spalde-v3-lexical
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We previously reported generation of induced hepatocyte-like (iHep) cells by transduction of Gata4, Hnf1α, and Foxa3 in p19 Arf null mouse embryonic fibroblasts (MEFs). Here, we show that Hnf1β and Foxa3, liver organogenesis transcription factors, are sufficient to reprogram MEFs into induced hepatic stem cells (iHepSCs). iHepSCs can be stably expanded in vitro and possess the potential of bidirectional differentiation into both hepatocytic and cholangiocytic lineages. In the injured liver of fumarylacetoacetate hydrolase (Fah)-deficient mice, repopulating iHepSCs become hepatocyte-like cells. They also engraft as cholangiocytes into bile ducts of mice with DDC-induced bile ductular injury. Lineage conversion into bipotential expandable iHepSCs provides a strategy to enable efficient derivation of both hepatocytes and cholangiocytes for use in disease modeling and tissue engineering. | Reprogramming fibroblasts into bipotential hepatic stem cells by defined factors. |
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FISH directly visualizes the spatial relationship of sequences but is usually applied to a few loci at a time. The frequency at which sequences are ligated together by formaldehyde cross-linking can be measured genome-wide by 3C methods, with higher frequencies thought to reflect shorter distances. FISH and 3C should therefore give the same views of genome organization, but this has not been tested extensively. We investigated the murine HoxD locus with 3C carbon copy (5C) and FISH in different developmental and activity states and in the presence or absence of epigenetic regulators. We identified situations in which the two data sets are concordant but found other conditions under which chromatin topographies extrapolated from 5C or FISH data are not compatible. We suggest that products captured by 3C do not always reflect spatial proximity, with ligation occurring between sequences located hundreds of nanometers apart, influenced by nuclear environment and chromatin composition. We conclude that results obtained at high resolution with either 3C methods or FISH alone must be interpreted with caution and that views about genome organization should be validated by independent methods. | Spatial genome organization: contrasting views from chromosome conformation capture and fluorescence in situ hybridization. |
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0.3930181860923767, "26666": 0.2719337046146393, "26780": 0.854249119758606, "26786": 0.022212404757738113, "27108": 0.9225212931632996, "27130": 0.4500300884246826, "27203": 0.07612881064414978, "27699": 0.06520967930555344, "27722": 0.12038381397724152, "27753": 0.0058422754518687725, "27805": 0.22626367211341858, "27891": 0.1358480453491211, "28093": 0.5909284353256226, "28268": 0.7408206462860107, "28321": 0.0797421783208847, "28436": 0.08961215615272522, "28648": 0.8845420479774475, "28667": 0.0842406153678894, "28965": 0.2447827309370041, "29050": 0.38374659419059753, "29101": 0.7951818704605103} | 20048431 | Objective:To describe the development of a European computerized 24-h dietary recall method for adolescents, and to investigate the feasibility of self-administration (self report) by comparison with administration by a dietician (interview).Methods:Two hundred and thirty-six adolescents (mean age 14.6 years (s.d.=1.7)) of eight European cities completed the 24-h recall (Young Adolescents Nutrition Assessment on Computer (YANA-C)) twice (once by self-report and once by interview).Results:A small but significant underestimate in energy (61 (s.e.=31) kcal) and fat (4.2 (s.e.=1.7) g) intake was found in the self-reports in comparison with the interviews; no significant differences were found for the intake of carbohydrates, proteins, fibre, calcium, iron and ascorbic acid. Spearman's correlations were highly significant for all nutrients and energy ranging between 0.86 and 0.91. Agreement in categorizing the respondents as consumers and non-consumers for the 29 food groups was high (kappa statistics ⩾0.73). Percentage omissions were on average 3.7%; percentage intrusions: 2.0%. Spearman's correlations between both modes were high for all food groups, for the total sample (⩾0.76) as well as for the consumers only (⩾0.72). Analysing the consumer only, on an average 54% of the consumed amounts were exactly the same; nevertheless, only for one group ‘rice and pasta’ a significant difference in consumption was found. Conclusion:Adaptation, translation and standardization of YANA-C make it possible to assess the dietary intake of adolescents in a broad international context. In general, good agreement between the administration modes was found, the latter offering significant potential for large-scale surveys where the amount of resources to gather data is limited. | Development and evaluation of a self-administered computerized 24-h dietary recall method for adolescents in Europe |
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0.23015019297599792, "26657": 0.052318159490823746, "26773": 0.3283478021621704, "26775": 0.08782484382390976, "26837": 0.7683706283569336, "27184": 0.10203468054533005, "27343": 0.2637155055999756, "27354": 0.08692999184131622, "27364": 0.2478361576795578, "27448": 0.08244366943836212, "27777": 0.15943801403045654, "28436": 0.16442140936851501, "28561": 0.14433705806732178, "28576": 0.09228714555501938, "28793": 1.3794349431991577, "28848": 0.23092569410800934, "28892": 0.12986256182193756, "29017": 0.6430866718292236, "29175": 0.49626702070236206, "29458": 0.1718502640724182} | 20052986 | Circadian rhythms are oscillations of physiology, behavior, and metabolism that have period lengths near 24 hours. In several model organisms and humans, circadian clock genes have been characterized and found to be transcription factors. Because of this, researchers have used microarrays to characterize global regulation of gene expression and algorithmic approaches to detect cycling. This article presents a new algorithm, JTK_CYCLE, designed to efficiently identify and characterize cycling variables in large data sets. Compared with COSOPT and the Fisher's G test, two commonly used methods for detecting cycling transcripts, JTK_CYCLE distinguishes between rhythmic and nonrhythmic transcripts more reliably and efficiently. JTK_CYCLE's increased resistance to outliers results in considerably greater sensitivity and specificity. Moreover, JTK_CYCLE accurately measures the period, phase, and amplitude of cycling transcripts, facilitating downstream analyses. Finally, JTK_CYCLE is several orders of magnitude faster than COSOPT, making it ideal for large-scale data sets. JTK_CYCLE was used to analyze legacy data sets including NIH3T3 cells, which have comparatively low amplitude oscillations. JTK_CYCLE's improved power led to the identification of a novel cluster of RNA-interacting genes whose abundance is under clear circadian regulation. These data suggest that JTK_CYCLE is an ideal tool for identifying and characterizing oscillations in genome-scale data sets. | JTK_CYCLE: an efficient nonparametric algorithm for detecting rhythmic components in genome-scale data sets. |
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At the onset of mitosis, centrosomes undergo a structural reorganization, termed maturation, which leads to increased microtubule nucleation activity. Centrosome maturation is regulated by several kinases, including Polo-like kinase 1 (Plk1). Here, we identify a centrosomal Plk1 substrate, termed Nlp (ninein-like protein), whose properties suggest an important role in microtubule organization. Nlp interacts with two components of the gamma-tubulin ring complex and stimulates microtubule nucleation. Plk1 phosphorylates Nlp and disrupts both its centrosome association and its gamma-tubulin interaction. Overexpression of an Nlp mutant lacking Plk1 phosphorylation sites severely disturbs mitotic spindle formation. We propose that Nlp plays an important role in microtubule organization during interphase, and that the activation of Plk1 at the onset of mitosis triggers the displacement of Nlp from the centrosome, allowing the establishment of a mitotic scaffold with enhanced microtubule nucleation activity. | Polo-like kinase 1 regulates Nlp, a centrosome protein involved in microtubule nucleation. |
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0.7863243818283081, "26236": 0.04953393340110779, "26261": 0.02792670577764511, "26402": 0.18492233753204346, "26404": 0.1011524572968483, "26721": 0.10818854719400406, "27144": 0.0797421783208847, "27152": 1.0506030321121216, "27321": 0.11604541540145874, "27833": 0.18329764902591705, "27896": 0.08961215615272522, "28727": 1.3086495399475098, "28940": 1.1337933540344238, "29477": 0.6853039860725403, "29490": 0.29036402702331543, "29657": 0.13925230503082275} | 20083834 | Background/Objective:To investigate the effect of soy protein containing isoflavones on homocysteine (Hcy), C-reactive protein (CRP), soluble E-selectin (sE-selectin), soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1).Subject/Methods:In a randomized crossover design, 34 postmenopausal women consumed soy protein isolate (26±5 g protein containing 44±8 mg isoflavones per day) or milk protein isolate (26±5 g protein per day) for 6 weeks each. Fasting blood samples were collected at the end of each diet period and end points analyzed by enzyme-linked immunosorbent assay. Results:Concentrations of Hcy, CRP, sE-selectin, sVCAM-1 and sICAM-1 were not different between soy and milk diet treatments. Results did not differ by equol production status or by baseline lipid concentration. Adjustment for intake of folate and methionine did not alter the Hcy results. Conclusions:These data suggest that decreasing vascular inflammation and Hcy concentration are not likely mechanisms by which soy consumption reduces coronary heart disease risk. | Consumption of isoflavone-rich soy protein does not alter homocysteine or markers of inflammation in postmenopausal women |
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0.9005423784255981, "24868": 0.006812678650021553, "24879": 0.0009760859538801014, "25107": 0.7701805830001831, "25502": 0.4926934838294983, "25627": 1.2599912881851196, "26089": 0.1510767638683319, "26131": 0.10555581003427505, "26228": 0.1358480453491211, "26244": 1.0492360591888428, "26427": 0.013579257763922215, "26633": 0.055094651877880096, "27079": 1.2605451345443726, "27178": 0.06795065850019455, "27325": 0.030771657824516296, "27400": 0.021256839856505394, "27694": 0.3810817003250122, "27790": 0.08692999184131622, "27830": 0.28963330388069153, "27854": 0.32553088665008545, "28550": 0.02792670577764511, "28591": 0.41065993905067444, "28613": 0.684319257736206, "28655": 0.04674193635582924, "28688": 0.13071982562541962, "28691": 0.05694137513637543, "28926": 0.1212492436170578, "29097": 0.5523349046707153, "29167": 0.25845035910606384, "29226": 0.04394211992621422} | 20101846 | Earth-abundant first-row (3d) transition metal–based catalysts have been developed for the oxygen-evolution reaction (OER); however, they operate at overpotentials substantially above thermodynamic requirements. Density functional theory suggested that non-3d high-valency metals such as tungsten can modulate 3d metal oxides, providing near-optimal adsorption energies for OER intermediates. We developed a room-temperature synthesis to produce gelled oxyhydroxides materials with an atomically homogeneous metal distribution. These gelled FeCoW oxyhydroxides exhibit the lowest overpotential (191 millivolts) reported at 10 milliamperes per square centimeter in alkaline electrolyte. The catalyst shows no evidence of degradation after more than 500 hours of operation. X-ray absorption and computational studies reveal a synergistic interplay between tungsten, iron, and cobalt in producing a favorable local coordination environment and electronic structure that enhance the energetics for OER. | Homogeneously dispersed multimetal oxygen-evolving catalysts |
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0.03360854089260101, "22684": 0.9232974052429199, "22718": 0.6833335757255554, "22828": 0.6538092494010925, "22859": 0.3416208028793335, "23138": 0.20580662786960602, "23208": 0.32058215141296387, "23359": 0.2478361576795578, "24153": 0.009718249551951885, "24251": 0.34370049834251404, "24327": 1.0464962720870972, "24501": 0.3012613356113434, "24699": 0.5110208988189697, "25458": 0.0770333781838417, "25778": 0.9958525896072388, "26021": 0.1011524572968483, "26180": 0.6911921501159668, "26226": 0.1358480453491211, "26629": 0.2667117714881897, "26739": 0.0029254043474793434, "26745": 0.8772575259208679, "27179": 0.6181373596191406, "27292": 0.890972912311554, "27598": 0.016465263441205025, "27615": 0.2493593990802765, "27885": 0.8500841856002808, "28173": 0.6332852244377136, "28483": 0.8534175157546997, "28616": 0.4196864068508148} | 20109325 | Chronic obstructive pulmonary disease (COPD) is a global health problem, and since 2001, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published its strategy document for the diagnosis and management of COPD. This executive summary presents the main contents of the second 5-year revision of the GOLD document that has implemented some of the vast knowledge about COPD accumulated over the last years. Today, GOLD recommends that spirometry is required for the clinical diagnosis of COPD to avoid misdiagnosis and to ensure proper evaluation of severity of airflow limitation. The document highlights that the assessment of the patient with COPD should always include assessment of (1) symptoms, (2) severity of airflow limitation, (3) history of exacerbations, and (4) comorbidities. The first three points can be used to evaluate level of symptoms and risk of future exacerbations, and this is done in a way that splits patients with COPD into four categories-A, B, C, and D. Nonpharmacologic and pharmacologic management of COPD match this assessment in an evidence-based attempt to relieve symptoms and reduce risk of exacerbations. Identification and treatment of comorbidities must have high priority, and a separate section in the document addresses management of comorbidities as well as COPD in the presence of comorbidities. The revised document also contains a new section on exacerbations of COPD. The GOLD initiative will continue to bring COPD to the attention of all relevant shareholders and will hopefully inspire future national and local guidelines on the management of COPD. | Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. |
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"25778": 0.2954642176628113, "26163": 0.6892333030700684, "26179": 0.14518201351165771, "26237": 0.19622190296649933, "26319": 0.20022670924663544, "26535": 0.10555581003427505, "26702": 0.02792670577764511, "26745": 0.02792670577764511, "26786": 0.5584990978240967, "27011": 0.6950984001159668, "27144": 1.2381477355957031, "27196": 0.36290550231933594, "27262": 1.0375399589538574, "27312": 0.1710275560617447, "27354": 0.1873544454574585, "27404": 0.2607102394104004, "27673": 0.47584590315818787, "27881": 0.14686977863311768, "28027": 0.14349138736724854, "28093": 0.38308101892471313, "28102": 0.11865071207284927, "28155": 0.26146242022514343, "28207": 0.06703783571720123, "28329": 0.7408206462860107, "28436": 0.12384103983640671, "28518": 0.04113444685935974, "28648": 0.06246116757392883, "28788": 0.15693697333335876, "29109": 0.08692999184131622, "29458": 0.7144040465354919} | 20127522 | PURPOSE Five or more circulating tumor cells (CTCs) per 7.5 mL of blood predicts for poorer progression-free survival (PFS) in patients with metastatic breast cancer (MBC). We conducted a prospective study to demonstrate that CTC results correlate strongly with radiographic disease progression at the time of and in advance of imaging. PATIENTS AND METHODS Serial CTC levels were obtained in patients starting a new treatment regimen for progressive, radiographically measurable MBC. Peripheral blood was collected for CTC enumeration at baseline and at 3- to 4-week intervals. Clinical outcomes were based on radiographic studies performed in 9- to 12-week intervals. RESULTS Sixty-eight patients were evaluable for the CTC-imaging correlations, and 74 patients were evaluable for the PFS analysis. Median follow-up was 13.3 months. A statistically significant correlation was demonstrated between CTC levels and radiographic disease progression in patients receiving chemotherapy or endocrine therapy. This correlation applied to CTC results obtained at the time of imaging (odds ratio [OR], 6.3), 3 to 5 weeks before imaging (OR, 3.1), and 7 to 9 weeks before imaging (OR, 4.9). Results from analyses stratified by type of therapy remained statistically significant. Shorter PFS was observed for patients with five or more CTCs at 3 to 5 weeks and at 7 to 9 weeks after the start of treatment. CONCLUSION We provide, to our knowledge, the first evidence of a strong correlation between CTC results and radiographic disease progression in patients receiving chemotherapy or endocrine therapy for MBC. These findings support the role of CTC enumeration as an adjunct to standard methods of monitoring disease status in MBC. | Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. |
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0.2160874605178833, "26384": 0.2034190446138382, "26513": 0.036437395960092545, "26786": 0.00875066313892603, "26787": 1.1425544023513794, "27011": 0.04394211992621422, "27491": 1.0748957395553589, "27539": 0.9240728616714478, "27697": 0.23787821829319, "27755": 0.45499902963638306, "27790": 0.20102575421333313, "27989": 0.3883931338787079, "28141": 0.4286321699619293, "28156": 0.33675122261047363, "28657": 0.2954642176628113, "28667": 0.3897167444229126, "28715": 0.08692999184131622, "29251": 0.22704219818115234} | 20128547 | Spinal cord injuries (SCIs) in humans and experimental animals are often associated with varying degrees of spontaneous functional recovery during the first months after injury. Such recovery is widely attributed to axons spared from injury that descend from the brain and bypass incomplete lesions, but its mechanisms are uncertain. To investigate the neural basis of spontaneous recovery, we used kinematic, physiological and anatomical analyses to evaluate mice with various combinations of spatially and temporally separated lateral hemisections with or without the excitotoxic ablation of intrinsic spinal cord neurons. We show that propriospinal relay connections that bypass one or more injury sites are able to mediate spontaneous functional recovery and supraspinal control of stepping, even when there has been essentially total and irreversible interruption of long descending supraspinal pathways in mice. Our findings show that pronounced functional recovery can occur after severe SCI without the maintenance or regeneration of direct projections from the brain past the lesion and can be mediated by the reorganization of descending and propriospinal connections. Targeting interventions toward augmenting the remodeling of relay connections may provide new therapeutic strategies to bypass lesions and restore function after SCI and in other conditions such as stroke and multiple sclerosis. | Recovery of supraspinal control of stepping via indirect propriospinal relay connections after spinal cord injury |
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"27539": 0.3499138653278351, "27897": 0.04113444685935974, "28082": 0.009718249551951885, "28297": 0.20501139760017395, "28352": 0.06612417846918106, "28496": 0.932563841342926, "28507": 0.2711893916130066, "28570": 0.09317722171545029, "28667": 0.5063233375549316, "28822": 0.4412745535373688, "29110": 0.1602703034877777, "29264": 0.7389566898345947, "29392": 0.16442140936851501, "29516": 0.06977381557226181} | 20130904 | BACKGROUND Gastric bypass patients with a range of disturbed eating patterns before surgery may be at risk of returning to old patterns postoperatively. Recent research has shown that binge eating is common among the obese before surgery as well as in the postoperative maintenance phase and appears to be linked to poorer outcome. Although "grazing" behavior has not been specifically studied, it is also a high-risk pattern. This paper is a descriptive investigation summarizing postoperative eating patterns in a group of patients. METHODS Patients completed self-report questionnaires before surgery and were seen for a preoperative mental health evaluation with particular focus on assessing eating patterns. Patients with high-risk eating patterns, both binge eating and "grazing", were identified, invited to attend a post-surgery therapy group, and were given additional follow-up questionnaires regarding postoperative eating patterns. RESULTS Consistent with recent studies, many high-risk patients reported recurrent loss of control over eating and, in some cases, subsequent weight gain. Although no longer able to eat large amounts, "grazing" became a more common pattern, appearing >or=6 months following surgery. CONCLUSION Different forms of overeating need to be assessed in this population, focusing on the subjective loss of control rather than on the quantity consumed. Although many patients do not meet strict criteria for binge eating disorder before surgery, these "grazers" are also high-risk. Former binge eaters often turn into "grazers" following surgery. Interventions are needed for at-risk patients. | "Grazing": a high-risk behavior. |
