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"26226": 0.3297532796859741, "26572": 0.5844172835350037, "26780": 0.42416930198669434, "27268": 0.9546096324920654, "27753": 0.906871497631073, "27794": 0.7463917136192322, "27833": 0.5696102976799011, "28093": 0.07431721687316895, "28163": 0.04113444685935974, "28225": 0.025073638185858727, "28227": 0.09406650811433792, "28268": 0.35128939151763916, "28353": 0.08064348995685577, "28403": 0.2969166338443756, "28767": 0.01934296265244484, "29048": 0.6941232681274414, "29107": 0.22548456490039825, "29125": 0.18816383183002472, "29491": 0.46670228242874146} | 12810152 | CONTEXT Hyperhomocysteinemia is caused by genetic and lifestyle influences, including low intakes of folate and vitamin B6. However, prospective data relating intake of these vitamins to risk of coronary heart disease (CHD) are not available. OBJECTIVE To examine intakes of folate and vitamin B6 in relation to the incidence of nonfatal myocardial infarction (MI) and fatal CHD. DESIGN Prospective cohort study. SETTING AND PATIENTS In 1980, a total of 80082 women from the Nurses' Health Study with no previous history of cardiovascular disease, cancer, hypercholesterolemia, or diabetes completed a detailed food frequency questionnaire from which we derived usual intake of folate and vitamin B6. MAIN OUTCOME MEASURE Nonfatal MI and fatal CHD confirmed by World Health Organization criteria. RESULTS During 14 years of follow-up, we documented 658 incident cases of nonfatal MI and 281 cases of fatal CHD. After controlling for cardiovascular risk factors, including smoking and hypertension and intake of alcohol, fiber, vitamin E, and saturated, polyunsaturated, and trans fat, the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95% confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake, 4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55 (95% CI, 0.41-0.74) among women in the highest quintile of both folate and vitamin B6 intake compared with the opposite extreme. Risk of CHD was reduced among women who regularly used multiple vitamins (RR=0.76; 95% CI, 0.65-0.90), the major source of folate and vitamin B6, and after excluding multiple vitamin users, among those with higher dietary intakes of folate and vitamin B6. In a subgroup analysis, compared with nondrinkers, the inverse association between a high-folate diet and CHD was strongest among women who consumed up to 1 alcoholic beverage per day (RR =0.69; 95% CI, 0.49-0.97) or more than 1 drink per day (RR=0.27; 95% CI, 0.13-0.58). CONCLUSION These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women. | Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. |
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0.3034266233444214, "28024": 0.129004567861557, "28086": 0.10993985831737518, "28123": 0.06520967930555344, "28228": 0.8143964409828186, "28488": 0.3191637098789215, "28691": 0.10379679501056671, "28788": 1.0788878202438354, "28931": 0.4450363218784332, "29129": 0.21765978634357452, "29170": 0.07341018319129944, "29290": 0.016465263441205025} | 12821938 | Sexual reproduction depends upon meiosis for the generation of haploid gamete nuclei, which unite after fertilization to form the diploid zygote. The oocytes of most animal species arrest during meiotic prophase, and complete meiosis in response to intercellular signaling in a process called meiotic maturation. Oocyte meiotic maturation is defined by the transition between diakinesis and metaphase of meiosis I and is accompanied by nuclear envelope breakdown, rearrangement of the cortical cytoskeleton, and meiotic spindle assembly. Thus, the meiotic maturation process is essential for meiosis and prepares the oocyte for fertilization. In C. elegans, the processes of meiotic maturation, ovulation, and fertilization are temporally coupled: sperm utilize the major sperm protein as a hormone to trigger oocyte meiotic maturation, and in turn, the maturing oocyte signals its own ovulation thereby facilitating fertilization. This chapter highlights recent advances in understanding meiotic maturation signaling and gametic interactions required for fertilization. | Control of oocyte meiotic maturation and fertilization. |
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0.025073638185858727, "24545": 0.3241194784641266, "24635": 0.4002431631088257, "24899": 0.684319257736206, "24939": 0.17431432008743286, "25145": 0.15442965924739838, "25262": 0.2674594223499298, "25308": 0.23479416966438293, "25505": 0.6118015646934509, "25705": 0.23556606471538544, "26282": 0.39433568716049194, "26396": 0.13755162060260773, "26489": 0.1401015669107437, "26591": 0.3019835948944092, "26603": 1.4515039920806885, "26825": 1.2655161619186401, "26835": 0.0354953333735466, "27142": 0.004870930220931768, "27158": 0.15275461971759796, "27602": 0.08244366943836212, "27777": 0.45499902963638306, "28041": 0.1873544454574585, "28252": 0.0770333781838417, "28377": 0.38441169261932373, "28424": 0.011650617234408855, "28636": 0.7047978043556213, "29003": 0.06977381557226181, "29105": 0.3325583338737488, "29109": 0.11256109178066254, "29470": 0.36290550231933594, "29494": 0.04674193635582924} | 12824568 | The organization of cells, emerging from cell-cell interactions, can give rise to collective properties. These properties are adaptive when together cells can face environmental challenges that they separately cannot. One particular challenge that is important for microorganisms is migration. In this study, we show how flagellum-independent migration is driven by the division of labor of two cell types that appear during Bacillus subtilis sliding motility. Cell collectives organize themselves into bundles (called "van Gogh bundles") of tightly aligned cell chains that form filamentous loops at the colony edge. We show, by time-course microscopy, that these loops migrate by pushing themselves away from the colony. The formation of van Gogh bundles depends critically on the synergistic interaction of surfactin-producing and matrix-producing cells. We propose that surfactin-producing cells reduce the friction between cells and their substrate, thereby facilitating matrix-producing cells to form bundles. The folding properties of these bundles determine the rate of colony expansion. Our study illustrates how the simple organization of cells within a community can yield a strong ecological advantage. This is a key factor underlying the diverse origins of multicellularity. | From Cell Differentiation to Cell Collectives: Bacillus subtilis Uses Division of Labor to Migrate |
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Using parabiosis and fate-mapping approaches, we confirmed that monocytes do not show significant contribution to tissue macrophages in the steady state. Similarly, we found that after depletion of lung macrophages, the majority of repopulation occurred by stochastic cellular proliferation in situ in a macrophage colony-stimulating factor (M-Csf)- and granulocyte macrophage (GM)-CSF-dependent manner but independently of interleukin-4. We also found that after bone marrow transplantation, host macrophages retained the capacity to expand when the development of donor macrophages was compromised. Expansion of host macrophages was functional and prevented the development of alveolar proteinosis in mice transplanted with GM-Csf-receptor-deficient progenitors. Collectively, these results indicate that tissue-resident macrophages and circulating monocytes should be classified as mononuclear phagocyte lineages that are independently maintained in the steady state. | Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. |
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The method proceeds in three main steps. First, the patient scalp is digitized in physical space with a magnetic-field digitizer, following a specific digitization pattern. Second, a registration process minimizes the mean square distance between those points and a segmented scalp surface extracted from the magnetic resonance image. Following this registration, the physician can follow the change in coil position in real-time through the visualization interface and adjust the coil position to the desired anatomical location. Third, amplitude of motor evoked potentials can be projected onto the segmented brain in order to create functional brain maps. The registration has subpixel accuracy in a study with simulated data, while we obtain a point to surface root-mean-square error of 1.17/spl plusmn/0.38 mm in a 24 subject study. | Registration and real-time visualization of transcranial magnetic stimulation with 3-D MR images |
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We show here that this desmoplastic reaction generates inordinately high interstitial fluid pressures (IFPs), exceeding those previously measured or theorized for solid tumors, and induces vascular collapse, while presenting substantial barriers to perfusion, diffusion, and convection of small molecule therapeutics. We identify hyaluronan, or hyaluronic acid (HA), as the primary matrix determinant of these barriers and show that systemic administration of an enzymatic agent can ablate stromal HA from autochthonous murine PDA, normalize IFP, and re-expand the microvasculature. In combination with the standard chemotherapeutic, gemcitabine, the treatment permanently remodels the tumor microenvironment and consistently achieves objective tumor responses, resulting in a near doubling of overall survival. | Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. |
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"24848": 0.06337817758321762, "25006": 0.25845035910606384, "25022": 0.8074519634246826, "25086": 0.5381823778152466, "25095": 0.22001366317272186, "25117": 0.3170322775840759, "25170": 0.1677299439907074, "25222": 0.2689530849456787, "25352": 0.8957691192626953, "25409": 0.7286425232887268, "25714": 0.23787821829319, "25937": 0.2089812457561493, "26237": 0.045809537172317505, "26243": 0.03831886500120163, "27133": 1.176850438117981, "27144": 0.06886265426874161, "27360": 0.11691460013389587, "27373": 0.4093637466430664, "27651": 0.018384648486971855, "27833": 0.0019512200960889459, "27915": 0.0913962796330452, "28093": 0.23556606471538544, "28207": 0.05139094591140747, "28436": 0.12038381397724152, "28517": 0.11865071207284927, "28578": 0.9687942266464233, "28689": 0.24325250089168549, "28774": 0.9900637865066528, "29458": 0.10818854719400406, "29513": 1.17624831199646, "29533": 0.11517547070980072, "29610": 0.07884006202220917} | 12869200 | We performed this meta-analysis of epidemiologic studies to investigate the associations between circulating adiponectin, leptin and adiponectin-leptin (A/L) ratio and endometrial cancer risk. Relevant manuscripts were identified by searching PubMed and ISI Web of Science databases as well as by manual searching the references cited in retrieved manuscripts. Random-effects models were used to estimate summary odds ratio (SOR) and 95% confidence intervals (CIs) for aforementioned associations. Fourteen manuscripts with 13 studies (five nested case-control and eight case-control studies) cumulatively involving a total of 1,963 endometrial cancer cases and 3,503 noncases were included in the analyses. Overall, comparing persons with circulating concentrations of adiponectin, leptin and A/L ratio in the top tertile with persons with concentrations of these biomarkers in the bottom tertile yielded SORs of 0.47 (95% CI: 0.34-0.65; I(2) = 63.7%; n = 13), 2.19 (95% CI: 1.44-3.31; I(2) = 64.2%; n = 7),and 0.45 (95% CI: 0.24-0.86; I(2) = 90.1%; n = 5), respectively. Notably, there was an 18% reduction in risk for per each 5 μg/mL increment in circulating adiponectin concentrations (SOR = 0.82; 95% CI: 0.74-0.90; I(2) = 49%; n = 8). Stratifying by study characteristics and whether these studies considered or adjusted for potential confounders, the findings were robust in the analyses of circulating adiponectin and leptin. No evidence of publication bias was detected. In conclusion, the findings from this meta-analysis suggest that increased circulating adiponectin and A/L ratio or decreased leptin concentrations were associated with reduced risk of endometrial cancer. Further prospective designed studies are warranted to confirm our findings. | Circulating adiponectin, leptin and adiponectin-leptin ratio and endometrial cancer risk: Evidence from a meta-analysis of epidemiologic studies. |
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0.045809537172317505, "26601": 0.037378571927547455, "26773": 0.15442965924739838, "26874": 0.9915141463279724, "27152": 0.08782484382390976, "27598": 0.5255602598190308, "27642": 0.6410312056541443, "27709": 1.094698429107666, "27846": 0.01934296265244484, "28086": 1.134421706199646, "28353": 0.15693697333335876, "28691": 0.05046287178993225, "28828": 0.1477125883102417, "28829": 0.08154398202896118, "28835": 0.0174254160374403, "28848": 0.14686977863311768} | 12871002 | We have studied the function of a conserved germline-specific nucleotidyltransferase protein, CDE-1, in RNAi and chromosome segregation in C. elegans. CDE-1 localizes specifically to mitotic chromosomes in embryos. This localization requires the RdRP EGO-1, which physically interacts with CDE-1, and the Argonaute protein CSR-1. We found that CDE-1 is required for the uridylation of CSR-1 bound siRNAs, and that in the absence of CDE-1 these siRNAs accumulate to inappropriate levels, accompanied by defects in both meiotic and mitotic chromosome segregation. Elevated siRNA levels are associated with erroneous gene silencing, most likely through the inappropriate loading of CSR-1 siRNAs into other Argonaute proteins. We propose a model in which CDE-1 restricts specific EGO-1-generated siRNAs to the CSR-1 mediated, chromosome associated RNAi pathway, thus separating it from other endogenous RNAi pathways. The conserved nature of CDE-1 suggests that similar sorting mechanisms may operate in other animals, including mammals. | CDE-1 Affects Chromosome Segregation through Uridylation of CSR-1-Bound siRNAs |
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By single-cell photoactivation of the T cell antigen receptor, we show that MTOC polarization is driven by localized accumulation of diacylglycerol (DAG). MTOC reorientation was closely preceded first by production of DAG and then by recruitment of the microtubule motor protein dynein. Blocking DAG production or disrupting the localization of DAG impaired MTOC recruitment. Localized DAG accumulation was also required for cytotoxic T cell–mediated killing. Furthermore, photoactivation of DAG itself was sufficient to induce transient polarization. Our data identify a DAG-dependent pathway that signals through dynein to control microtubule polarity in T cells. | Localized diacylglycerol drives the polarization of the microtubule-organizing center in T cells |
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"27177": 1.5348490476608276, "27321": 0.5584990978240967, "27441": 0.06337817758321762, "27572": 0.09938567131757736, "27717": 0.38574060797691345, "28032": 0.8649974465370178, "28156": 0.5404602885246277, "28290": 0.12814582884311676, "28361": 0.0913962796330452, "28389": 0.175953671336174, "28685": 0.1946154683828354, "28828": 0.30486753582954407, "28829": 0.3070250153541565, "28873": 0.23710809648036957} | 12880573 | The plcA gene of Listeria monocytogenes encodes a secreted phosphatidylinositol-specific phospholipase C (Pl-PLC). Recent studies have established that transposon mutations within plcA result in avirulence for mice and pleiotropic effects when examined in tissue-culture models of infection. Genetic analysis reveals that many of the effects of the transposon insertions are due to loss of readthrough transcription from plcA into the downstream gene prfA, which encodes an essential transcription factor of numerous L. monocytogenes virulence genes. Construction of an in-frame deletion within plcA had no effect on expression of prfA thus allowing direct assignment of a role of the Pl-PLC in pathogenesis. Pl-PLC was shown to play a significant role in mediating escape of L. monocytogenes from phagosomes of primary murine macrophages. Interestingly, this defect manifested itself in vivo in the liver but not in the spleen of infected mice. | Dual roles of plcA in Listeria monocytogenes pathogenesis. |
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"26591": 0.31560876965522766, "26773": 0.5045560002326965, "26835": 0.00875066313892603, "27258": 1.0312920808792114, "27427": 0.6921701431274414, "27441": 0.012615402229130268, "27631": 0.1946154683828354, "27697": 0.22626367211341858, "27790": 0.3070250153541565, "27806": 0.0770333781838417, "27854": 0.0354953333735466, "28024": 0.08692999184131622, "28215": 0.7057625651359558, "28281": 0.3547199070453644, "28691": 0.3012613356113434, "28848": 0.77198725938797, "29458": 0.46117570996284485} | 12881593 | Clp-controlled proteolysis in Bacillus subtilis seems to play a substantial role, particularly under stress conditions. Calibrated Western blot analyses were used to estimate the approximate numbers of heat-inducible Clp molecules within a single cell. According to these numbers, the different Clp ATPases do not seem to compete for the proteolytic subunit ClpP. Coimmunoprecipitation experiments revealed the predicted specific ClpX-ClpP, ClpC-ClpP, and ClpE-ClpP interactions. ClpE and ClpX are rapidly degraded in wild-type cells during permanent heat stress but remained almost stable in a clpP mutant, suggesting ClpP-dependent degradation. In particular, ClpCP appeared to be involved in the degradation of the short-lived ClpE ATPase, indicating a negative "autoregulatory" circuit for this particular Clp ATPase at the posttranslational level. Analysis of the half-life of stress-inducible clp mRNAs during exponential growth and heat shock revealed precise regulation of the synthesis of each Clp protein at the posttranscriptional level as well to meet the needs of B. subtilis. | Fine-tuning in regulation of Clp protein content in Bacillus subtilis. |
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"26187": 0.06795065850019455, "26305": 0.0058422754518687725, "26835": 0.7610978484153748, "27210": 0.6149744987487793, "27391": 0.03360854089260101, "27777": 0.7163142561912537, "27781": 0.812664806842804, "27854": 1.0087559223175049, "28170": 0.777387797832489, "28745": 1.2347444295883179, "28873": 0.45499902963638306, "28896": 0.22704219818115234, "29290": 0.25239890813827515, "29347": 0.8004589080810547, "29489": 0.29473719000816345} | 12885341 | West Nile virus (WNV) is the most common arthropod-borne flavivirus in the United States; however, the vector ligand(s) that participate in infection are not known. We now show that an Aedes aegypti C-type lectin, mosGCTL-1, is induced by WNV, interacts with WNV in a calcium-dependent manner, and facilitates infection in vivo and in vitro. A mosquito homolog of human CD45 in A. aegypti, designated mosPTP-1, recruits mosGCTL-1 to enable viral attachment to cells and to enhance viral entry. In vivo experiments show that mosGCTL-1 and mosPTP-1 function as part of the same pathway and are critical for WNV infection of mosquitoes. A similar phenomenon was also observed in Culex quinquefasciatus, a natural vector of WNV, further demonstrating that these genes participate in WNV infection. During the mosquito blood-feeding process, WNV infection was blocked in vivo with mosGCTL-1 antibodies. A molecular understanding of flaviviral-arthropod interactions may lead to strategies to control viral dissemination in nature. | A C-Type Lectin Collaborates with a CD45 Phosphatase Homolog to Facilitate West Nile Virus Infection of Mosquitoes |
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"25456": 0.6389714479446411, "25644": 0.5607312321662903, "25708": 1.1738357543945312, "25714": 0.77198725938797, "25761": 0.03360854089260101, "26236": 0.029824240133166313, "26305": 0.16359257698059082, "26402": 0.417115718126297, "26601": 0.4673144817352295, "26741": 0.007782140281051397, "26773": 0.3381449282169342, "26986": 0.08244366943836212, "27144": 0.025073638185858727, "27287": 0.3269403576850891, "27531": 0.026025565341114998, "27532": 0.03831886500120163, "27881": 0.14433705806732178, "28086": 1.1356772184371948, "28105": 1.1166772842407227, "28156": 0.25845035910606384, "28207": 0.036437395960092545, "28522": 0.3560888469219208, "28873": 0.01934296265244484, "29107": 0.06977381557226181, "29206": 0.9958525896072388, "29458": 0.11430477350950241, "29480": 0.638455867767334, "29490": 0.12986256182193756} | 12887068 | Over 70% of diffuse intrinsic pediatric gliomas, an aggressive brainstem tumor, harbor heterozygous mutations that create a K27M amino acid substitution (methionine replaces lysine 27) in the tail of histone H3.3. The role of the H3.3K27M mutation in tumorigenesis is not fully understood. Here, we use a human embryonic stem cell system to model this tumor. We show that H3.3K27M expression synergizes with p53 loss and PDGFRA activation in neural progenitor cells derived from human embryonic stem cells, resulting in neoplastic transformation. Genome-wide analyses indicate a resetting of the transformed precursors to a developmentally more primitive stem cell state, with evidence of major modifications of histone marks at several master regulator genes. Drug screening assays identified a compound targeting the protein menin as an inhibitor of tumor cell growth in vitro and in mice. | Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation |
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Furthermore, maximal efficiency of homologous DNA pairing and strand exchange is strongly dependent on the heterotrimeric single-stranded DNA binding factor hRPA and requires conditions that lessen interactions of the homologous duplex with the hRad51-single-stranded DNA nucleoprotein filament. The homologous DNA pairing and strand exchange system described should be valuable for dissecting the action mechanism of hRad51 and for deciphering its functional interactions with other recombination factors. | Basis for avid homologous DNA strand exchange by human Rad51 and RPA. |
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0.03925827145576477} | 12899460 | BACKGROUND The Euro-D depression scale consists of symptom clusters that may be differentially related to demographic and cognitive characteristics in older adults. This hypothesis needs further investigation and the role of measurement bias on substantive conclusions remains to be established. METHOD The study sample comprised 10,405 community-dwelling older adults from six Latin American countries. We applied a Multiple Indicators Multiple Causes (MIMIC) model for a concurrent investigation of measurement bias and of the association between Euro-D symptom clusters and background variables. RESULTS The factorial validity of Euro-D, with a two-dimensional structure--affective suffering and motivation disturbance, was consistently supported in all countries. Although complete measurement invariance could not be assumed across countries, measurement bias was minor. Both Euro-D factors were unrelated to age, but related to gender, as well as to impairment in memory and verbal fluency. Gender differences were larger for affective suffering than for motivation disturbance, whereas differences in verbal fluency impairment were more strongly related to motivation disturbance. LIMITATIONS Our analytic strategies could only examine invariance at the level of indicator thresholds. The generalisability of current findings needs to be examined in clinical populations. A wider set of cognitive tests is needed. We did not examine the compositional factors that could have accounted for the variation in Euro-D scores across countries, as this was beyond the aims of the paper. CONCLUSION The current study adds evidence for the construct validity of Euro-D and for the possible differential association of depression symptom-clusters with gender and verbal fluency in older adults. An understanding of the heterogeneity of late-life depression may carry clinical implications for the diagnosis and treatment of depression in old age. | A multiple indicators multiple causes model of late-life depression in Latin American countries |
