWAN), a multi-ethnic cohort of pre- and early perimenopausal women. From multivariable linear regression, the following menstrual or reproductive factors were independently associated with percent mammographic density (area of dense breast/breast area): older age at menarche (β = 10.3, P < 0.01, for >13 vs. <12 years), premenstrual cravings and bloating (β = −3.36, P = 0.02), younger age at first full-term birth (β = −8.12, P < 0.01 for ≤23 years versus no births), greater number of births (β = −6.80, P < 0.01 for ≥3 births versus no births), and premenopausal status (β = 3.78, P < 0.01 versus early perimenopausal). Only number of births remained associated with percent density after adjustment for age, race/ethnicity, study site, body mass index (BMI), and smoking. In addition, stratified analyses revealed that the association with number of births was confined to women within the lowest BMI tertile (β = −12.2, P < 0.01 for ≥3 births versus no births). Our data support a mechanism for parity and breast cancer that involves mammographic density among pre- and early perimenopausal women that may be modified by body size. | Menstrual and reproductive factors in relation to mammographic density: the Study of Women’s Health Across the Nation (SWAN) |
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0.09228714555501938, "25060": 0.2659635543823242, "25117": 0.0019512200960889459, "25206": 0.26146242022514343, "25469": 0.04953393340110779, "25937": 0.13071982562541962, "26305": 0.41001203656196594, "26572": 0.5180262327194214, "26601": 0.5718178153038025, "26657": 0.06886265426874161, "26741": 0.15442965924739838, "26780": 0.24859806895256042, "26874": 0.11778303235769272, "27197": 0.8500841856002808, "28227": 0.8264343738555908, "28268": 0.1011524572968483, "28290": 0.06703783571720123, "28403": 0.9591107368469238, "29125": 0.24554696679115295, "29166": 0.9294845461845398} | 22023404 | CONTEXT Vitamin D deficiency is associated with many adverse health outcomes, yet little is known about the genetic epidemiology of vitamin D or its metabolites. OBJECTIVE Our objective was to examine the relationship among three vitamin D-related genes and levels of 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] in Hispanics (HAs) and African Americans (AAs). DESIGN AND SETTING The cross-sectional Insulin Resistance Atherosclerosis Family Study recruited and examined subjects in: Los Angeles, California (AAs; 513 individuals from 42 families); San Luis Valley (SLV), Colorado (HAs; 513 individuals from 30 families); and San Antonio (SA), Texas (HAs; 504 individuals from 58 families). MAIN OUTCOME MEASURES Plasma levels of 25(OH)D and 1,25(OH)2D were measured. RESULTS Levels of 25(OH)D were highest in SLV-HAs [18.3 +/- 7.7 ng/ml (45.7 +/- 19.2 nmol/liter)], lower in SA-HAs [14.6 +/- 6.4 ng/ml (36.4 +/- 16.0 nmol/liter)], and lowest in AAs [11.0 +/- 5.4 ng/ml (27.5 +/- 13.5 nmol/liter)]. Levels of 1,25(OH)2D were similar in AAs [43.5 +/- 13.9 pg/ml (113.1 +/- 36.1 pmol/liter)] and SLV-HAs [43.2 +/- 13.3 pg/ml (112.3 +/- 34.6 pmol/liter)], but higher in SA-HAs [48.6 +/- 17.0 pg/ml (126.4 +/- 44.2 pmol/liter)]. After adjusting for gender and age within the site, two single nucleotide polymorphisms (SNPs) in the vitamin D binding protein gene (DBP), rs4588 and rs7041, were associated with 25(OH)D, and one SNP in the DBP, rs4588, was associated with 1,25(OH)2D at all three study centers. CONCLUSIONS SNPs in the DBP are associated with levels of 25(OH)D and 1,25(OH)2D in HA and AA participants in the Insulin Resistance Atherosclerosis Family Study. | Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans. |
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0.1384023278951645, "25473": 0.8989537954330444, "25609": 0.7898768186569214, "25714": 0.17922431230545044, "25761": 0.10026945173740387, "25937": 0.05694137513637543, "26243": 0.272677481174469, "26308": 1.3118107318878174, "26394": 0.9944084882736206, "26514": 0.5069117546081543, "26572": 0.5914691090583801, "26651": 0.2018241584300995, "26872": 0.00875066313892603, "26942": 0.7258110046386719, "27152": 0.1751343309879303, "27159": 0.02792670577764511, "27295": 0.7352184057235718, "27341": 0.06612417846918106, "27391": 0.9178520441055298, "27896": 0.11604541540145874, "28228": 0.08154398202896118, "28424": 0.47036975622177124, "28613": 0.07068414986133575, "28691": 0.15023678541183472, "28765": 0.7295845746994019, "28835": 0.175953671336174, "29290": 0.3870677351951599, "29304": 0.15359249711036682, "29610": 0.010684899985790253} | 22025252 | The formation of inositol phosphates in response to agonists was studied in brain slices, parotid gland fragments and in the insect salivary gland. The tissues were first incubated with [3H]inositol, which was incorporated into the phosphoinositides. All the tissues were found to contain glycerophosphoinositol, inositol 1-phosphate, inositol 1,4-bisphosphate and inositol 1,4,5-trisphosphate, which were identified by using anion-exchange and high-resolution anion-exchange chromatography, high-voltage paper ionophoresis and paper chromatography. There was no evidence for the existence of inositol 1:2-cyclic phosphate. A simple anion-exchange chromatographic method was developed for separating these inositol phosphates for quantitative analysis. Stimulation caused no change in the levels of glycerophosphoinositol in any of the tissues. The most prominent change concerned inositol 1,4-bisphosphate, which increased enormously in the insect salivary gland and parotid gland after stimulation with 5-hydroxytryptamine and carbachol respectively. Carbachol also induced a large increase in the level of inositol 1,4,5-trisphosphate in the parotid. Stimulation of brain slices with carbachol induced modest increase in the bis- and tris-phosphate. In all the tissues studied, there was a significant agonist-dependent increase in the level of inositol 1-phosphate. The latter may be derived from inositol 1,4-bisphosphate, because homogenates of the insect salivary gland contain a bisphosphatase in addition to a trisphosphatase. These results suggest that the earliest event in the stimulus-response pathway is the hydrolysis of polyphosphoinositides by a phosphodiesterase to yield inositol 1,4,5-trisphosphate and inositol 1,4-bisphosphate, which are subsequently hydrolysed to inositol 1-phosphate and inositol. The absence of inositol 1:2-cyclic phosphate could indicate that, at very short times after stimulation, phosphatidylinositol is not catabolized by its specific phosphodiesterase, or that any cyclic derivative liberated is rapidly hydrolysed by inositol 1:2-cyclic phosphate 2-phosphohydrolase. | Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides. |
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"26288": 1.0416836738586426, "26305": 0.015504186972975731, "26601": 0.06429435312747955, "26721": 0.02792670577764511, "27642": 0.015504186972975731, "27777": 0.08782484382390976, "27854": 0.45499902963638306, "27928": 0.11081436276435852, "28089": 0.5139457583427429, "28177": 0.2674594223499298, "28282": 1.2753846645355225, "28848": 0.6583697199821472, "28938": 0.1905880719423294, "29295": 0.009718249551951885, "29532": 0.7276995778083801} | 22029384 | L-glutamate, the principal excitatory transmitter in the brain, gates ion channels mediating fast neurotransmission. Subunit components of two related classes of glutamate receptor channels have been characterized by cDNA cloning and shown to carry either an arginine or a glutamine residue in a defined position of their putative channel-forming segment. The arginine residue in this segment profoundly alters, and dominates, the properties of ion flow, as demonstrated for one channel class. We now show that the genomic DNA sequences encoding the particular channel segment of all subunits harbor a glutamine codon (CAG), even though an arginine codon (CGG) is found in mRNAs of three subunits. Multiple genes and alternative exons were excluded as sources for the arginine codon; hence, we propose that transcripts for three subunits are altered by RNA editing. This process apparently edits subunit transcripts of the two glutamate receptor classes with different efficiency and selectivity. | RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. |