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Precursors belonging to this family, designated the preprodermaseptin, have a common N-terminal preproregion that is remarkably well conserved both within and between species, but a hypervariable C-terminal domain corresponding to antimicrobial peptides with very different lengths, sequences, charges and antimicrobial spectra. Each frog species has its own distinct panoply of 10-20 antimicrobial peptides so that the 5000 species of ranids and hylids may produce approximately 100,000 different peptide antibiotics. The strategy that these frogs have evolved to generate this enormous array of peptides includes repeated duplications of a 150 million years old ancestral gene, focal hypermutation of the antimicrobial peptide domain maybe involving a mutagenic DNA polymerase similar to Escherichia coli Pol V, and subsequent actions of positive (diversifying) selection. The hyperdivergence of skin antimicrobial peptides can be viewed as the successful evolution of a multi-drug defense system that provides frogs with maximum protection against rapidly changing microbial biota and minimizes the chance of microorganisms developing resistance to individual peptides. The impressive variations in the expression of frog skin antimicrobial peptides may be exploited for discovering new molecules and structural motifs targeting specific microorganisms for which the therapeutic armamentarium is scarce. | Molecular strategies in biological evolution of antimicrobial peptides. |
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"28156": 0.7389566898345947, "28268": 0.18816383183002472, "28483": 1.0264055728912354, "28696": 0.12384103983640671, "28873": 0.0354953333735466, "28896": 0.06154331564903259, "29090": 0.0058422754518687725, "29167": 0.09761575609445572, "29297": 0.00875066313892603} | 20148808 | The mammalian gastrointestinal tract harbors a microbial community with metabolic activity critical for host health, including metabolites that can modulate effector functions of immune cells. Mice treated with vancomycin have an altered microbiome and metabolite profile, exhibit exacerbated T helper type 2 cell (Th2) responses, and are more susceptible to allergic lung inflammation. Here we show that dietary supplementation with short-chain fatty acids (SCFAs) ameliorates this enhanced asthma susceptibility by modulating the activity of T cells and dendritic cells (DCs). Dysbiotic mice treated with SCFAs have fewer interleukin-4 (IL4)-producing CD4+ T cells and decreased levels of circulating immunoglobulin E (IgE). In addition, DCs exposed to SCFAs activate T cells less robustly, are less motile in response to CCL19 in vitro, and exhibit a dampened ability to transport inhaled allergens to lung draining nodes. Our data thus demonstrate that gut dysbiosis can exacerbate allergic lung inflammation through both T cell- and DC-dependent mechanisms that are inhibited by SCFAs. | Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acids |
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"25605": 0.1873544454574585, "25775": 0.44753631949424744, "25867": 0.010684899985790253, "26419": 0.07793712615966797, "26651": 0.2674594223499298, "26773": 0.020300358533859253, "26835": 0.1619328260421753, "27044": 1.0264055728912354, "27164": 0.09850110858678818, "27321": 0.11604541540145874, "27395": 0.009718249551951885, "27448": 0.14179791510105133, "27522": 0.0354953333735466, "27711": 0.2852376699447632, "27777": 0.4113073945045471, "27781": 0.5871354341506958, "27822": 0.12470348179340363, "28112": 0.04394211992621422, "28607": 0.12642613053321838, "28788": 0.4126010537147522, "28873": 1.468738079071045, "28896": 0.2231435477733612, "29290": 0.4093637466430664, "29408": 0.14179791510105133, "29451": 0.19381128251552582, "29610": 0.6064908504486084} | 20155713 | Expression of peripheral antigens in the thymus has been implicated in T cell tolerance and autoimmunity. Here we identified medullary thymic epithelial cells as being a unique cell type that expresses a diverse range of tissue-specific antigens. We found that this promiscuous gene expression was a cell-autonomous property of medullary epithelial cells and was maintained during the entire period of thymic T cell output. It may facilitate tolerance induction to self-antigens that would otherwise be temporally or spatially secluded from the immune system. However, the array of promiscuously expressed self-antigens appeared random rather than selected and was not confined to secluded self-antigens. | Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self |
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We hypothesized that STAT3, a latent transcriptional factor, may regulate the gene expression of SALL4. In support of this hypothesis, DNA sequence analysis of the SALL4 gene promoter revealed four putative STAT3-binding sites. Using a SALL4-luciferase reporter gene assay, we found that modulation of the STAT3 activity significantly up-regulated the luciferase activity. By chromatin immunoprecipitation, the segment of the SALL4 promoter showing the highest affinity to STAT3 was localized to -366 to -163, in which there was only one putative STAT3 binding site starting at -199. Site-directed mutagenesis of all four putative STAT3-binding sites in the SALL4 promoter significantly reduced its responsiveness to STAT3, although the most dramatic effect was seen at the binding site starting at -199. We further tested the functional relationship between STAT3 and SALL4 using MDA-MB-231, a breast cell line carrying constitutive SALL4 expression and STAT3 activity. Down-regulation of the STAT3 activity using a dominant-negative construct resulted in a significant decrease in the expression of SALL4. To conclude, our data suggest that STAT3 and SALL4 probably cooperate in both physiological and pathological states. | Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4. |
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"26773": 0.5903874635696411, "27633": 1.3060075044631958, "27822": 0.06977381557226181, "27854": 0.4196864068508148, "28636": 0.1332872211933136, "29107": 0.06886265426874161, "29290": 0.3601844012737274, "29720": 1.15000319480896} | 20183360 | Transforming growth factor β (TGFβ) is a potent and context-dependent regulator of tumor progression. TGFβ promotes the lung metastasis of basal-like (but not the luminal-like) breast cancer. Here, we demonstrated that fascin, a pro-metastasis actin bundling protein, was a direct target of the canonical TGFβ-Smad4 signaling pathway in basal-like breast cancer cells. TGFβ and Smad4 induced fascin overexpression by directly binding to a Smad binding element on the fascin promoter. We identified GATA3, a transcription factor crucial for mammary gland morphogenesis and luminal differentiation, as a negative regulator of TGFβ- and Smad4-induced fascin overexpression. When ectopically expressed in basal-like breast cancer cells, GATA-3 abrogated TGFβ- and Smad4-mediated overexpression of fascin and other TGFβ response genes, invadopodium formation, cell migration, and invasion, suggesting suppression of the canonical TGFβ-Smad signaling axis. Mechanistically, GATA3 abrogated the canonical TGFβ-Smad signaling by abolishing interactions between Smad4 and its DNA binding elements, potentially through physical interactions between the N-terminal of GATA3 and Smad3/4 proteins. Our findings provide mechanistic insight into how TGFβ-mediated cell motility and invasiveness are differentially regulated in breast cancer. | GATA3 transcription factor abrogates Smad4 transcription factor-mediated fascin overexpression, invadopodium formation, and breast cancer cell invasion. |
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20186513 | The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects. | The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. |
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0.4400174915790558, "27152": 0.3346569836139679, "27268": 0.6054253578186035, "27287": 0.6400018334388733, "27321": 0.06977381557226181, "27998": 0.33675122261047363, "28086": 1.173231601715088, "28156": 0.47827014327049255, "28406": 0.16276304423809052, "28667": 0.47766464948654175, "28788": 0.3723714053630829, "28817": 0.7537717819213867, "29129": 0.37640097737312317} | 20186814 | Muscle satellite cells have long been considered a distinct myogenic lineage responsible for postnatal growth, repair, and maintenance of skeletal muscle. Recent studies in mice, however, have revealed the potential for highly purified hematopoietic stem cells from bone marrow to participate in muscle regeneration. Perhaps more significantly, a population of putative stem cells isolated directly from skeletal muscle efficiently reconstitutes the hematopoietic compartment and participates in muscle regeneration following intravenous injection in mice. The plasticity of muscle stem cells has raised important questions regarding the relationship between the muscle-derived stem cells and the skeletal muscle satellite cells. Furthermore, the ability of hematopoietic cells to undergo myogenesis has prompted new investigations into the embryonic origin of satellite cells. Recent developmental studies suggest that a population of satellite cells is derived from progenitors in the embryonic vasculature. Taken together, these studies provide the first evidence that pluripotential stem cells are present within adult skeletal muscle. Tissue-specific stem cells, including satellite cells, may share a common embryonic origin and possess the capacity to activate diverse genetic programs in response to environmental stimuli. Manipulation of such tissue-specific stem cells may eventually revolutionize therapies for degenerative diseases, including muscular dystrophy. | A new look at the origin, function, and "stem-cell" status of muscle satellite cells. |
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0.045809537172317505, "28207": 0.3388410806655884, "28823": 0.791648268699646, "29277": 0.34922540187835693, "29353": 0.20580662786960602} | 20187433 | Family members are an integral part of a patient's cancer care from the moment the diagnosis is delivered to the conclusion of treatment. Family members bring with them a range of emotional reactions, interpersonal dynamics and expectations for the care the patient receives. This study is part of a multi-institutional project to continue to improve the process of cancer care. In this study, 19 focus groups (11 patient and 8 provider) were conducted concerning issues related to doctor-patient communication in eight cancer centers in the United States. The content of the conversations was analyzed and thematic categories emerged that highlight the various strengths and difficulties associated with family involvement. The focus groups' comments support the need for explicit conversations between professional caregivers, patients and their loved ones, in order to negotiate the expectations and needs of each team member. Implications for clinical practice and strategies for working with family members are offered. | Involving family members in cancer care: focus group considerations of patients and oncological providers. |
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0.4002431631088257, "29234": 0.2447827309370041, "29235": 1.3550496101379395, "29295": 0.020300358533859253, "29490": 0.0354953333735466} | 20188586 | BACKGROUND Real-time adherence monitoring is now possible through medication storage devices equipped with cellular technology. We assessed the effect of triggered cell phone reminders and counseling using objective adherence data on antiretroviral therapy (ART) adherence among Chinese HIV-infected patients. METHODS We provided ART patients in Nanning, China, with a medication device (Wisepill) to monitor their ART adherence electronically. After 3 months, we randomized subjects within optimal (≥95%) and suboptimal (<95%) adherence strata to intervention vs. control arms. In months 4-9, intervention subjects received individualized reminders triggered by late dose taking (no device opening by 30 minutes past dose time) and counseling using device-generated data. Controls received no reminders or data-informed counseling. We compared postintervention proportions achieving optimal adherence, mean adherence, and clinical outcomes. RESULTS Of 120 subjects enrolled, 116 (96.7%) completed the trial. Preintervention optimal adherence was similar in intervention vs. control arms (63.5% vs. 58.9%, respectively; P = 0.60). In the last intervention month, 87.3% vs. 51.8% achieved optimal adherence [risk ratio (RR): 1.7, 95% confidence interval (CI): 1.3 to 2.2] and mean adherence was 96.2% vs. 89.1% (P = 0.003). Among preintervention suboptimal adherers, 78.3% vs. 33.3% (RR: 2.4, CI: 1.2 to 4.5) achieved optimal adherence and mean adherence was 93.3% vs. 84.7% (P = 0.039). Proportions were 92.5% and 62.9% among optimal adherers, respectively (RR: 1.5, CI: 1.1 to 1.9) and mean adherence was 97.8% vs. 91.7% (P = 0.028). Postintervention clinical outcomes were not significant. CONCLUSIONS Real-time reminders significantly improved ART adherence in this population. This approach seems promising for managing HIV and other chronic diseases and warrants further investigation and adaptation in other settings. | Improving Adherence to Antiretroviral Therapy With Triggered Real-time Text Message Reminders: The China Adherence Through Technology Study. |
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However, the impact of these two processes on size and composition of the peripheral repertoire of regulatory T cells is unclear. Here we followed the fate of individual Foxp3(+)CD4(+)CD25(+) thymocytes and T cells in vivo in T cell receptor (TCR) transgenic mice that express a restricted but polyclonal repertoire of TCRs. By utilizing high-throughput single-cell analysis, we showed that Foxp3(+)CD4(+) peripheral T cells were derived from thymic precursors that expressed a different TCRs than Foxp3(-)CD4(+) medullary thymocytes and Foxp3(-)CD4(+) T cells. Furthermore, the diversity of TCRs on Foxp3(+)CD4(+) regulatory T cells exceeded the diversity of TCRs on Foxp3(-)CD4(+) naive T cells, even in mice that lack expression of tissue-specific antigens. Our results imply that higher TCR diversity on Foxp3(+) regulatory T cells helps these cells to match the specificities of autoreactive and naive T cells. | Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. |
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0.53589928150177, "24965": 0.32058215141296387, "25032": 0.3554046154022217, "25086": 0.11778303235769272, "25409": 0.2105647772550583, "25416": 0.11256109178066254, "25455": 0.5238267183303833, "25778": 0.9045027494430542, "25937": 0.08961215615272522, "26163": 0.259204238653183, "26268": 0.5762182474136353, "26572": 0.26446542143821716, "26739": 0.24325250089168549, "26745": 0.823009729385376, "26802": 0.0770333781838417, "26886": 0.1994270235300064, "27144": 0.04674193635582924, "27268": 0.11081436276435852, "27354": 0.2689530849456787, "27811": 0.11343330889940262, "28177": 0.026976587250828743, "28472": 0.04113444685935974, "28689": 0.12728634476661682, "28711": 0.3560888469219208, "28794": 0.02316705882549286, "29242": 0.015504186972975731, "29347": 1.276475191116333, "29458": 0.1229778528213501, "29477": 0.2231435477733612} | 20221907 | BACKGROUND Most gynecologists determine therapy based on current International Society of Gynecologic Pathologists (ISGP)/World Health Organization classification of endometrial hyperplasia, the reproducibility of which has been questioned. The Gynecologic Oncology Group (GOG) initiated a protocol to assess the efficacy of hormonal therapy of atypical endometrial hyperplasia (AEH). Primary goals of the first phase (Part A) were to prospectively determine reproducibility of referring institution's pathologist's diagnosis of AEH by a panel of 3 gynecologic pathologists and to determine reproducibility of diagnoses by panel members. METHODS Three hundred six women were entered on this protocol with a referring institution's pathologist diagnosis of AEH based on biopsy or curettage. Available slides were assessed independently and interpreted by each of a panel of 3 gynecologic pathologists who used International Society of Gynecologic Pathologists (ISGP)/World Health Organization criteria. The majority diagnosis was based on diagnostic concordance by at least 2 of the 3 panelists. RESULTS The referring institution's pathologist's diagnosis of AEH was supported by the majority of the panel in only 38% of cases. Overall kappa value for the panel diagnosis of AEH was 0.28. The majority diagnosis was adenocarcinoma in 29%, cycling endometrium in 7%, and nonatypical hyperplasia in 18% of cases. Unanimous agreement for any diagnosis was reached among all 3 of the panel in 40% of cases. For the panel, paired kappa values for any diagnosis ranged 0.34-0.43, with an overall kappa value of 0.40. CONCLUSION Reproducibility of referring institution's pathologists' diagnosis of AEH by a panel of gynecologic pathologists is poor. Both underestimation and overestimation of the severity of the lesion are very common. The level of reproducibility among subspecialist panel members for diagnosis of AEH in these specimens also is poor. Better criteria and better sampling are needed to improve reproducibility of this diagnosis, particularly if it is to be used for clinical decisions. | Reproducibility of the diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. |
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"27144": 1.1031591892242432, "27361": 0.7389566898345947, "27539": 0.7656494975090027, "27642": 0.791648268699646, "27777": 0.12556517124176025, "27838": 0.012615402229130268, "27854": 0.1477125883102417, "27989": 0.3982778787612915, "28024": 0.5197699069976807, "28027": 0.018384648486971855, "28184": 0.08513788133859634, "28424": 0.25239890813827515, "28518": 0.0606246218085289, "28548": 0.27786844968795776, "28583": 0.15777134895324707, "28691": 0.14349138736724854, "28805": 0.12642613053321838, "28935": 0.030771657824516296, "28940": 0.020300358533859253, "29172": 0.09761575609445572, "29176": 0.011650617234408855, "29206": 0.08513788133859634, "29290": 0.3750596046447754, "29494": 0.0354953333735466} | 20231138 | DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and its interaction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damage tolerance. Mutations affecting fork reversal also induced unrestrained fork progression and chromosomal breakage, suggesting fork remodeling as a global fork slowing and protection mechanism. Targeting these fork protection systems represents a promising strategy to potentiate cancer chemotherapy. | Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity |
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0.08871890604496002, "25277": 0.2749055027961731, "25519": 0.5640701055526733, "25635": 0.0058422754518687725, "25711": 0.025073638185858727, "25972": 0.1685553640127182, "26046": 0.5696102976799011, "26226": 0.10993985831737518, "26237": 1.102510929107666, "26698": 0.20739519596099854, "26777": 0.15275461971759796, "27244": 0.1011524572968483, "27290": 0.02887592278420925, "27565": 0.05417001247406006, "27815": 0.37974658608436584, "27969": 0.20660123229026794, "28139": 0.0038986403960734606, "28687": 0.04860413447022438, "29361": 0.2317005842924118, "29566": 0.13925230503082275} | 20240998 | OBJECTIVE To resolve uncertainty as to the risk of Sudden Infant Death Syndrome (SIDS) associated with sleeping in bed with your baby if neither parent smokes and the baby is breastfed. DESIGN Bed sharing was defined as sleeping with a baby in the parents' bed; room sharing as baby sleeping in the parents' room. Frequency of bed sharing during last sleep was compared between babies who died of SIDS and living control infants. Five large SIDS case-control datasets were combined. Missing data were imputed. Random effects logistic regression controlled for confounding factors. SETTING Home sleeping arrangements of infants in 19 studies across the UK, Europe and Australasia. PARTICIPANTS 1472 SIDS cases, and 4679 controls. Each study effectively included all cases, by standard criteria. Controls were randomly selected normal infants of similar age, time and place. RESULTS In the combined dataset, 22.2% of cases and 9.6% of controls were bed sharing, adjusted OR (AOR) for all ages 2.7; 95% CI (1.4 to 5.3). Bed sharing risk decreased with increasing infant age. When neither parent smoked, and the baby was less than 3 months, breastfed and had no other risk factors, the AOR for bed sharing versus room sharing was 5.1 (2.3 to 11.4) and estimated absolute risk for these room sharing infants was very low (0.08 (0.05 to 0.14)/1000 live-births). This increased to 0.23 (0.11 to 0.43)/1000 when bed sharing. Smoking and alcohol use greatly increased bed sharing risk. CONCLUSIONS Bed sharing for sleep when the parents do not smoke or take alcohol or drugs increases the risk of SIDS. Risks associated with bed sharing are greatly increased when combined with parental smoking, maternal alcohol consumption and/or drug use. A substantial reduction of SIDS rates could be achieved if parents avoided bed sharing. | Bed sharing when parents do not smoke: is there a risk of SIDS? An individual level analysis of five major case–control studies |
