spalde-v3-lexical
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"25468": 0.22001366317272186, "25525": 0.3106105625629425, "25582": 0.6338034868240356, "25690": 0.04113444685935974, "25708": 0.3416208028793335, "25714": 0.3141832649707794, "25761": 0.007782140281051397, "26131": 0.791648268699646, "26224": 0.8306987881660461, "26402": 0.3012613356113434, "26512": 0.08603433519601822, "26520": 0.025073638185858727, "26534": 0.22001366317272186, "26572": 0.3923587501049042, "26661": 0.09938567131757736, "26773": 0.48670899868011475, "26775": 0.35060185194015503, "26913": 0.46914875507354736, "27009": 0.010684899985790253, "27099": 0.4891071021556854, "27651": 0.06337817758321762, "27854": 0.08154398202896118, "28155": 0.7201237678527832, "28177": 0.9131608605384827, "28311": 0.6543170213699341, "28549": 0.30989447236061096, "28691": 0.4311734735965729, "28790": 0.30989447236061096, "29206": 0.8281423449516296, "29278": 0.07431721687316895, "29290": 0.6420594453811646, "29292": 0.02887592278420925} | 11291348 | The Maf oncoproteins are b-Zip transcription factors of the AP-1 superfamily. They are involved in developmental, metabolic, and tumorigenic processes. Maf proteins are overexpressed in about 50% of human multiple myelomas. Here, we show that Maf-transforming activity is controlled by GSK-3-dependent phosphorylation and that phosphorylation by GSK-3 can increase the oncogenic activity of a protein. Using microarray analysis, we identify a gene-expression subprogram regulated by GSK-3-mediated Maf phosphorylation involved in extracellular matrix remodeling and relevant to cancer progression. We also demonstrate that GSK-3 triggers MafA sequential phosphorylation on residues S61, T57, T53, and S49, inducing its ubiquitination and degradation. Paradoxically, this phosphorylation increases MafA-transcriptional activity through the recruitment of the coactivator P/CAF. We further demonstrate that P/CAF protects MafA from ubiquitination and degradation, suggesting that, upon the release of the coactivator complex, MafA becomes polyubiquitinated and degraded to allow the response to terminate. | GSK-3-mediated phosphorylation enhances Maf-transforming activity. |
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0.13157635927200317, "29206": 1.0655186176300049, "29290": 0.5816917419433594, "29295": 0.014542185701429844, "29494": 0.5232481360435486, "29543": 0.8567397594451904} | 11328820 | The early events leading to the development of rheumatoid arthritis (RA) remain unclear, but formation of autoantibodies to citrullinated protein antigens (ACPAs) is considered a key pathogenic event. Neutrophils isolated from patients with various autoimmune diseases display enhanced neutrophil extracellular trap (NET) formation, a phenomenon that exposes autoantigens in the context of immunostimulatory molecules. We investigated whether aberrant NETosis occurs in RA, determined its triggers, and examined its deleterious inflammatory consequences. Enhanced NETosis was observed in circulating and RA synovial fluid neutrophils compared to neutrophils from healthy controls and from patients with osteoarthritis (OA). Further, netting neutrophils infiltrated RA synovial tissue, rheumatoid nodules, and skin. NETosis correlated with ACPA presence and levels and with systemic inflammatory markers. RA sera and immunoglobulin fractions from RA patients with high levels of ACPA and/or rheumatoid factor significantly enhanced NETosis, and the NETs induced by these autoantibodies displayed distinct protein content. Indeed, during NETosis, neutrophils externalized the citrullinated autoantigens implicated in RA pathogenesis, and anti-citrullinated vimentin antibodies potently induced NET formation. Moreover, the inflammatory cytokines interleukin-17A (IL-17A) and tumor necrosis factor-α (TNF-α) induced NETosis in RA neutrophils. In turn, NETs significantly augmented inflammatory responses in RA and OA synovial fibroblasts, including induction of IL-6, IL-8, chemokines, and adhesion molecules. These observations implicate accelerated NETosis in RA pathogenesis, through externalization of citrullinated autoantigens and immunostimulatory molecules that may promote aberrant adaptive and innate immune responses in the joint and in the periphery, and perpetuate pathogenic mechanisms in this disease. | NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. |
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11335781 | The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies—and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it. | Is autoimmunity the Achilles' heel of cancer immunotherapy? |
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The mechanisms governing lineage choices of hES cells are largely unknown. Here, we report that we established two independent hES cell clones lacking a group of cell surface molecules, glycosyl-phosphatidyl-inositol-anchored proteins (GPI-APs). The GPI-AP deficiency in these two hES clones is due to the deficiency in the gene expression of PIG-A (phosphatidyl-inositol-glycan class A), which is required for the first step of GPI synthesis. GPI-AP-deficient hES cells were capable of forming embryoid bodies and initiating cell differentiation into the three embryonic germ layers. However, GPI-AP-deficient hES cells failed to form trophoblasts after differentiation induction by embryoid body formation or by adding exogenous BMP4. The defect in trophoblast formation was due to the lack of GPI-anchored BMP coreceptors, resulting in the impairment of full BMP4 signaling activation in the GPI-AP-deficient hES cells. These data reveal that GPI-AP-enhanced full activation of BMP signaling is required for human trophoblast formation. | Trophoblast differentiation defect in human embryonic stem cells lacking PIG-A and GPI-anchored cell-surface proteins. |