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"29490": 0.3177432417869568} | 12899612 | Although mesenchymal stem cells (MSCs) have been increasingly trialed to treat a variety of diseases, the underlying mechanisms remain still elusive. In this study, human umbilical cord (UC)-derived MSCs were stimulated by hypoxia, and the membrane microvesicles (MVs) in the supernatants were collected by ultracentrifugation, observed under an electron microscope, and the origin was identified with the flow cytometric technique. The results showed that upon hypoxic stimulus, MSCs released a large quantity of MVs of ~100 nm in diameter. The MVs were phenotypically similar to the parent MSCs, except that the majority of them were negative for the receptor of platelet-derived growth factor. DiI-labeling assay revealed that MSC-MVs could be internalized into human UC endothelial cells (UC-ECs) within 8 h after they were added into the culture medium. Carboxyfluorescein succinimidyl ester-labeling technique and MTT test showed that MSC-MVs promoted the proliferation of UC-ECs in a dose-dependent manner. Further, MVs could enhance in vitro capillary network formation of UC-ECs in a Matrigel matrix. In a rat hindlimb ischemia model, both MSCs and MSC-MVs were shown to improve significantly the blood flow recovery compared with the control medium (P<0.0001), as assessed by laser Doppler imaging analysis. These data indicate that MV releasing is one of the major mechanisms underlying the effectiveness of MSC therapy by promoting angiogenesis. | Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. |
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0.5151132941246033, "27144": 0.2652147710323334, "27184": 0.8853482007980347, "27321": 0.37102460861206055, "27484": 0.4624064862728119, "27781": 0.6027565002441406, "28046": 1.117316484451294, "28064": 0.2231435477733612, "28156": 0.417115718126297, "28164": 0.01934296265244484, "28177": 0.9455460906028748, "28228": 0.8264343738555908, "28472": 0.1212492436170578, "28479": 1.2129170894622803, "28549": 0.38374659419059753, "28835": 0.04207121208310127, "28848": 0.7934166193008423, "29290": 0.29255300760269165, "29336": 0.861702561378479, "29490": 0.1401015669107437} | 12903921 | It has been proved that oxidative stress increases when leukemia is accompanied by depression. This fact may indicate the role of oxidative stress in the development of depression in cancer patients. The aim of this study was to determine whether the acute myeloid leukemia of Brown Norway rats, which is accompanied by oxidative stress, evoked behavioral and receptor changes resembling alterations characteristic of rat models of depression. The rats were divided into two groups: leukemic rats and healthy control. Leukemia was induced through intraperitoneal injection of 10(7) promyelocytic leukemia cells to the Brown Norway rats. Depression-like behavior was evaluated in the forced swim test at 30 or 34 days after leukemic cells injection. The rats were killed after the evaluation and the spleen, brain cortex and hippocampus were excised. The red-ox state was assessed in homogenates of tissues by measuring total glutathione (GSH) content, the ferric ion reducing ability of plasma (FRAP) level, expression of heme oxygenase-1 (HO-1), biliverdin reductase (BvR) and ferritin mRNA, superoxide dismutase (SOD) activity, as well as malondialdehyde (MDA) concentration. Radioligand binding assay was used to assess of the effect of leukemia on cortical receptors. Leukemic cells were identified using RM-124 antibody by FACS Calibur flow cytometry. Leukemia influenced locomotory activity as well as forced swim test behavior in a 34-day series of experiments. Signs of oxidative stress in leukemic rats were observed in each examined stage of leukemia development. The FRAP values and glutathione contents, were significantly lowered whereas HO-1 mRNA expression, and malonodialdehyde concentrations were significantly increased in the spleen and brain structures of leukemic rats in comparison with the healthy controls. A significant increase in the potency of glycine to displace [(3)H]L-689,560 from the strychnine-insensitive glycine site of the N-methyl-D-aspartic (NMDA) receptors receptor complex in cortical homogenates of the leukemic rats in 30- and 34-day experimental series was observed in comparison with the control. Upregulation of 5-HT(2A) receptors was observed in rat cortex after 30 days of leukemia development but not in 34-days series compared with the control. It is concluded that disturbances in antioxidant system in brain cortex were accompanied by an activation of glycine sites of the NMDA receptor complex, regardless of stage of leukemia development, which are characteristic of model of depression. Findings of our study demonstrate the link between glutamatergic activity, oxidative stress and leukemia. | Evaluation of oxidative status and depression-like responses in Brown Norway rats with acute myeloid leukemia |
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0.6704301834106445, "26402": 0.5855054259300232, "26520": 1.5075435638427734, "26702": 0.1401015669107437, "27099": 0.4831010699272156, "27218": 0.8550800085067749, "27559": 0.8893690705299377, "27598": 0.3269403576850891, "27881": 0.2516399025917053, "27965": 0.2983669638633728, "28024": 0.7836518287658691, "28297": 0.2674594223499298, "28424": 0.09495500475168228, "28427": 0.0842406153678894, "28828": 0.1064341589808464, "28829": 0.2231435477733612, "29172": 0.04207121208310127, "29206": 0.09850110858678818, "29290": 0.2674594223499298, "29477": 0.013579257763922215, "29486": 0.4500300884246826, "29516": 0.0913962796330452, "29533": 1.0137293338775635} | 12909503 | DNA damage encountered by DNA replication forks poses risks of genome destabilization, a precursor to carcinogenesis. Damage checkpoint systems cause cell cycle arrest, promote repair and induce programed cell death when damage is severe. Checkpoints are critical parts of the DNA damage response network that act to suppress cancer. DNA damage and perturbation of replication machinery causes replication stress, characterized by accumulation of single-stranded DNA bound by replication protein A (RPA), which triggers activation of ataxia telangiectasia and Rad3 related (ATR) and phosphorylation of the RPA32, subunit of RPA, leading to Chk1 activation and arrest. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) [a kinase related to ataxia telangiectasia mutated (ATM) and ATR] has well characterized roles in DNA double-strand break repair, but poorly understood roles in replication stress-induced RPA phosphorylation. We show that DNA-PKcs mutant cells fail to arrest replication following stress, and mutations in RPA32 phosphorylation sites targeted by DNA-PKcs increase the proportion of cells in mitosis, impair ATR signaling to Chk1 and confer a G2/M arrest defect. Inhibition of ATR and DNA-PK (but not ATM), mimic the defects observed in cells expressing mutant RPA32. Cells expressing mutant RPA32 or DNA-PKcs show sustained H2AX phosphorylation in response to replication stress that persists in cells entering mitosis, indicating inappropriate mitotic entry with unrepaired damage. | Distinct roles for DNA-PK, ATM and ATR in RPA phosphorylation and checkpoint activation in response to replication stress |
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0.053244512528181076} | 12922760 | BACKGROUND G-quadruplexes (G4s) are stable non-canonical DNA secondary structures consisting of stacked arrays of four guanines, each held together by Hoogsteen hydrogen bonds. Sequences with the ability to form these structures in vitro, G4 motifs, are found throughout bacterial and eukaryotic genomes. The budding yeast Pif1 DNA helicase, as well as several bacterial Pif1 family helicases, unwind G4 structures robustly in vitro and suppress G4-induced DNA damage in S. cerevisiae in vivo. RESULTS We determined the genomic distribution and evolutionary conservation of G4 motifs in four fission yeast species and investigated the relationship between G4 motifs and Pfh1, the sole S. pombe Pif1 family helicase. Using chromatin immunoprecipitation combined with deep sequencing, we found that many G4 motifs in the S. pombe genome were associated with Pfh1. Cells depleted of Pfh1 had increased fork pausing and DNA damage near G4 motifs, as indicated by high DNA polymerase occupancy and phosphorylated histone H2A, respectively. In general, G4 motifs were underrepresented in genes. However, Pfh1-associated G4 motifs were located on the transcribed strand of highly transcribed genes significantly more often than expected, suggesting that Pfh1 has a function in replication or transcription at these sites. CONCLUSIONS In the absence of functional Pfh1, unresolved G4 structures cause fork pausing and DNA damage of the sort associated with human tumors. | The essential Schizosaccharomyces pombe Pfh1 DNA helicase promotes fork movement past G-quadruplex motifs to prevent DNA damage |
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0.31132611632347107, "28327": 0.7987030148506165, "28696": 0.11604541540145874, "28727": 0.10026945173740387, "29290": 0.12728634476661682, "29441": 0.1602703034877777, "29577": 0.06612417846918106} | 12932176 | The balance between excitatory and inhibitory synapses is crucial for normal brain function. Wnt proteins stimulate synapse formation by increasing synaptic assembly. However, it is unclear whether Wnt signaling differentially regulates the formation of excitatory and inhibitory synapses. Here, we demonstrate that Wnt7a preferentially stimulates excitatory synapse formation and function. In hippocampal neurons, Wnt7a increases the number of excitatory synapses, whereas inhibitory synapses are unaffected. Wnt7a or postsynaptic expression of Dishevelled-1 (Dvl1), a core Wnt signaling component, increases the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs), but not miniature inhibitory postsynaptic currents (mIPSCs). Wnt7a increases the density and maturity of dendritic spines, whereas Wnt7a-Dvl1-deficient mice exhibit defects in spine morphogenesis and mossy fiber-CA3 synaptic transmission in the hippocampus. Using a postsynaptic reporter for Ca(2+)/Calmodulin-dependent protein kinase II (CaMKII) activity, we demonstrate that Wnt7a rapidly activates CaMKII in spines. Importantly, CaMKII inhibition abolishes the effects of Wnt7a on spine growth and excitatory synaptic strength. These data indicate that Wnt7a signaling is critical to regulate spine growth and synaptic strength through the local activation of CaMKII at dendritic spines. Therefore, aberrant Wnt7a signaling may contribute to neurological disorders in which excitatory signaling is disrupted. | Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca²⁺/Calmodulin-dependent protein kinase II. |
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0.4494072198867798, "29180": 0.0317181795835495} | 12943966 | Ghrelin is a hunger hormone with gastroprokinetic properties but the factors controlling ghrelin secretion from the stomach are unknown. Bitter taste receptors (T2R) and the gustatory G proteins, α-gustducin (gust) and α-transducin, are expressed in the gut and are involved in the chemosensation of nutrients. This study aimed to investigate whether T2R-agonists affect (i) ghrelin release via α-gustducin and (ii) food intake and gastric emptying via the release of ghrelin. The mouse stomach contains two ghrelin cell populations: cells containing octanoyl and desoctanoyl ghrelin, which were colocalized with α-gustducin and α-transducin, and cells staining for desoctanoyl ghrelin. Gavage of T2R-agonists increased plasma octanoyl ghrelin levels in WT mice but the effect was partially blunted in gust(-/-) mice. Intragastric administration of T2R-agonists increased food intake during the first 30 min in WT but not in gust(-/-) and ghrelin receptor knockout mice. This increase was accompanied by an increase in the mRNA expression of agouti-related peptide in the hypothalamus of WT but not of gust(-/-) mice. The temporary increase in food intake was followed by a prolonged decrease (next 4 h), which correlated with an inhibition of gastric emptying. The delay in emptying, which was partially counteracted by ghrelin, was not mediated by cholecystokinin and GLP-1 but involved a direct inhibitory effect of T2R-agonists on gastric contractility. This study is unique in providing functional evidence that activation of bitter taste receptors stimulates ghrelin secretion. Modulation of endogenous ghrelin levels by tastants may provide novel therapeutic applications for the treatment of weight -and gastrointestinal motility disorders. | Bitter taste receptors and α-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. |
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"28522": 1.1561684608459473, "28636": 0.2763880789279938, "29290": 0.43623676896095276, "29480": 0.5540198087692261, "29494": 0.1808556467294693} | 12948892 | Evidence has been accumulated that glioblastoma cells release and exploit glutamate for proliferation and migration by autocrine or paracrine loops through Ca2+-permeable AMPA-type glutamate receptors. Here, we show that Ca2+ signaling mediated by AMPA receptor regulates the growth and motility of glioblastoma cells via activation of Akt. Ca2+ supplied through Ca2+-permeable AMPA receptor phosphorylated Akt at Ser-473, thereby facilitating proliferation and mobility. A dominant-negative form of Akt inhibited cell proliferation and migration accelerated by overexpression of Ca2+-permeable AMPA receptor. In contrast, introduction of a constitutively active form of Akt rescued tumor cells from apoptosis induced by the conversion of Ca2+-permeable AMPA receptor to Ca2+-impermeable receptors by the delivery of GluR2 cDNA. Therefore, Akt functions as downstream effectors for Ca2+-signaling mediated by AMPA receptor in glioblastoma cells. The activation of the glutamate-AMPA receptor-Akt pathway may contribute to the high degree of anaplasia and invasive growth of human glioblastoma. This novel pathway might give an alternative therapeutic target. | Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. |
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"23521": 0.39893341064453125, "23586": 0.5110208988189697, "23777": 0.15359249711036682, "23900": 0.3318578004837036, "23924": 0.06429435312747955, "24054": 0.176772341132164, "24255": 0.3560888469219208, "24388": 0.06337817758321762, "24710": 0.3601844012737274, "24797": 0.007782140281051397, "25095": 0.31560876965522766, "25117": 1.1738357543945312, "25194": 0.18411032855510712, "25352": 1.4487555027008057, "25456": 0.14179791510105133, "25458": 0.06154331564903259, "25562": 0.44753631949424744, "25761": 0.08782484382390976, "26089": 0.0317181795835495, "26244": 0.09228714555501938, "26266": 0.05786345899105072, "26402": 0.06520967930555344, "26721": 1.039613962173462, "26942": 1.0628231763839722, "27605": 0.3388410806655884, "27854": 1.4883290529251099, "28113": 0.8592242002487183, "29226": 0.02316705882549286, "29290": 0.12556517124176025, "29494": 0.09584271162748337, "29577": 0.011650617234408855} | 12956194 | Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists. | The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism |
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Here, by using parabiotic mice, we show that a preexisting pool of CD4 TRM cells in the genital mucosa was required for full protection from a lethal herpes simplex virus 2 (HSV-2) infection. Chemokines secreted by a local network of macrophages maintained vaginal CD4 TRM in memory lymphocyte clusters (MLCs), independently of circulating memory T cells. CD4 TRM cells within the MLCs were enriched in clones that expanded in response to HSV-2. Our results highlight the need for vaccine strategies that enable establishment of TRM cells for protection from a sexually transmitted virus and provide insights as to how such a pool might be established. | A local macrophage chemokine network sustains protective tissue-resident memory CD4 T cells |
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0.34300774335861206, "29401": 0.0174254160374403, "29458": 0.9591107368469238, "29566": 0.034552380442619324} | 12991445 | OBJECTIVE To determine the effects of smoking, plasma lipids, lipoproteins, apolipoproteins, and fibrinogen on the patency of saphenous vein femoropopliteal bypass grafts at one year. DESIGN Prospective study of patients with saphenous vein femoropopliteal bypass grafts entered into a multicentre trial. SETTING Surgical wards, outpatient clinics, and home visits coordinated by two tertiary referral centres in London and Birmingham. PATIENTS 157 Patients (mean age 66.6 (SD 8.2) years), 113 with patent grafts and 44 with occluded grafts one year after bypass. MAIN OUTCOME MEASURE Cumulative percentage patency at one year. RESULTS Markers for smoking (blood carboxyhaemoglobin concentration (p less than 0.05) and plasma thiocyanate concentration (p less than 0.01) and plasma concentrations of fibrinogen (p less than 0.001) and apolipoproteins AI (p less than 0.04) and (a) (p less than 0.05) were significantly higher in patients with occluded grafts. Serum cholesterol concentrations were significantly higher in patients with grafts that remained patent one year after bypass (p less than 0.005). Analysis of the smoking markers indicated that a quarter of patients (40) were untruthful in their claims to have stopped smoking. Based on smoking markers, patency of grafts in smokers was significantly lower at one year by life table analysis than in non-smokers (63% v 84%, p less than 0.02). Patency was significantly higher by life table analysis in patients with a plasma fibrinogen concentration below the median than in those with a concentration above (90% v 57%, p less than 0.0002). Surprisingly, increased plasma low density lipoprotein cholesterol concentration was significantly associated with improved patency at one year (85%) at values above the median compared with patency (only 68%) at values in the lower half of the range (p less than 0.02). CONCLUSIONS Plasma fibrinogen concentration was the most important variable predicting graft occlusion, followed by smoking markers. A more forceful approach is needed to stop patients smoking; therapeutic measures to improve patency of vein grafts should focus on decreasing plasma fibrinogen concentration rather than serum cholesterol concentration. | Influence of smoking and plasma factors on patency of femoropopliteal vein grafts. |
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0.0038986403960734606, "28831": 0.1221139207482338, "29290": 0.2247048318386078, "29295": 0.13755162060260773, "29336": 0.13499516248703003, "29431": 0.11691460013389587} | 12994780 | Rationale:Atypical antipsychotic drugs (AAD) induce significant weight gain in female C57BL/6J mice. The effect of dietary fat on weight gain and serum lipids in this model is unknown. Objectives: Test the hypothesis that the obesigenic effects of these drugs are greater in the presence of a high-fat diet. Methods:Female C57BL/6J mice were treated with atypical antipsychotics for 3 weeks and fed either a low-fat or high-fat diet (4.6 vs 15.6% fat by wt). Food intake (FI), body weight (BW), body composition, and serum lipids were measured during treatment with optimized doses of olanzapine, quetiapine, and risperidone. Energy intake (EI) and feed efficiency (FE) were calculated. Group differences in change were analyzed via repeated measures analysis of variance (ANOVA). Serum lipid concentrations, EI and FE were compared using two-way ANOVA.Results:AAD-treated mice gained significantly more weight than controls after 3 weeks (P<0.001). Treatment and diet had significant effects on FI and EI over time (P<0.001). AAD-treated mice had significantly higher FE than controls (P<0.05); however, there was no significant drug by diet interaction (P=0.65). Risperidone low-fat mice gained significantly more absolute fat mass than placebo low-fat mice (P<0.05). All treatment groups, except quetiapine low-fat and olanzapine high-fat, gained significantly more absolute lean mass than placebo controls (P<0.05). Cholesterol levels were significantly lower in quetiapine and risperidone than placebo (P<0.05). Risperidone low-fat mice had significantly higher triglyceride levels than placebo and risperidone high-fat mice (P<0.05).Conclusions:A high-fat diet does not increase AAD-induced BW gain in female mice during a 3-week treatment period. | No effect of dietary fat on short-term weight gain in mice treated with atypical antipsychotic drugs |
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Rewarming of frozen tissue is associated with blood reperfusion and the simultaneous generation of free oxygen radicals. In this review is discussed the current understanding of the mechanism of action of free oxygen radicals as related to cold injury during rewarming. Decreased energy stores during ischaemia lead to the accumulation of adenine nucleotides and liberation of free fatty acids due to the breakdown of lipid membranes. On rewarming, free fatty acids are metabolized via cyclo-oxygenase and adenine nucleotides are metabolized via the xanthine oxidase pathway. These may be the source of free oxygen radicals. Leukocytes may also play a major role in the pathogenesis of cold injury. Oxygen radical scavengers, such as superoxide dismutase and catalase, may help to reduce the cold induced injury but their action is limited due to the inability readily to cross the plasma membrane. Lipid soluble antioxidants are likely to be more effective scavengers because of their presence in membranes where peroxidative reactions can be arrested. | The role of free radicals in cold injuries. |