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"25761": 0.5261374711990356, "25817": 0.0029254043474793434, "25969": 0.5461324453353882, "26305": 0.12814582884311676, "26517": 0.5827828645706177, "26520": 0.0752234235405922, "26646": 0.05694137513637543, "26835": 0.33953672647476196, "27222": 0.02887592278420925, "27321": 0.1677299439907074, "27395": 0.5376120805740356, "27491": 0.2763880789279938, "27989": 0.37102460861206055, "27998": 0.7086513638496399, "28024": 0.5816917419433594, "28297": 0.7863243818283081, "28466": 1.109619140625, "28578": 1.1994705200195312, "28689": 0.8366385698318481, "28696": 0.10379679501056671, "28767": 0.24401791393756866, "28788": 0.3601844012737274, "28873": 0.3554046154022217, "28927": 0.011650617234408855, "29222": 0.11691460013389587, "29290": 0.32553088665008545, "29295": 0.03925827145576477, "29486": 0.5347557663917542, "29491": 0.2983669638633728, "29516": 0.28963330388069153} | 20261352 | OBJECTIVE To define the impact of chronic viremia and associated immune activation on B-cell exhaustion in HIV infection. DESIGN Progressive HIV infection is marked by B-cell anergy and exhaustion coupled with dramatic hypergammaglobulinemia. Although both upregulation of CD95 and loss of CD21 have been used as markers of infection-associated B-cell dysfunction, little is known regarding the specific profiles of dysfunctional B cells and whether persistent viral replication and its associated immune activation play a central role in driving B-cell dysfunction. METHODS Multiparameter flow cytometry was used to define the profile of dysfunctional B cells. The changes in the expression of CD21 and CD95 were tracked on B-cell subpopulations in patients with differential control of viral replication. RESULTS : Although the emergence of exhausted, CD21 tissue-like memory B cells followed similar patterns in both progressors and controllers, the frequency of CD21 activated memory B cells was lower in spontaneous controllers. CONCLUSION Our results suggest that the loss of CD21 and the upregulation of CD95 occur as separate events during the development of B-cell dysfunction. The loss of CD21 is a marker of B-cell exhaustion induced in the absence of appreciable viral replication, whereas the upregulation of CD95 is tightly linked to persistent viral replication and its associated immune activation. Thus, these dysfunctional profiles potentially represent two functionally distinct states within the B-cell compartment. | Decoupling activation and exhaustion of B cells in spontaneous controllers of HIV infection. |
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Here we show a label-free DNA imaging method with stimulated Raman scattering (SRS) microscopy for visualization of the cell nuclei in live animals and intact fresh human tissues with subcellular resolution. Relying on the distinct Raman spectral features of the carbon-hydrogen bonds in DNA, the distribution of DNA is retrieved from the strong background of proteins and lipids by linear decomposition of SRS images at three optimally selected Raman shifts. Based on changes on DNA condensation in the nucleus, we were able to capture chromosome dynamics during cell division both in vitro and in vivo. We tracked mouse skin cell proliferation, induced by drug treatment, through in vivo counting of the mitotic rate. Furthermore, we demonstrated a label-free histology method for human skin cancer diagnosis that provides comparable results to other conventional tissue staining methods such as H&E. Our approach exhibits higher sensitivity than SRS imaging of DNA in the fingerprint spectral region. Compared with spontaneous Raman imaging of DNA, our approach is three orders of magnitude faster, allowing both chromatin dynamic studies and label-free optical histology in real time. | Label-free DNA imaging in vivo with stimulated Raman scattering microscopy. |
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0.4002431631088257, "28207": 0.04767346754670143, "28227": 0.3283478021621704, "28290": 0.5952457785606384, "28424": 0.07612881064414978, "28621": 0.1889725625514984, "28691": 0.09850110858678818, "29206": 0.19381128251552582, "29467": 0.12470348179340363} | 20280410 | Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07–1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner. | A common variant in BRCA2 is associated with both breast cancer risk and prenatal viability |
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0.31560876965522766, "27480": 1.5581445693969727, "27593": 0.16690383851528168, "27678": 0.007782140281051397, "27698": 0.02792670577764511, "27703": 0.2689530849456787, "27815": 0.6684301495552063, "27885": 1.2290464639663696, "27969": 0.1970241367816925, "28086": 0.1685553640127182, "28155": 0.058784693479537964, "28156": 0.6128603219985962, "28212": 0.5209306478500366, "28413": 0.06703783571720123, "28466": 0.0174254160374403, "28674": 0.9425065517425537, "28685": 0.3318578004837036, "28828": 0.40285754203796387, "29107": 0.0317181795835495, "29166": 0.07612881064414978, "29295": 0.40546512603759766, "29347": 0.03360854089260101, "29543": 0.010684899985790253} | 20287253 | Congenital obstructive nephropathy is a consequence abnormal urinary tract development resulting in renal growth failure and injury manifested by progressive tubular atrophy and interstitial fibrosis. We have studied the renal cellular and physiological response to unilateral ureteral obstruction (UUO) in the neonatal rodent (guinea pig, rat, and mouse). Whereas in the adult, UUO stimulates renal cellular proliferation, UUO in the neonate reduces nephrogenesis, glomerular maturation, and tubular cellular proliferation. This is accompanied by a proportionately greater compensatory growth of the intact opposite kidney in the neonate. Impaired renal growth and tubular atrophy are likely owing at least in part to stimulation of renal tubular apoptosis. This, in turn, may result from a combination of factors, including loss of epithelial cell polarity, a reduction in the oncoprotein bcl-2 and epidermal growth factor (EGF), and increased expression of the fibrogenic cytokine, transforming growth factor-beta1 (TGF-beta1). Infusion of EGF stimulates cellular proliferation, suppresses apoptosis, and reduces tubular atrophy and interstitial fibrosis. TGF-beta1 is regulated by the renin-angiotensin system, which is markedly activated by UUO in the neonate. The functional consequences of obstructive nephropathy in early development are hyperfiltration by remaining nephrons, followed by progressive decrease in glomerular filtration rate that may only develop in later life. Improved management of congenital urinary tract obstruction will depend on a better understanding of the cellular mechanisms, which may lead to specific treatment using gene therapy or modulators of renal growth and development. | Pathophysiology of obstructive nephropathy in the newborn. |
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"27998": 0.5427330136299133, "28268": 0.08603433519601822, "28378": 0.02792670577764511, "28424": 0.2954642176628113, "28517": 0.030771657824516296, "28685": 0.10467668622732162, "28689": 0.07431721687316895, "28696": 0.03360854089260101, "28728": 0.06886265426874161, "28828": 0.4158279001712799, "28976": 0.1905880719423294, "29090": 0.11081436276435852, "29110": 0.8813109993934631, "29166": 0.16359257698059082, "29172": 0.0317181795835495, "29180": 0.6160298585891724, "29299": 0.35745587944984436, "29301": 0.659380316734314, "29516": 0.1602703034877777} | 20288322 | In the 20th century industrialized nations have become afflicted with an unprecedented pandemic of increased adiposity. In the United States, the epicenter of the epidemic, over 2/3 of the population, is overweight and 1 of every 6 Americans carries the diagnosis of metabolic syndrome. Although genes determine susceptibility to environmental factors, the epidemic is clearly due to increased consumption of calorie-dense, highly lipogenic foods, coupled with a marked decrease in physical exertion resulting from modern technologies. If this lifestyle continues, morbid consequences are virtually inevitable. They include type II diabetes and a cluster of disorders known as "the metabolic syndrome" usually appearing in middle age. The morbid consequences of the chronic caloric surplus are buffered before middle age by the partitioning of these calories as fat in the adipocyte compartment which is specifically designed to store triglycerides. Leptin has been proposed as the major hormonal regulator of the partitioning of surplus calories. However, multiple factors can determine the storage capacity of the fat tissue and when it is exceeded ectopic lipid deposition begins. The organs affected in metabolic syndrome include skeletal muscle, liver, heart and pancreas, which are now known to contain abnormal levels of triglycerides. While neutral fat is probably harmless, it is an index of ectopic lipid overload. Fatty acid derivatives can interfere with the function of the cell and ultimately lead to its demise through lipoapoptosis, the consequences of which are gradual organ failure. | Lipid homeostasis, lipotoxicity and the metabolic syndrome. |
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0.0752234235405922, "27184": 0.12728634476661682, "27384": 0.3141832649707794, "27484": 0.7398891448974609, "27824": 0.3325583338737488, "28102": 0.10467668622732162, "28290": 0.02887592278420925, "28309": 0.2969166338443756, "28335": 0.8550800085067749, "28436": 0.32553088665008545, "28696": 0.1221139207482338, "28739": 0.06154331564903259, "28823": 0.8933739066123962, "28964": 0.053244512528181076, "29076": 0.906871497631073, "29398": 0.022212404757738113, "29458": 0.09228714555501938} | 20302714 | Circadian rhythms are associated with the preference for sleep-wake timing, also known as morningness-eveningness (ME). Both circadian rhythms and ME are influenced by genetic factors. Studies show an association between eveningness and depression. This study investigates the heritability of ME and whether ME and depression share common genetic influences. Study participants (n = 1237) were from the Vietnam Era Twin Study of Aging, a longitudinal study of aging with a baseline in midlife. Participants received the Morningness-Eveningness Questionnaire (MEQ) and the Center for Epidemiologic Studies Depression (CES-D) Scale as part of an extensive neurocognitive and psychosocial assessment. MEQ correlations between members of twin pairs were 0.41 (95% CI 0.31-0.49) for monozygotic (MZ) twins and 0.28 for dizygotic (DZ) twins (95% CI 0.19-0.41). CES-D correlations were 0.38 (95% CI 0.28-0.46) for MZ twins and 0.24 (95% CI 0.14-0.36) for DZ twins. Greater eveningness (i.e. lower MEQ scores) was significantly related to more depression symptoms (phenotypic correlation = -0.15 (95% CI -0.21 to -0.09). In the best fitting model, the heritability estimates are 0.42 for the MEQ and 0.37 for the CES-D. A significant genetic correlation of -0.21 indicated that ME and depression share a significant amount of their underlying genetic variance. The genetic covariance between ME and depression accounted for 59.1% of the phenotypic correlation. Of the CES-D sub-scales, Depressed Mood and Interpersonal Difficulties were significantly heritable, while only Well-Being had a significant genetic correlation with ME. ME and depression are both heritable (ME 0.42, depression 0.37) and share common genetic factors, suggesting an overlap in etiology and the relevance of circadian rhythms to depression. Further study of this relationship may help elucidate etiological factors in depression and targets for treatment. | A twin-study of genetic contributions to morningness-eveningness and depression. |
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"27854": 0.25088030099868774, "28014": 1.0868242979049683, "28156": 0.638455867767334, "28286": 1.12241530418396, "28583": 0.058784693479537964, "28696": 1.1375575065612793, "29076": 0.9500881433486938, "29170": 0.045809537172317505, "29290": 0.19541899859905243, "29292": 0.013579257763922215, "29475": 0.8500841856002808, "29610": 0.00875066313892603} | 20310709 | Mice lacking the transcription factor T-bet in the innate immune system develop microbiota-dependent colitis. Here, we show that interleukin-17A (IL-17A)-producing IL-7Rα(+) innate lymphoid cells (ILCs) were potent promoters of disease in Tbx21(-/-)Rag2(-/-) ulcerative colitis (TRUC) mice. TNF-α produced by CD103(-)CD11b(+) dendritic cells synergized with IL-23 to drive IL-17A production by ILCs, demonstrating a previously unrecognized layer of cellular crosstalk between dendritic cells and ILCs. We have identified Helicobacter typhlonius as a key disease trigger driving excess TNF-α production and promoting colitis in TRUC mice. Crucially, T-bet also suppressed the expression of IL-7R, a key molecule involved in controlling intestinal ILC homeostasis. The importance of IL-7R signaling in TRUC disease was highlighted by the dramatic reduction in intestinal ILCs and attenuated colitis following IL-7R blockade. Taken together, these data demonstrate the mechanism by which T-bet regulates the complex interplay between mucosal dendritic cells, ILCs, and the intestinal microbiota. | The Transcription Factor T-bet Regulates Intestinal Inflammation Mediated by Interleukin-7 Receptor+ Innate Lymphoid Cells |
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"28007": 0.6112717390060425, "28024": 0.4974553883075714, "28207": 0.3560888469219208, "28674": 0.12642613053321838, "28774": 0.11517547070980072, "28788": 0.3588210940361023, "28873": 1.1192315816879272, "28896": 0.06886265426874161, "29461": 1.61021888256073, "29543": 0.436867892742157, "29610": 0.05139094591140747} | 20311968 | Cellular therapy with chimeric antigen receptor (CAR)-redirected cytotoxic T cells has shown impressive efficacy in the treatment of hematologic malignancies. We explored a regulatory T cell (Treg)-based therapy in the treatment of allergic airway inflammation, a model for asthma, which is characterized by an airway hyper-reactivity (AHR) and a chronic, T helper-2 (Th2) cell-dominated immune response to allergen. To restore the immune balance in the lung, we redirected Tregs by a CAR toward lung epithelia in mice upon experimentally induced allergic asthma, closely mimicking the clinical situation. Adoptively transferred CAR Tregs accumulated in the lung and in tracheobronchial lymph nodes, reduced AHR and diminished eosinophilic airway inflammation, indicated by lower cell numbers in the bronchoalveolar lavage fluid and decreased cell infiltrates in the lung. CAR Treg cells furthermore prevented excessive pulmonary mucus production as well as increase in allergen-specific IgE and Th2 cytokine levels in exposed animals. CAR Tregs were more efficient in controlling asthma than non-modified Tregs, indicating the pivotal role of specific Treg cell activation in the affected organ. Data demonstrate that lung targeting CAR Treg cells ameliorate key features of experimental airway inflammation, paving the way for cell therapy of severe allergic asthma. | Chimeric Antigen Receptor-Redirected Regulatory T Cells Suppress Experimental Allergic Airway Inflammation, a Model of Asthma |
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1.3494925498962402, "25502": 0.2637155055999756, "25644": 0.22782009840011597, "25714": 0.8022117614746094, "26243": 0.06154331564903259, "26356": 0.17840765416622162, "26402": 0.05970508232712746, "26651": 0.2719337046146393, "26773": 0.4400174915790558, "27169": 1.5187265872955322, "27781": 0.857568621635437, "27846": 0.7220231294631958, "27854": 0.3034266233444214, "29235": 0.8238670229911804, "29489": 0.18654440343379974, "29490": 0.11081436276435852} | 20313748 | Adherens junctions (AJs), which are organized by adhesion proteins and the underlying actin cytoskeleton, probably sense pulling forces from adjacent cells and modulate opposing forces to maintain tissue integrity, but the regulatory mechanism remains unknown at the molecular level. Although the possibility that α-catenin acts as a direct linker between the membrane and the actin cytoskeleton for AJ formation and function has been minimized, here we show that α-catenin recruits vinculin, another main actin-binding protein of AJs, through force-dependent changes in α-catenin conformation. We identified regions in the α-catenin molecule that are required for its force-dependent binding of vinculin by introducing mutant α-catenin into cells and using in vitro binding assays. Fluorescence recovery after photobleaching analysis for α-catenin mobility and the existence of an antibody recognizing α-catenin in a force-dependent manner further supported the notion that α-catenin is a tension transducer that translates mechanical stimuli into a chemical response, resulting in AJ development. | α-Catenin as a tension transducer that induces adherens junction development |
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"29110": 0.0797421783208847, "29171": 0.02792670577764511, "29336": 0.18329764902591705, "29458": 0.848413348197937} | 20321154 | BACKGROUND The bidirectional relationships between metabolic syndrome (MetS) and schizophrenia (SCZ) play a crucial role in clinical treatment of both diseases but such bidirectional causal effects have not been comprehensively elucidated. AIMS To investigate the influence of MetS on incident SCZ and the opposite direction as well as their predictors for each direction with a population-based cohort sample. METHOD We enrolled 76,545 subjects who had participated in a community-based health screening program during 1999-2004. After excluding those with the existing MetS or SCZ at baseline, the two normal prospective cohorts corresponding to each independent variable of MetS or SCZ, respectively, were followed over time to ascertain incident outcome of SCZ and MetS. The crude and adjusted hazard ratios for the effect of the predictor on each incident outcome were estimated after controlling for the possible confounding factors. RESULTS The overall incidence rate (per 10(5)person-years) of SCZ was 61.15. The incidence rate in patients with MetS was lower than those without (44.24 versus 64.20), indicating the presence of MetS failed to find an increased risk of developing incident SCZ. However, participants with abnormal waist circumference (WC) were two times (95% CI: 1.37 to 2.93) more likely to yield incident SCZ compared to those with normal WC. In the opposite direction, the incidence of MetS was statistically higher in patients with SCZ than those without SCZ (11.25% vs 7.94%, respectively), suggesting SCZ conferred a higher risk for yielding incident MetS (adjusted hazard ratio=1.89, 95% CI: 1.36, 2.63). CONCLUSIONS After examining the bidirectional causal relationships between SCZ and MetS with the theoretically sound and large population-based prospective cohort study, central obesity, one of the individual components of MetS, was corroborated as an independent predictor for incident SCZ. Patients diagnosed with SCZ were at greater risk of having incident cases of MetS. Such significant temporal bidirectional relationships between SCZ and central obesity suggest a reciprocal interaction exits between SCZ and central obesity. | A population-based cohort study to elucidate temporal relationship between schizophrenia and metabolic syndrome (KCIS no. PSY3). |
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0.12642613053321838, "26886": 0.4196864068508148, "27354": 0.757441520690918, "27451": 0.8682814836502075, "27824": 0.09938567131757736, "28093": 0.10993985831737518, "28329": 0.34508460760116577, "28575": 0.48068851232528687, "28823": 0.18492233753204346, "29458": 0.3416208028793335} | 20326526 | This series of studies describes the development of a measure of emotional intelligence based on the model of emotional intelligence developed by Salovey and Mayer [Salovey, P. & Mayer, J. D. (1990). Emotional intelligence. Imagination, Cognition and Personality, 9, 185–211.]. A pool of 62 items represented the different dimensions of the model. A factor analysis of the responses of 346 participants suggested the creation of a 33-item scale. Additional studies showed the 33-item measure to have good internal consistency and testretest reliability. Validation studies showed that scores on the 33-item measure 1. (a) correlated with eight of nine theoretically related constructs, including alexithymia, attention to feelings, clarity of feelings, mood repair, optimism and impulse control; 2. (b) predicted first-year college grades; 3. (c) were significantly higher for therapists than for therapy clients or for prisoners; 4. (d) were significantly higher for females than males, consistent with prior findings in studies of emotional skills; 5. (e) were not related to cognitive ability and 6. (f) were associated with the openness to experience trait of the big five personality dimensions. | DEVELOPMENT AND VALIDATION OF A MEASURE OF EMOTIONAL INTELLIGENCE |
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Because H. pylori is auxotrophic for cholesterol, we have explored the assimilation of cholesterol by H. pylori in infection. Here we show that H. pylori follows a cholesterol gradient and extracts the lipid from plasma membranes of epithelial cells for subsequent glucosylation. Excessive cholesterol promotes phagocytosis of H. pylori by antigen-presenting cells, such as macrophages and dendritic cells, and enhances antigen-specific T cell responses. A cholesterol-rich diet during bacterial challenge leads to T cell–dependent reduction of the H. pylori burden in the stomach. Intrinsic α-glucosylation of cholesterol abrogates phagocytosis of H. pylori and subsequent T cell activation. We identify the gene hp0421 as encoding the enzyme cholesterol-α-glucosyltransferase responsible for cholesterol glucosylation. Generation of knockout mutants lacking hp0421 corroborates the importance of cholesteryl glucosides for escaping phagocytosis, T cell activation and bacterial clearance in vivo. Thus, we propose a mechanism regulating the host–pathogen interaction whereby glucosylation of a lipid tips the scales towards immune evasion or response. | Cholesterol glucosylation promotes immune evasion by Helicobacter pylori |
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Here, we analyzed the role of myoepithelial cells and fibroblasts in the progression of in situ carcinomas using a model of human DCIS and primary breast tumors. Progression to invasion was promoted by fibroblasts and inhibited by normal myoepithelial cells. Molecular profiles of isolated luminal epithelial and myoepithelial cells identified an intricate interaction network involving TGFbeta, Hedgehog, cell adhesion, and p63 required for myoepithelial cell differentiation, the elimination of which resulted in loss of myoepithelial cells and progression to invasion. | Regulation of in situ to invasive breast carcinoma transition. |