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"25520": 0.304147332906723, "25707": 0.1905880719423294, "25761": 0.41065993905067444, "26244": 1.0933903455734253, "26402": 0.5324648022651672, "26524": 0.8861536383628845, "26557": 0.07431721687316895, "26601": 0.2674594223499298, "26702": 0.8161250352859497, "26773": 0.42096930742263794, "26986": 0.9546096324920654, "27854": 0.07793712615966797, "28498": 0.823009729385376, "28633": 0.2749055027961731, "29393": 0.36900100111961365} | 22036571 | The AMP-activated protein kinase (AMPK) is a ubiquitous mammalian protein kinase important in the adaptation of cells to metabolic stress. The enzyme is a heterotrimer, consisting of a catalytic alpha subunit and regulatory beta and gamma subunits, each of which is a member of a larger isoform family. The enzyme is allosterically regulated by AMP and by phosphorylation of the alpha subunit. The beta subunit is post-translationally modified by myristoylation and multi-site phosphorylation. In the present study, we have examined the impact of post-translational modification of the beta-1 subunit on enzyme activity, heterotrimer assembly and subcellular localization, using site-directed mutagenesis and expression of subunits in mammalian cells. Removal of the myristoylation site (G2A mutant) results in a 4-fold activation of the enzyme and relocalization of the beta subunit from a particulate extranuclear distribution to a more homogenous cell distribution. Mutation of the serine-108 phosphorylation site to alanine is associated with enzyme inhibition, but no change in cell localization. In contrast, the phosphorylation site mutations, SS24, 25AA and S182A, while having no effects on enzyme activity, are associated with nuclear redistribution of the subunit. Taken together, these results indicate that both myristoylation and phosphorylation of the beta subunit of AMPK modulate enzyme activity and subunit cellular localization, increasing the complexity of AMPK regulation. | Post-translational modifications of the beta-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. |
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0.757441520690918, "26773": 0.4419025182723999, "26786": 0.7398891448974609, "26906": 0.7845434546470642, "26996": 0.36358460783958435, "27142": 0.5461324453353882, "27226": 0.319873183965683, "28156": 0.66441810131073, "28268": 0.1358480453491211, "28283": 0.7907629609107971, "29180": 1.0960047245025635, "29206": 1.0464962720870972, "29384": 0.11256109178066254, "29458": 0.07341018319129944, "29516": 0.34300774335861206} | 22038539 | In mammals, caloric restriction consistently results in extended lifespan. Epigenetic information encoded by DNA methylation is tightly regulated, but shows a striking drift associated with age that includes both gains and losses of DNA methylation at various sites. Here, we report that epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans. Twenty-two to 30-year-old rhesus monkeys exposed to 30% caloric restriction since 7-14 years of age showed attenuation of age-related methylation drift compared to ad libitum-fed controls such that their blood methylation age appeared 7 years younger than their chronologic age. Even more pronounced effects were seen in 2.7-3.2-year-old mice exposed to 40% caloric restriction starting at 0.3 years of age. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression. We propose that epigenetic drift is a determinant of lifespan in mammals. Caloric restriction has been shown to increase lifespan in mammals. Here, the authors provide evidence that age-related methylation drift correlates with lifespan and that caloric restriction in mice and rhesus monkeys results in attenuation of age-related methylation drift. | Caloric restriction delays age-related methylation drift |
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0.043007105588912964, "27363": 0.22626367211341858, "27854": 0.2719337046146393, "28424": 1.2307592630386353, "28433": 0.21530038118362427, "28648": 0.20739519596099854, "28691": 0.24171993136405945, "28699": 0.8433839678764343, "29021": 0.15526613593101501, "29060": 0.6286086440086365, "29104": 0.4788752794265747, "29237": 0.9076598286628723, "29304": 0.10026945173740387, "29490": 0.39762192964553833} | 22042345 | Most protein complexes are inaccessible to high resolution structural analysis. We report the results of a combined approach of cross-linking, mass spectrometry, and bioinformatics to two human complexes containing large coiled-coil segments, the NDEL1 homodimer and the NDC80 heterotetramer. An important limitation of the cross-linking approach, so far, was the identification of cross-linked peptides from fragmentation spectra. Our novel approach overcomes the data analysis bottleneck of cross-linking and mass spectrometry. We constructed a purpose-built database to match spectra with cross-linked peptides, define a score that expresses the quality of our identification, and estimate false positive rates. We show that our analysis sheds light on critical structural parameters such as the directionality of the homodimeric coiled coil of NDEL1, the register of the heterodimeric coiled coils of the NDC80 complex, and the organization of a tetramerization region in the NDC80 complex. Our approach is especially useful to address complexes that are difficult in addressing by standard structural methods. | Structural analysis of multiprotein complexes by cross-linking, mass spectrometry, and database searching. |
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0.11604541540145874, "25538": 0.2516399025917053, "25644": 0.0354953333735466, "25714": 0.06703783571720123, "26013": 0.11343330889940262, "26033": 0.1677299439907074, "26224": 0.31132611632347107, "26236": 0.11343330889940262, "26402": 0.23324857652187347, "26435": 0.24859806895256042, "26512": 0.11256109178066254, "26520": 0.06795065850019455, "26534": 0.27044451236724854, "26601": 0.3777405619621277, "26702": 0.0842406153678894, "26773": 0.8682814836502075, "26775": 0.1734936386346817, "27144": 0.35403475165367126, "27233": 0.10906458646059036, "27237": 0.10026945173740387, "27781": 0.016465263441205025, "27854": 0.23402166366577148, "28207": 0.02792670577764511, "28794": 0.052318159490823746, "28848": 0.34715715050697327, "29206": 0.9591107368469238, "29290": 0.46486347913742065, "29490": 0.24631060659885406} | 22049489 | The lncRNA H19 has been recently shown to be upregulated and play important roles in gastric cancer tumorigenesis. However, the precise molecular mechanism of H19 and its mature product miR-675 in the carcinogenesis of gastric cancer remains unclear. In this study, we found that miR-675 was positively expressed with H19 and was a pivotal mediator in H19-induced gastric cancer cell growth promotion. Subsequently, the tumor suppressor Runt Domain Transcription Factor1 (RUNX1) was confirmed to be a direct target of miR-675 using a luciferase reporter assay and Western blotting analyses. A series of rescue assays indicated that RUNX1 mediated H19/miR-67-induced gastric cancer cell phenotypic changes. Moreover, the inverse relationship between the expression of RUNX1 and H19/miR-675 was also revealed in gastric cancer tissues and gastric cancer cell lines. Taken together, our study demonstrated that the novel pathway H19/miR-675/RUNX1 regulates gastric cancer development and may serve as a potential target for gastric cancer therapy. | The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1. |
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We report a case of a prepubertal child who developed unwanted erections after commencing a response-adjusted dosing regimen of sustained release methylphenidate. Despite priapism being a rare adverse reaction associated with methylphenidate, physicians and parents need to be aware as it can have significant long-term complications. | Methylphenidate-induced erections in a prepubertal child. |