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0.13755162060260773, "28268": 0.40806588530540466, "28696": 0.015504186972975731, "28805": 0.2881702482700348, "28892": 0.025073638185858727, "28935": 0.857568621635437, "29050": 0.022212404757738113, "29090": 0.5069117546081543, "29235": 0.0317181795835495, "29290": 0.3339579105377197, "29514": 0.3339579105377197, "29516": 0.1913948506116867, "29610": 0.35334911942481995} | 13001323 | Chronic feeding on high-calorie diets causes obesity and type 2 diabetes mellitus (T2DM), illnesses that affect hundreds of millions. Thus, understanding the pathways protecting against diet-induced metabolic imbalance is of paramount medical importance. Here, we show that mice lacking SIRT1 in steroidogenic factor 1 (SF1) neurons are hypersensitive to dietary obesity owing to maladaptive energy expenditure. Also, mutant mice have increased susceptibility to developing dietary T2DM due to insulin resistance in skeletal muscle. Mechanistically, these aberrations arise, in part, from impaired metabolic actions of the neuropeptide orexin-A and the hormone leptin. Conversely, mice overexpressing SIRT1 in SF1 neurons are more resistant to diet-induced obesity and insulin resistance due to increased energy expenditure and enhanced skeletal muscle insulin sensitivity. Our results unveil important protective roles of SIRT1 in SF1 neurons against dietary metabolic imbalance. | SIRT1 deacetylase in SF1 neurons protects against metabolic imbalance. |
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"28405": 0.2622140049934387, "28991": 1.12432062625885, "29206": 0.05694137513637543} | 13002003 | Despite the recent identification of the transcriptional regulatory circuitry involving SOX2, NANOG, and OCT-4, the intracellular signaling networks that control pluripotency of human embryonic stem cells (hESCs) remain largely undefined. Here, we demonstrate an essential role for the serine/threonine protein kinase mammalian target of rapamycin (mTOR) in regulating hESC long-term undifferentiated growth. Inhibition of mTOR impairs pluripotency, prevents cell proliferation, and enhances mesoderm and endoderm activities in hESCs. At the molecular level, mTOR integrates signals from extrinsic pluripotency-supporting factors and represses the transcriptional activities of a subset of developmental and growth-inhibitory genes, as revealed by genome-wide microarray analyses. Repression of the developmental genes by mTOR is necessary for the maintenance of hESC pluripotency. These results uncover a novel signaling mechanism by which mTOR controls fate decisions in hESCs. Our findings may contribute to effective strategies for tissue repair and regeneration. | mTOR supports long-term self-renewal and suppresses mesoderm and endoderm activities of human embryonic stem cells. |
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invasion through the release of matrix metalloproteinases (MMPs). Population studies have suggested that single nucleotide polymorphisms (SNPs) in MMP genes influence levels of expression and may be associated with breast cancer risk and with disease progression. This study directly examined the impact of MMP SNP genotype on the ability of host fibroblasts to promote tumor cell invasion. Primary breast fibroblasts were isolated from patients with (n = 13) or without (n = 19) breast cancer, and their ability to promote breast cancer cell invasion was measured in in vitro invasion assays. Fibroblast invasion-promoting capacity (IPC) was analyzed in relation to donor type (tumor or non-tumor patient), MMP-1, MMP-3, and MMP-9 SNP genotype and MMP activity using independent samples t test and analysis of variance. All statistical tests were two-sided. Tumor-derived fibroblasts promoted higher levels of invasion than normal fibroblasts (p = 0.041). When IPC was related to genotype, higher levels of IPC were generated by tumor fibroblasts with the high-expressing MMP-3 5A/5A genotype compared with the 5A/6A and 6A/6A genotypes (p = 0.05 and 0.07, respectively), and this was associated with enhanced MMP-3 release. The functional importance of MMP-3 was demonstrated by enhanced invasion in the presence of recombinant MMP-3, whereas reduction occurred in the presence of a specific MMP-3 inhibitor. An inverse relationship was demonstrated between fibroblast IPC and the high-expressing MMP-1 genotype (p = 0.031), but no relationship was seen with MMP-9 SNP status. In contrast, normal fibroblasts showed no variation in IPC in relation to MMP genotype, with MMP-3 5A/5A fibroblasts exhibiting significantly lower levels of IPC than their tumor-derived counterparts (p = 0.04). This study has shown that tumor-derived fibroblasts exhibit higher levels of IPC than normal fibroblasts and that the MMP-3 5A/5A genotype contributes to this through enhanced MMP-3 release. Despite a high-expressing genotype, normal fibroblasts do not exhibit higher IPC or enhanced MMP release. This suggests that more complex changes occur in tumor-derived fibroblasts, enabling full expression of the MMP SNP genotype and these possibly are epigenetic in nature. The results do suggest that, in women with breast cancer, a high-expressing MMP-3 genotype may promote tumor progression more effectively. | Intrinsic genetic characteristics determine tumor-modifying capacity of fibroblasts: matrix metalloproteinase-3 5A/5A genotype enhances breast cancer cell invasion |
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"22663": 0.6634125709533691, "22922": 0.30989447236061096, "23041": 0.012615402229130268, "23354": 0.13243216276168823, "23734": 0.6202403903007507, "23737": 0.8893690705299377, "24012": 0.036437395960092545, "24335": 0.12642613053321838, "24666": 0.24631060659885406, "24759": 0.5778634548187256, "25222": 0.22548456490039825, "25409": 1.3001704216003418, "25468": 0.39893341064453125, "25524": 0.04674193635582924, "25605": 0.18654440343379974, "25761": 0.030771657824516296, "25778": 0.32199856638908386, "25812": 1.8085448741912842, "26120": 0.4132472574710846, "26835": 0.0770333781838417, "26906": 0.19782574474811554, "27144": 0.5784112811088562, "27399": 0.18573370575904846, "27881": 0.7482418417930603, "27928": 0.0317181795835495, "28086": 0.08513788133859634, "28207": 0.4481603503227234, "28436": 0.14349138736724854, "28498": 0.0038986403960734606, "28699": 0.18978065252304077, "29206": 0.20421554148197174, "29290": 0.5795059204101562} | 13011249 | The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment. " Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. | Hallmarks of Cancer: The Next Generation |
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We find that BCR/ABL-induced reactive oxygen species (ROSs) cause chronic oxidative DNA damage resulting in double-strand breaks (DSBs) in S and G(2)/M cell cycle phases. These lesions are repaired by BCR/ABL-stimulated homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ) mechanisms. A high mutation rate is detected in HRR products in BCR/ABL-positive cells, but not in the normal counterparts. In addition, large deletions are found in NHEJ products exclusively in BCR/ABL cells. We propose that the following series of events may contribute to genomic instability of Ph-positive leukemias: BCR/ABL --> ROSs --> oxidative DNA damage --> DSBs in proliferating cells --> unfaithful HRR and NHEJ repair. | BCR/ABL oncogenic kinase promotes unfaithful repair of the reactive oxygen species-dependent DNA double-strand breaks. |
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At very low radiation doses the situation is much less clear, but the risks of low-dose radiation are of societal importance in relation to issues as varied as screening tests for cancer, the future of nuclear power, occupational radiation exposure, frequent-flyer risks, manned space exploration, and radiological terrorism. We review the difficulties involved in quantifying the risks of low-dose radiation and address two specific questions. First, what is the lowest dose of x- or gamma-radiation for which good evidence exists of increased cancer risks in humans? The epidemiological data suggest that it is approximately 10-50 mSv for an acute exposure and approximately 50-100 mSv for a protracted exposure. Second, what is the most appropriate way to extrapolate such cancer risk estimates to still lower doses? Given that it is supported by experimentally grounded, quantifiable, biophysical arguments, a linear extrapolation of cancer risks from intermediate to very low doses currently appears to be the most appropriate methodology. This linearity assumption is not necessarily the most conservative approach, and it is likely that it will result in an underestimate of some radiation-induced cancer risks and an overestimate of others. | Cancer risks attributable to low doses of ionizing radiation: assessing what we really know. |
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0.8143964409828186, "28689": 0.1808556467294693, "28711": 0.1064341589808464, "29477": 0.056018441915512085, "29486": 0.14433705806732178} | 13027590 | CONTEXT Chronic pelvic pain is a common condition with a major effect on health-related quality of life, work productivity, and health care use. Operative interruption of nerve trunks in the uterosacral ligaments by laparoscopic uterosacral nerve ablation (LUNA) is a treatment option for patients with chronic pelvic pain. OBJECTIVE To assess the effectiveness of LUNA in patients with chronic pelvic pain. DESIGN, SETTING, AND PARTICIPANTS Randomized controlled trial of 487 women with chronic pelvic pain lasting longer than 6 months without or with minimal endometriosis, adhesions, or pelvic inflammatory disease, who were recruited to the study by consultant gynecological surgeons from 18 UK hospitals between February 1998 and December 2005. Follow-up was conducted by questionnaires mailed at 3 and 6 months and at 1, 2, 3, and 5 years. INTERVENTION Bilateral LUNA or laparoscopy without pelvic denervation (no LUNA); participants were blinded to the treatment allocation. MAIN OUTCOME MEASURES The primary outcome was pain, which was assessed by a visual analogue scale. Data concerning the 3 types of pain (noncyclical pain, dysmenorrhea, and dyspareunia) were analyzed separately as was the worst pain level experienced from any of these 3 types of pain. The secondary outcome was health-related quality of life, which was measured using a generic instrument (EuroQoL EQ-5D and EQ-VAS). RESULTS After a median follow-up of 69 months, there were no significant differences reported on the visual analogue pain scales for the worst pain (mean difference between the LUNA group and the no LUNA group, -0.04 cm [95% confidence interval {CI}, -0.33 to 0.25 cm]; P = .80), noncyclical pain (-0.11 cm [95% CI, -0.50 to 0.29 cm]; P = .60), dysmenorrhea (-0.09 cm [95% CI, -0.49 to 0.30 cm]; P = .60), or dyspareunia (0.18 cm [95% CI, -0.22 to 0.62 cm]; P = .40). No differences were observed between the LUNA group and the no LUNA group for quality of life. CONCLUSION Among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation. TRIAL REGISTRATION controlled-trials.com Identifier: ISRCTN41196151. | Laparoscopic uterosacral nerve ablation for alleviating chronic pelvic pain: a randomized controlled trial. |
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0.35334911942481995, "25353": 0.1477125883102417, "25409": 0.7352184057235718, "25437": 0.2223619967699051, "25468": 0.040196798741817474, "25473": 0.24631060659885406, "25952": 0.11778303235769272, "25971": 0.09761575609445572, "26179": 0.09495500475168228, "26651": 0.13925230503082275, "26745": 0.6207655072212219, "27011": 0.5209306478500366, "27144": 0.19782574474811554, "27152": 0.22001366317272186, "27312": 0.1602703034877777, "27404": 0.13499516248703003, "28329": 0.04953393340110779, "28389": 0.05694137513637543, "28613": 1.1356772184371948, "28776": 0.0770333781838417, "28835": 0.5984715819358826, "29347": 0.037378571927547455} | 13030852 | Plasma alkaline phosphatase isoenzyme activities were determined in patients with breast cancer to diagnose and monitor bone and liver metastases. Bone alkaline phosphatase activity was increased in 21 of 50 patients (42%) with radiologically confirmed bone metastases, while total alkaline phosphatase activity was increased in only 10 of 50 (20%); liver alkaline phosphatase activity was raised in 12 of 25 patients (48%) with liver metastases. All patients with liver metastases had bone metastases. Bone alkaline phosphatase activity was significantly higher in patients with symptomatic bone disease. Isoenzyme determination provided additional information that would have changed patient management in five of 20 patients who were monitored serially. Measurement of alkaline phosphatase isoenzyme activity, though less sensitive than imaging procedures, can assist in screening for, and in early detection of, a high proportion of bone and liver metastases, and can provide useful objective evidence of their response to treatment. | Identification of bone and liver metastases from breast cancer by measurement of plasma alkaline phosphatase isoenzyme activity. |
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0.0038986403960734606, "26661": 0.08782484382390976, "26773": 0.5295937061309814, "27080": 0.08154398202896118, "27179": 0.5573811531066895, "27292": 0.890972912311554, "27354": 0.38441169261932373, "27605": 0.10379679501056671, "27887": 0.10555581003427505, "28024": 0.1477125883102417, "28406": 1.013020396232605, "28596": 0.00875066313892603, "28648": 0.6244332790374756, "28695": 0.7482418417930603, "28716": 0.0797421783208847, "28804": 0.08603433519601822, "28805": 0.09317722171545029, "28847": 0.21214580535888672, "29003": 0.0797421783208847, "29076": 0.06154331564903259, "29129": 0.5936289429664612, "29361": 0.20421554148197174} | 13031967 | The use of biotechnology-derived medicines has significantly increased in recent decades. Although biosimilars undergo rigorous characterization as well as clinical studies to document their safety and effectiveness, they are highly complex molecules and small changes in the purification and production process of a biosimilar can have major implications in its safety and effectiveness profile. In Latin America, regulatory authorities have begun to establish well-described and standardized pathways that permit a biosimilar to gain commercial licensure. In order to be certain that a biosimilar reaches its potential in ordinary clinical use, an intensive post-licensing monitoring system must be established since it is the only means to ascertain the true similarity between the original biologic and its biosimilar. Pharmacovigilance allows national authorities to determine a drug's performance in the marketplace. An effective tracking and pharmacovigilance system for biological medicines has many steps and processes. To aid policy makers in Latin American in addressing the many issues surrounding the establishment of an effective pharmacovigilance system, the Americas Health Foundation convened a group of experts to discuss the topic and develop recommendations for implementation. The group discussed current challenges and gaps in pharmacovigilance in Latin America, paying close attention to the major issues associated with traceability and pharmacovigilance of biosimilars following their approval. The recommendations developed should enable countries to accurately document the safety and performance of a biosimilar as experienced by patients under real-life conditions and have a significant impact on the successful implementation of pharmacovigilance of biosimilars throughout the region. | Recommendations on how to ensure the safety and effectiveness of biosimilars in Latin America: a point of view |
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"25644": 0.6123310327529907, "25714": 0.013579257763922215, "25761": 0.02412080205976963, "25876": 0.14179791510105133, "25932": 0.7881022095680237, "26131": 0.0770333781838417, "26244": 0.1619328260421753, "26305": 0.07068414986133575, "26402": 0.3409265875816345, "26512": 0.151916041970253, "26534": 0.13925230503082275, "26572": 0.3353555500507355, "26601": 0.7239188551902771, "26754": 0.43244171142578125, "26773": 0.5220900774002075, "26775": 0.1913948506116867, "26838": 0.04207121208310127, "27059": 0.35950297117233276, "27152": 0.14602625370025635, "27226": 0.151916041970253, "27233": 0.6634125709533691, "27467": 0.11517547070980072, "27491": 0.48068851232528687, "27574": 1.1121915578842163, "27709": 0.956112265586853, "28024": 0.09584271162748337, "28079": 0.29981520771980286, "28227": 0.3134697377681732, "28691": 0.26820653676986694, "28829": 0.026025565341114998, "28835": 0.0029254043474793434, "29167": 0.016465263441205025, "29358": 0.678390383720398} | 13036442 | A yeast strain lacking Met4p, the primary transcriptional regulator of the sulfur assimilation pathway, cannot synthesize methionine. This apparently simple auxotroph did not grow well in rich media containing excess methionine, forming small colonies on yeast extract/peptone/dextrose plates. Faster-growing large colonies were abundant when overnight cultures were plated, suggesting that spontaneous suppressors of the growth defect arise with high frequency. To identify the suppressor mutations, we used genome-wide single-nucleotide polymorphism and standard genetic analyses. The most common suppressors were loss-of-function mutations in OPI1, encoding a transcriptional repressor of phospholipid metabolism. Using a new system that allows rapid and specific degradation of Met4p, we could study the dynamic expression of all genes following loss of Met4p. Experiments using this system with and without Opi1p showed that Met4 activates and Opi1p represses genes that maintain levels of S-adenosylmethionine (SAM), the substrate for most methyltransferase reactions. Cells lacking Met4p grow normally when either SAM is added to the media or one of the SAM synthetase genes is overexpressed. SAM is used as a methyl donor in three Opi1p-regulated reactions to create the abundant membrane phospholipid, phosphatidylcholine. Our results show that rapidly growing cells require significant methylation, likely for the biosynthesis of phospholipids. | Coordinated regulation of sulfur and phospholipid metabolism reflects the importance of methylation in the growth of yeast |
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"29490": 0.1808556467294693} | 13042119 | This glossary was developed to provide technical references to support work in the field of the alternatives to animal testing. It was compiled from various existing reference documents coming from different sources and is meant to be a point of reference on alternatives to animal testing. Giving the ever-increasing number of alternative test methods and approaches being developed over the last decades, a combination, revision, and harmonization of earlier published collections of terms used in the validation of such methods is required. The need to update previous glossary efforts came from the acknowledgement that new words have emerged with the development of new approaches, while others have become obsolete, and the meaning of some terms has partially changed over time. With this glossary we intend to provide guidance on issues related to the validation of new or updated testing methods consistent with current approaches. Moreover, because of new developments and technologies, a glossary needs to be a living, constantly updated document. An Internet-based version based on this compilation may be found at http://altweb.jhsph.edu/, allowing the addition of new material. | Glossary of reference terms for alternative test methods and their validation. |
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0.018384648486971855, "26512": 0.25239890813827515, "26773": 0.46424978971481323, "26775": 0.3283478021621704, "27287": 0.8238670229911804, "27354": 0.8169882297515869, "27790": 0.24631060659885406, "27854": 0.10203468054533005, "27915": 0.8374842405319214, "28086": 0.3339579105377197, "28155": 0.007782140281051397, "28156": 0.14433705806732178, "28424": 0.06703783571720123, "28828": 0.004870930220931768, "29076": 1.117955207824707, "29217": 0.021256839856505394} | 13048272 | Combinatorial transcription factor (TF) interactions control cellular phenotypes and, therefore, underpin stem cell formation, maintenance, and differentiation. Here, we report the genome-wide binding patterns and combinatorial interactions for ten key regulators of blood stem/progenitor cells (SCL/TAL1, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1, and GFI1B), thus providing the most comprehensive TF data set for any adult stem/progenitor cell type to date. Genome-wide computational analysis of complex binding patterns, followed by functional validation, revealed the following: first, a previously unrecognized combinatorial interaction between a heptad of TFs (SCL, LYL1, LMO2, GATA2, RUNX1, ERG, and FLI-1). Second, we implicate direct protein-protein interactions between four key regulators (RUNX1, GATA2, SCL, and ERG) in stabilizing complex binding to DNA. Third, Runx1(+/-)::Gata2(+/-) compound heterozygous mice are not viable with severe hematopoietic defects at midgestation. Taken together, this study demonstrates the power of genome-wide analysis in generating novel functional insights into the transcriptional control of stem and progenitor cells. | Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulators. |
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"28309": 0.055094651877880096, "28687": 0.04487626627087593, "28873": 0.05046287178993225, "29323": 1.1413075923919678} | 13069283 | BACKGROUND Estrogen receptor-positive breast cancer tumors depend on estrogen signaling for their growth and replication and can be treated by anti-estrogen therapy with tamoxifen. Polymorphisms of the CYP2D6 and CYP2C19 genes are associated with an impaired response to tamoxifen. The study objective was to investigate the impact of genetic polymorphisms in CYP2D6 and CYP2C19 on the pharmacokinetics of tamoxifen and its metabolites in Spanish women with estrogen receptor-positive breast cancer who were candidates for tamoxifen therapy. METHODS We studied 90 women with estrogen receptor-positive breast cancer, using the AmpliChip CYP450 test to determine CYP2D6 and CYP2C19 gene variants. Plasma levels of tamoxifen and its metabolites were quantified by high-performance liquid chromatography. RESULTS The CYP2D6 phenotype was extensive metabolizer in 80%, intermediate metabolizer in 12.2%, ultra-rapid metabolizer in 2.2%, and poor metabolizer in 5.6% of patients, and the allele frequency was 35.0% for allele (*)1, 21.0% for *2, and 18.9% for *4. All poor metabolizers in this series were *4/*4, and their endoxifen and 4-hydroxy tamoxifen levels were 25% lower than those of extensive metabolizers. CYP2C19*2 allele, which has been related to breast cancer outcomes, was detected in 15.6% of the studied alleles. CONCLUSION CYP2D6*4/*4 genotype was inversely associated with 4-hydroxy tamoxifen and endoxifen levels. According to these results, CYP2D6 and CYP2C19 genotyping appears advisable before the prescription of tamoxifen therapy. | Influence of CYP2D6 Polymorphisms on Serum Levels of Tamoxifen Metabolites in Spanish Women with Breast Cancer |