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In this study, a combination of qualitative techniques from participatory rural appraisal and rapid assessment procedures was used to investigate the perceptions of health needs of shelter-based youth in Baltimore, MD in the U.S.A. The most common youth-identified health problems included STDs, HIV/AIDS, pregnancy, depression, drug use and injuries. These correlate well with more objective health status data for the same youth. The youth spoke of environmental safety threats of violence and victimization by adults, as well as racism and sexism in their lives. Youth reported that trusted adult figures such as grandmothers are important sources of health advice. Many homeless youth from less than ideal family situations remain in contact with and continue to seek advice from parents and other family members. Health interventions with urban street youth need to acknowledge the primacy of the social context for these youth, as well as the reality of violence as a daily health threat. | Health and access to care: perspectives of homeless youth in Baltimore City, U.S.A. |
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0.006812678650021553, "29461": 1.325395107269287} | 20344442 | Caspase recruitment domain-containing membrane-associated guanylate kinase protein-1 (CARMA1) is a critical component of the NF-kappaB signaling cascade mediated by TCR engagement. In addition to activation of naïve T cells, TCR signaling is important for the development of agonist-selected T-cell subsets such as Treg, NKT cells, and CD8-alpha alpha T cells. However, little is known about the role of CARMA1 in the development of these lineages. Here we show that CARMA1-deficient mice (CARMA1(-/-)) have altered populations of specific subsets of agonist-selected T cells. Specifically, CARMA1(-/-) mice have impaired natural and adaptive Treg development, whereas NKT cell numbers are normal compared with wild-type mice. Interestingly, CD8-alpha alpha T cells, which may also be able to develop through an extrathymic selection pathway, are enriched in the gut of CARMA1(-/-) mice, whereas memory-phenotype CD4(+) T cells (CD62L(low)/CD44(high)) are present at reduced numbers in the periphery. These results indicate that CARMA1 is essential for Treg development, but is not necessary for the development of other agonist-selected T-cell subsets. Overall, these data reveal an important but differential role for CARMA1-mediated TCR signaling in T-cell development. | Differential requirement for CARMA1 in agonist-selected T-cell development. |
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[n = 6]), stumptail (SIVstm [n = 1]), mandrill (SIVmnd [n = 1]), and African green (SIVagm [n = 1]) primates were examined for their ability to infect human cells and for their coreceptor requirements. All isolates infected human peripheral blood mononuclear cells (PBMCs) from a CCR5(+/+) donor, and seven of eight isolates tested also infected CCR5(-/-) PBMCs. Analysis of coreceptor utilization using GHOST and U87 cell lines revealed that all of the isolates tested used CCR5 and the orphan receptors STRL33 and GPR15. Coreceptors such as CCR2b, CCR3, CCR8, and CX3CR1 were also utilized by some primary SIV isolates. More importantly, we found that CXCR4 was used as a coreceptor by the SIVstm, the SIVagm, and four of the SIVsm isolates in GHOST and U87 cells. These data suggest that primary SIV isolates from diverse primate species can utilize CXCR4 for viral entry, similar to what has been described for human immunodeficiency viruses. | Simian immunodeficiency viruses of diverse origin can use CXCR4 as a coreceptor for entry into human cells. |
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a homologue of uncoupling protein (UCP) from rat skeletal muscle. We also cloned rat UCP-2 cDNA from rat brown adipose tissue (BAT). The UCP cloned from rat skeletal muscle showed 57% and 72% identity with rat UCP-1 and UCP-2. The mRNA was expressed abundantly in the skeletal muscle, moderately in the BAT, and slightly in the white adipose tissue (WAT) with a major band at 2.5 kb and a minor band at 2.8 kb, while the UCP-2 gene expression was widely detected in the whole body with substantial levels in the WAT and with slight levels in the skeletal muscle and BAT. The rat UCP cloned in the present study showed 86% identity with the recently cloned human UCP-3, which was also expressed abundantly in the skeletal muscle with a signal of 2.4 kb. Therefore, the rat UCP was considered to be rat UCP-3. In rats fed high-fat diet the UCP-3 gene expression was augmented 2-fold in the skeletal muscle while UCP-2 mRNA levels were increased significantly (1.6-fold) in the epididymal WAT. Augmented expression of UCPs may provide defense against high-fat induced obesity and impairment of glucose metabolism. | Cloning of rat uncoupling protein-3 and uncoupling protein-2 cDNAs: their gene expression in rats fed high-fat diet. |
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"28283": 0.9842413663864136, "28691": 0.15023678541183472, "28715": 0.16276304423809052, "29206": 1.1846466064453125} | 20368353 | The basic determinant of chromosome inheritance, the centromere, is specified in many eukaryotes by an epigenetic mark. Using gene targeting in human cells and fission yeast, chromatin containing the centromere-specific histone H3 variant CENP-A is demonstrated to be the epigenetic mark that acts through a two-step mechanism to identify, maintain and propagate centromere function indefinitely. Initially, centromere position is replicated and maintained by chromatin assembled with the centromere-targeting domain (CATD) of CENP-A substituted into H3. Subsequently, nucleation of kinetochore assembly onto CATD-containing chromatin is shown to require either the amino- or carboxy-terminal tail of CENP-A for recruitment of inner kinetochore proteins, including stabilizing CENP-B binding to human centromeres or direct recruitment of CENP-C, respectively. | A two-step mechanism for epigenetic specification of centromere identity and function |
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This phenomenon might be explained by the so-called cancer stem cell (CSC) theory. Recent technological developments have allowed a deeper understanding and characterization of CSCs. Even though the application of this theory to hematopoietic malignancies and solid tumors holds promise for new ways to treat cancer, it also brings some skepticism. Efficacious therapeutic approaches targeting the CSC population should be explored to overcome therapeutic failure and improve patient outcomes. This review will focus on the intrinsic and extrinsic regulation of CSCs, as well as the development of therapeutic approaches against CSCs, predominantly focusing on gastrointestinal malignancies. | Cancer stem cell theory in gastrointestinal malignancies: recent progress and upcoming challenges |
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1.0621482133865356, "29146": 0.7898768186569214, "29160": 0.29619070887565613, "29464": 0.009718249551951885} | 20374609 | We analyzed the in vitro splicing pathways of three multi-intervening-sequence (IVS) pre-mRNAs: human beta-globin, which contains two IVSs (K. M. Lang, V. L. van Santen, and R. A. Spritz, EMBO J. 4:1991-1996, 1985); rat alpha-lactalbumin, which contains three IVSs; and murine interleukin-3, which contains four IVSs. We found that there are highly preferred pathways of IVS removal from these multi-IVS pre-mRNAs in vitro. The three IVSs of rat alpha-lactalbumin pre-mRNA were excised sequentially from 5' to 3'; in most molecules, IVS1 was removed first, followed by IVS2 and finally by IVS3. The splicing pathway of interleukin-3 pre-mRNA in vitro was more complex. The four IVSs were excised in a highly preferred temporal order, but the order was not strictly sequential or directional. In most molecules, IVS1 and IVS4 were removed first, either simultaneously or in rapid succession. Subsequently, IVS2 was excised, followed by IVS3. The observed splicing pathways apparently resulted from differences in lag times and maximum excision rates of the different IVSs. We detected no exon skipping during splicing of these transcripts in vitro. These observations have implication for proposed models of splice site selection. | In vitro splicing pathways of pre-mRNAs containing multiple intervening sequences? |
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0.28597161173820496, "26282": 0.25088030099868774, "26305": 0.006812678650021553, "26601": 0.04113444685935974, "26952": 0.13499516248703003, "27354": 0.15860503911972046, "27642": 0.10379679501056671, "28177": 0.045809537172317505, "28370": 0.11343330889940262, "28940": 0.25845035910606384, "29003": 0.07793712615966797, "29296": 0.4909018874168396} | 20375264 | MOTIVATION Large-scale genome projects generate a rapidly increasing number of sequences, most of them biochemically uncharacterized. Research in bioinformatics contributes to the development of methods for the computational characterization of these sequences. However, the installation and application of these methods require experience and are time consuming. RESULTS We present here an automatic system for preliminary functional annotation of protein sequences that has been applied to the analysis of sets of sequences from complete genomes, both to refine overall performance and to make new discoveries comparable to those made by human experts. The GeneQuiz system includes a Web-based browser that allows examination of the evidence leading to an automatic annotation and offers additional information, views of the results, and links to biological databases that complement the automatic analysis. System structure and operating principles concerning the use of multiple sequence databases, underlying sequence analysis tools, lexical analyses of database annotations and decision criteria for functional assignments are detailed. The system makes automatic quality assessments of results based on prior experience with the underlying sequence analysis tools; overall error rates in functional assignment are estimated at 2.5-5% for cases annotated with highest reliability ('clear' cases). Sources of over-interpretation of results are discussed with proposals for improvement. A conservative definition for reporting 'new findings' that takes account of database maturity is presented along with examples of possible kinds of discoveries (new function, family and superfamily) made by the system. System performance in relation to sequence database coverage, database dynamics and database search methods is analysed, demonstrating the inherent advantages of an integrated automatic approach using multiple databases and search methods applied in an objective and repeatable manner. AVAILABILITY The GeneQuiz system is publicly available for analysis of protein sequences through a Web server at http://www.sander.ebi.ac. uk/gqsrv/submit | Automated genome sequence analysis and annotation. |
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"28938": 0.04860413447022438, "28991": 0.19220098853111267, "29607": 0.7153595685958862} | 20381484 | S-nitrosylation of proteins by nitric oxide is a major mode of signalling in cells. S-nitrosylation can mediate the regulation of a range of proteins, including prominent nuclear proteins, such as HDAC2 (ref. 2) and PARP1 (ref. 3). The high reactivity of the nitric oxide group with protein thiols, but the selective nature of nitrosylation within the cell, implies the existence of targeting mechanisms. Specificity of nitric oxide signalling is often achieved by the binding of nitric oxide synthase (NOS) to target proteins, either directly or through scaffolding proteins such as PSD-95 (ref. 5) and CAPON. As the three principal isoforms of NOS--neuronal NOS (nNOS), endothelial NOS (eNOS) and inducible NOS (iNOS)--are primarily non-nuclear, the mechanisms by which nuclear proteins are selectively nitrosylated have been elusive. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is physiologically nitrosylated at its Cys 150 residue. Nitrosylated GAPDH (SNO-GAPDH) binds to Siah1, which possesses a nuclear localization signal, and is transported to the nucleus. Here, we show that SNO-GAPDH physiologically transnitrosylates nuclear proteins, including the deacetylating enzyme sirtuin-1 (SIRT1), histone deacetylase-2 (HDAC2) and DNA-activated protein kinase (DNA-PK). Our findings reveal a novel mechanism for targeted nitrosylation of nuclear proteins and suggest that protein-protein transfer of nitric oxide groups may be a general mechanism in cellular signal transduction. | GAPDH Mediates Nitrosylation of Nuclear Proteins |
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"26657": 0.02887592278420925, "26773": 0.2607102394104004, "26775": 0.32129061222076416, "27295": 0.03925827145576477, "27321": 0.1510767638683319, "27777": 0.09317722171545029, "27854": 0.2317005842924118, "27929": 0.11865071207284927, "28156": 0.43623676896095276, "28227": 0.6096806526184082, "28788": 0.21214580535888672, "28873": 0.10467668622732162, "29295": 0.5551415085792542, "29490": 0.026976587250828743, "29610": 0.23864774405956268} | 20388894 | IL-4 promotes the differentiation of naive CD4+ T cells into IL-4-producing T helper 2 (Th2) cells. Previous work provided suggestive but not conclusive evidence that the transcription factor c-Maf directed the tissue-specific expression of IL-4. It was not known whether c-Maf controlled the transcription of other Th2 cytokine genes. To elucidate the role of c-Maf in vivo, we examined cytokine production in mice lacking c-Maf (c-maf(-/-)). CD4+ T cells and NK T cells from c-maf(-/-) mice were markedly deficient in IL-4 production. However, the mice produced normal levels of IL-13 and IgE, and, when differentiated in the presence of exogenous IL-4, c-maf(-/-) T cells produced approximately normal levels of other Th2 cytokines. We conclude that c-Maf has a critical and selective function in IL-4 gene transcription in vivo. | The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. |
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"29206": 0.15610189735889435, "29490": 0.42225050926208496} | 20399078 | The recommended treatment for patients with chronic hepatitis C, pegylated interferon-α (PEG-IFN-α) plus ribavirin (RBV), does not provide sustained virologic response (SVR) in all patients. We report a genome-wide association study (GWAS) to null virological response (NVR) in the treatment of patients with hepatitis C virus (HCV) genotype 1 within a Japanese population. We found two SNPs near the gene IL28B on chromosome 19 to be strongly associated with NVR (rs12980275, P = 1.93 × 10−13, and rs8099917, 3.11 × 10−15). We replicated these associations in an independent cohort (combined P values, 2.84 × 10−27 (OR = 17.7; 95% CI = 10.0–31.3) and 2.68 × 10−32 (OR = 27.1; 95% CI = 14.6–50.3), respectively). Compared to NVR, these SNPs were also associated with SVR (rs12980275, P = 3.99 × 10−24, and rs8099917, P = 1.11 × 10−27). In further fine mapping of the region, seven SNPs (rs8105790, rs11881222, rs8103142, rs28416813, rs4803219, rs8099917 and rs7248668) located in the IL28B region showed the most significant associations (P = 5.52 × 10−28–2.68 × 10−32; OR = 22.3–27.1). Real-time quantitative PCR assays in peripheral blood mononuclear cells showed lower IL28B expression levels in individuals carrying the minor alleles (P = 0.015). | Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C |
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"26807": 0.09938567131757736, "26927": 1.076228141784668, "26982": 0.15693697333335876, "27870": 0.890972912311554, "28086": 0.31845372915267944, "28148": 0.8772575259208679, "28228": 0.20501139760017395, "28739": 0.11517547070980072, "28848": 0.3519764244556427, "28976": 0.12814582884311676, "29197": 0.3141832649707794, "29206": 0.07341018319129944, "29290": 0.5045560002326965, "29295": 0.0058422754518687725} | 20402596 | In rice (Oryza sativa), the shoot-borne crown roots are the major root type and are initiated at lower stem nodes as part of normal plant development. However, the regulatory mechanism of crown root development is poorly understood. In this work, we show that a WUSCHEL-related Homeobox (WOX) gene, WOX11, is involved in the activation of crown root emergence and growth. WOX11 was found to be expressed in emerging crown roots and later in cell division regions of the root meristem. The expression could be induced by exogenous auxin or cytokinin. Loss-of-function mutation or downregulation of the gene reduced the number and the growth rate of crown roots, whereas overexpression of the gene induced precocious crown root growth and dramatically increased the root biomass by producing crown roots at the upper stem nodes and the base of florets. The expressions of auxin- and cytokinin-responsive genes were affected in WOX11 overexpression and RNA interference transgenic plants. Further analysis showed that WOX11 directly repressed RR2, a type-A cytokinin-responsive regulator gene that was found to be expressed in crown root primordia. The results suggest that WOX11 may be an integrator of auxin and cytokinin signaling that feeds into RR2 to regulate cell proliferation during crown root development. | The WUSCHEL-related homeobox gene WOX11 is required to activate shoot-borne crown root development in rice. |
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"26287": 0.32553088665008545, "26461": 0.3910386264324188, "26462": 0.11343330889940262, "26906": 0.1332872211933136, "27794": 0.4531385898590088, "28102": 0.16690383851528168, "28156": 0.5540198087692261, "28283": 0.8117979168891907, "28440": 0.15860503911972046, "28466": 0.043007105588912964, "28483": 0.7067264318466187, "28562": 0.05046287178993225, "28767": 0.2539152204990387, "28788": 0.029824240133166313, "28817": 0.11778303235769272, "28964": 0.09050461649894714, "29025": 0.07793712615966797, "29166": 0.1401015669107437, "29392": 0.5092619061470032, "29494": 0.37371641397476196, "29516": 0.3810817003250122} | 20418809 | A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and strength. Although the etiology of sarcopenia is unknown, the correlation during aging between the loss of activity of satellite cells, which are endogenous muscle stem cells, and impaired muscle regenerative capacity has led to the hypothesis that the loss of satellite cell activity is also a cause of sarcopenia. We tested this hypothesis in male sedentary mice by experimentally depleting satellite cells in young adult animals to a degree sufficient to impair regeneration throughout the rest of their lives. A detailed analysis of multiple muscles harvested at various time points during aging in different cohorts of these mice showed that the muscles were of normal size, despite low regenerative capacity, but did have increased fibrosis. These results suggest that lifelong reduction of satellite cells neither accelerated nor exacerbated sarcopenia and that satellite cells did not contribute to the maintenance of muscle size or fiber type composition during aging, but that their loss may contribute to age-related muscle fibrosis. | Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia |
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in parasitic protozoa is now several decades old. Recently, fresh assertions have been made that predominant clonal evolution explains the population structures of several key protozoan pathogens. Here, we present an alternative perspective. On the assumption that much apparent clonality may be an artefact of inadequate sampling and study design, we review current research to define why sex might be so difficult to detect in protozoan parasite populations. In doing so, we contrast laboratory models of genetic exchange in parasitic protozoa with natural patterns of genetic diversity and consider the fitness advantage of sex at different evolutionary scales. We discuss approaches to improve the accuracy of efforts to characterize genetic exchange in the field. We also examine the implications of the first population genomic studies for the debate around sex and clonality in parasitic protozoa and discuss caveats for the future. | Reproductive clonality in protozoan pathogens--truth or artefact? |
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0.47584590315818787, "28570": 0.034552380442619324, "28667": 0.817850649356842, "28929": 0.12814582884311676, "29258": 0.04674193635582924, "29290": 0.49923527240753174, "29295": 0.08782484382390976, "29455": 0.13071982562541962, "29516": 0.0009760859538801014} | 20420780 | DNA double-strand breaks (DSBs) are repaired via nonhomologous end-joining (NHEJ) or homologous recombination (HR), but cellular repair processes remain elusive. We show here that the ATP-dependent chromatin-remodeling factors, ACF1 and SNF2H, accumulate rapidly at DSBs and are required for DSB repair in human cells. If the expression of ACF1 or SNF2H is suppressed, cells become extremely sensitive to X-rays and chemical treatments producing DSBs, and DSBs remain unrepaired. ACF1 interacts directly with KU70 and is required for the accumulation of KU proteins at DSBs. The KU70/80 complex becomes physically more associated with the chromatin-remodeling factors of the CHRAC complex, which includes ACF1, SNF2H, CHRAC15, and CHRAC17, after treatments producing DSBs. Furthermore, the frequency of NHEJ as well as HR induced by DSBs in chromosomal DNA is significantly decreased in cells depleted of either of these factors. Thus, ACF1 and its complexes play important roles in DSBs repair. | The ACF1 complex is required for DNA double-strand break repair in human cells. |