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0.2105647772550583, "28778": 0.2822965085506439, "28788": 0.029824240133166313, "28807": 0.2018241584300995, "28873": 0.5080875158309937, "29090": 0.05046287178993225, "29107": 0.14433705806732178, "29206": 0.04674193635582924, "29490": 0.055094651877880096, "29596": 0.15526613593101501, "29607": 0.3141832649707794} | 22059387 | Inflammation mediated by infection is an important factor causing carcinogenesis. Opisthorchis viverrini (OV) infection is a risk factor of cholangiocarcinoma (CHCA), probably through chronic inflammation. Formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), and expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) were assessed in the liver of hamsters infected with OV. We newly produced specific anti-8-nitroguanine antibody without cross-reaction. Double immunofluorescence staining revealed that 8-oxodG and 8-nitroguanine were formed mainly in the same inflammatory cells and epithelium of bile ducts from day 7 and showed the strongest immunoreactivity on days 21 and 30, respectively. It is noteworthy that 8-oxodG and 8-nitroguanine still remained in epithelium of bile ducts on day 180, although amount of alanine aminotransferase activity returned to normal level. A time course of 8-nitroguanine was associated with iNOS expression. Furthermore, this study demonstrated that HO-1 expression and subsequent iron accumulation may be involved in enhancement of oxidative DNA damage in epithelium of small bile ducts. In conclusion, nitrative and oxidative DNA damage via iNOS expression in hamsters infected with OV may participate in CHCA carcinogenesis. | Mechanism of NO-mediated oxidative and nitrative DNA damage in hamsters infected with Opisthorchis viverrini: a model of inflammation-mediated carcinogenesis. |
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However, reliance on statistics with known asymptotic distribution is now unnecessary, as Monte Carlo simulations can be performed to estimate the significance level of any test statistic. We have implemented a Monte Carlo method for four 'chi-squared' test statistics, three of which involved combination of alleles, and evaluated their performance on a real data set. Combining rare alleles to avoid small expected cell counts, and considering each allele in turn against the rest, reduced the power to detect a genuine association when the number of alleles was very large. We should either not combine alleles at all, or combine them in such a way that preserves the evidence for an association. | Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. |
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Here, using Myh11-CreERT2 ROSA floxed STOP eYFP Apoe−/− mice to perform SMC lineage tracing, we find that traditional methods for detecting SMCs based on immunostaining for SMC markers fail to detect >80% of SMC-derived cells within advanced atherosclerotic lesions. These unidentified SMC-derived cells exhibit phenotypes of other cell lineages, including macrophages and mesenchymal stem cells (MSCs). SMC-specific conditional knockout of Krüppel-like factor 4 (Klf4) resulted in reduced numbers of SMC-derived MSC- and macrophage-like cells, a marked reduction in lesion size, and increases in multiple indices of plaque stability, including an increase in fibrous cap thickness as compared to wild-type controls. On the basis of in vivo KLF4 chromatin immunoprecipitation–sequencing (ChIP-seq) analyses and studies of cholesterol-treated cultured SMCs, we identified >800 KLF4 target genes, including many that regulate pro-inflammatory responses of SMCs. Our findings indicate that the contribution of SMCs to atherosclerotic plaques has been greatly underestimated, and that KLF4-dependent transitions in SMC phenotype are critical in lesion pathogenesis. | KLF4-dependent phenotypic modulation of smooth muscle cells has a key role in atherosclerotic plaque pathogenesis |
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1.0828639268875122, "28329": 0.2539152204990387, "28466": 0.28963330388069153, "28685": 0.4812922179698944, "28767": 0.44753631949424744, "28828": 0.9371650815010071, "28868": 0.3662964701652527, "29048": 0.684319257736206, "29398": 0.026976587250828743, "29458": 0.030771657824516296, "29577": 0.1808556467294693, "29610": 0.28963330388069153} | 22107641 | OBJECTIVE The purpose of this study was to determine whether microstructural abnormalities in the white matter of the dorsolateral prefrontal cortex are associated with late-life depression. METHOD Seventeen elderly depressed subjects were compared with 16 elderly subjects who were not depressed. Diffusion tensor imaging was used to measure the fractional anisotropy of the white matter in the dorsolateral prefrontal cortex's superior and middle frontal gyri bilaterally and in the left occipital lobe as a control region. The authors compared results between groups while controlling for age, sex, and comorbid medical disorders. RESULTS Even after controlling for age, sex, hypertension, and heart disease, the authors found significantly lower fractional anisotropy values in the right superior frontal gyrus white matter of depressed patients than comparison subjects. CONCLUSIONS Microstructural changes in the white matter of the right superior frontal gyrus are associated with late-life depression. Further work is needed to determine how these changes contribute to depression outcomes. | Late-life depression and microstructural abnormalities in dorsolateral prefrontal cortex white matter. |
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0.8941729068756104, "29721": 0.7333439588546753} | 22116439 | Tau aggregation and amyloid β protein (Aβ) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aβ production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3β, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD. | Pioglitazone prevents tau oligomerization. |
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"26163": 0.6598852276802063, "26224": 0.2983669638633728, "26237": 0.24248650670051575, "26462": 0.1619328260421753, "26651": 0.012615402229130268, "26745": 0.2145126610994339, "26786": 0.02316705882549286, "27019": 0.2822965085506439, "27144": 0.0174254160374403, "27881": 0.5433003902435303, "28436": 0.20580662786960602, "28689": 0.9131608605384827, "28723": 0.1358480453491211, "28739": 0.7105726003646851, "29207": 0.03831886500120163, "29295": 0.09317722171545029, "29299": 0.8941729068756104, "29458": 0.9100211262702942} | 22123421 | BACKGROUND Mean platelet volume (MPV) is a platelet volume index. Classically, MPV was recognized as a hallmark of platelet activation. Recent studies have revealed that the MPV and MPV/platelet count (PC) ratio can predict long-term mortality in patients with ischemic cardio-vascular disease. In addition, these indices were correlated with the pathophysiological characteristics of patients with various disorders, including malignant tumors. PATIENTS AND METHODS We retrospectively analyzed various hematological indices of patients with advanced non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the contribution of platelet volume indices to survival in these patients. RESULTS A total of 268 patients were enrolled in the study. The median age of the patients was 68 years (range: 31-87 years). We compared various hematological indices between the NSCLC group and an age- and sex-matched comparator group. MPV was significantly decreased in the NSCLC group compared to the comparator group. In contrast, the PC was significantly increased in the NSCLC group. Consequently, the MPV/PC ratio was also decreased in the NSCLC group (0.397 vs. 0.501). In receiver operating characteristics (ROC) curve analysis, the MPV/PC ratio was associated with a sensitivity of 62.3% and a specificity of 74.6% at a cutoff value of 0.408730 (area under the curve [AUC], 0.72492)]. Univariate analysis revealed that overall survival (OS) was significantly shorter in the group with a low MPV/PC ratio than in the other group (median survival time [MST]: 10.3 months vs. 14.5 months, log-rank, P=0.0245). Multivariate analysis confirmed that a low MPV/PC ratio was an independent unfavorable predictive factor for OS (hazard ratio [HR]: 1.668, 95% confidence interval [CI]: 1.235-2.271, P=0.0008). CONCLUSION These data clearly demonstrate that the MPV/PC ratio was closely associated with survival in patients with advanced NSCLC. | Prognostic impact of the mean platelet volume/platelet count ratio in terms of survival in advanced non-small cell lung cancer. |