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0.1011524572968483, "27777": 0.3656192123889923, "27781": 0.7845434546470642, "27854": 0.17431432008743286, "27881": 0.7565253376960754, "28086": 0.1485546976327896, "28207": 0.05417001247406006, "28522": 0.7863243818283081, "28691": 0.11865071207284927, "28696": 0.009718249551951885, "28817": 0.7314660549163818, "28873": 0.016465263441205025, "28939": 0.9425065517425537, "29206": 0.3241194784641266, "29290": 0.3325583338737488, "29441": 0.13071982562541962} | 13070316 | Tumor angiogenesis is an essential process for supplying rapidly growing malignant tissues with essential nutrients and oxygen. An angiogenic switch allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic disease. Monocyte-derived macrophages recruited and reprogrammed by tumor cells serve as a major source of angiogenic factors boosting the angiogenic switch. Tumor endothelium releases angiopoietin-2 and further facilitates recruitment of TIE2 receptor expressing monocytes (TEM) into tumor sites. Tumor-associated macrophages (TAM) sense hypoxia in avascular areas of tumors, and react by production of angiogenic factors such as VEGFA. VEGFA stimulates chemotaxis of endothelial cells (EC) and macrophages. In some tumors, TAM appeared to be a major source of MMP9. Elevated expression of MMP9 by TAM mediates extracellular matrix (ECM) degradation and the release of bioactive VEGFA. Other angiogenic factors released by TAM include basic fibroblast growth factor (bFGF), thymidine phosphorylase (TP), urokinase-type plasminogen activator (uPA), and adrenomedullin (ADM). The same factors used by macrophages for the induction of angiogenesis [like vascular endothelial growth factor A (VEGF-A) and MMP9] support lymphangiogenesis. TAM can express LYVE-1, one of the established markers of lymphatic endothelium. TAM support tumor lymphangiogenesis not only by secretion of pro-lymphangiogenic factors but also by trans-differentiation into lymphatic EC. New pro-angiogenic factor YKL-40 belongs to a family of mammalian chitinase-like proteins (CLP) that act as cytokines or growth factors. Human CLP family comprises YKL-40, YKL-39, and SI-CLP. Production of all three CLP in macrophages is antagonistically regulated by cytokines. It was recently established that YKL-40 induces angiogenesis in vitro and in animal tumor models. YKL-40-neutralizing monoclonal antibody blocks tumor angiogenesis and progression. The role of YKL-39 and SI-CLP in tumor angiogenesis and lymphangiogenesis remains to be investigated. | Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis |
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1.06349778175354, "25501": 0.3241194784641266, "25612": 0.16690383851528168, "25613": 0.24018502235412598, "25837": 0.030771657824516296, "25848": 0.12642613053321838, "26121": 0.18978065252304077, "26163": 0.1889725625514984, "26616": 0.3526630103588104, "26629": 0.06520967930555344, "26633": 0.3464667797088623, "26745": 0.20102575421333313, "27423": 0.2749055027961731, "27615": 0.2247048318386078, "27776": 0.15693697333335876, "28321": 0.3353555500507355, "28393": 0.3381449282169342, "28768": 0.16690383851528168, "28836": 0.1619328260421753, "28896": 0.07159364968538284, "29073": 0.3177432417869568, "29234": 0.12642613053321838, "29396": 0.06703783571720123, "29458": 0.01934296265244484, "29537": 0.07341018319129944} | 13071728 | BACKGROUND The World Health Organization (WHO) released revised guidelines in 2015 recommending that all people living with HIV, regardless of CD4 count, initiate antiretroviral therapy (ART) upon diagnosis. However, few studies have projected the global resources needed for rapid scale-up of ART. Under the Health Policy Project, we conducted modeling analyses for 97 countries to estimate eligibility for and numbers on ART from 2015 to 2020, along with the facility-level financial resources required. We compared the estimated financial requirements to estimated funding available. METHODS AND FINDINGS Current coverage levels and future need for treatment were based on country-specific epidemiological and demographic data. Simulated annual numbers of individuals on treatment were derived from three scenarios: (1) continuation of countries' current policies of eligibility for ART, (2) universal adoption of aspects of the WHO 2013 eligibility guidelines, and (3) expanded eligibility as per the WHO 2015 guidelines and meeting the Joint United Nations Programme on HIV/AIDS "90-90-90" ART targets. We modeled uncertainty in the annual resource requirements for antiretroviral drugs, laboratory tests, and facility-level personnel and overhead. We estimate that 25.7 (95% CI 25.5, 26.0) million adults and 1.57 (95% CI 1.55, 1.60) million children could receive ART by 2020 if countries maintain current eligibility plans and increase coverage based on historical rates, which may be ambitious. If countries uniformly adopt aspects of the WHO 2013 guidelines, 26.5 (95% CI 26.0 27.0) million adults and 1.53 (95% CI 1.52, 1.55) million children could be on ART by 2020. Under the 90-90-90 scenario, 30.4 (95% CI 30.1, 30.7) million adults and 1.68 (95% CI 1.63, 1.73) million children could receive treatment by 2020. The facility-level financial resources needed for scaling up ART in these countries from 2015 to 2020 are estimated to be US$45.8 (95% CI 45.4, 46.2) billion under the current scenario, US$48.7 (95% CI 47.8, 49.6) billion under the WHO 2013 scenario, and US$52.5 (95% CI 51.4, 53.6) billion under the 90-90-90 scenario. After projecting recent external and domestic funding trends, the estimated 6-y financing gap ranges from US$19.8 billion to US$25.0 billion, depending on the costing scenario and the U.S. President's Emergency Plan for AIDS Relief contribution level, with the gap for ART commodities alone ranging from US$14.0 to US$16.8 billion. The study is limited by excluding above-facility and other costs essential to ART service delivery and by the availability and quality of country- and region-specific data. CONCLUSIONS The projected number of people receiving ART across three scenarios suggests that countries are unlikely to meet the 90-90-90 treatment target (81% of people living with HIV on ART by 2020) unless they adopt a test-and-offer approach and increase ART coverage. Our results suggest that future resource needs for ART scale-up are smaller than stated elsewhere but still significantly threaten the sustainability of the global HIV response without additional resource mobilization from domestic or innovative financing sources or efficiency gains. As the world moves towards adopting the WHO 2015 guidelines, advances in technology, including the introduction of lower-cost, highly effective antiretroviral regimens, whose value are assessed here, may prove to be "game changers" that allow more people to be on ART with the resources available. | The HIV Treatment Gap: Estimates of the Financial Resources Needed versus Available for Scale-Up of Antiretroviral Therapy in 97 Countries from 2015 to 2020 |
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0.20660123229026794, "25006": 0.3615458607673645, "25426": 0.029824240133166313, "25456": 0.37304413318634033, "25714": 0.6096806526184082, "25743": 0.03360854089260101, "25817": 0.8550800085067749, "26189": 0.04767346754670143, "26356": 1.3630777597427368, "26402": 0.42990362644195557, "26572": 0.4926934838294983, "26601": 0.8091925978660583, "26616": 0.28963330388069153, "26702": 0.025073638185858727, "26773": 0.4500300884246826, "26775": 0.29981520771980286, "27099": 0.09495500475168228, "27216": 0.20660123229026794, "27651": 0.2105647772550583, "27777": 0.10026945173740387, "27793": 0.9147270321846008, "28179": 0.401551216840744, "28828": 0.08154398202896118, "28829": 0.2447827309370041, "28848": 0.6430866718292236, "29494": 0.010684899985790253} | 13072112 | A number of proteins and drugs have been implicated in the process of transcriptional elongation by RNA polymerase (Pol) II, but the factors that govern the elongation rate (nucleotide additions per min) and processivity (nucleotide additions per initiation event) in vivo are poorly understood. Here, we show that a mutation in the Rpb2 subunit of Pol II reduces both the elongation rate and processivity in vivo. In contrast, none of the putative elongation factors tested affect the elongation rate, although mutations in the THO complex and in Spt4 significantly reduce processivity. The drugs 6-azauracil and mycophenolic acid reduce both the elongation rate and processivity, and this processivity defect is aggravated by mutations in Spt4, TFIIS, and CTDK-1. Our results suggest that, in vivo, a reduced rate of Pol II elongation leads to premature dissociation along the chromatin template and that Pol II processivity can be uncoupled from elongation rate. | Distinction and relationship between elongation rate and processivity of RNA polymerase II in vivo. |
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0.8100618124008179, "26534": 0.3499138653278351, "26557": 0.6223390698432922, "26571": 0.04207121208310127, "26786": 0.6773988008499146, "26906": 0.18248429894447327, "26941": 0.23479416966438293, "26982": 0.7881022095680237, "27108": 0.16110190749168396, "27166": 0.1602703034877777, "27364": 0.12728634476661682, "27684": 0.18167030811309814, "27965": 0.06612417846918106, "28046": 1.0966572761535645, "28215": 0.4926934838294983, "28424": 0.1229778528213501, "28466": 0.5370414853096008, "28517": 0.13414156436920166, "28767": 0.15777134895324707, "28964": 0.5033760666847229, "29060": 0.4248080551624298, "29105": 0.6492279767990112, "29516": 0.07793712615966797} | 13072113 | Caenorhabditis elegans is a powerful model for analysis of the conserved mechanisms that modulate healthy aging. In the aging nematode nervous system, neuronal death and/or detectable loss of processes are not readily apparent, but because dendrite restructuring and loss of synaptic integrity are hypothesized to contribute to human brain decline and dysfunction, we combined fluorescence microscopy and electron microscopy (EM) to screen at high resolution for nervous system changes. We report two major components of morphological change in the aging C. elegans nervous system: (1) accumulation of novel outgrowths from specific neurons, and (2) physical decline in synaptic integrity. Novel outgrowth phenotypes, including branching from the main dendrite or new growth from somata, appear at a high frequency in some aging neurons, but not all. Mitochondria are often associated with age-associated branch sites. Lowered insulin signaling confers some maintenance of ALM and PLM neuron structural integrity into old age, and both DAF-16/FOXO and heat shock factor transcription factor HSF-1 exert neuroprotective functions. hsf-1 can act cell autonomously in this capacity. EM evaluation in synapse-rich regions reveals a striking decline in synaptic vesicle numbers and a diminution of presynaptic density size. Interestingly, old animals that maintain locomotory prowess exhibit less synaptic decline than same-age decrepit animals, suggesting that synaptic integrity correlates with locomotory healthspan. Our data reveal similarities between the aging C. elegans nervous system and mammalian brain, suggesting conserved neuronal responses to age. Dissection of neuronal aging mechanisms in C. elegans may thus influence the development of brain healthspan-extending therapies. | Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system. |
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0.2763880789279938, "25882": 0.07884006202220917, "25947": 1.0601204633712769, "26237": 1.0742288827896118, "26319": 0.0009760859538801014, "26786": 0.6754127144813538, "27090": 0.2969166338443756, "27118": 0.956112265586853, "27523": 0.04767346754670143, "27794": 0.13414156436920166, "27805": 0.23864774405956268, "28283": 1.0001721382141113, "28321": 0.22001366317272186, "28428": 0.10555581003427505, "28488": 0.16607704758644104, "29101": 0.8281423449516296, "29458": 0.06703783571720123} | 13083189 | OBJECTIVES Despite recognition of the important influence of environmental determinants on physical activity patterns, minimal empirical research has been done to assess the impact of environmental/contextual determinants of physical activity. This article aims to investigate environmental and sociodemographic determinants of physical activity and inactivity patterns among subpopulations of US adolescents. We define environmental determinants as modifiable factors in the physical environment that impose a direct influence on the opportunity to engage in physical activity. The present research examines environmental and sociodemographic determinants of physical activity and inactivity with the implication that these findings can point toward societal-level intervention strategies for increasing physical activity and decreasing inactivity among adolescents. STUDY DESIGN AND METHODOLOGY The study population consists of nationally representative data from the 1996 National Longitudinal Study of Adolescent Health on 17 766 US adolescents enrolled in US middle and high schools (including 3933 non-Hispanic blacks, 3148 Hispanics, and 1337 Asians). Hours/week of inactivity (TV/video viewing and video/computer games) and times/week of moderate to vigorous physical activity were collected by questionnaire. Outcome variables were moderate to vigorous physical activity and inactivity, which were broken into categories (physical activity: 0-2 times/week, 3-4 times/week, and >/=5 times/week; inactivity: 0-10 hours/week, 11-24 hours/week, and >/=25 hours/week). Sociodemographic and environmental correlates of physical activity and inactivity were used as exposure and control variables and included sex, age, urban residence, participation in school physical education program, use of community recreation center, total reported incidents of serious crime in neighborhood, socioeconomic status, ethnicity, generation of residence in the United States, presence of mother/father in household, pregnancy status, work status, in-school status, region, and month of interview. Logistic regression models of high versus low and medium physical activity and inactivity were used to investigate sex and ethnic interactions in relation to environmental and sociodemographic factors to examine evidence for the potential impact of physical education and recreation programs and sociodemographic factors on physical activity and inactivity patterns. RESULTS Moderate to vigorous physical activity was lower and inactivity higher for non-Hispanic black and Hispanic adolescents. Participation in school physical education programs was considerably low for these adolescents and decreased with age. Participation in daily school physical education (PE) program classes (adjusted odds ratio [AOR]: 2.21; confidence interval [CI]: 1.82-2.68) and use of a community recreation center (AOR: 1.75; CI: 1.56-1.96) were associated with an increased likelihood of engaging in high level moderate to vigorous physical activity. Maternal education was inversely associated with high inactivity patterns; for example, having a mother with a graduate or professional degree was associated with an AOR of.61 (CI:.48-.76) for high inactivity. High family income was associated with increased moderate to vigorous physical activity (AOR: 1.43; CI: 1.22-1.67) and decreased inactivity (AOR:.70; CI:.59-.82). High neighborhood serious crime level was associated with a decreased likelihood of falling in the highest category of moderate to vigorous physical activity (AOR:.77; CI:.66-.91). CONCLUSIONS These results show important associations between modifiable environmental factors, such as participation in school PE and community recreation programs, with activity patterns of adolescents. Despite the marked and significant impact of participation in school PE programs on physical activity patterns of US adolescents, few adolescents participated in such school PE programs; only 21.3% of all adolescents | Determinants of adolescent physical activity and inactivity patterns. |
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0.20022670924663544, "25437": 0.29255300760269165, "25986": 0.29981520771980286, "26094": 1.3479716777801514, "26319": 0.304147332906723, "26402": 0.12384103983640671, "26629": 0.0038986403960734606, "26996": 0.5021947622299194, "27354": 0.11081436276435852, "27484": 0.23864774405956268, "27605": 0.6613984704017639, "27794": 0.9232974052429199, "28055": 0.129004567861557, "28085": 0.11430477350950241, "28093": 0.06246116757392883, "28283": 0.20818853378295898, "28731": 0.02316705882549286, "28804": 0.19622190296649933, "28805": 0.010684899985790253, "28849": 0.13243216276168823, "28926": 0.030771657824516296, "29234": 0.36426326632499695, "29361": 0.25694093108177185, "29444": 0.0029254043474793434} | 13097856 | CONTEXT In 2002, an estimated 877,000 lives were lost worldwide through suicide. Some developed nations have implemented national suicide prevention plans. Although these plans generally propose multiple interventions, their effectiveness is rarely evaluated. OBJECTIVES To examine evidence for the effectiveness of specific suicide-preventive interventions and to make recommendations for future prevention programs and research. DATA SOURCES AND STUDY SELECTION Relevant publications were identified via electronic searches of MEDLINE, the Cochrane Library, and PsychINFO databases using multiple search terms related to suicide prevention. Studies, published between 1966 and June 2005, included those that evaluated preventative interventions in major domains; education and awareness for the general public and for professionals; screening tools for at-risk individuals; treatment of psychiatric disorders; restricting access to lethal means; and responsible media reporting of suicide. DATA EXTRACTION Data were extracted on primary outcomes of interest: suicidal behavior (completion, attempt, ideation), intermediary or secondary outcomes (treatment seeking, identification of at-risk individuals, antidepressant prescription/use rates, referrals), or both. Experts from 15 countries reviewed all studies. Included articles were those that reported on completed and attempted suicide and suicidal ideation; or, where applicable, intermediate outcomes, including help-seeking behavior, identification of at-risk individuals, entry into treatment, and antidepressant prescription rates. We included 3 major types of studies for which the research question was clearly defined: systematic reviews and meta-analyses (n = 10); quantitative studies, either randomized controlled trials (n = 18) or cohort studies (n = 24); and ecological, or population- based studies (n = 41). Heterogeneity of study populations and methodology did not permit formal meta-analysis; thus, a narrative synthesis is presented. DATA SYNTHESIS Education of physicians and restricting access to lethal means were found to prevent suicide. Other methods including public education, screening programs, and media education need more testing. CONCLUSIONS Physician education in depression recognition and treatment and restricting access to lethal methods reduce suicide rates. Other interventions need more evidence of efficacy. Ascertaining which components of suicide prevention programs are effective in reducing rates of suicide and suicide attempt is essential in order to optimize use of limited resources. | Suicide prevention strategies: a systematic review. |
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0.11256109178066254, "26601": 0.5629584193229675, "26688": 0.8917738795280457, "26835": 0.8525851964950562, "27099": 0.5607312321662903, "27226": 0.09228714555501938, "27642": 0.6608943343162537, "27781": 0.21372433006763458, "27895": 0.015504186972975731, "28156": 0.11604541540145874, "28173": 1.1249549388885498, "28873": 0.28890204429626465, "28896": 0.09672962874174118, "28911": 0.32058215141296387, "28931": 0.574020504951477, "29170": 0.16276304423809052, "29172": 0.06429435312747955, "29226": 0.5220900774002075, "29290": 0.3485364317893982, "29461": 1.0305955410003662} | 13106686 | Immune sensing of DNA is critical for antiviral immunity but can also trigger autoimmune diseases such as lupus erythematosus (LE). Here we have provided evidence for the involvement of a damage-associated DNA modification in the detection of cytosolic DNA. The oxidized base 8-hydroxyguanosine (8-OHG), a marker of oxidative damage in DNA, potentiated cytosolic immune recognition by decreasing its susceptibility to 3' repair exonuclease 1 (TREX1)-mediated degradation. Oxidizative modifications arose physiologically in pathogen DNA during lysosomal reactive oxygen species (ROS) exposure, as well as in neutrophil extracellular trap (NET) DNA during the oxidative burst. 8-OHG was also abundant in UV-exposed skin lesions of LE patients and colocalized with type I interferon (IFN). Injection of oxidized DNA in the skin of lupus-prone mice induced lesions that closely matched respective lesions in patients. Thus, oxidized DNA represents a prototypic damage-associated molecular pattern (DAMP) with important implications for infection, sterile inflammation, and autoimmunity. | Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. |
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OPN and the cytokine interleukin (IL)-18 have been shown to be overexpressed in an array of human cardiac pathologies. In the present study, we determined the role of IL-18 in the regulation of cardiac OPN expression and the subsequent interstitial fibrosis and diastolic dysfunction. We demonstrated parallel increases in IL-18, OPN expression, and interstitial fibrosis in murine models of left ventricular pressure and volume overload. Exogenous recombinant (r)IL-18 administered for 2 wk increased cardiac OPN expression, interstitial fibrosis, and diastolic dysfunction. Stimulation of the T helper (Th)1 lymphocyte phenotype with a selective toll-like receptor (TLR)9 agonist induced cardiac IL-18 and OPN expression, which was associated with increased cardiac fibrillar collagen concentrations and interstitial fibrosis resulting in diastolic dysfunction. rIL-18 induced OPN expression and protein levels in primary of cardiac fibroblast cultures. Conditioned media from TLR9-stimulated T lymphocyte cultures induced IL-18 and OPN expression in cardiac fibroblasts, while blockade of the IL-18 receptor with a neutralizing antibody abolished the increase in OPN expression. Furthermore, a mutation in the transcriptional factor interferon regulatory factor (IRF)1 or IRF1 small interfering RNA (siRNA) resulted in the decreased expression of IL-18 and OPN in cardiac fibroblasts. With pressure overload, IRF1-mutant mice showed downregulation of IL-18 and OPN expression in cardiac tissue, reduced cardiac fibrotic development, and increased left ventricular function compared with wild type. These results provide direct evidence that the induction of IL-18 regulates OPN-mediated cardiac fibrosis and diastolic dysfunction. | IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice. |