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"29295": 0.30558720231056213, "29458": 0.7737906575202942} | 20422174 | Controversy exists in the United States regarding the proper evaluation and management of low-grade squamous intraepithelial lesion (LSIL) and equivocal (atypical squamous cells of undetermined significance [ASCUS, now ASC-US]) cervical cytologic interpretations. To address this issue, the National Cancer Institute initiated the ASCUS-LSIL Triage Study (ALTS). ALTS is a multicenter, randomized clinical trial designed to evaluate 3 alternative methods of management, namely, immediate colposcopy, cytologic follow-up, and triage by human papillomavirus (HPV) DNA testing. This article summarizes the major findings of ALTS that have been published to date. Patients with ASCUS (n = 3488) or LSIL (n = 1572) were randomly assigned to research arms between November 1996 and December 1998, and were monitored for 2 years. The disease outcome was histologic cervical intraepithelial neoplasia (CIN) 3/cancer. The prevalence of oncogenic HPV was too high to permit effective triage of LSIL using HPV DNA testing by Hybrid Capture 2. However, for the women referred with a cytologic interpretation of ASCUS, HPV triage proved useful, with sensitivity equivalent to immediate colposcopy and a halving of colposcopic referrals. Among older women with ASCUS, HPV testing remained sensitive for detecting CIN 3 and cancer, but the referral percentage was dramatically lower compared to younger women. ALTS yielded insight into the performance of cytology and histopathology; experienced pathologists differed significantly in their interpretations of cervical abnormalities, especially histologic CIN 1 and cytologic ASCUS. Nonetheless, it was possible to distinguish a relatively uncommon type of ASCUS, equivocal for high-grade squamous intraepithelial lesion, that has a high positive predictive value for identifying women with underlying high-grade CIN. Many additional analyses are underway. | Findings to date from the ASCUS-LSIL Triage Study (ALTS). |
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anticancer agents are derived from plants and terrestrial microorganisms. The isolation of C-nucleosides from the Caribbean sponge, Cryptotheca crypta, four decades ago, provided the basis for the synthesis of cytarabine, the first marine-derived anticancer agent to be developed for clinical use. Cytarabine is currently used in the routine treatment of patients with leukaemia and lymphoma. Gemcitabine, one of its fluorinated derivatives, has also been approved for use in patients with pancreatic, breast, bladder, and non-small-cell lung cancer. Over the past decade, several new experimental anticancer agents derived from marine sources have entered preclinical and clinical trials. This field has expanded significantly as a result of improvements in the technology of deep-sea collection, extraction, and large-scale production through aquaculture and synthesis. In this paper, examples of marine-derived experimental agents that are currently undergoing preclinical and early clinical evaluation are briefly discussed. A summary of the available information on the results of phase I and II trials of agents such as aplidine, ecteinascidin-734 (ET-734), dolastatin 10 and bryostatin 1 is also presented. | Marine organisms as a source of new anticancer agents. |
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"24328": 0.07159364968538284, "24412": 0.28155985474586487, "24456": 0.08782484382390976, "24471": 0.5640701055526733, "24577": 0.26146242022514343, "24848": 0.21214580535888672, "25409": 0.4067663550376892, "25604": 0.43244171142578125, "25654": 0.09850110858678818, "25659": 0.1685553640127182, "25714": 0.2576959431171417, "25719": 0.03360854089260101, "25937": 0.45870962738990784, "26029": 0.8109301924705505, "26402": 0.16607704758644104, "26661": 0.10818854719400406, "27011": 0.9650808572769165, "27144": 0.6754127144813538, "27663": 0.07068414986133575, "27896": 0.2689530849456787, "28006": 1.0361549854278564, "28139": 0.5393219590187073, "28517": 0.18573370575904846, "28687": 0.030771657824516296, "29323": 1.0312920808792114, "29598": 0.4764525294303894} | 20454006 | Diindolylmethane (DIM), a bioactive metabolite of indole-3-carbinol found in cruciferous vegetables, has proposed cancer chemoprevention activity in the breast. There is limited evidence of clinically relevant activity of DIM or long-term safety data of its regular use. A randomized, double-blind, placebo-controlled trial was conducted to determine the activity and safety of combined use of BioResponse DIM® (BR-DIM) with tamoxifen. Women prescribed tamoxifen (n = 130) were randomly assigned oral BR-DIM at 150 mg twice daily or placebo, for 12 months. The primary study endpoint was change in urinary 2/16α-hydroxyestrone (2/16α-OHE1) ratio. Changes in 4-hydroxyestrone (4-OHE1), serum estrogens, sex hormone-binding globulin (SHBG), breast density, and tamoxifen metabolites were assessed. Ninety-eight women (51 placebo, 47 DIM) completed intervention; compliance with treatment was >91%. BR-DIM increased the 2/16α-OHE1 ratio (+3.2 [0.8, 8.4]) compared to placebo (−0.7 [−1.7, 0.8], P < 0.001). Serum SHBG increased with BR-DIM compared to placebo (+25 ± 22 and +1.1 ± 19 nmol/L, respectively). No change in breast density measured by mammography or by MRI was observed. Plasma tamoxifen metabolites (endoxifen, 4-OH tamoxifen, and N-desmethyl-tamoxifen) were reduced in women receiving BR-DIM versus placebo (P < 0.001). Minimal adverse events were reported and did not differ by treatment arm. In patients taking tamoxifen for breast cancer, daily BR-DIM promoted favorable changes in estrogen metabolism and circulating levels of SHBG. Further research is warranted to determine whether BR-DIM associated decreases in tamoxifen metabolites, including effects on endoxifen levels, attenuates the clinical benefit of tamoxifen. Trial Registration: ClinicalTrials.gov NCT01391689. | A randomized, placebo-controlled trial of diindolylmethane for breast cancer biomarker modulation in patients taking tamoxifen |
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"25028": 0.6950984001159668, "25194": 0.3485364317893982, "25284": 0.77198725938797, "25409": 0.4891071021556854, "25458": 0.13414156436920166, "25952": 0.4673144817352295, "25971": 0.5180262327194214, "26208": 0.04860413447022438, "26243": 0.21530038118362427, "26601": 1.057410478591919, "26702": 0.21135559678077698, "26721": 0.6989894509315491, "26745": 0.6461620330810547, "26874": 0.09495500475168228, "27011": 0.5784112811088562, "27373": 0.7295845746994019, "27404": 0.3683255612850189, "27989": 0.23864774405956268, "28466": 0.23092569410800934, "28685": 0.4067663550376892, "28828": 0.5914691090583801, "28911": 0.10555581003427505, "29263": 0.6931471824645996, "29320": 0.8748174905776978, "29336": 0.02412080205976963} | 20456030 | Mitochondria play a pivotal role in energy metabolism, programmed cell death and oxidative stress. Mutated mitochondrial DNA in diseased cells compromises the structure of key enzyme complexes and, therefore, mitochondrial function, which leads to a myriad of health-related conditions such as cancer, neurodegenerative diseases, diabetes and aging. Early detection of mitochondrial and metabolic anomalies is an essential step towards effective diagnoses and therapeutic intervention. Reduced nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) play important roles in a wide range of cellular oxidation-reduction reactions. Importantly, NADH and FAD are naturally fluorescent, which allows noninvasive imaging of metabolic activities of living cells and tissues. Furthermore, NADH and FAD autofluorescence, which can be excited using distinct wavelengths for complementary imaging methods and is sensitive to protein binding and local environment. This article highlights recent developments concerning intracellular NADH and FAD as potential biomarkers for metabolic and mitochondrial activities. | Intracellular coenzymes as natural biomarkers for metabolic activities and mitochondrial anomalies. |
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between CD4(+) and CD8(+) CD3gamma-deficient (gamma(-)) mature T cells. In the present study, we have furthered our understanding and extended the observations to primary T lymphocytes from normal (gamma(+)) individuals. Surface TCR.CD3 components from CD4(+) gamma(-) T cells, other than CD3gamma, were detectable and similar in size to CD4(+) gamma(+) controls. Their native TCR.CD3 complex was also similar to CD4(+) gamma(+) controls, except for an alphabeta(deltaepsilon)(2)zeta(2) instead of an alphabetagammaepsilondeltaepsilonzeta(2) stoichiometry. In contrast, the surface TCRalpha, TCRbeta, and CD3delta chains of CD8(+) gamma(-) T cells did not possess their usual sizes. Using confocal immunofluorescence, TCRalpha was hardly detectable in CD8(+) gamma(-) T cells. Blue native gels (BN-PAGE) demonstrated the existence of a heterogeneous population of TCR.CD3 in these cells. Using primary peripheral blood T lymphocytes from normal (gamma(+)) donors, we performed a broad epitopic scan. In contrast to all other TCR.CD3-specific monoclonal antibodies, RW2-8C8 stained CD8(+) better than it did CD4(+) T cells, and the difference was dependent on glycosylation of the TCR.CD3 complex but independent of T cell activation or differentiation. RW2-8C8 staining of CD8(+) T cells was shown to be more dependent on lipid raft integrity than that of CD4(+) T cells. Finally, immunoprecipitation studies on purified primary CD4(+) and CD8(+) T cells revealed the existence of TCR glycosylation differences between the two. Collectively, these results are consistent with the existence of conformational or topological lineage-specific differences in the TCR.CD3 from CD4(+) and CD8(+) wild type T cells. The differences may be relevant for cis interactions during antigen recognition and signal transduction. | Biochemical differences in the alphabeta T cell receptor.CD3 surface complex between CD8+ and CD4+ human mature T lymphocytes. |
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0.26146242022514343, "29251": 0.151916041970253, "29364": 0.004870930220931768} | 20459964 | Neutrophil is a key cell in pathophysiology of granulomatosis with polyangiitis. Recently, neutrophil extracellular traps were described in this disease. Mitochondrial DNA is also released during traps formation. We measured circulating cell-free mitochondrial and genomic DNA in serum of patients with granulomatosis with polyangiitis. Subjects with the disease (14 active and 11 in remission stage) and 10 healthy controls were enrolled. Quantitative real-time polymerase chain reaction (PCR) was used to measure 79 base pairs (bp) and 230 bp mtDNA fragments. Alu repeats were quantified to evaluate abundance of nuclear DNA in serum at the presence of plasmid control. Both fragments of mtDNA (79 bp and 230 bp) and genomic DNA were elevated significantly in granulomatosis with polyangiitis compared to controls. Only the shorter 79 bp mtDNA correlated with active stage of granulomatosis with polyangiitis and clinical symptoms. A mechanism of extracellular release of mitochondrial DNA accompanies the active stage of the disease. Circulating mtDNA is extremely high in untreated patients. This suggests that biomarker properties of mtDNA are useful for monitoring of treatment. | Circulating mitochondrial DNA in serum of patients with granulomatosis with polyangiitis. |
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0.2026219218969345, "28227": 0.13243216276168823, "28517": 0.14686977863311768, "28696": 0.007782140281051397, "28788": 0.27934664487838745, "28817": 0.0029254043474793434, "29720": 0.7755908370018005} | 20460020 | Efficient local monocyte/macrophage recruitment is critical for tissue repair. Recruited macrophages are polarized toward classical (proinflammatory) or alternative (prohealing) activation in response to cytokines, with tight temporal regulation crucial for efficient wound repair. Estrogen acts as a potent anti-inflammatory regulator of cutaneous healing. However, an understanding of estrogen/estrogen receptor (ER) contribution to macrophage polarization and subsequent local effects on wound healing is lacking. Here we identify, to our knowledge previously unreported, a role whereby estrogen receptor α (ERα) signaling preferentially polarizes macrophages from a range of sources to an alternative phenotype. Cell-specific ER ablation studies confirm an in vivo role for inflammatory cell ERα, but not ERβ, in poor healing associated with an altered cytokine profile and fewer alternatively activated macrophages. Furthermore, we reveal intrinsic changes in ERα-deficient macrophages, which are unable to respond to alternative activation signals in vitro. Collectively, our data reveal that inflammatory cell-expressed ERα promotes alternative macrophage polarization, which is beneficial for timely healing. Given the diverse physiological roles of ERs, these findings will likely be of relevance to many pathologies involving excessive inflammation. | Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair. |
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cognition that are collectively termed HIV-associated neurocognitive disorders (HAND) still occur in approximately 50% of those infected by the virus. Currently there is not a biomarker that can identify HIV-infected people who are at risk for the development of HAND. Previous studies have identified particular sphingolipid species that are dysregulated in HAND, but the neurocognitive correlates of these biochemical findings are not currently understood. To address this question, we compared cerebrospinal fluid (CSF) levels of sphingomyelin, ceramide, and sterol species with performance on standard neurological tests designed to assess the function of multiple cognitive and motor domains in HIV-infected subjects. We found that sphingomyelin:ceramide ratios for acyl chain lengths of C16∶0, C18∶0, C22∶0, and C24∶0 were associated with worse performance on several indices of memory. The most striking finding was for the acyl chain of C18∶0 that consistently associatedwith performance onmultiple tests of memory. These findings suggest that the sphingomyelin:ceramide ratio for C18∶0 may be a reasonable surrogate marker for memory dysfunction in HIV-infected subjects. | Disturbance in cerebral spinal fluid sphingolipid content is associated with memory impairment in subjects infected with the human immunodeficiency virus |
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"25775": 0.13499516248703003, "25783": 0.1946154683828354, "25990": 0.09850110858678818, "26018": 0.07068414986133575, "26181": 0.11778303235769272, "26210": 0.7701805830001831, "26237": 1.1051015853881836, "26242": 0.12642613053321838, "26319": 0.4132472574710846, "26351": 0.1477125883102417, "26462": 0.037378571927547455, "26657": 0.7683706283569336, "26820": 0.12556517124176025, "27166": 0.05786345899105072, "27241": 0.0354953333735466, "27794": 0.8195732831954956, "28093": 0.6149744987487793, "28413": 0.38308101892471313, "28436": 0.10026945173740387, "28507": 0.0038986403960734606, "28674": 0.14433705806732178, "28689": 0.1751343309879303, "28696": 0.1734936386346817, "28739": 0.13414156436920166, "29172": 0.10467668622732162, "29311": 0.15275461971759796, "29458": 0.16524957120418549} | 20473074 | OBJECTIVE To examine associations between mean daily fluid balance during intensive care unit study enrollment and clinical outcomes in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level (RENAL) replacement therapy study. DESIGN Statistical analysis of data from multicenter, randomized, controlled trials. SETTING Thirty-five intensive care units in Australia and New Zealand. PATIENTS Cohort of 1453 patients enrolled in the RENAL study. INTERVENTIONS We analyzed the association between daily fluid balance on clinical outcomes using multivariable logistic regression, Cox proportional hazards, time-dependent analysis, and repeated measure analysis models. MEASUREMENTS AND MAIN RESULTS During intensive care unit stay, mean daily fluid balance among survivors was -234 mL/day compared with +560 mL/day among nonsurvivors (p < .0001). Mean cumulative fluid balance over the same period was -1941 vs. +1755 mL (p = .0003). A negative mean daily fluid balance during study treatment was independently associated with a decreased risk of death at 90 days (odds ratio 0.318; 95% confidence interval 0.24-0.43; p < .000.1) and with increased survival time (p < .0001). In addition, a negative mean daily fluid balance was associated with significantly increased renal replacement-free days (p = .0017), intensive care unit-free days (p < .0001), and hospital-free days (p = .01). These findings were unaltered after the application of different statistical models. CONCLUSIONS In the RENAL study, a negative mean daily fluid balance was consistently associated with improved clinical outcomes. Fluid balance may be a target for specific manipulation in future interventional trials of critically ill patients receiving renal replacement therapy. | An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial. |
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"23995": 0.4654768109321594, "24363": 0.05970508232712746, "24467": 0.7500885725021362, "24497": 0.5607312321662903, "24658": 0.890972912311554, "24757": 0.5517725944519043, "24948": 0.7845434546470642, "25042": 0.11168810725212097, "25519": 0.14686977863311768, "25860": 0.6813592314720154, "26236": 0.20022670924663544, "26453": 0.026025565341114998, "26485": 0.4002431631088257, "27523": 0.42926809191703796, "27615": 0.14179791510105133, "28767": 0.018384648486971855, "28896": 0.1212492436170578, "29569": 0.5168620347976685} | 20491205 | The prison population is increasing and the health problems of prisoners are considerable. Prison is designed with punishment, correction and rehabilitation to the community in mind and these goals may conflict with the aims of health care. A literature review showed that the main issues in prison health care are mental health, substance abuse and communicable diseases. Women prisoners and older prisoners have needs which are distinct from other prisoners. Health promotion and the health of the community outside prisons are desirable aims of prison health care. The delivery of effective health care to prisoners is dependent upon partnership between health and prison services and telemedicine is one possible mode of delivery. | Prison health care: a review of the literature. |
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Although LTP has suffered considerable growing pains over the years, LTP has finally come of age. Here the rich history of LTP is reviewed. These are exciting times and the pace of discovery is remarkable. | A Brief History of Long-Term Potentiation |
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"28156": 0.6144463419914246, "28227": 0.672426164150238, "28228": 0.8949713706970215, "28268": 0.2516399025917053, "28389": 0.020300358533859253, "28696": 0.21135559678077698, "29050": 0.10555581003427505, "29090": 0.1485546976327896, "29125": 0.29981520771980286, "29180": 1.0492360591888428, "29290": 0.469759464263916, "29516": 0.2852376699447632, "29610": 0.04394211992621422} | 20501163 | In patients with cancer, the wasting syndrome, cachexia, is associated with caloric deficiency. Here, we describe tumor-induced alterations of the host metabolic response to caloric deficiency that cause intratumoral immune suppression. In pre-cachectic mice with transplanted colorectal cancer or autochthonous pancreatic ductal adenocarcinoma (PDA), we find that IL-6 reduces the hepatic ketogenic potential through suppression of PPARalpha, the transcriptional master regulator of ketogenesis. When these mice are challenged with caloric deficiency, the resulting relative hypoketonemia triggers a marked rise in glucocorticoid levels. Multiple intratumoral immune pathways are suppressed by this hormonal stress response. Moreover, administering corticosterone to elevate plasma corticosterone to a level that is lower than that occurring in cachectic mice abolishes the response of mouse PDA to an immunotherapy that has advanced to clinical trials. Therefore, tumor-induced IL-6 impairs the ketogenic response to reduced caloric intake, resulting in a systemic metabolic stress response that blocks anti-cancer immunotherapy. | Tumor-Induced IL-6 Reprograms Host Metabolism to Suppress Anti-tumor Immunity |
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"28215": 0.8247235417366028, "28498": 0.9287132620811462} | 20524091 | Self-renewal and differentiation of stem cells are tightly regulated processes subject to intrinsic and extrinsic signals. Molecular chaperones and co-chaperones, especially heat shock proteins (Hsp), are ubiquitous molecules involved in the modulation of protein conformational and complexation states. The function of Hsp, which are typically associated with stress response and tolerance, is well characterized in differentiated cells, while their role in stem cells remains unclear. It appears that embryonic stem cells exhibit increased stress tolerance and concomitant high levels of chaperone expression. This review critically evaluates stem cell research from a molecular chaperone perspective. Furthermore, we propose a model of chaperone-modulated self-renewal in mouse embryonic stem cells. | Chaperoning stem cells: a role for heat shock proteins in the modulation of stem cell self-renewal and differentiation? |