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is important in the postmarketing surveillance of biologicals, since changes in the manufacturing process may give rise to product- or batch-specific risks. With the expected expansion of the biosimilar market, there have been concerns about the ability to trace individual products within pharmacovigilance databases. AREAS COVERED The authors discuss the present challenges in the traceability of biologicals in relation to pharmacovigilance, by exploring the processes involved in ensuring traceability. They explore both the existing systems that are in place for the recording of exposure information in clinical practice, as well as the critical steps involved in the transfer of exposure data to various pharmacovigilance databases. EXPERT OPINION The existing systems ensure the traceability of biologicals down to the manufacturer within pharmacy records, but do not support the routine recording of batch information. Expected changes in supply chain standards provide opportunities to systematically record detailed exposure information. Spontaneous reporting systems are the most vulnerable link in ensuring traceability, due to the manual nature of data transfer. Efforts to improve the traceability should, in the short term, be focused toward encouraging health professionals and patients to systematically record and report detailed exposure information. Long-term solutions lie in expanding the accessibility to, and increasing the electronic exchange of exposure data. | Traceability of biologicals: present challenges in pharmacovigilance. |
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"27854": 1.2704625129699707, "27881": 0.11430477350950241, "28696": 0.16524957120418549, "28788": 0.25088030099868774, "28873": 0.26146242022514343, "28938": 0.11256109178066254, "29090": 0.18004031479358673, "29170": 0.020300358533859253, "29268": 0.12038381397724152, "29290": 0.007782140281051397} | 22134353 | Natural killer (NK) cells are able to lyse infected and tumor cells while sparing healthy cells. Recognition of diseased cells by NK cells is governed by several activating and inhibitory receptors. We review numerous pathways that have been implicated in the regulation of self-ligands for activating receptors, including NKG2D, DNAM-1, LFA-1, NKp30, NKp44, NKp46, NKp65, and NKp80 found on NK cells and some T cells. Understanding how the regulation of self-encoded ligand expression is regulated may provide novel avenues for future therapeutic approaches to infections and cancer. | Regulation of self-ligands for activating natural killer cell receptors. |
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"26534": 0.0354953333735466, "26773": 0.755608320236206, "26775": 0.450652539730072, "27029": 0.05417001247406006, "27116": 0.05417001247406006, "27171": 0.3723714053630829, "27854": 0.1011524572968483, "28024": 0.19622190296649933, "28086": 1.3921366930007935, "28405": 0.24171993136405945, "28488": 0.018384648486971855, "28788": 0.09584271162748337, "28848": 0.27342069149017334, "28964": 0.1212492436170578, "28976": 0.007782140281051397, "28991": 1.2726531028747559, "29206": 0.1873544454574585, "29320": 0.05786345899105072} | 22150633 | Embryonic stem (ES) cells are unique in their ability to self-renew indefinitely and maintain pluripotency. These properties require transcription factors that specify the gene expression programme of ES cells. It has been possible to reverse the highly differentiated state of somatic cells back to a pluripotent state with a combination of four transcription factors: Klf4 is one of the reprogramming factors required, in conjunction with Oct4, Sox2 and c-Myc. Maintenance of self-renewal and pluripotency of ES cells requires Oct4, Sox2 and c-Myc, but Klf4 is dispensable. Here, we show that Krüppel-like factors are required for the self-renewal of ES cells. Simultaneous depletion of Klf2, Klf4 and Klf5 lead to ES cell differentiation. Chromatin immunoprecipitation coupled to microarray assay reveals that these Klf proteins share many common targets of Nanog, suggesting a close functional relationship between these factors. Expression analysis after triple RNA interference (RNAi) of the Klfs shows that they regulate key pluripotency genes, such as Nanog. Taken together, our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression that is unique to ES cells. | A core Klf circuitry regulates self-renewal of embryonic stem cells |
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0.2105647772550583, "26591": 0.26446542143821716, "26632": 1.0795515775680542, "26773": 0.42799583077430725, "26775": 0.12384103983640671, "26835": 0.503966212272644, "26986": 0.043007105588912964, "27152": 0.06886265426874161, "27427": 0.43623676896095276, "27441": 0.24018502235412598, "27699": 0.0009760859538801014, "27718": 0.27934664487838745, "27895": 0.0019512200960889459, "28156": 0.3262358605861664, "28177": 0.13755162060260773, "28227": 0.6054253578186035, "28297": 0.0029254043474793434, "28788": 0.06520967930555344, "28848": 0.7510106563568115, "28873": 0.21214580535888672, "29090": 0.8100618124008179, "29109": 0.06703783571720123, "29290": 0.6624060273170471} | 22153455 | Although gram-positive infections account for the majority of cases of sepsis, the molecular mechanisms underlying their effects remains poorly understood. We investigated how cell wall components of gram-positive bacteria contribute to the development of sepsis. Experimental observations derived from cultured primary macrophages and the cell line indicate that gram-positive bacterial endotoxins induce hypoxia-inducible factor 1α (HIF-1α) mRNA and protein expression. Inoculation of live or heat-inactivated gram-positive bacteria with macrophages induced HIF-1 transcriptional activity in macrophages. Concordant with these results, myeloid deficiency of HIF-1α attenuated gram-positive bacterial endotoxin-induced cellular motility and proinflammatory gene expression in macrophages. Conversely, gram-positive bacteria and their endotoxins reduced expression of the myeloid anti-inflammatory transcription factor Krüppel-like transcription factor 2 (KLF2). Sustained expression of KLF2 reduced and deficiency of KLF2 enhanced gram-positive endotoxins induced HIF-1α mRNA and protein expression in macrophages. More importantly, KLF2 attenuated gram-positive endotoxins induced cellular motility and proinflammatory gene expression in myeloid cells. Consistent with these results, mice deficient in myeloid HIF-1α were protected from gram-positive endotoxin-induced sepsis mortality and clinical symptomatology. By contrast, myeloid KLF2-deficient mice were susceptible to gram-positive sepsis induced mortality and clinical symptoms. Collectively, these observations identify HIF-1α and KLF2 as critical regulators of gram-positive endotoxin-mediated sepsis. | A myeloid hypoxia-inducible factor 1α-Krüppel-like factor 2 pathway regulates gram-positive endotoxin-mediated sepsis. |