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"28964": 0.1358480453491211, "29109": 0.15275461971759796, "29320": 0.36697331070899963} | 13116880 | The mammalian blood system, containing more than 10 distinct mature cell types, stands on one specific cell type, hematopoietic stem cell (HSC). Within the system, only HSCs possess the ability of both multipotency and self-renewal. Multipotency is the ability to differentiate into all functional blood cells. Self-renewal is the ability to give rise to HSC itself without differentiation. Since mature blood cells (MBCs) are predominantly short-lived, HSCs continuously provide more differentiated progenitors while properly maintaining the HSC pool size throughout life by precisely balancing self-renewal and differentiation. Thus, understanding the mechanisms of self-renewal and differentiation of HSC has been a central issue. In this review, we focus on the hierarchical structure of the hematopoietic system, the current understanding of microenvironment and molecular cues regulating self-renewal and differentiation of adult HSCs, and the currently emerging systems approaches to understand HSC biology. | Hematopoietic stem cell: self-renewal versus differentiation. |
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RNA-Seq is revolutionizing the way transcript abundances are measured. A key challenge in transcript quantification from RNA-Seq data is the handling of reads that map to multiple genes or isoforms. This issue is particularly important for quantification with de novo transcriptome assemblies in the absence of sequenced genomes, as it is difficult to determine which transcripts are isoforms of the same gene. A second significant issue is the design of RNA-Seq experiments, in terms of the number of reads, read length, and whether reads come from one or both ends of cDNA fragments. RESULTS We present RSEM, an user-friendly software package for quantifying gene and isoform abundances from single-end or paired-end RNA-Seq data. RSEM outputs abundance estimates, 95% credibility intervals, and visualization files and can also simulate RNA-Seq data. In contrast to other existing tools, the software does not require a reference genome. Thus, in combination with a de novo transcriptome assembler, RSEM enables accurate transcript quantification for species without sequenced genomes. On simulated and real data sets, RSEM has superior or comparable performance to quantification methods that rely on a reference genome. Taking advantage of RSEM's ability to effectively use ambiguously-mapping reads, we show that accurate gene-level abundance estimates are best obtained with large numbers of short single-end reads. On the other hand, estimates of the relative frequencies of isoforms within single genes may be improved through the use of paired-end reads, depending on the number of possible splice forms for each gene. CONCLUSIONS RSEM is an accurate and user-friendly software tool for quantifying transcript abundances from RNA-Seq data. As it does not rely on the existence of a reference genome, it is particularly useful for quantification with de novo transcriptome assemblies. In addition, RSEM has enabled valuable guidance for cost-efficient design of quantification experiments with RNA-Seq, which is currently relatively expensive. | RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome |
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"24710": 0.3012613356113434, "24848": 0.02792670577764511, "24873": 0.6543170213699341, "25185": 0.04113444685935974, "25644": 0.056018441915512085, "26001": 0.26820653676986694, "26134": 0.22859740257263184, "26243": 0.6075552701950073, "26282": 0.13243216276168823, "26572": 0.10555581003427505, "26591": 0.04860413447022438, "26633": 0.3923587501049042, "26773": 0.6512666940689087, "26835": 0.417115718126297, "27400": 0.14349138736724854, "27441": 1.333663821220398, "27921": 0.371698260307312, "28024": 0.3777405619621277, "28041": 0.045809537172317505, "28081": 0.175953671336174, "28148": 0.025073638185858727, "29083": 0.255429208278656, "29276": 0.015504186972975731, "29290": 0.7105726003646851, "29374": 0.04113444685935974, "29390": 0.08871890604496002, "29458": 0.10555581003427505} | 13135544 | We have constructed a synthetic ecosystem consisting of two Escherichia coli populations, which communicate bi-directionally through quorum sensing and regulate each other's gene expression and survival via engineered gene circuits. Our synthetic ecosystem resembles canonical predator-prey systems in terms of logic and dynamics. The predator cells kill the prey by inducing expression of a killer protein in the prey, while the prey rescue the predators by eliciting expression of an antidote protein in the predator. Extinction, coexistence and oscillatory dynamics of the predator and prey populations are possible depending on the operating conditions as experimentally validated by long-term culturing of the system in microchemostats. A simple mathematical model is developed to capture these system dynamics. Coherent interplay between experiments and mathematical analysis enables exploration of the dynamics of interacting populations in a predictable manner. | A synthetic Escherichia coli predator–prey ecosystem |
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0.012615402229130268} | 13162391 | A funnel trap that fitted over holes leading into hollow trees was used to capture adult phlebotomine sand flies, Lutzomyia shannoni Dyar, on Ossabaw Island, Chatham County, Ga. These insects rested in hollow trees during the day and were collected by funnel traps as they egressed from the tree holes at night. The trap is lightweight, durable, inexpensive, waterproof, and selective. Using this trap, greater than 100 healthy L. shannoni ++were captured per night by a single investigator during July and August 1988 when adult flies were abundant on the island. | Funnel trap for the capture of phlebotomine sand flies (Diptera: Psychodidae) from tree holes. |
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"29170": 0.2674594223499298, "29290": 0.5139457583427429, "29444": 0.6558387279510498, "29566": 0.18329764902591705} | 13172737 | Withdrawal from chronic cocaine reduces extracellular glutamate levels in the nucleus accumbens by decreasing cystine/glutamate exchange (xc-). Activating xc- with N-acetylcysteine restores extracellular glutamate and prevents cocaine-induced drug seeking. It was hypothesized that the activation of xc- prevents drug seeking by increasing glutamatergic tone on presynaptic group II metabotropic glutamate receptors (mGluR2/3) and thereby inhibiting excitatory transmission. In the first experiment, the capacity of glutamate derived from xc- to regulate excitatory transmission via mGluR2/3 was determined. Physiological levels of cystine (100-300 nm) were restored to acute tissue slices from the nucleus accumbens or prefrontal cortex. Cystine increased glutamate efflux and decreased miniature EPSC (mEPSC) and spontaneous EPSC (sEPSC) frequency as well as evoked EPSC amplitude. These effects of cystine were presynaptic, because there was no change in mEPSC or sEPSC amplitude, and an increase in the evoked EPSC paired-pulse facilitation ratio. The cystine-induced reduction in EPSCs was reversed by blocking either xc- or mGluR2/3. In the second experiment, blocking mGluR2/3 prevented the ability of N-acetylcystine to inhibit the reinstatement of drug seeking in rats trained to self-administer cocaine. These data demonstrate that nonsynaptic glutamate derived from xc- modulates synaptic glutamate release and thereby regulates cocaine-induced drug seeking. | Cystine/glutamate exchange regulates metabotropic glutamate receptor presynaptic inhibition of excitatory transmission and vulnerability to cocaine seeking. |
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"28770": 0.1332872211933136, "29458": 0.2447827309370041} | 13179318 | In traditional Kaplan-Meier or Cox regression analysis, usually a risk factor measured at baseline is related to mortality thereafter. During follow-up, however, things may change: either the effect of a fixed baseline risk factor may vary over time, resulting in a weakening or strengthening of associations over time, or the risk factor itself may vary over time. In this paper, short-term versus long-term effects (so-called time-dependent effects) of a fixed baseline risk factor are addressed. An example is presented showing that underweight is a strong risk factor for mortality in dialysis patients, especially in the short run. In contrast, overweight is a risk factor for mortality, which is stronger in the long run than in the short run. In addition, the analysis of how time-varying risk factors (so-called time-dependent risk factors) are related to mortality is demonstrated by paying attention to the pitfall of adjusting for sequelae. The proper analysis of effects over time should be driven by a clear research question. Both kinds of research questions, that is those of time-dependent effects as well those of time-dependent risk factors, can be analyzed with time-dependent Cox regression analysis. It will be shown that using time-dependent risk factors usually implies focusing on short-term effects only. | Survival analysis: time-dependent effects and time-varying risk factors. |
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"26014": 0.18816383183002472, "26402": 0.3269403576850891, "26534": 0.08513788133859634, "26773": 0.4926934838294983, "26838": 0.058784693479537964, "27099": 0.14179791510105133, "27295": 0.0354953333735466, "27544": 0.22001366317272186, "27756": 0.319873183965683, "27854": 0.3903779089450836, "28228": 0.6902132034301758, "28517": 0.0029254043474793434, "28696": 0.058784693479537964, "28767": 0.11517547070980072, "29300": 0.6155022978782654} | 13189693 | Neuregulin 1 (NRG1) is a secreted trophic factor that activates the postsynaptic erbB4 receptor tyrosine kinase. Both NRG1 and erbB4 have been repeatedly associated with schizophrenia, but their downstream targets are not well characterized. ErbB4 is highly abundant in interneurons, and NRG1-mediated erbB4 activation has been shown to modulate interneuron function, but the role for NRG1-erbB4 signaling in regulating interneuron dendritic growth is not well understood. Here we show that NRG1/erbB4 promote the growth of dendrites in mature interneurons through kalirin, a major dendritic Rac1-GEF. Recent studies have shown associations of the KALRN gene with schizophrenia. Our data point to an essential role of phosphorylation in kalirin-7's C terminus as the critical site for these effects. As reduced interneuron dendrite length occurs in schizophrenia, understanding how NRG1-erbB4 signaling modulates interneuron dendritic morphogenesis might shed light on disease-related alterations in cortical circuits. | Control of interneuron dendritic growth through NRG1/erbB4-mediated kalirin-7 disinhibition |
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0.0009760859538801014, "28873": 0.13670019805431366, "29264": 0.7665573358535767, "29458": 0.9131608605384827, "29490": 0.02792670577764511} | 13205096 | BACKGROUND In patients with acute myeloid leukemia (AML), the presence or absence of recurrent cytogenetic aberrations is used to identify the appropriate therapy. However, the current classification system does not fully reflect the molecular heterogeneity of the disease, and treatment stratification is difficult, especially for patients with intermediate-risk AML with a normal karyotype. METHODS We used complementary-DNA microarrays to determine the levels of gene expression in peripheral-blood samples or bone marrow samples from 116 adults with AML (including 45 with a normal karyotype). We used unsupervised hierarchical clustering analysis to identify molecular subgroups with distinct gene-expression signatures. Using a training set of samples from 59 patients, we applied a novel supervised learning algorithm to devise a gene-expression-based clinical-outcome predictor, which we then tested using an independent validation group comprising the 57 remaining patients. RESULTS Unsupervised analysis identified new molecular subtypes of AML, including two prognostically relevant subgroups in AML with a normal karyotype. Using the supervised learning algorithm, we constructed an optimal 133-gene clinical-outcome predictor, which accurately predicted overall survival among patients in the independent validation group (P=0.006), including the subgroup of patients with AML with a normal karyotype (P=0.046). In multivariate analysis, the gene-expression predictor was a strong independent prognostic factor (odds ratio, 8.8; 95 percent confidence interval, 2.6 to 29.3; P<0.001). CONCLUSIONS The use of gene-expression profiling improves the molecular classification of adult AML. | Use of gene-expression profiling to identify prognostic subclasses in adult acute myeloid leukemia. |
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1.1381834745407104, "26760": 0.4487839937210083, "27155": 0.2954642176628113, "27166": 0.045809537172317505, "27593": 0.347847044467926, "27805": 0.06429435312747955, "27937": 0.6096806526184082, "28144": 0.4002431631088257, "28166": 0.0797421783208847, "28170": 0.6603899002075195, "28400": 0.47463157773017883, "28582": 0.007782140281051397, "28648": 0.13157635927200317, "29192": 0.19862671196460724, "29464": 0.5045560002326965, "29466": 0.4974553883075714, "29494": 0.02412080205976963} | 13205803 | The Centers for Disease Control and Prevention Office of Workforce and Career Development is committed to developing a competent, sustainable, and diverse public health workforce through evidence-based training, career and leadership development, and strategic workforce planning to improve population health outcomes. This article reviews the previous efforts in identifying priorities of public health workforce research, which are summarized as eight major research themes. We outline a strategic framework for public health workforce research that includes six functional areas (ie, definition and standards, data, methodology, evaluation, policy, and dissemination and translation). To conceptualize and prioritize development of an actionable public health research agenda, we constructed a matrix of key challenges in workforce analysis by public health workforce categories. Extensive reviews were conducted to identify valuable methods, models, and approaches to public health workforce research. We explore new tools and approaches for addressing priority areas for public health workforce and career development research and assess how tools from multiple disciplines of social sciences can guide the development of a research framework for advancing public health workforce research and policy. | Perspectives on public health workforce research. |
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Gene targeting is a process in which a DNA molecule introduced into a cell replaces the corresponding chromosomal segment by homologous recombination, and thus presents a precise way to manipulate the genome. In the past, the application of gene targeting to mammalian cells has been limited by its low efficiency. Zinc finger nucleases (ZFNs) show promise in improving the efficiency of gene targeting by introducing DNA double-strand breaks in target genes, which then stimulate the cell's endogenous homologous recombination machinery. Recent results have shown that ZFNs can be used to create targeting frequencies of up to 20% in a human disease-causing gene. Future work will be needed to translate these in vitro findings to in vivo applications and to determine whether zinc finger nucleases create undesired genomic instability. | Gene targeting using zinc finger nucleases |
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"25196": 0.15693697333335876, "25269": 0.2749055027961731, "25524": 0.20022670924663544, "25952": 0.4400174915790558, "25971": 0.28670501708984375, "26223": 0.09938567131757736, "26226": 0.19541899859905243, "26520": 0.06154331564903259, "26572": 0.011650617234408855, "26773": 0.20102575421333313, "26775": 0.603290855884552, "26986": 0.5557019114494324, "26989": 0.5341835021972656, "27216": 0.1930064558982849, "27226": 0.12728634476661682, "27351": 0.2622140049934387, "27354": 0.31204116344451904, "28024": 0.012615402229130268, "28155": 0.12384103983640671, "28406": 0.06886265426874161, "28648": 0.2696990668773651, "28727": 0.09761575609445572, "28789": 0.06429435312747955, "28848": 1.1469062566757202, "29458": 0.02412080205976963, "29461": 0.259204238653183, "29490": 0.0174254160374403} | 13223806 | Real-time reverse transcription followed by polymerase chain reaction (RT-PCR) is the most suitable method for the detection and quantification of mRNA. It offers high sensitivity, good reproducibility and a wide quantification range. Today, relative expression is increasingly used, where the expression of a target gene is standardised by a non-regulated reference gene. Several mathematical algorithms have been developed to compute an expression ratio, based on real-time PCR efficiency and the crossing point deviation of an unknown sample versus a control. But all published equations and available models for the calculation of relative expression ratio allow only for the determination of a single transcription difference between one control and one sample. Therefore a new software tool was established, named REST (relative expression software tool), which compares two groups, with up to 16 data points in a sample and 16 in a control group, for reference and up to four target genes. The mathematical model used is based on the PCR efficiencies and the mean crossing point deviation between the sample and control group. Subsequently, the expression ratio results of the four investigated transcripts are tested for significance by a randomisation test. Herein, development and application of REST is explained and the usefulness of relative expression in real-time PCR using REST is discussed. The latest software version of REST and examples for the correct use can be downloaded at http://www.wzw.tum.de/gene-quantification/. | relative expression results in real-time |
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"24605": 0.1718502640724182, "24668": 0.04953393340110779, "24895": 0.2822965085506439, "24936": 0.7809720039367676, "24952": 0.39367714524269104, "25148": 0.9680526852607727, "25167": 0.10291612148284912, "25169": 0.045809537172317505, "25336": 0.034552380442619324, "25353": 0.7845434546470642, "25416": 0.7408206462860107, "25538": 0.9333322048187256, "25817": 0.1401015669107437, "25918": 0.9037119746208191, "26033": 1.533164143562317, "26056": 0.5784112811088562, "26461": 0.09761575609445572, "26563": 0.09761575609445572, "26708": 0.0019512200960889459, "26745": 0.3318578004837036, "26886": 0.3526630103588104, "27427": 0.47584590315818787, "27699": 0.07431721687316895, "27718": 0.567951500415802, "28025": 0.6970458030700684, "28297": 0.9409833550453186, "28522": 0.38574060797691345, "29160": 0.854249119758606, "29371": 1.0278041362762451, "29423": 1.1714173555374146, "29486": 0.37102460861206055} | 13223957 | OBJECTIVE The cardinal indication for surgical treatment of gallstones is pain attacks. However, following cholecystectomy, 20% of patients remain symptomatic. It is unclear to what extent post-cholecystectomy symptoms can be ascribed to persistence of preoperative symptoms or to new pathology. The pain and digestive pattern in gallstone patients has not been defined in a recent setting with ultrasonography as the diagnostic method. The aim of this study was to characterize a pain pattern that is typical for gallstone disease and to describe the extent of associated dyspepsia. MATERIAL AND METHODS A total of 220 patients with symptomatic gallstone disease including complicated disease (acute cholecystitis and common bile duct stones) were interviewed using detailed questionnaires to disclose pain patterns and symptoms of indigestion. RESULTS All patients had pain in the right upper quadrant (RUQ) including the upper midline epigastrium. The pain was localized to the right subcostal area in 20% and to the upper epigastrium in 14%, and in the rest (66%) it was more evenly distributed. An area of maximal pain could be defined in 90%. Maximal pain was located under the costal arch in 51% of patients and in the epigastrium in 41%, but in 3% behind the sternum and in 5% in the back. The pain was referred to the back in 63% of the patients. The mean visual analogue scale (VAS) score was very high: 90 mm on a 0-100 scale. A pattern of incipient or low-grade warning pain with a subsequent relatively steady state until subsiding in the same fashion was present in 90% of the patients. An urge to walk around was experienced by 71%. Pain attacks usually occurred in the late evening or at night (77%), with 85% of the attacks lasting for more than one hour and almost never less than half an hour. Sixty-six percent of the patients were intolerant to at least one kind of food, but only 48% to fatty foods. Symptoms of functional indigestion (gastroesophageal reflux, dyspepsia or irritable bowel symptoms) were seen in the vast majority in association with attacks. CONCLUSIONS Gallstone-associated pain follows a certain pattern in the majority of patients. The pain is located in a defined area with a point of maximum intensity, is usually referred, and occurs mainly at night with duration of more than one hour. The majority of patients experience functional indigestion, mainly of the reflux type or dyspepsia. | Pain attacks in non-complicated and complicated gallstone disease have a characteristic pattern and are accompanied by dyspepsia in most patients: the results of a prospective study. |
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"28321": 0.45623743534088135, "28353": 0.24018502235412598, "28428": 0.5930894017219543, "28436": 0.02412080205976963, "28648": 0.026025565341114998, "28879": 0.15526613593101501, "28993": 0.7701805830001831, "29048": 0.472198486328125, "29101": 0.7647408246994019, "29160": 0.7067264318466187, "29166": 0.2622140049934387, "29299": 0.4818955361843109, "29305": 0.12556517124176025, "29449": 0.8357921838760376, "29458": 0.450652539730072, "29536": 1.0920805931091309} | 13230773 | CONTEXT Population surveys indicate that physical activity levels are low in the United States. One consequence of inactivity, low cardiorespiratory fitness, is an established risk factor for cardiovascular disease (CVD) morbidity and mortality, but the prevalence of cardiorespiratory fitness has not been quantified in representative US population samples. OBJECTIVES To describe the prevalence of low fitness in the US population aged 12 through 49 years and to relate low fitness to CVD risk factors in this population. DESIGN, SETTING, AND PARTICIPANTS Inception cohort study using data from the cross-sectional nationally representative National Health and Nutrition Examination Survey 1999-2002. Participants were adolescents (aged 12-19 years; n = 3110) and adults (aged 20-49 years; n = 2205) free from previously diagnosed CVD who underwent submaximal graded exercise treadmill testing to achieve at least 75% to 90% of their age-predicted maximum heart rate. Maximal oxygen consumption (VO2max) was estimated by measuring the heart rate response to reference levels of submaximal work. MAIN OUTCOME MEASURES Low fitness defined using percentile cut points of estimated VO2max from existing external referent populations; anthropometric and other CVD risk factors measured according to standard methods. RESULTS Low fitness was identified in 33.6% of adolescents (approximately 7.5 million US adolescents) and 13.9% of adults (approximately 8.5 million US adults); the prevalence was similar in adolescent females (34.4%) and males (32.9%) (P = .40) but was higher in adult females (16.2%) than in males (11.8%) (P = .03). Non-Hispanic blacks and Mexican Americans were less fit than non-Hispanic whites. In all age-sex groups, body mass index and waist circumference were inversely associated with fitness; age- and race-adjusted odds ratios of overweight or obesity (body mass index > or =25) ranged from 2.1 to 3.7 (P<.01 for all), comparing persons with low fitness with those with moderate or high fitness. Total cholesterol levels and systolic blood pressure were higher and levels of high-density lipoprotein cholesterol were lower among participants with low vs high fitness. CONCLUSION Low fitness in adolescents and adults is common in the US population and is associated with an increased prevalence of CVD risk factors. | Prevalence and cardiovascular disease correlates of low cardiorespiratory fitness in adolescents and adults. |