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0.13157635927200317, "24755": 0.7638313174247742, "24759": 0.02316705882549286, "25006": 0.3743882179260254, "25032": 0.3325583338737488, "25070": 0.9108069539070129, "25121": 0.08513788133859634, "25222": 0.3883931338787079, "25519": 0.9348671436309814, "26226": 0.3346569836139679, "26462": 0.09495500475168228, "26837": 0.19862671196460724, "26906": 0.040196798741817474, "27339": 0.2983669638633728, "27351": 0.7638313174247742, "27843": 0.28155985474586487, "28093": 0.12814582884311676, "28353": 0.38441169261932373, "28915": 0.16524957120418549, "29166": 0.20102575421333313, "29278": 0.2607102394104004, "29458": 0.14939609169960022} | 20526907 | OBJECTIVE To quantify the effects of quantity and frequency of alcohol consumption on risk of acute myocardial infarction and coronary death. DESIGN Case-control study. SETTING Lower Hunter region of New South Wales, Australia, 1983-94. SUBJECTS Men and women aged 35-69 years. MAIN OUTCOME MEASURE Acute myocardial infarction or coronary death. RESULTS Alcohol consumption patterns were compared between 11,511 cases of acute myocardial infarction or coronary death and 6077 controls randomly selected from the same study population. After adjusting for the effects of age, smoking, and medical history, men and women who consumed one or two drinks of alcohol on five or six days a week had a reduction in risk of a major coronary event compared with men and women who were non-drinkers (odds ratios: men 0.31 (95% confidence interval 0.22 to 0.45); women 0.33 (0.18 to 0.59)). A similar reduction in risk was found after excluding non-drinkers who were formerly moderate to heavy drinkers. An acute protective effect of alcohol consumption was also found for regular drinkers who consumed one or two drinks in the 24 hours preceding the onset of symptoms (odds ratios: men 0.74 (0.51 to 1.09); women 0.43 (0.20 to 0.95)). CONCLUSIONS Frequency and quantity of alcohol consumption are important in assessing the risk of a major coronary event. Risk is lowest among men who report one to four drinks daily on five or six days a week and among women who report one or two drinks daily on five or six days a week. | How much alcohol and how often? Population based case-control study of alcohol consumption and risk of a major coronary event. |
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0.05694137513637543, "27992": 0.10026945173740387, "28086": 1.02149498462677, "28156": 0.5805994272232056, "28173": 0.7872136831283569, "28426": 0.034552380442619324, "28723": 0.35060185194015503, "28751": 0.08603433519601822, "28788": 0.20580662786960602, "28799": 1.254435658454895, "28815": 0.01934296265244484, "28847": 0.8941729068756104, "28901": 0.026025565341114998, "28964": 0.2607102394104004, "29101": 0.11081436276435852, "29129": 0.7528522610664368, "29206": 0.11343330889940262, "29290": 0.38574060797691345, "29441": 0.1332872211933136} | 20532591 | White adipose tissue displays high plasticity. We developed a system for the inducible, permanent labeling of mature adipocytes that we called the AdipoChaser mouse. We monitored adipogenesis during development, high-fat diet (HFD) feeding and cold exposure. During cold-induced 'browning' of subcutaneous fat, most 'beige' adipocytes stem from de novo–differentiated adipocytes. During HFD feeding, epididymal fat initiates adipogenesis after 4 weeks, whereas subcutaneous fat undergoes hypertrophy for a period of up to 12 weeks. Gonadal fat develops postnatally, whereas subcutaneous fat develops between embryonic days 14 and 18. Our results highlight the extensive differences in adipogenic potential in various fat depots. | Tracking adipogenesis during white adipose tissue development, expansion and regeneration |
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"27421": 0.9485763907432556, "27532": 0.23092569410800934, "27854": 0.1384023278951645, "27989": 0.04860413447022438, "28156": 0.1401015669107437, "28375": 0.0038986403960734606, "28915": 0.554580807685852, "29129": 0.24401791393756866, "29172": 0.6848117709159851, "29181": 1.0382318496704102, "29251": 0.30989447236061096, "29278": 0.08692999184131622, "29295": 0.129004567861557, "29391": 0.23092569410800934} | 20544428 | Recent studies have highlighted the involvement of the peripheral immune system in delayed cellular degeneration after stroke. In the permanent middle cerebral artery occlusion (MCAO) model of stroke, the spleen decreases in size. This reduction occurs through the release of splenic immune cells. Systemic treatment with human umbilical cord blood cells (HUCBC) 24 h post-stroke blocks the reduction in spleen size while significantly reducing infarct volume. Splenectomy 2 weeks prior to MCAO also reduces infarct volume, further demonstrating the detrimental role of this organ in stroke-induced neurodegeneration. Activation of the sympathetic nervous system after MCAO results in elevated catecholamine levels both at the level of the spleen, through direct splenic innervation, and throughout the systemic circulation upon release from the adrenal medulla. These catecholamines bind to splenic alpha and beta adrenoreceptors. This study examines whether catecholamines regulate the splenic response to stroke. Male Sprague-Dawley rats either underwent splenic denervation 2 weeks prior to MCAO or received injections of carvedilol, a pan adrenergic receptor blocker, prazosin, an alpha1 receptor blocker, or propranolol, a beta receptor blocker. Denervation was confirmed by reduced splenic expression of tyrosine hydroxylase. Denervation prior to MCAO did not alter infarct volume or spleen size. Propranolol treatment also had no effects on these outcomes. Treatment with either prazosin or carvedilol prevented the reduction in spleen size, yet only carvedilol significantly reduced infarct volume (p < 0.05). These results demonstrate that circulating blood borne catecholamines regulate the splenic response to stroke through the activation of both alpha and beta adrenergic receptors. | Blockade of adrenoreceptors inhibits the splenic response to stroke. |
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0.11256109178066254, "25643": 0.21372433006763458, "25845": 0.3777405619621277, "26243": 0.00875066313892603, "26445": 0.029824240133166313, "26591": 0.1485546976327896, "26601": 0.14602625370025635, "26942": 0.8247235417366028, "27144": 0.06154331564903259, "27339": 0.7665573358535767, "27606": 1.024303913116455, "27697": 0.13071982562541962, "27755": 0.176772341132164, "27777": 0.016465263441205025, "27790": 0.24018502235412598, "28032": 0.6950984001159668, "28696": 0.07159364968538284, "28715": 0.045809537172317505, "28774": 0.029824240133166313, "28807": 0.021256839856505394, "29278": 0.13157635927200317} | 20554003 | Anti-inflammatory therapy decreases infarct size and enhances stroke recovery. Thiazolidinedione peroxisome proliferator-activated receptor (PPAR)gamma agonists have potent anti-inflammatory and insulin-sensitizing anti-diabetic actions. Thirty stroke patients with type 2 diabetes admitted for acute inpatient stroke rehabilitation receiving pioglitazone or rosiglitazone were matched for age, sex, initial FIMTM score and interval post-stroke with 30 stroke patients with type 2 diabetes not receiving thiazolidinediones. Relevant outcome variables were compared for both groups. The thiazolidinedione treated group showed significantly greater mean improvement in FIMTM score compared to control group (25.6 ± 10.2 SD vs. 19.8 ± 10.5, respectively, P = 0.015). There was no significant difference in length of rehabilitation hospital stay (24.2 ± 7.6 vs. 25.1 ± 7.4 days, P = 0.657) or final discharge destination (home/institution, 19/11 versus 17/13, P = 0.792). Use of thiazolidinediones was associated with enhanced functional recovery in stroke patients with type 2 diabetes. | Effects of Thiazolidinediones on Stroke Recovery: A Case-Matched Controlled Study |
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0.24171993136405945, "27895": 0.04953393340110779, "28465": 0.04674193635582924, "28522": 0.053244512528181076, "28817": 0.9732321500778198, "28938": 0.007782140281051397, "29170": 0.5156965255737305, "29290": 0.6548244953155518, "29441": 0.1212492436170578} | 20568364 | While significant progress has been made in understanding the induction of tumor vasculature by secreted angiogenic factors, little is known regarding contact-dependent signals that promote tumor angiogenesis. Here, we report that the Notch ligand Jagged1 induced by growth factors via mitogen-activating protein kinase (MAPK) in head and neck squamous cell carcinoma (HNSCC) cells triggered Notch activation in neighboring endothelial cells (ECs) and promoted capillary-like sprout formation. Jagged1-expressing HNSCC cells significantly enhanced neovascularization and tumor growth in vivo. Moreover, the level of Jagged1 was significantly correlated with tumor blood vessel content and associated with HNSCC development. Our results elucidate a novel mechanism by which the direct interplay between tumor cells and ECs promotes angiogenesis through MAPK and Notch signaling pathways. | Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. |
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"26601": 0.8091925978660583, "26721": 0.1212492436170578, "27142": 0.4624064862728119, "27570": 0.6389714479446411, "27790": 0.10906458646059036, "28527": 0.1358480453491211, "28829": 0.7018978595733643, "28848": 1.039613962173462, "28927": 0.3297532796859741, "29060": 0.4794800877571106, "29146": 0.6482070088386536} | 20585600 | To explore the structural basis of alternative splicing, we have analyzed the splicing of pre-mRNAs containing an optional exon, E4, from the preprotachykinin gene. This gene encodes substance P and related tachykinin peptides by alternative splicing of a common pre-mRNA. We have shown that alternative splicing of preprotachykinin pre-mRNA occurs by preferential skipping of optional E4. The competing mechanism that incorporates E4 into the final spliced RNA is constrained by an initial block to splicing of the immediate upstream intervening sequence (IVS), IVS3. This block is relieved by sequential splicing, in which the immediate downstream IVS4 is removed first. The structural change resulting from the first splicing event is directly responsible for activation of IVS3 splicing. This structural rearrangement replaces IVS4 sequences with E5 and its adjacent IVS5 sequences. To determine how this structural change promoted IVS3 splicing, we asked what structural change(s) would restore activity of IVS3 splicing-defective mutants. The most significant effect was observed by a 2-nucleotide substitution that converted the 5' splice site of E4 to an exact consensus match, GUAAGU. Exon 5 sequences alone were found not to promote splicing when present in one or multiple copies. However, when a 15-nucleotide segment of IVS5 containing GUAAGU was inserted into a splicing-defective mutant just downstream of the hybrid exon segment E4E5, splicing activity was recovered. Curiously, the 72-nucleotide L2 exon of adenovirus, without its associated 5' splice site, activates splicing when juxtaposed to E4. Models for the activation of splicing by an RNA structural change are discussed. | A Sequential splicing mechanism promotes selection of an optimal exon by repositioning a downstream 5' splice site in preprotachykinin pre-mRNA. |
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"23924": 1.0828639268875122, "23969": 0.00875066313892603, "24110": 0.6921701431274414, "24133": 0.029824240133166313, "24209": 0.006812678650021553, "24226": 0.19381128251552582, "24278": 0.6764062643051147, "24355": 0.02316705882549286, "24387": 0.20977331697940826, "24915": 0.6754127144813538, "24939": 0.5284429788589478, "24964": 0.2247048318386078, "25126": 0.04767346754670143, "25212": 1.1487655639648438, "25331": 0.176772341132164, "25426": 0.045809537172317505, "25458": 0.0842406153678894, "25502": 0.22626367211341858, "25644": 0.10026945173740387, "25971": 0.11168810725212097, "26031": 0.39893341064453125, "26228": 0.20421554148197174, "26773": 0.4938860833644867, "26786": 0.08603433519601822, "26837": 0.24018502235412598, "27384": 0.10555581003427505, "27453": 0.2160874605178833, "27822": 1.1089750528335571, "28436": 0.3601844012737274, "28688": 0.1710275560617447, "28696": 0.08154398202896118, "28892": 0.026976587250828743, "28965": 0.22157983481884003} | 20602517 | The endogenous circadian rhythm of melatonin, driven by the suprachiasmatic nucleus, exhibits a close association with the endogenous circadian component of the sleep propensity rhythm and the endogenous circadian component of the variation in electroencephalogram (EEG) oscillations such as sleep spindles and slow waves. This association is maintained even when the sleep-wake cycle is desynchronized from the endogenous circadian rhythm of melatonin. Administration of melatonin during the day increases daytime sleep propensity as indexed by both the latency to sleep onset and sleep consolidation. The EEG during daytime sleep after melatonin administration exhibits characteristics reminiscent of the nocturnal sleep EEG, that is, increased sleep spindle activity and reduced slow-wave sleep and slow-wave activity, as detected by quantitative EEG analysis. Administration of higher doses of melatonin (5 mg or more) prior to nocturnal sleep results in an increase in rapid eye movement (REM) sleep. These data demonstrate that melatonin exerts effects on the main characteristics of human sleep, that is, latency to sleep onset, sleep consolidation, slow waves, sleep spindles, and REM sleep. There is a need for further studies using physiological doses and delivery systems that generate physiological plasma melatonin profiles to firmly establish the role of the endogenous circadian rhythm of melatonin in the circadian regulation of sleep. | Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. |
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DESIGN Cross-sectional survey. SETTING A ten-bed medical-surgical intensive care unit (ICU) in a tertiary care university hospital. PATIENTS The study group included 882 elderly patients (> or =65 yrs of age) and 1,827 controls (<65 yrs of age) treated during the period of 1995 to 2000. INTERVENTION None. MEASUREMENTS AND MAIN RESULTS Mortality was assessed during the ICU and hospital stays, and 12, 24, and 36 months after ICU discharge. The cumulative 3-yr mortality rate among the elderly (57%) was higher (p < .05) than that among the controls (40%). The majority (66%) of the elderly nonsurvivors died within 1 month after intensive care discharge. All elderly patients with day-1 Sequential Organ Failure (SOFA) scores >15 died during the ICU stay. QOL was assessed with EQ-5D and RAND-36 measures from 10 months to 7 yrs after discharge. The majority (88%) of the elderly survivors assessed their present health state as good or satisfactory; 66% found it to be similar or better than 12 months earlier, and 48% similar or better than their preadmission state. QOL measures by RAND-36 revealed that aging decreased their competencies most in physical functioning, physical role limitations, and vitality, but the elderly had better values in mental health than the controls. However, QALYs of the elderly respondents were 21% to 35% lower than the mean QALY minus 2 sd units of the age- and gender-adjusted general population. CONCLUSIONS High age alone is not a valid reason to refuse intensive care, but the benefits perceived by intensive care seem to decrease with aging, if reflected as QALYs. However, 97% of the elderly survivors lived at home and 88% of them considered their QOL satisfactory or good after hospital discharge. Therefore, more reliable information on the outcome for the elderly is clearly needed. | Long-term survival, quality of life, and quality-adjusted life-years among critically ill elderly patients. |
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0.009718249551951885, "26835": 0.8004589080810547, "27046": 0.021256839856505394, "27169": 0.8666408061981201, "27321": 0.29036402702331543, "27602": 0.09938567131757736, "27673": 0.045809537172317505, "27781": 0.05970508232712746, "28105": 0.11517547070980072, "28183": 0.7881022095680237, "28636": 0.9515975713729858, "28674": 0.08513788133859634, "28696": 0.13925230503082275, "28736": 0.13243216276168823, "28788": 0.8349450826644897, "28873": 0.0752234235405922, "29397": 1.0828639268875122} | 20608982 | PURPOSE OF REVIEW As the migration of neutrophils from blood to inflamed tissues is an essential component of innate immunity and a key contributing factor to the pathogenesis of inflammatory disorders, this aspect of leukocyte biology continues to be a highly dynamic field of research. This review summarizes recent findings in this area, focusing on the mechanisms that mediate neutrophil transmigration, an area where significant progress has been made. RECENT FINDINGS The topics to be covered will include responses that are prerequisite to neutrophil migration through venular walls, such as leukocyte luminal crawling and cellular and molecular changes in leukocytes and endothelial cells (e.g. formation of protrusions) that collectively support leukocyte transendothelial cell migration. Advances in both paracellular and transcellular neutrophil migration through endothelial cells will be discussed, addressing the associated roles and regulation of expression of endothelial cell luminal and junctional adhesion molecules. Beyond the endothelium, migration through the vascular pericyte coverage and basement membrane will be reviewed. SUMMARY The unquestionable role of neutrophils in the development and progression of inflammatory conditions suggests that a better understanding of the tissue-specific and stimulus-specific mechanisms that mediate this response may identify novel pathways that could be exploited for the development of more specific anti-inflammatory interventions. | Recent developments and complexities in neutrophil transmigration. |
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0.06154331564903259, "25323": 0.42096930742263794, "25409": 1.0735615491867065, "25430": 0.25845035910606384, "25468": 0.43623676896095276, "25778": 0.0913962796330452, "25851": 0.9348671436309814, "26057": 0.06154331564903259, "26179": 0.08692999184131622, "26237": 1.1018621921539307, "26319": 0.3601844012737274, "26462": 0.2719337046146393, "26475": 0.04953393340110779, "26745": 0.3005385100841522, "26906": 0.13925230503082275, "27144": 0.2637155055999756, "27354": 0.07159364968538284, "27419": 0.040196798741817474, "27794": 0.45994341373443604, "27881": 0.28890204429626465, "28093": 0.08782484382390976, "28207": 0.38308101892471313, "28321": 0.7408206462860107, "28603": 0.4349733293056488, "28648": 0.20818853378295898, "28739": 0.07431721687316895, "28793": 0.07884006202220917, "28951": 0.13755162060260773, "29224": 0.016465263441205025, "29299": 0.08782484382390976, "29458": 0.7426811456680298} | 20610390 | OBJECTIVES To investigate incidence, mortality and case survival trends for cancer of unknown primary site (CUP) and consider clinical implications. METHOD South Australian Cancer Registry data were used to calculate age-standardised incidence and mortality rates from 1977 to 2004. Disease-specific survivals, socio-demographic, histological and secular predictors of CUP, compared with cancers of known primary site, and of CUP histological types, using multivariable logistic regression were investigated. RESULTS Incidence and mortality rates increased approximately 60% between 1977--80 and 1981--84. Rates peaked in 1993--96. Male to female incidence and mortality rate ratios approximated 1.3:1. Incidence and mortality rates increased with age. The odds of unspecified histological type, compared with the more common adenocarcinomas, were higher for males than females, non-metropolitan residents, low socio-economic areas, and for 1977--88 than subsequent diagnostic periods. CUP represented a higher proportion of cancers in Indigenous patients. Case survival was 7% at 10 years from diagnosis. Factors predictive of lower case survival included older age, male sex, Indigenous status, lower socio-economic status, and unspecified histology type. CONCLUSION Results point to poor CUP outcomes, but with a modest improvement in survival. The study identifies socio-demographic groups at elevated risk of CUP and of worse treatment outcomes where increased research and clinical attention are required. | Exploring the epidemiological characteristics of cancers of unknown primary site in an Australian population: implications for research and clinical care. |
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"25778": 0.1718502640724182, "26243": 0.09228714555501938, "26255": 0.09050461649894714, "26402": 0.0009760859538801014, "26989": 0.5844172835350037, "27144": 1.248288631439209, "27343": 0.0019512200960889459, "27554": 0.42926809191703796, "28156": 0.4126010537147522, "28696": 0.029824240133166313, "28788": 0.09317722171545029, "28873": 0.13414156436920166, "29290": 0.09850110858678818} | 20610557 | In recent years, the immune-potentiating effects of some widely used chemotherapeutic agents have been increasingly appreciated. This provides a rationale for combining conventional chemotherapy with immunotherapy strategies to achieve durable therapeutic benefits. Previous studies have implicated the immunomodulatory effects of melphalan, an alkylating agent commonly used to treat multiple myeloma, but the underlying mechanisms remain obscure. In the present study, we investigated the impact of melphalan on endogenous immune cells as well as adoptively transferred tumor-specific CD4(+) T cells in tumor-bearing mice. We showed that melphalan treatment resulted in a rapid burst of inflammatory cytokines and chemokines during the cellular recovery phase after melphalan-induced myelodepletion and leukodepletion. After melphalan treatment, tumor cells exhibited characteristics of immunogenic cell death, including membrane translocation of the endoplasmic reticulum-resident calreticulin and extracellular release of high-mobility group box 1. Additionally, there was enhanced tumor Ag uptake by dendritic cells in the tumor-draining lymph node. Consistent with these immunomodulatory effects, melphalan treatment of tumor-bearing mice led to the activation of the endogenous CD8(+) T cells and, more importantly, effectively drove the clonal expansion and effector differentiation of adoptively transferred tumor-specific CD4(+) T cells. Notably, the combination of melphalan and CD4(+) T cell adoptive cell therapy was more efficacious than either treatment alone in prolonging the survival of mice with advanced B cell lymphomas or colorectal tumors. These findings provide mechanistic insights into melphalan's immunostimulatory effects and demonstrate the therapeutic potential of combining melphalan with adoptive cell therapy utilizing antitumor CD4(+) T cells. | Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells. |