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0.2034190446138382, "27441": 0.02792670577764511, "27585": 0.09761575609445572, "27631": 0.29255300760269165, "27759": 0.3027053773403168, "27793": 0.05139094591140747, "27876": 1.005902886390686, "27965": 0.16442140936851501, "27998": 0.7220231294631958, "28227": 0.603290855884552, "28507": 0.32199856638908386, "28691": 0.1685553640127182, "28739": 0.4824984669685364, "28742": 0.7182208299636841, "28775": 0.14349138736724854, "28873": 0.23710809648036957, "28931": 0.5635144114494324, "29111": 0.5427330136299133, "29215": 0.5718178153038025, "29226": 0.1946154683828354, "29297": 0.35745587944984436, "29342": 0.07068414986133575} | 22159299 | Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative intracellular pathogen that causes disease in a variety of hosts. S. Typhimurium actively invade host cells and typically reside within a membrane-bound compartment called the Salmonella-containing vacuole (SCV). The bacteria modify the fate of the SCV using two independent type III secretion systems (TTSS). TTSS are known to damage eukaryotic cell membranes and S. Typhimurium has been suggested to damage the SCV using its Salmonella pathogenicity island (SPI)-1 encoded TTSS. Here we show that this damage gives rise to an intracellular bacterial population targeted by the autophagy system during in vitro infection. Approximately 20% of intracellular S. Typhimurium colocalized with the autophagy marker GFP-LC3 at 1 h postinfection. Autophagy of S. Typhimurium was dependent upon the SPI-1 TTSS and bacterial protein synthesis. Bacteria targeted by the autophagy system were often associated with ubiquitinated proteins, indicating their exposure to the cytosol. Surprisingly, these bacteria also colocalized with SCV markers. Autophagy-deficient (atg5-/-) cells were more permissive for intracellular growth by S. Typhimurium than normal cells, allowing increased bacterial growth in the cytosol. We propose a model in which the host autophagy system targets bacteria in SCVs damaged by the SPI-1 TTSS. This serves to retain intracellular S. Typhimurium within vacuoles early after infection to protect the cytosol from bacterial colonization. Our findings support a role for autophagy in innate immunity and demonstrate that Salmonella infection is a powerful model to study the autophagy process. | Autophagy controls Salmonella infection in response to damage to the Salmonella-containing vacuole. |
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0.004870930220931768, "23924": 0.22782009840011597, "24054": 1.0533316135406494, "24269": 0.9951307773590088, "24374": 0.37035053968429565, "24594": 0.31132611632347107, "24848": 1.1211429834365845, "25194": 0.6634125709533691, "25209": 0.016465263441205025, "25456": 0.9485763907432556, "25644": 0.5584990978240967, "25714": 0.8500841856002808, "25761": 0.23324857652187347, "26243": 0.07341018319129944, "26402": 0.8764448165893555, "26520": 0.2659635543823242, "26534": 0.19381128251552582, "26773": 0.4356052577495575, "26819": 0.1221139207482338, "27295": 0.43623676896095276, "27531": 0.9907892942428589, "27854": 0.34370049834251404, "28290": 0.06886265426874161, "28691": 0.1384023278951645, "28696": 0.1602703034877777, "28774": 0.018384648486971855, "28788": 0.15359249711036682, "29206": 0.08692999184131622, "29290": 0.45623743534088135, "29610": 0.42799583077430725, "29721": 0.66441810131073} | 22174015 | The PI3K-Akt-mTORC1 axis contributes to the activation, survival, and proliferation of CD4(+) T cells upon stimulation through TCR and CD28. Here, we demonstrate that the suppression of this axis by deletion of p85α or PI3K/mTORC1 inhibitors as well as T cell-specific deletion of raptor, an essential component of mTORC1, impairs Th17 differentiation in vitro and in vivo in a S6K1/2-dependent fashion. Inhibition of PI3K-Akt-mTORC1-S6K1 axis impairs the downregulation of Gfi1, a negative regulator of Th17 differentiation. Furthermore, we demonstrate that S6K2, a nuclear counterpart of S6K1, is induced by the PI3K-Akt-mTORC1 axis, binds RORγ, and carries RORγ to the nucleus. These results point toward a pivotal role of PI3K-Akt-mTORC1-S6K1/2 axis in Th17 differentiation. | PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORγ. |
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0.013579257763922215, "26534": 0.14518201351165771, "26741": 0.17840765416622162, "26835": 0.011650617234408855, "26874": 0.21293537318706512, "27321": 0.7267557382583618, "27480": 0.03831886500120163, "27544": 0.1477125883102417, "27642": 0.04674193635582924, "27756": 0.44753631949424744, "27890": 0.014542185701429844, "27934": 0.036437395960092545, "28086": 1.276475191116333, "28156": 0.255429208278656, "28242": 0.28450319170951843, "28466": 0.012615402229130268, "28685": 0.4831010699272156, "28765": 0.029824240133166313, "28767": 0.21765978634357452, "28788": 0.23247487843036652, "28797": 0.259204238653183, "28828": 0.8057082891464233, "28829": 0.25239890813827515, "29145": 1.300702452659607, "29206": 0.11430477350950241, "29300": 0.2184450328350067, "29458": 0.08692999184131622} | 22178316 | Schizophrenia may arise from subtle abnormalities in brain development due to alterations in the functions of candidate susceptibility genes such as Disrupted-in-schizophrenia 1 (DISC1) and Neuregulin 1 (NRG1). To provide novel insights into the functions of DISC1 in brain development, we mapped the expression of zebrafish disc1 and set out to characterize its role in early embryonic development using morpholino antisense methods. These studies revealed a critical requirement for disc1 in oligodendrocyte development by promoting specification of olig2-positive cells in the hindbrain and other brain regions. Since NRG1 has well-documented roles in myelination, we also analyzed the roles of nrg1 and ErbB signalling in zebrafish brain development and we observed strikingly similar defects to those seen in disc1 morphant embryos. In addition to their effects on oligodendrocyte development, knock-down of disc1 or nrg1 caused near total loss of olig2-positive cerebellar neurones, but caused no apparent loss of spinal motor neurones. These findings suggest that disc1 and nrg1 function in common or related pathways controlling development of oligodendrocytes and neurones from olig2-expressing precursor cells. Like DISC1 and NRG1, OLIG2 and ERBB4 are promising candidate susceptibility genes for schizophrenia. Hence our findings in the zebrafish embryo suggest that hitherto unappreciated neurodevelopmental connections may exist between key human schizophrenia susceptibility genes. These connections could be investigated in Disc1 and Nrg1 mouse models and in genetically defined groups of patients in order to determine whether they are relevant to the pathobiology of schizophrenia. GenBank accession number for Danio rerio disc1: EU273350. | Disrupted-in-schizophrenia 1 and neuregulin 1 are required for the specification of oligodendrocytes and neurones in the zebrafish brain. |
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"26651": 0.08513788133859634, "26721": 0.040196798741817474, "26775": 0.22001366317272186, "27144": 0.2026219218969345, "27152": 0.1221139207482338, "27391": 0.1064341589808464, "27781": 0.8374842405319214, "27854": 0.0770333781838417, "28353": 1.2627575397491455, "28727": 0.11256109178066254, "28794": 0.0058422754518687725, "28873": 0.3269403576850891, "28893": 0.16690383851528168, "29295": 0.5495203733444214, "29514": 0.02412080205976963} | 22180793 | The transition from androgen-dependent to castration-resistant prostate cancer (CRPC) is a lethal event of uncertain molecular etiology. Comparing gene expression in isogenic androgen-dependent and CRPC xenografts, we found a reproducible increase in N-cadherin expression, which was also elevated in primary and metastatic tumors of individuals with CRPC. Ectopic expression of N-cadherin in nonmetastatic, androgen-dependent prostate cancer models caused castration resistance, invasion and metastasis. Monoclonal antibodies against the ectodomain of N-cadherin reduced proliferation, adhesion and invasion of prostate cancer cells in vitro. In vivo, these antibodies slowed the growth of multiple established CRPC xenografts, blocked local invasion and metastasis and, at higher doses, led to complete regression. N-cadherin–specific antibodies markedly delayed the time to emergence of castration resistance, markedly affected tumor histology and angiogenesis, and reduced both AKT serine-threonine kinase activity and serum interleukin-8 (IL-8) secretion. These data indicate that N-cadherin is a major cause of both prostate cancer metastasis and castration resistance. Therapeutic targeting of this factor with monoclonal antibodies may have considerable clinical benefit. | Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance |