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1.3730231523513794, "29290": 0.3012613356113434, "29461": 1.1994705200195312, "29486": 0.3318578004837036} | 13231899 | Vaccines are largely ineffective for patients with established cancer, as advanced disease requires potent and sustained activation of CD8(+) cytotoxic T lymphocytes (CTLs) to kill tumor cells and clear the disease. Recent studies have found that subsets of dendritic cells (DCs) specialize in antigen cross-presentation and in the production of cytokines, which regulate both CTLs and T regulatory (Treg) cells that shut down effector T cell responses. Here, we addressed the hypothesis that coordinated regulation of a DC network, and plasmacytoid DCs (pDCs) and CD8(+) DCs in particular, could enhance host immunity in mice. We used functionalized biomaterials incorporating various combinations of an inflammatory cytokine, immune danger signal, and tumor lysates to control the activation and localization of host DC populations in situ. The numbers of pDCs and CD8(+) DCs, and the endogenous production of interleukin-12, all correlated strongly with the magnitude of protective antitumor immunity and the generation of potent CD8(+) CTLs. Vaccination by this method maintained local and systemic CTL responses for extended periods while inhibiting FoxP3 Treg activity during antigen clearance, resulting in complete regression of distant and established melanoma tumors. The efficacy of this vaccine as a monotherapy against large invasive tumors may be a result of the local activity of pDCs and CD8(+) DCs induced by persistent danger and antigen signaling at the vaccine site. These results indicate that a critical pattern of DC subsets correlates with the evolution of therapeutic antitumor responses and provide a template for future vaccine design. | In situ regulation of DC subsets and T cells mediates tumor regression in mice. |
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| 13235609 | Inhibition of VEGF signaling leads to a proinvasive phenotype in mouse models of glioblastoma multiforme (GBM) and in a subset of GBM patients treated with bevacizumab. Here, we demonstrate that vascular endothelial growth factor (VEGF) directly and negatively regulates tumor cell invasion through enhanced recruitment of the protein tyrosine phosphatase 1B (PTP1B) to a MET/VEGFR2 heterocomplex, thereby suppressing HGF-dependent MET phosphorylation and tumor cell migration. Consequently, VEGF blockade restores and increases MET activity in GBM cells in a hypoxia-independent manner, while inducing a program reminiscent of epithelial-to-mesenchymal transition highlighted by a T-cadherin to N-cadherin switch and enhanced mesenchymal features. Inhibition of MET in GBM mouse models blocks mesenchymal transition and invasion provoked by VEGF ablation, resulting in substantial survival benefit. | VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. |
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"28788": 0.006812678650021553, "29060": 0.02316705882549286, "29129": 0.06795065850019455, "29206": 0.15359249711036682, "29290": 0.6734226942062378, "29349": 0.2018241584300995, "29610": 0.14264501631259918} | 13242763 | Trophectoderm (TE), the first differentiated cell lineage of mammalian embryogenesis, forms the placenta, a structure unique to mammalian development. The differentiation of TE is a hallmark event in early mammalian development, but molecular mechanisms underlying this first differentiation event remain obscure. Embryonic stem (ES) cells can be induced to differentiate into the TE lineage by forced repression of the POU-family transcription factor, Oct3/4. We show here that this event can be mimicked by overexpression of Caudal-related homeobox 2 (Cdx2), which is sufficient to generate proper trophoblast stem (TS) cells. Cdx2 is dispensable for trophectoderm differentiation induced by Oct3/4 repression but essential for TS cell self-renewal. In preimplantation embryos, Cdx2 is initially coexpressed with Oct3/4 and they form a complex for the reciprocal repression of their target genes in ES cells. This suggests that reciprocal inhibition between lineage-specific transcription factors might be involved in the first differentiation event of mammalian development. | Interaction between Oct3/4 and Cdx2 Determines Trophectoderm Differentiation |
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reportedly enriched for tumor stem cells (TSCs) or tumor-initiating cells (TICs). Approximately 40% of freshly isolated GBM specimens, however, do not contain CD133+ tumor cells, raising the possibility that CD133 may not be a universal enrichment marker for GBM TSCs/TICs. Here we demonstrate that stage-specific embryonic antigen 1(SSEA-1/LeX)+ GBM cells fulfill the functional criteria for TSC/TIC, since (1) SSEA-1+ cells are highly tumorigenic in vivo, unlike SSEA-1- cells; (2) SSEA-1+ cells can give rise to both SSEA-1+ and SSEA-1- cells, thereby establishing a cellular hierarchy; and (3) SSEA-1+ cells have self-renewal and multilineage differentiation potentials. A distinct subpopulation of SSEA-1+ cells was present in all but one of the primary GBMs examined (n = 24), and most CD133+ tumor cells were also SSEA-1+, suggesting that SSEA-1 may be a general TSC/TIC enrichment marker in human GBMs. | SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma. |
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"29206": 0.12642613053321838} | 13245542 | We isolated a mutant allele of dnaX, encoding the tau and gamma subunits of the DNA polymerase III holoenzyme, that causes extreme cell filamentation but does not affect either cell growth or DNA replication. This phenotype results from a defect in daughter chromosome decatenation during rapid growth. In these cells, ParC, one subunit of topoisomerase IV, no longer associated with the replication factory, as occurs in wild-type cells, and was instead distributed uniformly on the nucleoid; the distribution of ParE, the other subunit of topoisomerase IV, was unaffected. In addition, the majority of topoisomerase IV activity in synchronized cell populations was restricted to late in the cell cycle, when replication was essentially complete. These observations suggest that topoisomerase IV activity in vivo might be dependent on release of ParC from the replication factory. | Temporal regulation of topoisomerase IV activity in E. coli. |
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"27881": 0.15275461971759796, "28207": 0.06154331564903259, "28329": 0.757441520690918, "28518": 0.08513788133859634, "28847": 0.5963221788406372, "28987": 0.07250232994556427, "29323": 0.9348671436309814, "29558": 1.2215901613235474} | 13256155 | BACKGROUND Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. METHODS The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. FINDINGS Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30). INTERPRETATION The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy. | Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. |
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The cAMP response element-binding protein (CREB) is a principal regulator of genes involved in coordinating the hepatic response to fasting, but its mechanism of gene activation remains controversial. We derived CRTC2 (CREB-regulated transcription coactivator 2, previously TORC2)-deficient mice to assess the contribution of this cofactor to hepatic glucose metabolism in vivo. CRTC2 mutant hepatocytes showed reduced glucose production in response to glucagon, which correlated with decreased CREB binding to several gluconeogenic genes. However, despite attenuated expression of CREB target genes, including PEPCK, G6Pase, and PGC-1alpha, no hypoglycemia was observed in mutant mice. Collectively, these results provide genetic evidence supporting a role for CRTC2 in the transcriptional response to fasting, but indicate only a limited contribution of this cofactor to the maintenance of glucose homeostasis. | CRTC2 (TORC2) contributes to the transcriptional response to fasting in the liver but is not required for the maintenance of glucose homeostasis. |
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1.070887804031372, "25793": 0.07793712615966797, "26118": 0.7565253376960754, "26131": 0.0038986403960734606, "26136": 0.5833279490470886, "26483": 0.02316705882549286, "26926": 0.4734157919883728, "27301": 0.07884006202220917, "27602": 0.8780695199966431, "27749": 0.5979346632957458, "28070": 0.010684899985790253, "28314": 0.42225050926208496, "28424": 0.09317722171545029, "28440": 0.3464667797088623, "28736": 0.3012613356113434, "28795": 0.4228905141353607, "29137": 0.24401791393756866, "29266": 0.5092619061470032} | 13277118 | BACKGROUND Polar bears (Ursus maritimus) are among those species most susceptible to the rapidly changing arctic climate, and their survival is of global concern. Despite this, little is known about polar bear species history. Future conservation strategies would significantly benefit from an understanding of basic evolutionary information, such as the timing and conditions of their initial divergence from brown bears (U. arctos) or their response to previous environmental change. RESULTS We used a spatially explicit phylogeographic model to estimate the dynamics of 242 brown bear and polar bear matrilines sampled throughout the last 120,000 years and across their present and past geographic ranges. Our results show that the present distribution of these matrilines was shaped by a combination of regional stability and rapid, long-distance dispersal from ice-age refugia. In addition, hybridization between polar bears and brown bears may have occurred multiple times throughout the Late Pleistocene. CONCLUSIONS The reconstructed matrilineal history of brown and polar bears has two striking features. First, it is punctuated by dramatic and discrete climate-driven dispersal events. Second, opportunistic mating between these two species as their ranges overlapped has left a strong genetic imprint. In particular, a likely genetic exchange with extinct Irish brown bears forms the origin of the modern polar bear matriline. This suggests that interspecific hybridization not only may be more common than previously considered but may be a mechanism by which species deal with marginal habitats during periods of environmental deterioration. | Ancient Hybridization and an Irish Origin for the Modern Polar Bear Matriline |
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"28939": 0.18573370575904846, "28940": 0.07793712615966797, "29206": 0.8869584798812866} | 13277623 | FBW7 (F-box and WD repeat domain-containing 7) is the substrate recognition component of an evolutionary conserved SCF (complex of SKP1, CUL1 and F-box protein)-type ubiquitin ligase. SCFFBW7 degrades several proto-oncogenes that function in cellular growth and division pathways, including MYC, cyclin E, Notch and JUN. FBW7 is also a tumour suppressor, the regulatory network of which is perturbed in many human malignancies. Numerous cancer-associated mutations in FBW7 and its substrates have been identified, and loss of FBW7 function causes chromosomal instability and tumorigenesis. This Review focuses on structural and functional aspects of FBW7 and its role in the development of cancer. | FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation |
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0.7683706283569336, "26745": 0.6410312056541443, "26886": 0.4944818615913391, "27794": 1.001607894897461, "27891": 0.7191727757453918, "28093": 0.2184450328350067, "28436": 0.010684899985790253, "28466": 0.13499516248703003, "28689": 0.06977381557226181, "28767": 1.4441578388214111, "28794": 0.21530038118362427, "29048": 0.6128603219985962, "29222": 0.3409265875816345, "29299": 0.255429208278656, "29458": 0.0354953333735466, "29516": 0.04207121208310127} | 13282296 | CONTEXT Although acute hypoglycemia may be associated with cognitive impairment in children with type 1 diabetes, no studies to date have evaluated whether hypoglycemia is a risk factor for dementia in older patients with type 2 diabetes. OBJECTIVE To determine if hypoglycemic episodes severe enough to require hospitalization are associated with an increased risk of dementia in a population of older patients with type 2 diabetes followed up for 27 years. DESIGN, SETTING, AND PATIENTS A longitudinal cohort study from 1980-2007 of 16,667 patients with a mean age of 65 years and type 2 diabetes who are members of an integrated health care delivery system in northern California. MAIN OUTCOME MEASURE Hypoglycemic events from 1980-2002 were collected and reviewed using hospital discharge and emergency department diagnoses. Cohort members with no prior diagnoses of dementia, mild cognitive impairment, or general memory complaints as of January 1, 2003, were followed up for a dementia diagnosis through January 15, 2007. Dementia risk was examined using Cox proportional hazard regression models, adjusted for age, sex, race/ethnicity, education, body mass index, duration of diabetes, 7-year mean glycated hemoglobin, diabetes treatment, duration of insulin use, hyperlipidemia, hypertension, cardiovascular disease, stroke, transient cerebral ischemia, and end-stage renal disease. RESULTS At least 1 episode of hypoglycemia was diagnosed in 1465 patients (8.8%) and dementia was diagnosed in 1822 patients (11%) during follow-up; 250 patients had both dementia and at least 1 episode of hypoglycemia (16.95%). Compared with patients with no hypoglycemia, patients with single or multiple episodes had a graded increase in risk with fully adjusted hazard ratios (HRs): for 1 episode (HR, 1.26; 95% confidence interval [CI], 1.10-1.49); 2 episodes (HR, 1.80; 95% CI, 1.37-2.36); and 3 or more episodes (HR, 1.94; 95% CI, 1.42-2.64). The attributable risk of dementia between individuals with and without a history of hypoglycemia was 2.39% per year (95% CI, 1.72%-3.01%). Results were not attenuated when medical utilization rates, length of health plan membership, or time since initial diabetes diagnosis were added to the model. When examining emergency department admissions for hypoglycemia for association with risk of dementia (535 episodes), results were similar (compared with patients with 0 episodes) with fully adjusted HRs: for 1 episode (HR, 1.42; 95% CI, 1.12-1.78) and for 2 or more episodes (HR, 2.36; 95% CI, 1.57-3.55). CONCLUSIONS Among older patients with type 2 diabetes, a history of severe hypoglycemic episodes was associated with a greater risk of dementia. Whether minor hypoglycemic episodes increase risk of dementia is unknown. | Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. |
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0.09406650811433792, "27131": 0.07341018319129944, "27395": 0.3903779089450836, "27651": 0.022212404757738113, "27854": 0.1994270235300064, "27989": 0.055094651877880096, "28156": 0.47827014327049255, "28187": 0.0354953333735466, "28227": 0.7124901413917542, "28829": 0.5255602598190308, "28873": 0.0038986403960734606, "28927": 0.1510767638683319, "29125": 0.8796916007995605} | 13283919 | CRACM1 (also called Orai1) constitutes the pore subunit of store-operated calcium release–activated calcium channels. A point mutation in the gene encoding CRACM1 is associated with severe combined immunodeficiency disease in humans. Here we generated CRACM1-deficient mice in which β-galactosidase activity 'reported' CRACM1 expression. CRACM1-deficient mice were smaller in size. Mast cells derived from CRACM1-deficient mice showed grossly defective degranulation and cytokine secretion, and the allergic reactions elicited in vivo were inhibited in CRACM1-deficient mice. We detected robust CRACM1 expression in skeletal muscles and some regions of the brain, heart and kidney but not in the lymphoid regions of thymus and spleen. In contrast, we found CRACM2 expression to be much higher in mouse T cells. In agreement with those findings, the store-operated calcium influx and development and proliferation of CRACM1-deficient T cells was unaffected. Thus, CRACM1 is crucial in mouse mast cell effector function, but mouse T cell calcium release–activated calcium channels are functional in the absence of CRACM1. | Defective mast cell effector functions in mice lacking the CRACM1 pore subunit of store-operated calcium release–activated calcium channels |
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They act via base-pairing with mRNA transcripts that harbour target sequences, resulting in accelerated mRNA decay and/or translational attenuation. Given miRNAs mediate the expression of molecules involved in many aspects of normal cell development and functioning, it is not surprising that aberrant miRNA expression is closely associated with many human diseases. Their pivotal role in driving a range of normal cellular physiology as well as pathological processes has established miRNAs as potential therapeutics, as well as potential diagnostic and prognostic tools in human health. MicroRNA-7 (miR-7) is a highly conserved miRNA which displays restricted spatiotemporal expression during development and in maturity. In humans and mice, mature miR-7 is generated from three different genes, illustrating unexpected redundancy and also the importance of this miRNA in regulating key cellular processes. In this review we examine the expanding role of miR-7 in the context of health, with emphasis on organ differentiation and development, as well as in various mammalian diseases, particularly of the brain, heart, endocrine pancreas and skin, as well as in cancer. The more we learn about miR-7, the more we realise the complexity of its regulation and potential functional application both from a biomarker and therapeutic perspective. | MicroRNA-7: A miRNA with expanding roles in development and disease. |
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"27268": 0.6729245185852051, "27480": 1.1462857723236084, "27642": 0.11604541540145874, "27756": 0.04767346754670143, "28086": 0.3615458607673645, "28102": 0.04674193635582924, "28144": 0.10026945173740387, "28405": 0.19782574474811554, "28685": 0.12470348179340363, "28767": 0.450652539730072, "28828": 0.3547199070453644, "28829": 0.5255602598190308, "28927": 0.2719337046146393, "29101": 0.175953671336174, "29206": 0.13755162060260773, "29217": 0.11081436276435852, "29290": 0.3877306580543518, "29440": 0.6989894509315491, "29458": 0.1401015669107437, "29494": 0.6400018334388733, "29516": 0.12728634476661682} | 13293033 | Down syndrome (DS) is the most frequent cause of human congenital mental retardation. Cognitive deficits in DS result from perturbations of normal cellular processes both during development and in adult tissues, but the mechanisms underlying DS etiology remain poorly understood. To assess the ability of induced pluripotent stem cells (iPSCs) to model DS phenotypes, as a prototypical complex human disease, we generated bona fide DS and wild-type (WT) nonviral iPSCs by episomal reprogramming. DS iPSCs selectively overexpressed chromosome 21 genes, consistent with gene dosage, which was associated with deregulation of thousands of genes throughout the genome. DS and WT iPSCs were neurally converted at >95% efficiency and had remarkably similar lineage potency, differentiation kinetics, proliferation, and axon extension at early time points. However, at later time points DS cultures showed a twofold bias toward glial lineages. Moreover, DS neural cultures were up to two times more sensitive to oxidative stress-induced apoptosis, and this could be prevented by the antioxidant N-acetylcysteine. Our results reveal a striking complexity in the genetic alterations caused by trisomy 21 that are likely to underlie DS developmental phenotypes, and indicate a central role for defective early glial development in establishing developmental defects in DS brains. Furthermore, oxidative stress sensitivity is likely to contribute to the accelerated neurodegeneration seen in DS, and we provide proof of concept for screening corrective therapeutics using DS iPSCs and their derivatives. Nonviral DS iPSCs can therefore model features of complex human disease in vitro and provide a renewable and ethically unencumbered discovery platform. | Integration-free induced pluripotent stem cells model genetic and neural developmental features of down syndrome etiology. |
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"25284": 0.37640097737312317, "25426": 0.7115318179130554, "25524": 0.3588210940361023, "25672": 0.06795065850019455, "25690": 0.4132472574710846, "25714": 0.7134475708007812, "25807": 0.030771657824516296, "26010": 0.03360854089260101, "26224": 0.012615402229130268, "26244": 0.1401015669107437, "26290": 0.6022219061851501, "26305": 0.34922540187835693, "26601": 0.43875885009765625, "26702": 0.19381128251552582, "26741": 0.3897167444229126, "26786": 0.46055975556373596, "26972": 0.0174254160374403, "27351": 0.15275461971759796, "27574": 0.0913962796330452, "28156": 0.33325836062431335, "28290": 0.1401015669107437, "28619": 1.292155385017395, "28815": 1.0655186176300049, "28848": 0.38041436672210693, "28896": 0.09406650811433792, "29206": 0.07068414986133575} | 13296399 | Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (Rho(S334)) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of Rho(S334), which prevented retinal degeneration and improved visual function. | In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa |