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0.01934296265244484, "24310": 0.02887592278420925, "24327": 0.1685553640127182, "24395": 0.14602625370025635, "24442": 0.26446542143821716, "24479": 0.021256839856505394, "24501": 0.12384103983640671, "24862": 0.026976587250828743, "25022": 0.20022670924663544, "25323": 0.20660123229026794, "25550": 0.24018502235412598, "25775": 0.1332872211933136, "25778": 0.15526613593101501, "26163": 0.07250232994556427, "26180": 1.483910083770752, "26243": 0.0354953333735466, "26261": 1.138809084892273, "26651": 0.2470736801624298, "26989": 0.08244366943836212, "27108": 0.04674193635582924, "27144": 0.06703783571720123, "27165": 0.083342544734478, "27833": 0.14518201351165771, "28093": 0.1229778528213501, "28228": 0.981317400932312, "29514": 1.0312920808792114} | 20611846 | BACKGROUND Although inhaled corticosteroids have an established role in the treatment of asthma, studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma. A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma. METHODS The effect of treatment with inhaled fluticasone propionate (1000 microg daily) or placebo for 3 weeks was studied in a double blind, prospective, randomised, placebo controlled study of 38 steroid naïve adult asthmatic patients (21 non-smokers). Efficacy was assessed using morning and evening peak expiratory flow (PEF) readings, spirometric parameters, bronchial hyperreactivity, and sputum eosinophil counts. Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients. RESULTS There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone (27 l/min v -5 l/min). Non-smokers had a statistically significant increase in mean morning PEF (27 l/min), mean forced expiratory volume in 1 second (0.17 l), and geometric mean PC20 (2.6 doubling doses), and a significant decrease in the proportion of sputum eosinophils (-1.75%) after fluticasone compared with placebo. No significant changes were observed in the smoking asthmatic patients for any of these parameters. CONCLUSIONS Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma. This finding has important implications for the management of patients with mild asthma who smoke. | Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. |
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"25456": 1.0655186176300049, "25714": 0.5551415085792542, "25761": 0.08692999184131622, "25952": 0.020300358533859253, "26000": 0.9100211262702942, "26014": 0.4673144817352295, "26096": 0.006812678650021553, "26244": 0.4818955361843109, "26305": 0.0606246218085289, "26402": 0.6629094481468201, "26520": 0.09938567131757736, "26721": 0.17759032547473907, "26741": 0.23479416966438293, "26786": 0.1873544454574585, "27152": 0.015504186972975731, "27605": 0.1332872211933136, "27777": 0.020300358533859253, "27781": 0.5191890001296997, "27790": 0.20022670924663544, "27854": 0.19622190296649933, "28406": 0.9287132620811462, "28847": 0.06246116757392883, "29060": 0.45499902963638306, "29226": 0.09317722171545029, "29458": 0.055094651877880096, "29490": 0.31132611632347107} | 20620012 | Through phosphorylation, protein kinases can alter the activity, localization, protein association, and stability of their targets. Despite the importance to our understanding of all aspects of cell biology, progress toward identifying bona fide substrates of specific protein kinases has been slow. Traditionally used techniques to identify true kinase substrates, such as genetics, yeast two-hybrid screens, and biochemical purification, are often laborious and unreliable. However, several new approaches have recently been developed and used successfully to identify genuine in vivo substrates of certain protein kinases. These methods include screening for phosphorylation of proteins from phage expression libraries, peptide library screens to determine optimal motifs favored by specific kinases, the use of phospho-motif antibodies, and an approach that uses structurally altered kinases and allele-specific adenosine triphosphate analogs and kinase inhibitors. We describe these approaches and discuss their utility and inherent caveats. | Hitting the target: emerging technologies in the search for kinase substrates. |
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0.05786345899105072, "27226": 0.004870930220931768, "27373": 0.4837033152580261, "27717": 0.09406650811433792, "28014": 1.0973093509674072, "28424": 0.1510767638683319, "28691": 0.1011524572968483, "28712": 0.05417001247406006, "29226": 0.6118015646934509, "29243": 0.09850110858678818} | 20630805 | Histone posttranslational modifications are key components of diverse processes that modulate chromatin structure. These marks function as signals during various chromatin-based events, and act as platforms for recruitment, assembly or retention of chromatin-associated factors. The best-known function of histone phosphorylation takes place during cellular response to DNA damage, when phosphorylated histone H2A(X) demarcates large chromatin domains around the site of DNA breakage. However, multiple studies have also shown that histone phosphorylation plays crucial roles in chromatin remodeling linked to other nuclear processes. In this review, we summarize the current knowledge of histone phosphorylation and describe the many kinases and phosphatases that regulate it. We discuss the key roles played by this histone mark in DNA repair, transcription and chromatin compaction during cell division and apoptosis. Additionally, we describe the intricate crosstalk that occurs between phosphorylation and other histone modifications and allows for sophisticated control over the chromatin remodeling processes. | Histone phosphorylation: a chromatin modification involved in diverse nuclear events. |
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"26563": 0.33115679025650024, "26651": 0.016465263441205025, "26708": 0.36426326632499695, "27144": 0.16524957120418549, "27162": 0.5506471395492554, "27480": 0.05694137513637543, "27642": 0.1221139207482338, "27678": 0.05046287178993225, "27776": 0.004870930220931768, "27815": 0.18329764902591705, "28046": 0.21135559678077698, "28093": 0.9310253858566284, "28122": 0.3409265875816345, "28188": 0.036437395960092545, "28207": 0.17267228662967682, "28225": 0.0029254043474793434, "28228": 0.8877626657485962, "28436": 0.009718249551951885, "28648": 0.4879087805747986, "28687": 0.037378571927547455, "28864": 0.025073638185858727, "28965": 0.2034190446138382, "29242": 0.06246116757392883, "29295": 0.1685553640127182, "29299": 0.5307431221008301, "29327": 0.7352184057235718, "29336": 0.1693800985813141, "29477": 0.0842406153678894, "29514": 0.7352184057235718, "29610": 0.07341018319129944} | 20645335 | OBJECTIVE To systematically review and integrate data on the neurodevelopmental outcome of children after administration of a single course of antenatal corticosteroids for threatened preterm labor. DATA SOURCES MEDLINE, Scopus, CENTRAL, and www.clinicaltrials.gov (inception to August 2014) using combinations of the terms "prenatal," "antenatal," "cortico*," "*steroid*," "betamethasone," "dexamethasone," "neurodevelopment*," "*development*," and "follow-up. " We perused the references of the retrieved articles. METHODS OF STUDY SELECTION We included randomized and nonrandomized trials reporting on the neurodevelopmental outcomes of children whose mothers were administered a single course of betamethasone or dexamethasone antenatally for threatened preterm birth as opposed to placebo or no treatment. TABULATION, INTEGRATION, AND RESULTS Summary risk ratio (RR) was calculated for dichotomous data; standardized mean difference was calculated for trials that measured the same outcome but used different methods. Heterogeneity was assessed using the I statistic. Sensitivity and subgroup analyses were planned according to study design, specific steroid, and mean gestational age at birth. A single course of antenatal corticosteroids was associated with reduced risk for cerebral palsy (seven studies; treated: 390 of 5,199, untreated: 146 of 1,379; RR 0.678, 95% confidence interval [CI] 0.564-0.815), psychomotor development index less than 70 (two studies; treated: 783 of 3,049, untreated: 258 of 969; RR 0.829, 95% CI 0.737-0.933), and severe disability (five studies; treated: 1,567 of 4,840, untreated: 475 of 1,211; RR 0.787, 95% CI 0.729-0.850). Steroid treatment increased the rates of intact survival (six studies; treated: 1,082 of 2,013, untreated: 273 of 561; RR 1.186, 95% CI 1.056-1.332). Betamethasone was found to significantly decrease the risk for severe disability and increase the rate of intact survival. Dexamethasone increased the rate of intact survival; however, data for dexametasone and the other planned subgroup analyses were limited (fewer than 1,000 children at most). The major limitations involved inclusion of nonrandomized studies and scarcity of data on finer neurodevelopmental outcomes. CONCLUSION A single course of antenatal corticosteroids in women at high risk for preterm birth appears to improve most neurodevelopmental outcomes in offspring born before 34 weeks of gestation. | Neurodevelopmental Outcome After a Single Course of Antenatal Steroids in Children Born Preterm: A Systematic Review and Meta-analysis. |
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0.2247048318386078, "26268": 0.3723714053630829, "26462": 0.012615402229130268, "26520": 0.0029254043474793434, "26572": 0.25845035910606384, "26739": 0.0009760859538801014, "26745": 0.7009293437004089, "26786": 0.11778303235769272, "26886": 0.043007105588912964, "27011": 0.2696990668773651, "27144": 0.2145126610994339, "27312": 0.12038381397724152, "27404": 0.5301685929298401, "27569": 0.08782484382390976, "27598": 0.34508460760116577, "27811": 0.11517547070980072, "27881": 0.9680526852607727, "28207": 0.3601844012737274, "28378": 0.10818854719400406, "28436": 0.0019512200960889459, "28723": 0.151916041970253, "29025": 0.10203468054533005, "29160": 0.4286321699619293, "29191": 0.36967599391937256, "29288": 0.32270604372024536, "29458": 0.8212929964065552} | 20645538 | PURPOSE Minimal (< 10 mm thick) pleural effusion (PE) may represent an early phase of malignant PE, but its clinical relevance has rarely been studied. Therefore, we examined the proportion of minimal PE in patients with non-small-cell lung cancer (NSCLC) and its impact on survival. We also considered possible accumulation mechanisms in our data set. PATIENTS AND METHODS On the basis of PE status from chest computed tomography scans at diagnosis, 2,061 patients were classified into three groups: no PE, minimal PE, and malignant PE. Twenty-one variables associated with four factors-patient, stage migration, tumor, and treatment-were investigated for correlation with survival. RESULTS Minimal PE presented in 272 patients (13.2%). Of 2,061 patients, the proportion of each stage was the following: 5.2% stage I, 10.9% stage II, 13.2% stage IIIA, 23.8% stage IIIB, and 13.9% stage IV. Minimal PE correlated significantly with shorter survival time than did no PE (median survival time, 7.7 v 17.7 months; log-rank P < .001), even after full adjustment with all variables (adjusted hazard ratio, 1.40; 95% CI, 1.21 to 1.62). Prognostic impact of minimal PE was higher in early versus advanced stages (Pinteraction = .001). In 237 patients (87.8%) with minimal PE, pleural invasion or attachment as a direct mechanism was observed, and it was an independent factor predicting worse survival (P = .03). CONCLUSION Minimal PE is a commonly encountered clinical concern in staging NSCLCs. Its presence is an important prognostic factor of worse survival, especially in early-stage disease. | Prognostic impact of minimal pleural effusion in non-small-cell lung cancer. |
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However, the relationship between the choice of the targeted receptor and the quality and quantity of responses remains poorly understood. We describe a strategy for expression of Ags including hydrophobic proteins as soluble fusion proteins that are optimized for proteasome-dependent MHC class I-restricted cross-presentation and form stable complexes with a wide variety of targeting Abs. Upon s.c. immunization, these complexes were initially taken up by CD169+ lymph node subcapsular sinus macrophages. In the OVA model system, receptor-targeted antigenic complexes primed specific T and B cell responses in vitro and in vivo at least 100-fold more efficiently than Ag alone. Comparison of 10 targeting receptors allowed us to establish a ranking with respect to priming of CD8+ T cell responses and demonstrated striking differences with respect to the relative efficacy of CD8+ and CD4+ T cell subset and B cell priming. The described fusion proteins should help in developing optimized strategies for targeted delivery of protein Ags in the context of tolerization or vaccination. | Fusion proteins for versatile antigen targeting to cell surface receptors reveal differential capacity to prime immune responses. |
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Investigation of the specificity of this process has been complicated by TAP-independent factors that influence the amount of peptide that accumulates in the ER in transport assays. We have developed an overexpression system in which binding of peptides to the TAP substrate-binding site and peptide transport by TAP can be quantified separately. Efficiency of peptide accumulation in the ER parallels affinity for the TAP substrate-binding site, but can be modified by interaction with the glycosylation system within the ER and, probably, peptide efflux. Random peptide mixtures of 9-16 aa display significantly higher affinity for the binding site than mixtures of shorter or longer peptides. Peptide binds to TAP heteromers in the absence of ATP and is released by the binding of ATP, suggesting a model for TAP function. | A sequential model for peptide binding and transport by the transporters associated with antigen processing. |
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"25086": 0.33953672647476196, "25409": 0.3683255612850189, "25481": 0.3784096837043762, "25613": 0.04207121208310127, "25918": 0.015504186972975731, "25957": 0.10026945173740387, "26210": 0.15442965924739838, "26261": 0.10026945173740387, "26383": 0.043007105588912964, "26462": 0.5295937061309814, "26745": 0.680370569229126, "26906": 0.24325250089168549, "27011": 0.5336109399795532, "27144": 0.5162794589996338, "27159": 0.27342069149017334, "27491": 0.15943801403045654, "27532": 0.22001366317272186, "27788": 0.3005385100841522, "27881": 0.11343330889940262, "28024": 0.3777405619621277, "28177": 0.5957841277122498, "28207": 0.06703783571720123, "28297": 0.05417001247406006, "28667": 1.0423725843429565, "28943": 0.030771657824516296, "29251": 0.5573811531066895, "29264": 0.6160298585891724, "29486": 0.0752234235405922, "29535": 0.3019835948944092} | 20649735 | OBJECTIVE We investigated the outcome of repeated gamma knife radiosurgery (GKS) for local or remote recurrence after initial radiosurgery. MATERIAL AND METHODS We retrospectively reviewed 204 patients who were treated with GKS. Among them 43 patients (21%) underwent GKS more than once. The second GKS was given for recurrence at the previously treated sites in 16 patients, new lesions at remote sites in 13, and both local recurrence and new lesions in 14. RESULTS The median survival from the first GKS was 36 (7-190) weeks in all patients and 68 (16-156) weeks in 43 patients with repeated GKS. The median time from the first GKS to the second was 37 weeks. The median survival from the second radiosurgical intervention was 32 (7-132) weeks. Local control rate at 6 months after salvage GKS was 90.7%. RPA class was the commonly dominant prognostic factor in both initial and salvage GKS. CONCLUSION Recurrence is common for patients with metastatic brain tumors after initial radiosurgery. Local control and survival time after salvage treatment are comparable with those after initial radiosurgery. GKS as a salvage treatment may provide additional survival benefit in selected patients. | Outcome of repeated radiosurgery for recurrent metastatic brain tumors. |
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0.5893046259880066, "26534": 0.08961215615272522, "26563": 0.175953671336174, "26572": 0.08244366943836212, "26591": 0.9310253858566284, "26773": 0.08154398202896118, "26877": 0.14939609169960022, "27144": 0.1485546976327896, "27295": 0.13499516248703003, "27321": 0.36967599391937256, "27717": 0.11256109178066254, "27781": 0.06520967930555344, "27849": 0.5180262327194214, "27854": 0.347847044467926, "27870": 1.2677175998687744, "28086": 0.09938567131757736, "28155": 0.8517522215843201, "28156": 0.21765978634357452, "28207": 1.0933903455734253, "28687": 0.14602625370025635, "28712": 0.42990362644195557, "28848": 0.47463157773017883, "28873": 0.11168810725212097, "28940": 1.2347444295883179, "29090": 0.4734157919883728, "29290": 0.5324648022651672, "29490": 0.4145384132862091, "29514": 0.6970458030700684} | 20659283 | Pregnane X receptor (PXR) is an important component of the body's adaptive defense system responsible for the elimination of various toxic xenobiotics. PXR activation by endogenous and exogenous chemicals, including steroids, antibiotics, bile acids, and herbal compounds, results in induction of drug metabolism. We investigated the ability of the isoflavones genistein, daidzein, and the daidzein metabolite equol to activate human and mouse PXR in vitro using cell-based transient transfection studies and primary hepatocytes and in vivo in a mouse model. In transient transfection assays, the isoflavones genistein and daidzein activate full-length, wild-type mouse PXR, but not a mutant form, with genistein being the most potent. In contrast, equol was a more potent activator of human PXR than genistein or daidzein. In a mammalian 2-hybrid assay, isoflavones induced recruitment of the coactivator steroid receptor coactivator 1 to PXR. When tested against the native human Cytochrome P450 3A4 (CYP3A4) promoter, equol was the more potent activator and treatment of human hepatocytes with equol increased CYP3A4 mRNA and immunoreactive protein expression. Treatment of wild-type, but not PXR(-/-), mouse hepatocytes showed that genistein and daidzein induced the expression of Cytochrome P450 3A11 (Cyp3A11) mRNA, whereas equol had no effect. Cyp3A11 mRNA was also induced in vivo in mice fed a soy protein-containing diet. The results presented herein demonstrate that there is a species-specific difference in the activation of PXR by isoflavones and equol. | Human CYP3A4 and murine Cyp3A11 are regulated by equol and genistein via the pregnane X receptor in a species-specific manner. |
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"28835": 1.0471819639205933, "29160": 0.20580662786960602, "29295": 0.4425300657749176} | 20672596 | Maximum activities of some key enzymes of metabolism were studied in elicited (inflammatory) macrophages of the mouse and lymph-node lymphocytes of the rat. The activity of hexokinase in the macrophage is very high, as high as that in any other major tissue of the body, and higher than that of phosphorylase or 6-phosphofructokinase, suggesting that glucose is a more important fuel than glycogen and that the pentose phosphate pathway is also important in these cells. The latter suggestion is supported by the high activities of both glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase. However, the rate of glucose utilization by 'resting' macrophages incubated in vitro is less than the 10% of the activity of 6-phosphofructokinase: this suggests that the rate of glycolysis is increased dramatically during phagocytosis or increased secretory activity. The macrophages possess higher activities of citrate synthase and oxoglutarate dehydrogenase than do lymphocytes, suggesting that the tricarboxylic acid cycle may be important in energy generation in these cells. The activity of 3-oxoacid CoA-transferase is higher in the macrophage, but that of 3-hydroxybutyrate dehydrogenase is very much lower than those in the lymphocytes. The activity of carnitine palmitoyltransferase is higher in macrophages, suggesting that fatty acids as well as acetoacetate could provide acetyl-CoA as substrate for the tricarboxylic acid cycle. No detectable rate of acetoacetate or 3-hydroxybutyrate utilization was observed during incubation of resting macrophages, but that of oleate was 1.0 nmol/h per mg of protein or about 2.2% of the activity of palmitoyltransferase. The activity of glutaminase is about 4-fold higher in macrophages than in lymphocytes, which suggests that the rate of glutamine utilization could be very high. The rate of utilization of glutamine by resting incubated macrophages was similar to that reported for rat lymphocytes, but was considerably lower than the activity of glutaminase. | Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages. |