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"27152": 0.9115922451019287, "27631": 0.7755908370018005, "27781": 0.12814582884311676, "28170": 0.1510767638683319, "28619": 1.1524739265441895, "28637": 0.1685553640127182, "28667": 0.5162794589996338, "28848": 0.4794800877571106, "28896": 0.25845035910606384, "28901": 0.20660123229026794, "28976": 0.20421554148197174, "29146": 0.27044451236724854, "29598": 0.5816917419433594} | 11336632 | Horizontal gene transfer (HGT) in bacteria and archaea occurs through phage transduction, transformation, or conjugation, and the latter is particularly important for the spread of antibiotic resistance. Clustered, regularly interspaced, short palindromic repeat (CRISPR) loci confer sequence-directed immunity against phages. A clinical isolate of Staphylococcus epidermidis harbors a CRISPR spacer that matches the nickase gene present in nearly all staphylococcal conjugative plasmids. Here we show that CRISPR interference prevents conjugation and plasmid transformation in S. epidermidis. Insertion of a self-splicing intron into nickase blocks interference despite the reconstitution of the target sequence in the spliced mRNA, which indicates that the interference machinery targets DNA directly. We conclude that CRISPR loci counteract multiple routes of HGT and can limit the spread of antibiotic resistance in pathogenic bacteria. | CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNA |
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"26014": 0.469759464263916, "26242": 0.25088030099868774, "26305": 0.2576959431171417, "26462": 0.07793712615966797, "26702": 0.13071982562541962, "26745": 0.38174858689308167, "26835": 0.817850649356842, "27144": 1.1076855659484863, "27159": 0.21135559678077698, "27179": 0.5290185213088989, "27398": 0.15610189735889435, "27528": 0.28670501708984375, "28086": 0.052318159490823746, "28207": 0.637939989566803, "28723": 0.31204116344451904, "28788": 0.3019835948944092, "28828": 0.1384023278951645, "29109": 0.20102575421333313, "29217": 0.0174254160374403, "29251": 0.25845035910606384, "29598": 0.6492279767990112} | 11344428 | Leukemia in donor cells (donor cell leukemia; DCL) has been reported as a rare but severe complication of allogeneic stem cell transplantation (SCT). However, the incidence, potential pathogenetic factors, therapeutic options and outcome of patients suffering from DCL and the leukemia risk of their donors are not well defined. A questionnaire survey was carried out within European Blood and Marrow Transplantation Group (EBMT) centers. Ninety-one EBMT centers participated in this survey, covering 10489 allogeneic SCT between 12/1982 and 09/2003. Fourteen cases of DCL, most with a myeloid phenotype (7 cases of acute myeloid leukemia, 3 each of acute lymphocytic leukemia and 1 case of chronic myeloid leukemia) were identified. Demonstration of donor cell origin included molecular analysis of chimerism in most cases. DCL type and cytogenetic alterations were independent from the original disease. The median time between transplantation and diagnosis of DCL was 17 months (4-164). No type of conditioning, donor, graft manipulation, graft-versus-host disease prophylaxis or subsequent complications were identified as risk factors for DCL. Chemotherapy induced remissions in DCL and 2 of 5 patients remain alive in remission after a second transplant. None of the stem cell donors developed hematologic malignancies (median follow-up period of 9 years; range 6-30 years). DCL is an extremely rare complication of allogeneic SCT in which treatment attempts with chemotherapy and a second SCT are justified. Donors are not at an increased risk of developing hematologic malignancies. | Development of leukemia in donor cells after allogeneic stem cell transplantation--a survey of the European Group for Blood and Marrow Transplantation (EBMT). |
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"23900": 0.0913962796330452, "24260": 1.1018621921539307, "24534": 0.00875066313892603, "24590": 0.026025565341114998, "24735": 0.11951763927936554, "25121": 0.040196798741817474, "25331": 0.22782009840011597, "25468": 0.39367714524269104, "25494": 0.23092569410800934, "25608": 0.6254787445068359, "26226": 0.053244512528181076, "26288": 0.0009760859538801014, "26462": 0.6000806093215942, "26745": 0.25694093108177185, "26835": 0.2689530849456787, "26906": 0.2667117714881897, "26927": 0.9485763907432556, "28024": 0.021256839856505394, "28295": 0.4132472574710846, "28376": 0.026025565341114998, "28389": 0.4950772523880005, "28739": 0.022212404757738113, "28879": 0.10203468054533005, "28989": 0.026976587250828743, "29017": 0.07884006202220917, "29248": 0.08692999184131622, "29299": 0.18654440343379974} | 11349166 | BACKGROUND Since 2004, several reported transfusion transmissions of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom have reawakened concerns about the possible risk of similar transmissions