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"26014": 0.535327672958374, "26244": 0.08782484382390976, "26402": 0.8682814836502075, "26514": 0.6492279767990112, "26520": 0.10026945173740387, "26534": 0.13157635927200317, "26773": 0.6389714479446411, "26786": 0.13157635927200317, "26989": 0.09938567131757736, "27006": 0.42225050926208496, "27651": 0.08961215615272522, "27989": 0.01934296265244484, "28156": 0.14179791510105133, "28177": 0.997294545173645, "28350": 0.08154398202896118, "28466": 0.04394211992621422, "28487": 0.175953671336174, "28619": 0.11256109178066254, "28696": 0.10906458646059036, "28767": 0.7960633039474487, "28828": 0.2247048318386078, "28835": 0.319873183965683, "29290": 0.26296505331993103} | 22185730 | Abnormal hyperphosphorylation of tau appears to be crucial in neurofibrillary degeneration in Alzheimer's disease (AD). Previous studies suggest that a down-regulation of protein phosphatase 2A (PP2A), the major tau phosphatase in human brain, contributes to tau hyperphosphorylation in AD. However, the effects of PP2A down-regulation on site-specific tau hyperphosphorylation is not well understood. In the present study, we showed that PP2A dephosphorylated tau at several phosphorylation sites with different efficiencies. Among the sites studied, Thr205, Thr212, Ser214, and Ser262 were the most favorable sites, and Ser199 and Ser404 were the least favorable sites for PP2A in vitro. Inhibition of PP2A with okadaic acid in metabolically active rat brain slices caused inhibition of glycogen synthase kinase-3beta (GSK-3beta) via an increase in its phosphorylation at Ser9. GSK-3beta phosphorylated tau at many sites, with Ser199, Thr205, and Ser396 being the most favorable sites in cells. The overall alterations in tau phosphorylation induced by PP2A inhibition were the result of the combined effects of both reduced tau dephosphorylation due to PP2A inhibition directly and reduced phosphorylation by GSK-3beta due to its inhibition. Because the impacts of tau phosphorylation on its biological activity and on neurofibrillary degeneration are site-specific, this study provides a new insight into the role of PP2A down-regulation in neurofibrillary degeneration in AD. | PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. |
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0.07341018319129944, "28156": 0.3297532796859741, "28227": 0.7163142561912537, "29109": 1.0144377946853638, "29206": 0.06703783571720123} | 22186938 | Human artificial chromosomes (HACs) are autonomous molecules that can function and segregate as normal chromosomes in human cells. De novo HACs have successfully been used as gene expression vectors to complement genetic deficiencies in human cultured cells. HACs now offer the possibility of studying the regulation and expression of large genes in a variety of cell types from different tissues and correcting gene deficiencies caused by human inherited diseases. Complementary gene expression studies in mice, especially in mouse models of human genetic diseases, are also important in determining if large human transgenes can be expressed appropriately from artificial chromosomes. Toward this aim we are establishing artificial chromosomes in murine cells as novel gene expression vectors. Initially we transferred HAC vectors into murine cells, but were unable to generate de novo HACs at a reasonable frequency. We then transferred HACs previously established in human HT1080 cells to three different murine cell types by microcell fusion, followed by positive selection. We observed that the HACs in murine cells bound centromere protein C (CENP-C), a marker of active centromeres, and were detected under selection but rapidly lost when selection was removed. These results suggest that the HACs maintain at least a partially functional centromere complex in murine cells, but other factors are required for stability and segregation. Artificial chromosomes containing mouse centromeric sequences may be required for better stability and maintenance in murine cells. | Human artificial chromosomes containing chromosome 17 alphoid DNA maintain an active centromere in murine cells but are not stable. |
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"27572": 0.2607102394104004, "27633": 0.17922431230545044, "27642": 0.06977381557226181, "27777": 0.06246116757392883, "27989": 0.12556517124176025, "27998": 0.7333439588546753, "28031": 0.1889725625514984, "28184": 0.6634125709533691, "28424": 0.15526613593101501, "28596": 0.08961215615272522, "28691": 0.46302130818367004, "29111": 0.6254787445068359, "29129": 1.0001721382141113, "29320": 0.3318578004837036} | 22190276 | Phagocytosis mediates the clearance of apoptotic bodies and also the elimination of microbial pathogens. The nascent phagocytic vacuole formed upon particle engulfment lacks microbicidal and degradative activity. These capabilities are acquired as the phagosome undergoes maturation; a progressive remodeling of its membrane and contents that culminates in the formation of phagolysosomes. Maturation entails orderly sequential fusion of the phagosomal vacuole with specialized endocytic and secretory compartments. Concomitantly, the phagosomal membrane undergoes both inward and outward vesiculation and tubulation followed by fission, thereby recycling components and maintaining its overall size. Here, we summarize what is known about the molecular machinery that governs this complex metamorphosis of phagosome maturation. | How nascent phagosomes mature to become phagolysosomes. |
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0.6487176418304443, "26601": 0.02412080205976963, "26835": 0.2852376699447632, "26910": 0.5404602885246277, "27152": 0.3519764244556427, "27211": 1.1166772842407227, "27549": 0.056018441915512085, "27790": 0.04953393340110779, "27854": 0.2478361576795578, "28282": 0.8731874823570251, "28406": 0.2607102394104004, "28424": 0.040196798741817474, "28517": 0.05046287178993225, "28518": 0.38574060797691345, "28691": 0.2026219218969345, "28775": 1.178053855895996, "28901": 0.26146242022514343, "29060": 0.4818955361843109, "29378": 0.07431721687316895, "29458": 0.5838727951049805, "29490": 0.1913948506116867} | 22191759 | Cathelicidins are a novel family of antimicrobial peptide precursors from mammalian myeloid cells. They are characterized by a conserved N-terminal region while the C-terminal antimicrobial domain can vary considerably in both primary sequence and length. Four cathelicidins, proBac5, proBac7, prododecapeptide and proBMAP-28, have been concurrently purified from bovine neutrophils, using simple and rapid methodologies. The correlation of ES-MS data from the purified proteins with their cDNA-deduced sequences has revealed several common features of their primary sequence, such as the presence of N-terminal 5-oxoproline (pyroglutamate) residues and two disulfide bridges in a 1-2, 3-4 arrangement. The N-terminal domains of the cathelicidins present one or two Asp-Pro bonds, which are particularly acid-labile in proBac5 and proBac7, but stable in prododecapeptide. This suggests that the spatial organization around these bonds may vary in different cathelicidins, and favour hydrolysis in some cases. An unexpected feature of the prododecapeptide is that it exists as dimers formed by three possible combinations of its two isoforms. The isolation of a truncated, monomeric form of this protein, lacking the cysteine-containing antimicrobial dodecapeptide, indicates that dimerization occurs via disulfide bridge formation at the level of the C-terminal domain and that the dodecapeptide is likely released as a dimer from its precursor. Sequence-based secondary structure predictions and CD results indicate for cathelicidins a 30-50% content of extended conformation and <20% content of alpha-helical conformation, with the alpha-helical segment placed near the N-terminus. Finally, similarity searching and topology-based structure prediction underline a significant sequential and structural similarity between the conserved N-terminal domain of cathelicidins and cystatin-like domains, placing this family within the cystatin superfamily. When assayed against cathepsin L, unlike the potent cystatin inhibitors, three of the four cathelicidins show only a poor inhibitory activity (Ki = 0.6-3 microM). | Purification and structural characterization of bovine cathelicidins, precursors of antimicrobial peptides. |