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0.1994270235300064, "26163": 0.9248477816581726, "26641": 0.1485546976327896, "26651": 0.34023189544677734, "26657": 0.09050461649894714, "26698": 0.2493593990802765, "26780": 0.7076893448829651, "26788": 0.12642613053321838, "26819": 0.0842406153678894, "26989": 0.2223619967699051, "27159": 0.03266380727291107, "27354": 0.015504186972975731, "27641": 0.03831886500120163, "27651": 0.22937409579753876, "27989": 0.2689530849456787, "28227": 0.8083226680755615, "28268": 0.41001203656196594, "28403": 0.3141832649707794, "28436": 0.04767346754670143, "28466": 0.11951763927936554, "28696": 0.960606575012207, "28739": 0.11430477350950241, "28829": 0.0029254043474793434, "28929": 0.20102575421333313, "29125": 1.0920805931091309, "29477": 0.04394211992621422, "29610": 0.18654440343379974} | 13312471 | Vitamin D insufficiency is common, however within individuals, not all manifest the biochemical effects of PTH excess. This further extends to patients with established osteoporosis. The mechanism underlying the blunted PTH response is unclear but may be related to magnesium (Mg) deficiency. The aims of this study were to compare in patients with established osteoporosis and differing degrees of vitamin D and PTH status : (1) the presence of Mg deficiency using the standard Mg loading test (2) evaluate the effects of Mg loading on the calcium-PTH endocrine axis (3) determine the effects of oral, short term Mg supplementation on the calcium-PTH endocrine axis and bone turnover. 30 patients (10 women in 3 groups) were evaluated prospectively measuring calcium, PTH, Mg retention (Mg loading test), dietary nutrient intake (calcium, vitamin D, Mg) and bone turnover markers (serum CTX & P1CP). Multivariate analysis controlling for potential confounding baseline variable was undertaken for the measured outcomes. All subjects, within the low vitamin D and low PTH group following the magnesium loading test had evidence of Mg depletion [mean(SD) retention 70.3%(12.5)] and showed an increase in calcium 0.06(0.01) mmol/l [95% CI 0.03, 0.09, p=0.007], together with a rise in PTH 13.3 ng/l (4.5) [95% CI 3.2, 23.4, p=0.016] compared to baseline. Following oral supplementation bone turnover increased: CTX 0.16 (0.06) mcg/l [95%CI 0.01, 0.32 p=0.047]; P1CP 13.1 (5.7) mcg/l [95% CI 0.29, 26.6 p=0.049]. In subjects with a low vitamin D and raised PTH mean retention was 55.9%(14.8) and in the vitamin replete group 36.1%(14.4), with little change in both acute markers of calcium homeostasis and bone turnover markers following both the loading test and oral supplementation. This study confirms that in patients with established osteoporosis, there is also a distinct group with a low vitamin D and a blunted PTH level and that Mg deficiency (as measured by the Mg loading test) is an important contributing factor. | Vitamin D insufficiency and the blunted PTH response in established osteoporosis: the role of magnesium deficiency |
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0.757441520690918, "26219": 0.011650617234408855, "26305": 0.036437395960092545, "26572": 1.036847710609436, "26646": 0.13925230503082275, "26745": 0.176772341132164, "26835": 0.9915141463279724, "27099": 0.5220900774002075, "27169": 0.7408206462860107, "27321": 0.7987030148506165, "27532": 0.14264501631259918, "27781": 0.11778303235769272, "28625": 0.8600510358810425, "28767": 0.08513788133859634, "28788": 0.319873183965683, "28873": 0.23710809648036957, "28896": 0.22859740257263184, "29017": 0.33115679025650024, "29170": 0.04487626627087593, "29175": 1.61021888256073} | 13322804 | PURPOSE OF REVIEW The availability of a growing number of immunomodulatory medications over the past few years has been associated with various JC virus (JCV)-associated brain syndromes in patients with autoimmune diseases, including multiple sclerosis, Crohn's disease, and psoriasis that had not been previously recognized as predisposing factors for progressive multifocal leukoencephalopathy. This review covers the three novel syndromes discovered in the last decade that are caused by JCV infection of neurons and meningeal cells. RECENT FINDINGS For more than 30 years, JCV was thought to exclusively infect oligodendrocytes and astrocytes in the white matter of the brain of immunosuppressed individuals. We now recognize that JCV-infected glial cells are frequently located at the gray-white matter junction or exclusively within the gray matter causing demyelination in the cortex. Mutations in JCV can trigger a change in tropism leading to involvement of other cell types, such as neurons and meningeal cells, causing clinically distinct entities. These new features of JCV infection provide challenges for clinicians taking care of affected patients and investigators studying the biology of this polyomavirus, its pathogenesis, and tropism. SUMMARY We hope that increasing awareness of these syndromes will lead to early diagnosis, and pave the way for new avenues of research to better understand all aspects of JCV pathogenesis and develop efficient therapies for our patients. However, we need to remain vigilant and open to the possibility that additional JC variants or yet unknown polyomaviruses may also be associated with neurological diseases. | Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area. |
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0.10731173306703568, "25849": 0.06703783571720123, "25930": 0.03925827145576477, "26402": 0.24171993136405945, "26520": 0.3443928062915802, "26775": 0.09584271162748337, "26927": 0.42353010177612305, "27144": 0.38574060797691345, "27263": 0.2659635543823242, "27881": 0.3318578004837036, "27937": 0.0038986403960734606} | 13329980 | AIMS AND BACKGROUND The PI3 kinase signalling pathway is now accepted as being at least as important as the ras-MAP kinase pathway in cell survival and proliferation, and hence its potential role in cancer is of great interest. The purpose of this review is briefly to examine evidence for an involvement of PI3K in human cancers, discuss the mechanisms by which its activation promotes tumor progression, and consider its utility as a novel target for anticancer therapy. METHODS AND STUDY DESIGN A Medline review of recent literature concerning the role of PI3 kinase in tumor progression--mechanisms of action and clinical implications. RESULTS Evidence is presented that misregulation of the PI3 kinase pathway is a feature of many common cancers, either by loss of the suppressor protein PTEN, or by constitutive activation of PI3 kinase isoforms or downstream elements such as AKT and mTOR. This activation potentiates not only cell survival and proliferation, but also cytoskeletal deformability and motility; key elements in tumor invasion. In addition the PI3K pathway is implicated in many aspects of angiogenesis, including upregulation of angiogenic cytokines due to tumor hypoxia or oncogene activation and endothelial cell responses to them. These cytokines signal though receptors such as VEGF-R, FGF-R and Tie-2 and potentiate processes essential for neoangiogenesis including cell proliferation, migration, differentiation into tubules and "invasion" of these capillary sprouts into extracellular matrix (ECM). CONCLUSIONS A more complete understanding of the role of the PI3 kinase pathway in cancer will lead the way to the development of more potent and selective inhibitors which should be a useful adjunct to conventional therapies, potentially interfering with tumor progression at several pivotal points; in particular cell survival, invasion and angiogenesis. | Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. |
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Method: The energy, nutrient and anti-nutrient (dietary fibre and phytic acid) content (per 100 g as eaten, per 100 kcal, and per day) of twenty-three plant-based complementary foods consumed in developing countries was calculated from food composition values based on chemical analysis for the trace minerals, non-starch polysaccharide and phytic acid, and the literature. Results were compared with the estimated nutrient needs (per day; per 100 kcal) from complementary foods for infants 9–11 months, assuming a breast milk intake of average volume and composition and three complementary feedings per day, each of 250 g. Results: Complementary foods should provide approximately 25–50% of total daily requirements for protein, riboflavin and copper; 50–75% for thiamin, calcium and manganese; and 75–100% for phosphorus, zinc and iron. Most or all appear to meet the estimated daily nutrient needs (per day; per 100 kcal) from complementary foods for protein, thiamin and copper (per day), but not for calcium, iron, and in some cases zinc, even if moderate bioavailability for iron and zinc is assumed. Some of those based on rice are also inadequate in riboflavin (per day; per 100 kcal).Conclusions: Even if strategies to improve the bioavailability of iron and zinc are employed, they are probably insufficient to overcome the deficits in calcium, iron and zinc. Therefore, research on the feasibility of fortifying plant-based complementary foods in developing countries with calcium, iron and zinc is urgently required. Sponsorship: This study was supported by the Micronutrient Initiative through the Canadian International Development Agency. | Complementary foods for infant feeding in developing countries: their nutrient adequacy and improvement |
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"25172": 0.6343214511871338, "25353": 0.2696990668773651, "25737": 0.2105647772550583, "26118": 0.034552380442619324, "26305": 0.23556606471538544, "26402": 0.040196798741817474, "26462": 0.8772575259208679, "26657": 0.19381128251552582, "26661": 0.15693697333335876, "26775": 0.08064348995685577, "26786": 0.4950772523880005, "26906": 0.4938860833644867, "27133": 0.052318159490823746, "27711": 0.00875066313892603, "27718": 0.4132472574710846, "28156": 0.8187123537063599, "28179": 0.8567397594451904, "28227": 0.8264343738555908, "28266": 0.1889725625514984, "28290": 0.021256839856505394, "28375": 0.684319257736206, "28466": 0.22157983481884003, "28562": 0.41001203656196594, "28696": 0.08513788133859634, "28767": 0.10993985831737518, "28828": 0.3070250153541565, "28829": 0.03360854089260101, "28964": 0.46608972549438477, "29046": 0.10379679501056671, "29516": 0.16110190749168396} | 13350374 | Mice deficient in the circadian transcription factor BMAL1 (brain and muscle ARNT-like protein) have impaired circadian behavior and demonstrate loss of rhythmicity in the expression of target genes. Here we report that Bmal1(-/-) mice have reduced lifespans and display various symptoms of premature aging including sarcopenia, cataracts, less subcutaneous fat, organ shrinkage, and others. The early aging phenotype correlates with increased levels of reactive oxygen species in some tissues of the Bmal1(-/- )animals. These findings, together with data on CLOCK/BMAL1-dependent control of stress responses, may provide a mechanistic explanation for the early onset of age-related pathologies in the absence of BMAL1. | Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. |
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1.0144377946853638, "29295": 0.05970508232712746, "29361": 0.009718249551951885, "29490": 0.5301685929298401} | 13368032 | To develop safer and more effective vectors for gene therapy of X-linked severe combined immunodeficiency (SCID-X1), we have evaluated new self-inactivating lentiviral vectors based on the HIV virus. The CL20i4-hgamma(c)-Revgen vector contains the entire human common gamma chain (gamma(c)) genomic sequence driven by the gamma(c) promoter. The CL20i4-EF1alpha-hgamma(c)OPT vector uses a promoter fragment from the eukaryotic elongation factor alpha (EF1alpha) gene to express a codon-optimized human gamma(c) cDNA. Both vectors contain a 400-bp insulator fragment from the chicken beta-globin locus within the self-inactivating long-terminal repeat. Transduction of bone marrow cells using either of these vectors restored T, B, and natural killer lymphocyte development and function in a mouse SCID-X1 transplantation model. Transduction of human CD34(+) bone marrow cells from SCID-X1 patients with either vector restored T-cell development in an in vitro assay. In safety studies using a Jurkat LMO2 activation assay, only the CL20i4-EF1alpha-hgamma(c)OPT vector lacked the ability to transactivate LMO2 protein expression, whereas the CL20i4-hgamma(c)-Revgen vector significantly activated LMO2 protein expression. In addition, the CL20i4-EF1alpha-hgamma(c)OPT vector has not caused any tumors in transplanted mice. We conclude that the CL20i4-EF1alpha-hgamma(c)OPT vector may be suitable for testing in a clinical trial based on these preclinical demonstrations of efficacy and safety. | A self-inactivating lentiviral vector for SCID-X1 gene therapy that does not activate LMO2 expression in human T cells. |
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"26874": 0.17267228662967682, "26976": 0.05139094591140747, "27009": 0.15526613593101501, "27163": 0.0058422754518687725, "27166": 0.043007105588912964, "27354": 0.38041436672210693, "27441": 0.13499516248703003, "27642": 0.0009760859538801014, "27710": 0.056018441915512085, "27814": 0.13925230503082275, "27833": 0.9170717000961304, "27928": 0.2763880789279938, "28093": 0.3325583338737488, "28154": 0.8450632095336914, "28290": 0.02887592278420925, "28321": 0.04860413447022438, "28353": 0.1064341589808464, "28389": 0.3005385100841522, "28436": 0.04487626627087593, "28828": 0.02412080205976963, "28873": 0.4374985992908478, "29107": 0.16690383851528168, "29166": 0.09850110858678818, "29206": 0.05417001247406006, "29295": 0.18167030811309814, "29458": 0.4041621685028076, "29602": 0.175953671336174} | 13373629 | BACKGROUND Recent genome-wide association studies (GWAS) have mapped several novel loci influencing blood lipid levels in Caucasians. We sought to explore whether the genetic variants at newly identified lipid-associated loci were associated with CHD susceptibility in a Chinese Han population. METHODOLOGY/PRINCIPAL FINDINGS We conducted a two-stage case-control study in a Chinese Han population. The first-stage, consisting of 1,376 CHD cases and 1,376 sex and age- frequency matched controls, examined 5 novel lipid-associated single-nucleotide polymorphisms (SNPs) identified from GWAS among Caucasians in relation to CHD risk in Chinese. We then validated significant SNPs in the second-stage, consisting of 1,269 cases and 2,745 controls. We also tested associations between SNPs within the five novel loci and blood lipid levels in 4,121 controls. We identified two novel SNPs (rs599839 in CELSR2-PSRC1-SORT1 and rs16996148 in NCAN-CILP2) that were significantly associated with reduced CHD risk in Chinese (odds ratios (95% confidence intervals) in the dominant model 0.76 (0.61-0.90; P = 0.001), 0.67 (0.57-0.77; P = 3.4×10(-8)), respectively). Multiple linear regression analyses using dominant model showed that rs599839 was significantly associated with decreased LDL levels (P = 0.022) and rs16996148 was significantly associated with increased LDL and HDL levels (P = 2.9×10(-4) and 0.001, respectively). CONCLUSIONS/SIGNIFICANCE We identified two novel SNPs (rs599839 and rs16996148) at newly identified lipid-associated loci that were significantly associated with CHD susceptibility in a Chinese Han population. | Genetic Variants at Newly Identified Lipid Loci Are Associated with Coronary Heart Disease in a Chinese Han Population |
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The hypothesis that rotenone enhancement of neuronal cell death is attributable to oxidative stress was tested in an acute glutamate excitotoxicity model using primary cultures of rat cerebellar granule neurons. As little as 5 nM rotenone increased mitochondrial superoxide (O2*-) levels and potentiated glutamate-induced cytoplasmic Ca2+ deregulation, the first irreversible stage of necrotic cell death. However, the potent cell-permeant O2*- trap manganese tetrakis (N-ethylpyridinium-2yl) porphyrin failed to prevent the effects of the inhibitor. The bioenergetic consequences of rotenone addition were quantified by monitoring cell respiration. Glutamate activation of NMDA receptors used the full respiratory capacity of the in situ mitochondria, and >80% of the glutamate-stimulated respiration was attributable to increased cellular ATP demand. Rotenone at 20 nM inhibited basal and carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated cell respiration and caused respiratory failure in the presence of glutamate. ATP synthase inhibition by oligomycin was also toxic in the presence of glutamate. We conclude that the cell vulnerability in the rotenone model of partial complex I deficiency under these specific conditions is primarily determined by spare respiratory capacity rather than oxidative stress. | Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. |
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"26785": 0.9658246636390686, "27065": 0.791648268699646, "27144": 1.1822543144226074, "27152": 1.0409941673278809, "27292": 0.4267219603061676, "27419": 0.06246116757392883, "27881": 0.03831886500120163, "28046": 1.024303913116455, "28286": 1.0768938064575195, "28389": 0.6588751673698425, "28674": 0.06154331564903259, "29090": 0.259204238653183, "29166": 0.9333322048187256, "29174": 0.38374659419059753, "29324": 0.1064341589808464, "29592": 0.11691460013389587} | 13380980 | Many treatments have been proposed for non-resectable primary or secondary hepatic cancer but the results have generally been disappointing. Isolated Hepatic Perfusion (IHP) was first attempted four decades ago but it gained acceptance only recently, after spectacular tumour responses were obtained by isolated limb perfusion with melphalan and tumour necrosis factor (TNF) for melanomas and sarcomas. Surgical isolation of the liver is a technically demanding operation that allows the safe administration of high doses of chemotherapeutics and TNF. Percutaneous techniques using balloon occlusion catheters are simpler but result in higher leakage rates from the perfusion circuit into the systemic circulation. Several phase I-II trials indicate that IHP can yield high tumour response rates, even when there is resistance to systemic chemotherapy. However, no significant advantage in overall survival has been demonstrated so far. IHP offers unique pharmacokinetic advantages for locoregional chemotherapy and biotherapy. It might also allow gene therapy with limited systemic exposure and toxicity. At present, IHP nevertheless remains an experimental treatment modality which should therefore be used in controlled trials only. | Isolated liver perfusion for non-resectable liver tumours: a review. |
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"25100": 0.0019512200960889459, "25644": 0.684319257736206, "26244": 0.3012613356113434, "26356": 0.12384103983640671, "26512": 0.05417001247406006, "26563": 0.6275664567947388, "26572": 0.037378571927547455, "26601": 0.2317005842924118, "26773": 0.32764431834220886, "26838": 0.1332872211933136, "27642": 0.15860503911972046, "27749": 0.02887592278420925, "28086": 0.07884006202220917, "28691": 0.08244366943836212, "28848": 1.2873153686523438, "29146": 0.9455460906028748} | 13384318 | Pre-mRNA splicing is a fundamental process required for the expression of most metazoan genes. It is carried out by the spliceosome, which catalyzes the removal of noncoding intronic sequences to assemble exons into mature mRNAs prior to export and translation. Given the complexity of higher eukaryotic genes and the relatively low level of splice site conservation, the precision of the splicing machinery in recognizing and pairing splice sites is impressive. Introns ranging in size from <100 up to 100,000 bases are removed efficiently. At the same time, a large number of alternative splicing events are observed between different cell types, during development, or during other biological processes. This extensive alternative splicing implies a significant flexibility of the spliceosome to identify and process exons within a given pre-mRNA. To reach this flexibility, splice site selection in higher eukaryotes has evolved to depend on multiple parameters such as splice site strength, the presence or absence of splicing regulators, RNA secondary structures, the exon/intron architecture, and the process of pre-mRNA synthesis itself. The relative contributions of each of these parameters control how efficiently splice sites are recognized and flanking introns are removed. | Combinatorial control of exon recognition. |
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"24335": 0.9045027494430542, "24374": 0.4286321699619293, "24594": 0.4400174915790558, "24868": 0.010684899985790253, "25125": 0.9769153594970703, "25194": 0.6456501483917236, "25323": 0.06246116757392883, "25456": 0.469759464263916, "25714": 0.5805994272232056, "26402": 1.0567318201065063, "26642": 0.18004031479358673, "26651": 0.2184450328350067, "26835": 1.1255888938903809, "27144": 0.30558720231056213, "27159": 0.10203468054533005, "27295": 0.5596157908439636, "27325": 0.1229778528213501, "27343": 0.20739519596099854, "27354": 0.1946154683828354, "27528": 0.1970241367816925, "27781": 0.5318912267684937, "27814": 0.03360854089260101, "27998": 0.6704301834106445, "28041": 0.016465263441205025, "28767": 0.04953393340110779, "28774": 0.0606246218085289, "28788": 0.6038249135017395, "28873": 1.1822543144226074, "29222": 0.17020416259765625} | 13398997 | The CD28/cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocker belatacept selectively inhibits alloreactive T cell responses but is associated with a high incidence of acute rejection following renal transplantation,which led us to investigate the etiology of belatacept–resistant graft rejection. T cells can differentiate into functionally distinct subsets of memory T cellsthat collectively enable protection against diverse classes of pathogens and can cross-react with allogeneicantigen and mediate graft rejection. T helper 17(Th17) cells are a pro-inflammatory CD4+ lineage that provides immunity to pathogens and are pathogenic in autoimmune disease. We found that T helper 1 (Th1)and Th17 memory compartments contained a similar frequency of divided cells following allogeneic stimulation. Compared to Th1 cells, Th17 memory cells expressed significantly higher levels of the coinhibitory molecule CTLA-4. Stimulation in the presence of belatacept inhibited Th1 responses but augmented Th17 cells due to greater sensitivity to coinhibition by CTLA-4. Th17 cells from renal transplant recipients were resistant to ex vivo CD28/CTLA-4 blockade with belatacept, and an elevated frequency of Th17 memory cells was associated with acute rejection during belatacept therapy. These data highlight important differences in costimulatory and coinhibitory requirements of CD4+ memory subsets, and demonstrate that the heterogeneity of pathogen-derived memory has implications for immunomodulation strategies. | High CTLA-4 expression on Th17 cells results in increased sensitivity to CTLA-4 coinhibition and resistance to belatacept. |
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"27605": 0.0029254043474793434, "27773": 0.010684899985790253, "27781": 0.176772341132164, "27821": 0.34370049834251404, "27854": 0.23787821829319, "27881": 0.014542185701429844, "28156": 0.12814582884311676, "28518": 0.22001366317272186, "29060": 0.6823468804359436, "29175": 0.11081436276435852, "29206": 0.8829278349876404} | 13400643 | The pharmacological inhibition of general transcriptional regulators has the potential to block growth through targeting multiple tumorigenic signalling pathways simultaneously. Here, using an innovative cell-based screen, we identify a structurally unique small molecule (named JIB-04) that specifically inhibits the activity of the Jumonji family of histone demethylases in vitro, in cancer cells, and in tumours in vivo. Unlike known inhibitors, JIB-04 is not a competitive inhibitor of α-ketoglutarate. In cancer, but not in patient-matched normal cells, JIB-04 alters a subset of transcriptional pathways and blocks viability. In mice, JIB-04 reduces tumour burden and prolongs survival. Importantly, we find that patients with breast tumours that overexpress Jumonji demethylases have significantly lower survival. Thus, JIB-04, a novel inhibitor of Jumonji demethylases in vitro and in vivo, constitutes a unique potential therapeutic and research tool against cancer, and validates the use of unbiased cellular screens to discover chemical modulators with disease relevance. | A small molecule modulates Jumonji histone demethylase activity and selectively inhibits cancer growth |