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"29720": 0.22626367211341858} | 20675284 | Transforming growth factor-beta (TGF-beta) inhibits the growth of endothelial cells derived from various sources, including human umbilical vein, bovine aorta, and rat heart. Long-term exposure of rat heart endothelial cells to TGF-beta also induces dramatic changes in morphology that are characteristic of senescent cells. These changes are accompanied by a decrease in the number of high-affinity receptors for epidermal growth factor (EGF), with almost no change in total receptor number. Additionally, the EGF-induced expression of specific competence genes (c-myc, JE, KC) is decreased, whereas the induction of c-fos gene expression by EGF is unaltered by TGF-beta treatment. These data suggest that growth inhibitors such as TGF-beta may act by altering the cell's response to growth-stimulatory factors. | TGF-beta inhibition of endothelial cell proliferation: alteration of EGF binding and EGF-induced growth-regulatory (competence) gene expression. |
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"28873": 0.2689530849456787, "29290": 0.48068851232528687} | 20690388 | Natural killer (NK) cell activation is strictly regulated to ensure that healthy cells are preserved, but tumour-transformed or virus-infected cells are recognized and eliminated. To carry out this selective killing, NK cells have an ample repertoire of receptors on their surface. Signalling by inhibitory and activating receptors by interaction with their ligands will determine whether the NK cell becomes activated and kills the target cell. Here, we show reduced expression of NKp46, NKp30, DNAM-1, CD244 and CD94/NKG2C activating receptors on NK cells from acute myeloid leukaemia patients. This reduction may be induced by chronic exposure to their ligands on leukaemic blasts. The analysis of ligands for NK cell-activating receptors showed that leukaemic blasts from the majority of patients express ligands for NK cell-activating receptors. DNAM-1 ligands are frequently expressed on blasts, whereas the expression of the NKG2D ligand MICA/B is found in half of the patients and CD48, a ligand for CD244, in only one-fourth of the patients. The decreased expression of NK cell-activating receptors and/or the heterogeneous expression of ligands for major receptors on leukaemic blasts can lead to an inadequate tumour immunosurveillance by NK cells. A better knowledge of the activating receptor repertoire on NK cells and their putative ligands on blasts together with the possibility to modulate their expression will open new possibilities for the use of NK cells in immunotherapy against leukaemia. | Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands |
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Plasma interleukin (IL)-6 concentration is increased with exercise and it has been demonstrated that contracting muscles can produce IL-The question addressed in the present study was whether the IL-6 production by contracting skeletal muscle is of such a magnitude that it can account for the IL-6 accumulating in the blood. 2. This was studied in six healthy males, who performed one-legged dynamic knee extensor exercise for 5 h at 25 W, which represented 40% of peak power output (Wmax). Arterial-femoral venous (a-fv) differences over the exercising and the resting leg were obtained before and every hour during the exercise. Leg blood flow was measured in parallel by the ultrasound Doppler technique. IL-6 was measured by enzyme-linked immunosorbent assay (ELISA). 3. Arterial plasma concentrations for IL-6 increased 19-fold compared to rest. The a-fv difference for IL-6 over the exercising leg followed the same pattern as did the net IL-6 release. Over the resting leg, there was no significant a-fv difference or net IL-6 release. The work was produced by 2.5 kg of active muscle, which means that during the last 2 h of exercise, the median IL-6 production was 6.8 ng min-1 (kg active muscle)-1 (range, 3.96-9.69 ng min-1 kg-1). 4. The net IL-6 release from the muscle over the last 2 h of exercise was 17-fold higher than the elevation in arterial IL-6 concentration and at 5 h of exercise the net release during 1 min was half of the IL-6 content in the plasma. This indicates a very high turnover of IL-6 during muscular exercise. We suggest that IL-6 produced by skeletal contracting muscle contributes to the maintenance of glucose homeostasis during prolonged exercise. | Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. |
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0.1873544454574585, "26461": 0.22782009840011597, "27718": 0.5903874635696411, "27805": 0.24018502235412598, "27928": 0.6451379656791687, "28227": 0.030771657824516296, "28586": 0.25694093108177185} | 20697217 | OBJECTIVE To examine the symptoms of hypoglycemia in children with insulin-dependent diabetes, from the perspective both of the child and of the child's parents, and to compare the symptom reporting of the diabetic children with that of adult diabetic patients. RESEARCH DESIGN AND METHODS Interviews were conducted with 100 parents and 43 of their children. The frequency and intensity of symptoms of hypoglycemia were documented using a structured interview and classified into groups using Principal Components Analysis (PCA). RESULTS Diabetic children and their parents showed close agreement concerning the relative frequency and the intensity of symptoms reported. PCA of the symptom reports showed that diabetic children and their parents identified the same distinct subgroups of hypoglycemia-related symptoms: behavioral disturbance and autonomic-neuroglycopenic subgroups. CONCLUSIONS Hypoglycemic symptoms in children with diabetes clearly differ from those experienced by insulin-treated adults and, in particular, include behavioral changes as primary features of a low blood glucose. These observations have important implications for parental education on hypoglycemia. | Symptoms of hypoglycemia in children with IDDM. |
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0.371698260307312, "26661": 0.011650617234408855, "26745": 0.10555581003427505, "27354": 0.2674594223499298, "28155": 0.014542185701429844, "28353": 0.3416208028793335, "28433": 0.5968599319458008, "28684": 0.3019835948944092, "28691": 0.11865071207284927, "28835": 1.1089750528335571, "29060": 0.5290185213088989, "29167": 0.2184450328350067, "29458": 0.9123768210411072} | 20707861 | Comparative protein structure modeling predicts the three-dimensional structure of a given protein sequence (target) based primarily on its alignment to one or more proteins of known structure (templates). The prediction process consists of fold assignment, target-template alignment, model building, and model evaluation. This unit describes how to calculate comparative models using the program MODELLER and how to use the ModBase database of such models, and discusses all four steps of comparative modeling, frequently observed errors, and some applications. Modeling lactate dehydrogenase from Trichomonas vaginalis (TvLDH) is described as an example. The download and installation of the MODELLER software is also described. © 2016 by John Wiley & Sons, Inc. | Comparative Protein Structure Modeling Using MODELLER. |
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IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions. | IL-6 as a keystone cytokine in health and disease |
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The fourth rRNA, the 5S rRNA, is transcribed by RNA polymerase III and is assembled into the 5S ribonucleoprotein particle (RNP), containing ribosomal proteins Rpl5/uL18 and Rpl11/uL5, prior to its incorporation into preribosomes. In mammals, the 5S RNP is also a central regulator of the homeostasis of the tumor suppressor p53. The nucleolar localization of the 5S RNP and its assembly into preribosomes are performed by a specialized complex composed of Rpf2 and Rrs1 in yeast or Bxdc1 and hRrs1 in humans. Here we report the structural and functional characterization of the Rpf2-Rrs1 complex alone, in complex with the 5S RNA, and within pre-60S ribosomes. We show that the Rpf2-Rrs1 complex contains a specialized 5S RNA E-loop-binding module, contacts the Rpl5 protein, and also contacts the ribosome assembly factor Rsa4 and the 25S RNA. We propose that the Rpf2-Rrs1 complex establishes a network of interactions that guide the incorporation of the 5S RNP in preribosomes in the initial conformation prior to its rotation to form the central protuberance found in the mature large ribosomal subunit. | Chaperoning 5S RNA assembly. |
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0.05970508232712746, "24260": 0.23092569410800934, "24269": 0.37640097737312317, "24278": 0.0317181795835495, "24501": 0.29036402702331543, "24587": 0.5668440461158752, "25022": 0.4764525294303894, "25276": 0.06795065850019455, "25456": 0.21214580535888672, "25714": 0.9139442443847656, "26180": 0.5882205963134766, "26402": 0.37707099318504333, "26632": 0.5957841277122498, "26651": 0.15359249711036682, "26786": 0.04674193635582924, "26835": 0.10731173306703568, "26942": 0.817850649356842, "27059": 0.5116065740585327, "27099": 0.01934296265244484, "27152": 0.04860413447022438, "27781": 0.012615402229130268, "27854": 0.2531573474407196, "27885": 0.6358738541603088, "28674": 1.0305955410003662, "28788": 0.11517547070980072, "28835": 0.8731874823570251, "28873": 0.27342069149017334, "29290": 0.33115679025650024, "29357": 0.08064348995685577, "29543": 0.35813871026039124} | 20732789 | Cigarette smoke is the main cause of chronic obstructive pulmonary disease (COPD), where it can contribute to the observed airway inflammation. PGE(2) is produced within human airways, and both pro- and anti-inflammatory activities have been reported. We quantitated PGE(2) concentrations in induced sputum supernatants from different groups of subjects and correlated the obtained values to neutrophil infiltration as well as to the expression of cyclooxygenase-2 (COX-2). Cigarette smoke extract (CSE) was used to evaluate the effect of smoking on COX-2 and PGE(2) receptor expression as well as on PGE(2) release in neutrophils and alveolar macrophages (AM) obtained from normal donors. The effects of PGE(2) and of PGE receptor agonists and antagonists were evaluated on the adhesion of neutrophil to a human bronchial epithelial cell line (16HBE). PGE(2) levels, COX-2 expression, and neutrophil infiltration were significantly higher in normal smokers and COPD smokers (P < 0.0001) compared with controls and COPD former smokers. Induced sputum supernatant caused neutrophil adhesion to 16HBE that was significantly reduced, in COPD smokers only, by PGE(2) immunoprecipitation. In vitro experiments confirmed that CSE increased PGE(2) release and COX-2 and PGE(2) receptor expression in neutrophils and AM; PGE(2) enhanced the adhesion of neutrophils to 16HBE, and a specific E-prostanoid 4 (EP(4)) receptor antagonist blunted its effect. These results suggest that CSE promote the induction of COX-2 and contributes to the proinflammatory effects of PGE(2) in the airways of COPD subjects. | Chronic obstructive pulmonary disease and neutrophil infiltration: role of cigarette smoke and cyclooxygenase products. |
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0.9037119746208191, "28775": 0.956112265586853, "28873": 0.2026219218969345, "29290": 0.4788752794265747} | 20738970 | Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase) plays an important role in apoptosis of epithelial cells. The goal of this study was to investigate whether Etk is involved in apoptosis of small cell lung cancer (SCLC) cells and correlated with the expression levels of apoptosis-associated proteins such as Bcl-2, Bcl-X(L) and p53. One hundred and seventy-one cases of lung cancer specimens including seventy-one SCLCs and one hundred NSCLCs were immunostained for Etk, Bcl-2, Bcl-X(L) and p53. Parental SCLC H446 cell line, and its subline (H446-Etk) that overexpresses Etk, were used to study the role of Etk in apoptosis induced by doxorubicin. It was found that high expression of Etk occurs in 74.6% of SCLC cases, but only in 40% of NSCLC cases, and there is marked difference in the expression levels of Bcl-2, Bcl-X(L) and p53 between Etk-positive and Etk-negative SCLC cases. Furthermore, the levels of Bcl-2 and Bcl-X(L) significantly increased in H446-Etk cells than that in H446 cells after doxorubicin treatment, and were positively associated with Etk expression. However, p53 did not correspond with Etk expression although its expression decreased greatly with apoptosis both in H446-Etk and H446 cells. After doxorubicin treatment, the cell viability was significantly higher in H446-Etk cells than in parental H446 cells. Downregulation of Etk by Etk siRNA sensitized H446 cells to doxorubicin. Our results indicate that upregulation of tyrosine kinase Etk may be a new mechanism involved in protection of SCLC cells from apoptosis. Bcl-2 and Bcl-X(L) but not p53 may contribute to doxorubicin-induced apoptosis through Etk pathway. | Non-receptor tyrosine kinase Etk is involved in the apoptosis of small cell lung cancer cells. |
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A number of cellular transport processes support this organization, including active targeting of proteins and passive corralling between compartments. The axon initial segment (AIS), which separates the somatodendritic and axonal compartments, has a key role in neuronal physiology, as both the initiation site of action potentials and the gatekeeper of the axonal arborization. Over the years, the AIS main components and their interactions have been progressively unraveled, as well as their role in the AIS assembly and maintenance. Two mechanisms have been shown to contribute to the regulation of protein transport at the AIS: a surface diffusion barrier and an intracellular traffic filter. However, a molecular understanding of these processes is still lacking. In the view of recent results on the AIS cytoskeleton structure, we will discuss how a better knowledge of the AIS architecture can help understanding its role in the regulation of protein transport and the maintenance of axonal identity. | No Pasaran! Role of the axon initial segment in the regulation of protein transport and the maintenance of axonal identity. |
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"28616": 0.3923587501049042, "28667": 0.3910386264324188, "28739": 0.3269403576850891, "28994": 0.5313173532485962, "29172": 0.10291612148284912, "29277": 0.15610189735889435, "29299": 0.4654768109321594, "29300": 0.2223619967699051, "29458": 0.26146242022514343} | 20746604 | OBJECTIVE To examine the association between the use of right heart catheterization (RHC) during the first 24 hours of care in the intensive care unit (ICU) and subsequent survival, length of stay, intensity of care, and cost of care. DESIGN Prospective cohort study. SETTING Five US teaching hospitals between 1989 and 1994. SUBJECTS A total of 5735 critically ill adult patients receiving care in an ICU for 1 of 9 prespecified disease categories. MAIN OUTCOME MEASURES Survival time, cost of care, intensity of care, and length of stay in the ICU and hospital, determined from the clinical record and from the National Death Index. A propensity score for RHC was constructed using multivariable logistic regression. Case-matching and multivariable regression modeling techniques were used to estimate the association of RHC with specific outcomes after adjusting for treatment selection using the propensity score. Sensitivity analysis was used to estimate the potential effect of an unidentified or missing covariate on the results. RESULTS By case-matching analysis, patients with RHC had an increased 30-day mortality (odds ratio, 1.24; 95% confidence interval, 1.03-1.49). The mean cost (25th, 50th, 75th percentiles) per hospital stay was $49 300 ($17 000, $30 500, $56 600) with RHC and $35 700 ($11 300, $20 600, $39 200) without RHC. Mean length of stay in the ICU was 14.8 (5, 9, 17) days with RHC and 13.0 (4, 7, 14) days without RHC. These findings were all confirmed by multivariable modeling techniques. Subgroup analysis did not reveal any patient group or site for which RHC was associated with improved outcomes. Patients with higher baseline probability of surviving 2 months had the highest relative risk of death following RHC. Sensitivity analysis suggested that a missing covariate would have to increase the risk of death 6-fold and the risk of RHC 6-fold for a true beneficial effect of RHC to be misrepresented as harmful. CONCLUSION In this observational study of critically ill patients, after adjustment for treatment selection bias, RHC was associated with increased mortality and increased utilization of resources. The cause of this apparent lack of benefit is unclear. The results of this analysis should be confirmed in other observational studies. These findings justify reconsideration of a randomized controlled trial of RHC and may guide patient selection for such a study. | The effectiveness of right heart catheterization in the initial care of critically ill patients. SUPPORT Investigators. |
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0.15610189735889435, "26835": 0.45623743534088135, "26957": 0.29036402702331543, "26980": 0.004870930220931768, "27058": 1.1537069082260132, "27144": 1.0874829292297363, "27152": 0.0174254160374403, "27226": 0.08782484382390976, "27354": 0.04113444685935974, "27574": 0.10203468054533005, "27777": 0.0752234235405922, "27781": 0.5267143249511719, "28024": 0.15693697333335876, "28297": 0.6744182109832764, "28389": 0.672426164150238, "28436": 0.3070250153541565, "28745": 1.1375575065612793, "28788": 0.09850110858678818, "28873": 0.2659635543823242, "28896": 0.02412080205976963, "28922": 0.09495500475168228, "29107": 0.16690383851528168, "29206": 1.0546929836273193, "29251": 0.8264343738555908, "29458": 0.016465263441205025, "29486": 0.3297532796859741, "29533": 0.036437395960092545} | 20754359 | After cell-to-cell transmission, HTLV-I increases its viral genome by de novo infection and proliferation of infected cells. Proliferation of infected cells is clonal and persistent in vivo. During the carrier state, infected cells are selected in vivo by the host's immune system, the genetic and epigenetic environment of proviral integration sites, and other factors. In leukemic cells, tax gene expression is frequently impaired by genetic and epigenetic mechanisms. Such loss of Tax expression enables ATL cells to escape the host immune system. On the other hand, ATL cells acquire the ability to proliferate without Tax by intracellular genetic and epigenetic changes. Despite advances in support and the development of novel treatment agents, the prognosis for ATLL remains poor. A number of therapies, however, do appear to improve prognosis compared to CHOP (VEPA). These include interferon-α plus zidovudine (probably after 1–2 cycles of CHOP), intensive chemotherapy as in LSG-15 with G-CSF support and Allo-SCT (which includes the potential for cure). Emerging novel approaches include HDAC inhibitors, monoclonal antibodies, and proteasome inhibitors. Comparison between different therapeutic approaches is complicated by the range of natural history of ATLL, different recruitments of naïve-to-therapy, refractory or relapsed patients, and variations in the reporting of outcome that frequently excludes difficult-to-evaluate patients. Moreover, results from relatively small proof-of-principle studies have not been extended with randomized, controlled trials. As a result, currently, there is no clear evidence to support the value of any particular treatment approach over others. To avoid further unnecessary patient suffering and to identify optimal therapy as rapidly as possible, large randomized, controlled trials encompassing multicenter, international collaborations will be necessary. | Natural history of adult T-cell leukemia/lymphoma and approaches to therapy |
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It is becoming clear that the plasma membrane is a heterogeneous entity, containing diverse structures on nano-meso-scales (2-200 nm) with a variety of lifetimes, where certain membrane molecules stay together for limited durations. Molecular interactions occur in the time-dependent inhomogeneous two-dimensional liquid of the plasma membrane, which might be a key for plasma membrane functions. | Hierarchical organization of the plasma membrane: investigations by single-molecule tracking vs. fluorescence correlation spectroscopy. |
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Less documented is how this translates into chemical stability and antimalarial activity across a range of conditions applying to in vitro testing and clinical situations. Dihydroartemisinin (DHA) is studied here because it is an antimalarial drug on its own and the main metabolite of other artemisinins. The behaviors of DHA in phosphate-buffered saline, plasma, or erythrocyte lysate at different temperatures and pH ranges were examined. The antimalarial activity of the residual drug was evaluated using the chemosensitivity assay on Plasmodium falciparum, and the extent of decomposition of DHA was established through use of high-performance liquid chromatography with electrochemical detection analysis. The role of the Fe(II)-heme was investigated by blocking its reactivity using carbon monoxide (CO). A significant reduction in the antimalarial activity of DHA was seen after incubation in plasma and to a lesser extent in erythrocyte lysate. Activity was reduced by half after 3 h and almost completely abolished after 24 h. Serum-enriched media also affected DHA activity. Effects were temperature and pH dependent and paralleled the increased rate of decomposition of DHA from pH 7 upwards and in plasma. These results suggest that particular care should be taken in conducting and interpreting in vitro studies, prone as their results are to experimental and drug storage conditions. Disorders such as fever, hemolysis, or acidosis associated with malaria severity may contribute to artemisinin instability and reduce their clinical efficacy. | Stability of the antimalarial drug dihydroartemisinin under physiologically relevant conditions: implications for clinical treatment and pharmacokinetic and in vitro assays. |
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