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0.004870930220931768, "26927": 0.09050461649894714, "26992": 0.08603433519601822, "27119": 0.30989447236061096, "27322": 0.06154331564903259, "27355": 0.21765978634357452, "27694": 0.018384648486971855, "27794": 0.12814582884311676, "28048": 0.0770333781838417, "28093": 0.02792670577764511, "28102": 0.06703783571720123, "28170": 0.11951763927936554, "28203": 0.8805016279220581, "28321": 0.66441810131073, "28348": 0.12728634476661682, "28425": 0.055094651877880096, "28436": 0.28890204429626465, "28636": 0.02412080205976963, "28648": 0.39893341064453125, "28907": 0.11604541540145874, "28936": 0.0009760859538801014, "29347": 0.6446255445480347, "29458": 0.07068414986133575, "29516": 0.20818853378295898} | 22194407 | This paper seeks to establish the strength of association between contemporary tuberculosis (TB) in England and Wales and several potential aetiological factors. It presents an ecological analysis of standardised annual TB mortality rates for the 403 local authority districts between 1982 and 1992, disaggregated by age and sex. Social, demographic and ethnicity measures from the 1981 and 1991 censuses and standardised annual AIDS-related mortality rates for young men are used to calculate Poisson regression models. A strong association was found between all TB mortality groups and overcrowding at the household level. For women, no other measures improved the explanatory power of the models. In multiple regressions, both poverty and AIDS-related mortality explained additional variation in the model for younger men. The link between ethnicity and tuberculosis notifications was not reflected in this analysis of mortality. For all groups no evidence of a positive relationship with ethnicity was found, once overcrowding had been accounted for. The significance of household as opposed to district level crowding suggests that prolonged contact is required for disease transmission. Regression analysis indicates that it is the overcrowding and poverty among ethnic populations that is significant for their tuberculosis mortality. The fact that the relationship between AIDS and TB is confined to the group most typical of AIDS patients provides evidence that AIDS has little influence on the level of tuberculosis mortality in the wider population. Explanations for the observed relationship include preferential certification, migration for treatment and shortcomings in health care provision. | Tuberculosis mortality in England and Wales during 1982-1992: its association with poverty, ethnicity and AIDS. |
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0.029824240133166313, "27152": 0.6999598741531372, "27321": 0.1994270235300064, "27598": 0.3588210940361023, "27989": 0.07884006202220917, "27998": 0.66441810131073, "28041": 0.026025565341114998, "28227": 0.7047978043556213, "28466": 0.15693697333335876, "28728": 0.07159364968538284, "28767": 0.06795065850019455, "28788": 0.3850763738155365, "28873": 0.3877306580543518, "29172": 0.08154398202896118, "29222": 0.29109421372413635, "29516": 0.13925230503082275} | 22198971 | CD4 memory T cells surviving in the absence of MHC class II contact lose their characteristic memory function. To investigate the mechanisms underlying the impaired function of memory T cells in the absence of MHC class II molecules, we analyzed gene expression profiles of resting memory T cells isolated from MHC class II-competent or -deficient hosts. The analysis focused on five transcripts related to T cell activation, metabolism, and survival that are underexpressed in resting memory T cells from MHC class II-deficient hosts compared with MHC class II-competent hosts. CD4 memory cells isolated from MHC class II-deficient hosts display alterations in their degree of differentiation as well as metabolic activity, and these changes are already manifest in the effector phase despite the presence of Ag-expressing dendritic cells. Our data suggest that the absence of interactions with noncognate MHC class II molecules compromises the progressive accumulation of signals that ensure optimal survival and fitness to sustain the metabolic activity of activated T cells and shape the functional capacity of the future memory compartment. Signals via AKT coordinate survival and metabolic pathways and may be one of the crucial events linking interaction with MHC class II molecules to the successful generation of a long-lived functional memory CD4 T cell population. | Noncognate interaction with MHC class II molecules is essential for maintenance of T cell metabolism to establish optimal memory CD4 T cell function. |
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The function of TAK1 in T cells is unclear, however. We show here that T cell–specific deletion of the gene encoding TAK1 resulted in reduced development of thymocytes, especially of regulatory T cells expressing the transcription factor Foxp3. In mature thymocytes, TAK1 was required for interleukin 7–mediated survival and T cell receptor–dependent activation of transcription factor NF-κB and the kinase Jnk. In effector T cells, TAK1 was dispensable for T cell receptor–dependent NF-κB activation and cytokine production, but was important for proliferation and activation of the kinase p38 in response to interleukins 2, 7 and 15. Thus, TAK1 is essential for the integration of T cell receptor and cytokine signals to regulate the development, survival and function of T cells. | The kinase TAK1 integrates antigen and cytokine receptor signaling for T cell development, survival and function |
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1.0250049829483032, "23900": 0.5151132941246033, "24018": 0.04674193635582924, "24273": 0.013579257763922215, "24353": 0.040196798741817474, "24685": 0.6941232681274414, "24757": 0.026025565341114998, "26453": 0.20739519596099854, "26497": 0.23402166366577148, "27001": 0.055094651877880096, "27204": 0.16524957120418549, "27520": 0.31489628553390503, "28321": 0.014542185701429844, "28389": 0.03831886500120163, "28436": 0.5290185213088989, "28767": 0.35060185194015503, "29068": 0.8366385698318481, "29098": 0.5568217039108276, "29277": 0.19220098853111267} | 22227889 | This study examines factors associated with caregiver burden in 82 HIV-positive (HIV+) and 162 HIV-negative (HIV-) partners of men with AIDS. We expected HIV+ caregivers to report more burden than HIV- caregivers because of the toll of their disease on their resources. HIV+ caregivers did report more burden and, compared with the HIV- caregivers, they were more religious or spiritual, had less income, and coped by using more positive reappraisal and cognitive escape-avoidance and by seeking social support. Comparisons of HIV+ caregivers with 61 HIV+ partners of healthy men indicated that most differences between HIV+ and HIV- caregivers were associated with HIV seropositivity rather than caregiving. However, of the variables associated with HIV seropositivity, only religiosity or spirituality contributed independently to burden in HIV+ caregivers, suggesting a relatively weak link between HIV seropositivity and caregiver burden. The model explained 62% of the variance in burden in HIV+ caregivers and 36% of the variance in HIV- caregivers. | Caregiver burden in HIV-positive and HIV-negative partners of men with AIDS. |