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0.8813109993934631} | 13411519 | Following cell surface receptor activation, the alpha subunit of the Gq subclass of GTP-binding proteins activates the phosphoinositide signalling pathway. Here we examined the expression and localization of Gq protein alpha subunits in the adult mouse brain by in situ hybridization and immunohistochemistry. Of the four members of the Gq protein alpha subunits, Galphaq and Galpha11 were transcribed predominantly in the brain. The highest transcriptional level of Galphaq was observed in cerebellar Purkinje cells (PCs) and hippocampal pyramidal cells, while that of Galpha11 was noted in hippocampal pyramidal cells. Antibody against the C-terminal peptide common to Galphaq and Galpha11 strongly labelled the cerebellar molecular layer and hippocampal neuropil layers. In these regions, immunogold preferentially labelled the cytoplasmic face of postsynaptic cell membrane of PCs and pyramidal cells. Immunoparticles were distributed along the extra-junctional cell membrane of spines, dendrites and somata, but were almost excluded from the junctional membrane. By double immunofluorescence, Galphaq/Galpha11 was extensively colocalized with metabotropic glutamate receptor mGluR1alpha in dendritic spines of PCs and with mGluR5 in those of hippocampal pyramidal cells. Together with concentrated localization of mGluR1alpha and mGluR5 in a peri-junctional annulus on PC and pyramidal cell synapses (Baude et al. 1993, Neuron, 11, 771-787; Luján et al. 1996, Eur. J. Neurosci., 8, 1488-1500), the present molecular-anatomical findings suggest that peri-junctional stimulation of the group I metabotropic glutamate receptors is mediated by Galphaq and/or Galpha11, leading to the activation of the intracellular effector, phospholipase Cbeta. | Gq protein alpha subunits Galphaq and Galpha11 are localized at postsynaptic extra-junctional membrane of cerebellar Purkinje cells and hippocampal pyramidal cells. |
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"29037": 1.001607894897461, "29206": 0.10026945173740387} | 13439128 | The Bloom's syndrome (BS) gene, BLM, plays an important role in the maintenance of genomic stability in somatic cells. A candidate for BLM was identified by direct selection of a cDNA derived from a 250 kb segment of the genome to which BLM had been assigned by somatic crossover point mapping. In this novel mapping method, cells were used from persons with BS that had undergone intragenic recombination within BLM. cDNA analysis of the candidate gene identified a 4437 bp cDNA that encodes a 1417 amino acid peptide with homology to the RecQ helicases, a subfamily of DExH box-containing DNA and RNA helicases. The presence of chain-terminating mutations in the candidate gene in persons with BS proved that it was BLM. | The Bloom's syndrome gene product is homologous to RecQ helicases |
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In childhood, the most important periods of risk appear to be the periods of adiposity rebound and adolescence. Caution regarding the period of adiposity rebound is still warranted, because it is not yet clear that early rebound is attributable to changes in body fat. Families and schools represent the most important foci for preventive efforts in children and adolescents. One productive approach is to proceed from an examination of factors that affect energy balance to the identification of more proximal influences on those factors. This approach may help to narrow the strategies necessary to prevent or treat childhood obesity. For example, television viewing affects both energy intake and energy expenditure, and therefore represents a logical target for interventions. Anticipatory guidance by pediatricians may offer an effective mechanism by which to change parental attitudes and practices regarding television viewing. A similar process is used to emphasize the potential influence of school-based interventions directed at changes in food choices and sedentary behavior. | Preventing obesity in children and adolescents. |
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0.09850110858678818, "26524": 0.8845420479774475, "26563": 0.37371641397476196, "26578": 0.06337817758321762, "26773": 0.45499902963638306, "26802": 1.0748957395553589, "27152": 0.016465263441205025, "27226": 0.02412080205976963, "27268": 0.4879087805747986, "27642": 0.1889725625514984, "27709": 0.23864774405956268, "28023": 0.9531047344207764, "28086": 1.4339678287506104, "28156": 0.6160298585891724, "28327": 0.8772575259208679, "28788": 0.10731173306703568, "28828": 0.1677299439907074, "29107": 0.022212404757738113, "29415": 0.13499516248703003} | 13441537 | Abstract Culture of preimplantation mammalian embryos and cells can influence their subsequent growth and differentiation. Previously, we reported that culture of mouse embryonic stem cells is associated with deregulation of genomic imprinting and affects the potential for these cells to develop into normal fetuses. The purpose of our current study was to determine whether culture of preimplantation mouse embryos in a chemically defined medium (M16) with or without fetal calf serum (FCS) can affect their subsequent development and imprinted gene expression. Only one third of the blastocysts that had been cultured from two-cell embryos in M16 medium complemented with FCS developed into viable Day 14 fetuses after transfer into recipients. These M16 + FCS fetuses were reduced in weight as compared with controls and M16 fetuses and had decreased expression of the imprinted H19 and insulin-like growth factor 2 genes associated with a gain of DNA methylation at an imprinting control region upstream of H19. They also displayed increased expression of the imprinted gene Grb10. The growth factor receptor binding gene Grb7, in contrast, was strongly reduced in its expression in most of the M16 + FCS fetuses. No alterations were detected for the imprinted gene Mest. Preimplantation culture in the presence of serum can influence the regulation of multiple growth-related imprinted genes, thus leading to aberrant fetal growth and development. | Culture of Preimplantation Mouse Embryos Affects Fetal Development and the Expression of Imprinted Genes1 |
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IAs are found in 2.3% of adults; the mean age at detection is 52 years. Prevalence is <0.5% in young adults. Early studies suggest that 10%-50% of patients with aortic coarctation have IAs. Screening recommendations are variable. We sought to examine the prevalence of IAs through screening with MRA. MATERIALS AND METHODS Consecutive patients older than 16 years of age with coarctation undergoing brain MRA between May 1999 and October 2007 were included. MRA was performed by using a 1.5T scanner with a 3D time-of-flight protocol; simultaneous MR imaging was performed of the heart and aorta. Cerebral MRAs were double-reported by a neuroradiologist. Statistics are described as mean ± SD and median ± range. Continuous variables were compared by using Student t tests and Mann-Whitney U tests (categoric variables, by using the Fisher exact test). RESULTS One hundred seventeen MRAs were double-reported. The median age was 29 ± 11 years (range, 16-59 years). IAs were found in 12 patients (10.3%). The mean diameter of IAs was 3.9 mm (range, 2.0-8.0 mm). Patients with aneurysms were older (median, 37 years; range, 16-50 years) than those without (median, 23 years; range, 16-59 years; Z = -2.01, P = .04). Hypertension was more common in those with IAs (IA 83% versus no IA 43%, P = .01). There was no association between ascending aortopathy, bicuspid aortic valves, and IAs. CONCLUSIONS Patients with coarctation have a higher prevalence of IAs, occurring at an earlier age than in population studies. Whether routine screening is appropriate for this group of patients is unclear. Hypertension is likely to be an important pathophysiologic factor. | Results of screening for intracranial aneurysms in patients with coarctation of the aorta. |
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"28828": 0.6892333030700684, "28846": 0.03360854089260101, "28847": 0.4145384132862091, "28915": 0.09317722171545029, "28926": 0.28670501708984375, "29076": 1.1337933540344238, "29137": 0.053244512528181076, "29290": 0.13071982562541962, "29320": 0.08692999184131622, "29458": 0.26820653676986694} | 13448422 | This review discusses some of the mechanisms inherent in diabetes that predispose patients to increased cardiac morbidity and mortality. Single photon emission computerized tomography or photon emission tomography with radioactive labeled analogues of norepinephrine have shown that cardiac sympathetic dysfunction and incompetence are early and also late abnormalities in patients with Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus. Furthermore, myocardial blood flow assessment with photon emission tomography has shown that in patients without myocardial perfusion deficits, endothelial-dependent vasodilatation is severely reduced in relation to cardiac sympathetic dysfunction. In addition, signs of endothelial activation have also been found early in patients with Type I and Type II diabetes in whom vascular disease has not been clinically detected. This activation in conjunction with glycaemic control is important in determining macrovascular mortality. Cardiac sympathetic dysfunction is partially restored to normal with near normalisation of glycaemia. Interpretations. Recently unrecognized “subtle” changes predispose the heart to failure, after ischaemia-induced remodelling, and arteriosclerotic plaques to instability and rupture. These changes act in conjunction with effects, driven by hyperglycaemia and diabetes, on the endothelium of large blood vessels, e. g. on nitric oxide release or on protein kinase-C β activation. Meticulous glucose control early on and rapid recompensation of hyperglycaemia in patients with acute coronary syndrome are part of a successful intensive multifactorial approach to prevent the heart in diabetes converting from ailing to failing. [Diabetologia (2000) 43: 1455–1469] | A new look at the heart in diabetes mellitus: from ailing to failing |
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"27781": 0.15693697333335876, "27814": 0.66441810131073, "27815": 0.6286086440086365, "27838": 0.43875885009765625, "27854": 0.3723714053630829, "28154": 0.49864232540130615, "28156": 0.3916989266872406, "28286": 0.8500841856002808, "28311": 1.304418921470642, "28842": 0.347847044467926, "28873": 0.2231435477733612, "29206": 0.11778303235769272, "29489": 0.27786844968795776, "29610": 0.09584271162748337} | 13450938 | In the mouse, ZFP57 contains three classical Cys2His2 zinc finger domains (ZF) and recognizes the methylated TGC(met)CGC target sequence using the first and the second ZFs. In this study, we demonstrate that the human ZFP57 (hZFP57) containing six Cys2His2 ZFs, binds the same methylated sequence through the third and the fourth ZFs, and identify the aminoacids critical for DNA interaction. In addition, we present evidences indicating that hZFP57 mutations and hypomethylation of the TNDM1 ICR both associated with Transient Neonatal Diabetes Mellitus type 1 result in loss of hZFP57 binding to the TNDM1 locus, likely causing PLAGL1 activation. | Genetic and epigenetic mutations affect the DNA binding capability of human ZFP57 in transient neonatal diabetes type 1 |
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"24110": 0.5438674688339233, "24255": 0.22782009840011597, "24394": 0.3547199070453644, "25194": 0.4873090982437134, "25761": 0.0354953333735466, "26243": 0.3916989266872406, "26394": 0.9724938273429871, "26402": 0.083342544734478, "26773": 0.011650617234408855, "26942": 0.6989894509315491, "27166": 0.13670019805431366, "27295": 0.3743882179260254, "27321": 1.200646996498108, "27453": 0.02887592278420925, "27651": 0.2145126610994339, "27854": 0.06520967930555344, "28177": 0.10993985831737518, "28228": 0.16442140936851501, "28282": 1.1610734462738037, "28319": 0.19622190296649933, "28501": 0.2918238639831543, "28625": 1.486563801765442, "28788": 0.38574060797691345, "29441": 0.0913962796330452, "29477": 0.1064341589808464} | 13458119 | Astrocytes can release glutamate in a calcium-dependent manner and consequently signal to adjacent neurons. Whether this glutamate release pathway is used during physiological signaling or is recruited only under pathophysiological conditions is not well defined. One reason for this lack of understanding is the limited knowledge about the levels of calcium necessary to stimulate glutamate release from astrocytes and about how they compare with the range of physiological calcium levels in these cells. We used flash photolysis to raise internal calcium in astrocytes, while monitoring astrocytic calcium levels and glutamate, which evoked slow inward currents that were recorded electrophysiologically from single neurons grown on microislands of astrocytes. With this approach, we demonstrate that modest changes of astrocytic calcium, from 84 to 140 nM, evoke substantial glutamatergic currents in neighboring neurons (-391 pA), with a Hill coefficient of 2.1 to 2.7. Because the agonists glutamate, norepinephrine, and dopamine all raise calcium in astrocytes to levels exceeding 1.8 microM, these quantitative studies demonstrate that the astrocytic glutamate release pathway is engaged at physiological levels of internal calcium. Consequently, the calcium-dependent release of glutamate from astrocytes functions within an appropriate range of astrocytic calcium levels to be used as a signaling pathway within the functional nervous system. | Physiological astrocytic calcium levels stimulate glutamate release to modulate adjacent neurons. |
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"25608": 0.0029254043474793434, "25990": 0.1602703034877777, "26163": 0.8281423449516296, "26180": 0.13071982562541962, "26290": 0.1011524572968483, "26419": 0.06977381557226181, "26534": 0.17267228662967682, "26657": 0.21135559678077698, "27144": 0.23633737862110138, "27354": 0.08871890604496002, "27710": 1.0285027027130127, "27833": 0.4444103240966797, "27846": 1.0037577152252197, "28006": 0.00875066313892603, "28070": 0.20102575421333313, "28225": 0.004870930220931768, "28279": 0.07159364968538284, "28287": 0.009718249551951885, "28329": 0.04860413447022438, "28696": 0.0009760859538801014, "28893": 0.11168810725212097, "29048": 0.09406650811433792, "29166": 0.36426326632499695, "29191": 0.034552380442619324, "29288": 0.10467668622732162, "29458": 0.31132611632347107} | 13464392 | OBJECTIVE Hypoproteinemia, fluid retention, and weight gain are associated with development of acute lung injury and mortality in critically ill patients, without proof of cause and effect. We designed a clinical trial to determine whether diuresis and colloid replacement in hypoproteinemic patients with acute lung injury would improve pulmonary physiology. DESIGN Prospective, randomized, double-blind, placebo-controlled trial. SETTING All adult intensive care units from two university hospitals. PATIENTS Thirty-seven mechanically-ventilated patients with acute lung injury and serum total protein </=5.0 g/dL. INTERVENTIONS Five-day protocolized regimen of 25 g of human serum albumin every 8 hrs with continuous infusion furosemide, or dual placebo, targeted to diuresis, weight loss, and serum total protein. MEASUREMENTS AND MAIN RESULTS Measured outcomes included change in weight, serum total protein, fluid balance, hemodynamics, respiratory system compliance, and oxygenation. Baseline characteristics were similar between groups (treatment, n = 19; control, n = 18), with trauma being the major cause of acute lung injury. Diuresis and weight loss over 5 days (5.3 kg more in the treatment group, p =.04) was accompanied by improvements in the Pao2/Fio2 ratio in the treatment group within 24 hrs (from 171 to 236, p =.02). Respiratory mechanics were unchanged. Mean arterial pressure increased from 80 to 88 mm Hg (p =.10), and heart rate decreased from 110 to 95 beats/min (p =.008) over time in the treatment group. No difference in mortality was observed, with favorable trends in measures of intensive care. CONCLUSIONS Albumin and furosemide therapy improves fluid balance, oxygenation, and hemodynamics in hypoproteinemic patients with acute lung injury. Determining the effect of this simple therapy on cost, outcomes, and other patient populations requires further study. | Albumin and furosemide therapy in hypoproteinemic patients with acute lung injury. |
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0.08692999184131622} | 13466517 | The techniques available for the interrogation and analysis of neuroimaging data have a large influence in determining the flexibility, sensitivity, and scope of neuroimaging experiments. The development of such methodologies has allowed investigators to address scientific questions that could not previously be answered and, as such, has become an important research area in its own right. In this paper, we present a review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data. The majority of the research laid out in this paper has been implemented as freely available software tools within FMRIB's Software Library (FSL). | Advances in functional and structural mr image analysis and implementation as fsl |
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aspects of metformin action remained ill-defined. Recent advances revealed that this drug, in addition to its glucose-lowering action, might be promising for specifically targeting metabolic differences between normal and abnormal metabolic signalling. The knowledge gained from dissecting the principal mechanisms by which metformin works can help us to develop novel treatments. The centre of metformin's mechanism of action is the alteration of the energy metabolism of the cell. Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon. Stimulation of 5′-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer. | Metformin—mode of action and clinical implications for diabetes and cancer |
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0.8187123537063599, "28896": 0.6394867897033691, "29490": 0.3241194784641266} | 13469921 | Recent cross-sectional analyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responses are developed by 10%-30% of HIV-1+ subjects. The timing of the initial development of such anti-viral responses is unknown. It is also unknown whether the emergence of these responses coincides with the appearance of antibody specificities to a single or multiple regions of the viral envelope glycoprotein (Env). Here we analyzed the cross-neutralizing antibody responses in longitudinal plasmas collected soon after and up to seven years after HIV-1 infection. We find that anti-HIV-1 cross-neutralizing antibody responses first become evident on average at 2.5 years and, in rare cases, as early as 1 year following infection. If cross-neutralizing antibody responses do not develop during the first 2-3 years of infection, they most likely will not do so subsequently. Our results indicate a potential link between the development of cross-neutralizing antibody responses and specific activation markers on T cells, and with plasma viremia levels. The earliest cross-neutralizing antibody response targets a limited number of Env regions, primarily the CD4-binding site and epitopes that are not present on monomeric Env, but on the virion-associated trimeric Env form. In contrast, the neutralizing activities of plasmas from subjects that did not develop cross-neutralizing antibody responses target epitopes on monomeric gp120 other than the CD4-BS. Our study provides information that is not only relevant to better understanding the interaction of the human immune system with HIV but may guide the development of effective immunization protocols. Since antibodies to complex epitopes that are present on the virion-associated envelope spike appear to be key components of earliest cross-neutralizing activities of HIV-1+ plasmas, then emphasis should be made to elicit similar antibodies by vaccination. | Characteristics of the Earliest Cross-Neutralizing Antibody Response to HIV-1 |
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determine if women are more likely than men to have heart failure (HF) with preserved systolic function after adjustment for potential confounders, including age. BACKGROUND Although prior evidence suggests an independent association between female gender and preserved left ventricular systolic function (LVSF) in patients with HF, existing studies are limited by referral biases, small sample sizes, or the inability to adjust for a wide range of potential confounding variables. METHODS This is a cross-sectional study using data from retrospective medical chart abstraction of a national sample of Medicare beneficiaries hospitalized with the principal discharge diagnosis of HF in acute-care nongovernmental hospitals in the U.S. between April 1998 and March 1999. Patients were eligible for this analysis if they were age 65 years or older, had documentation of LVSF, and corroboration of the diagnosis of HF. We used multivariable logistic regression to identify the correlates of preserved LVSF, which was defined as qualitatively normal function or quantitatively reported ejection fraction > or =0.50. Stratified regressions by gender were performed to identify significant interactions. RESULTS Of the 19,710 patients in the analysis, preserved LVSF was present in 6,700 (35%), 79% of whom were women. In contrast, among the 12,956 patients with impaired LVSF, only 49% were women. Patients with preserved LVSF were 1.5 years older than those with impaired LVSF. After adjustment for age and other patient factors, female gender remained strongly associated with preserved LVSF (calculated risk ratio = 1.71; 95% confidence interval 1.63 to 1.78). The association was consistent in all age groups, and was similar in patients with or without coronary artery disease, hypertension, pulmonary disease, renal insufficiency, or atrial fibrillation. CONCLUSIONS In elderly patients hospitalized with HF, preserved systolic function is primarily a condition of women, independent of important demographic and clinical characteristics. | Gender, age, and heart failure with preserved left ventricular systolic function. |
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