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"25125": 1.3545457124710083, "25323": 0.2493593990802765, "25353": 0.38041436672210693, "25357": 0.4950772523880005, "25455": 0.34715715050697327, "25457": 1.022197961807251, "25473": 0.04394211992621422, "25870": 0.00875066313892603, "25972": 0.8925741910934448, "26419": 0.3750596046447754, "26563": 0.1734936386346817, "26578": 0.33953672647476196, "26745": 0.6254787445068359, "26777": 0.1734936386346817, "27159": 0.1401015669107437, "27165": 0.8509185314178467, "27312": 0.9084475636482239, "27480": 0.11081436276435852, "27678": 0.175953671336174, "27703": 0.19541899859905243, "27718": 0.151916041970253, "27885": 0.820433497428894, "28086": 0.151916041970253, "28141": 0.5909284353256226, "28207": 0.42990362644195557, "28296": 0.6684301495552063, "28466": 0.08244366943836212, "28828": 0.007782140281051397, "29392": 0.22392450273036957} | 22236223 | Pregnancy in women with different renal diseases has important consequences for the developing fetus and maternal health. Kidneys and the urinary tract have to adapt to the pregnancy status and therefore suffer significant anatomical, hemodynamic and endocrine changes. Failure to adapt can aggravate the preexisting maternal disease and can also create suboptimal environment for fetal development and increase the risk of obstetric complications. Knowledge and correct interpretation of the renal functional tests is necessary for the modern obstetrician, avoiding an incorrect diagnosis for renal disease where only specific renal changes during pregnancy are present, but meanwhile a correct evaluation of the renal function and changes can detect a pathology that can aggravate both the mother’s and the baby’s condition. Improvement and better understanding of the renal pathophysiology in pregnancy made possible that pregnant woman look forward for a good outcome, including here also the women with renal transplant. Nowadays is underlined the concept of multidisciplinary teamwork, a very important concept of modern medicine. The obstetrician should consider nephrologists as key players in the team and in our opinion should refer to them the pregnant women for a routine check-up of the renal status in the 2nd or beginning of 3rd trimester by ultrasound, beside the usual blood and urine analysis. The nephrologists and urologists should be involved in the management of severe medical conditions, such as preeclampsia, acute and chronic renal failure and never the less in the complex management of dialysis or renal transplant patients. In pregnancy it can be encountered several renal diseases, some of them preexisting the pregnancy and other developed or being direct influenced by pregnancy. This chapter will discuss briefly the basic evaluation of renal status in order to present and better understand the acute and chronic renal disorders in pregnancy. The chapter will focus on the most common preexisting diseases in pregnancy such as: chronic glomerulonephritis, secondary glomerular nephropathies, interstitial nephropathies (chronic pyelonephritis, renal tuberculosis), diabetes nephropathy, unique surgical kidney, chronic renal failure. From the renal diseases directly influenced by pregnancy it will be discussed: asymptomatic bacteriuria, symptomatic urinary infection, urolithiasis and acute renal failure in pregnancy. It will be presented also the management of dialysis in pregnancy and pregnant women with renal transplant. | Renal Disease and Pregnancy |
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1.1774523258209229, "27633": 0.5573811531066895, "27703": 0.8973627090454102, "27777": 0.6107416749000549, "28031": 0.11430477350950241, "28086": 0.2607102394104004, "28156": 0.7295845746994019, "28227": 0.49982786178588867, "28406": 0.23787821829319, "28424": 0.1332872211933136, "28466": 0.0029254043474793434, "28674": 0.05046287178993225, "28788": 0.7473171949386597, "28828": 0.27342069149017334, "28829": 0.16276304423809052, "28893": 0.013579257763922215, "29107": 0.10291612148284912, "29181": 1.0229004621505737, "29199": 0.40285754203796387, "29235": 0.38574060797691345} | 22241778 | The human kidneys filter 180 l of blood every day via about 2.5 million glomeruli. The three layers of the glomerular filtration apparatus consist of fenestrated endothelium, specialized extracellular matrix known as the glomerular basement membrane (GBM) and the podocyte foot processes with their modified adherens junctions known as the slit diaphragm (SD). In this study we explored the contribution of podocyte beta1 integrin signaling for normal glomerular function. Mice with podocyte specific deletion of integrin beta1 (podocin-Cre beta1-fl/fl mice) are born normal but cannot complete postnatal renal development. They exhibit detectable proteinuria on day 1 and die within a week. The kidneys of podocin-Cre beta1-fl/fl mice exhibit normal glomerular endothelium but show severe GBM defects with multilaminations and splitting including podocyte foot process effacement. The integrin linked kinase (ILK) is a downstream mediator of integrin beta1 activity in epithelial cells. To further explore whether integrin beta1-mediated signaling facilitates proper glomerular filtration, we generated mice deficient of ILK in the podocytes (podocin-Cre ILK-fl/fl mice). These mice develop normally but exhibit postnatal proteinuria at birth and die within 15 weeks of age due to renal failure. Collectively, our studies demonstrate that podocyte beta1 integrin and ILK signaling is critical for postnatal development and function of the glomerular filtration apparatus. | Integrin beta1-mediated matrix assembly and signaling are critical for the normal development and function of the kidney glomerulus. |
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"26462": 0.24401791393756866, "26534": 0.15860503911972046, "26775": 0.18654440343379974, "26874": 0.02792670577764511, "26906": 0.35745587944984436, "27642": 0.055094651877880096, "27673": 0.2674594223499298, "28070": 0.09406650811433792, "28089": 0.5784112811088562, "28266": 0.20022670924663544, "28440": 0.32553088665008545, "28466": 0.13414156436920166, "28562": 0.1889725625514984, "28696": 0.18411032855510712, "28767": 0.38374659419059753, "28892": 0.23324857652187347, "28964": 0.5941681861877441, "29091": 0.1685553640127182, "29172": 0.08244366943836212, "29206": 1.1255888938903809, "29494": 0.011650617234408855} | 22264117 | During aging, the mechanisms that normally maintain health and stress resistance strikingly decline, resulting in decrepitude, frailty, and ultimately death. Exactly when and how this decline occurs is unknown. Changes in transcriptional networks and chromatin state lie at the heart of age-dependent decline. These epigenomic changes are not only observed during aging but also profoundly affect cellular function and stress resistance, thereby contributing to the progression of aging. We propose that the dysregulation of transcriptional and chromatin networks is a crucial component of aging. Understanding age-dependent epigenomic changes will yield key insights into how aging begins and progresses and should lead to the development of new therapeutics that delay or even reverse aging and age-related diseases. | The Aging Epigenome. |
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"28809": 0.20421554148197174, "29076": 0.004870930220931768, "29174": 0.9005423784255981, "29226": 0.2822965085506439, "29361": 0.15610189735889435, "29494": 0.1718502640724182} | 22267225 | Over the past three decades great efforts have been made in search of cancer chemoprevention strategies. The increase in knowledge of the long process from normal to cancer cell has enabled interventions in terms of lifestyle modifications, natural compounds or drugs to block or reverse the process. Great successes have been achieved, especially for breast and colorectal cancer. However, these strategies have yet to find clinical application on a large scale. In this article we identify the achievements, the pitfalls and the next steps to be taken to improve the efficacy and applicability of chemoprevention strategies. Among the crucial key points to be implemented are educational activities for physicians to appropriately disseminate the aim and indeed the culture of chemoprevention. It is essential to improve the risk-benefit balance, seeking the minimal active doses, intermittent schedules, a better characterization of the risk categories via a more personalized intervention based on individual characteristics, and ensure the containment of costs of public and private health prevention programs. | Cancer chemoprevention: Much has been done, but there is still much to do. State of the art and possible new approaches. |
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