of nonvariant or classic forms of CJD. STUDY DESIGN AND METHODS Patients with a CJD diagnosis and a history of donating blood were reported to the study coordinator. Through review of blood distribution and hospital records, the recipients of blood components from these donors were identified. We then determined each recipient's vital status and, if deceased, the cause(s) of death identified by matching the recipient's personal identifiers with the Centers for Disease Control and Prevention's National Death Index database. We conducted such searches after recipients were enrolled in this study and annually thereafter for those who remained alive. RESULTS The study included a total of 36 blood donors who subsequently developed CJD and 436 recipients. Through 2006, 91 of these recipients were still alive, 329 were deceased, and 16 were lost to follow-up. After transfusion, these three groups had survived a total of 2096.0 person-years. A total of 144 recipients survived 5 years or longer after transfusion and 68 of them had received blood donated 60 or fewer months before the onset of CJD in the donor. We identified no recipient with CJD. CONCLUSIONS The current results of this large, ongoing lookback study show no evidence of transfusion transmission of CJD. They reinforce the conclusion that the risk, if any, of transfusion transmission of prion disease by CJD donors is significantly lower than the comparable risk of such transmission by vCJD donors. | Lack of evidence of transfusion transmission of Creutzfeldt-Jakob disease in a US surveillance study. |
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"24473": 0.040196798741817474, "24535": 0.11951763927936554, "24558": 0.9842413663864136, "24600": 0.04767346754670143, "25003": 1.4505887031555176, "25169": 0.07159364968538284, "25409": 0.9147270321846008, "25468": 0.25845035910606384, "25524": 0.1913948506116867, "25714": 0.06703783571720123, "25761": 0.2493593990802765, "26013": 0.22782009840011597, "26014": 0.7182208299636841, "26520": 0.09672962874174118, "26646": 1.3931070566177368, "26702": 0.14095009863376617, "26835": 0.06337817758321762, "26986": 0.036437395960092545, "27144": 0.055094651877880096, "27550": 0.11343330889940262, "27881": 0.7210738658905029, "28024": 0.23787821829319, "28207": 0.010684899985790253, "28329": 1.0382318496704102, "28424": 0.0797421783208847, "28498": 1.072225570678711, "28911": 0.07612881064414978, "29206": 0.9907892942428589, "29290": 0.24018502235412598, "29491": 0.02792670577764511, "29598": 0.0354953333735466} | 11359243 | Altered DNA methylation occurs ubiquitously in human cancer from the earliest measurable stages. A cogent approach to understanding the mechanism and timing of altered DNA methylation is to analyze it in the context of carcinogenesis by a defined agent. Epstein-Barr virus (EBV) is a human oncogenic herpesvirus associated with lymphoma and nasopharyngeal carcinoma, but also used commonly in the laboratory to immortalize human B-cells in culture. Here we have performed whole-genome bisulfite sequencing of normal B-cells, activated B-cells, and EBV-immortalized B-cells from the same three individuals, in order to identify the impact of transformation on the methylome. Surprisingly, large-scale hypomethylated blocks comprising two-thirds of the genome were induced by EBV immortalization but not by B-cell activation per se. These regions largely corresponded to hypomethylated blocks that we have observed in human cancer, and they were associated with gene-expression hypervariability, similar to human cancer, and consistent with a model of epigenomic change promoting tumor cell heterogeneity. We also describe small-scale changes in DNA methylation near CpG islands. These results suggest that methylation disruption is an early and critical step in malignant transformation. | Large-scale hypomethylated blocks associated with Epstein-Barr virus-induced B-cell immortalization. |
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short-lived cell types, such as blood, skin, and sperm, throughout adult life. Stem cells maintain a long-term capacity to divide, producing daughter cells that either self-renew or initiate differentiation. Although the surrounding microenvironment or "niche" influences stem cell fate decisions, few signals that emanate from the niche to specify stem cell self-renewal have been identified. Here we demonstrate that the apical hub cells in the Drosophila testis act as a cellular niche that supports stem cell self-renewal. Hub cells express the ligand Unpaired (Upd), which activates the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in adjacent germ cells to specify self-renewal and continual maintenance of the germ line stem cell population. | Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. |
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"29392": 0.04767346754670143} | 11360768 | OBJECTIVE To evaluate the effects of dietary and lifestyle interventions in pregnancy on maternal and fetal weight and to quantify the effects of these interventions on obstetric outcomes. DESIGN Systematic review and meta-analysis. DATA SOURCES Major databases from inception to January 2012 without language restrictions. STUDY SELECTION Randomised controlled trials that evaluated any dietary or lifestyle interventions with potential to influence maternal weight during pregnancy and outcomes of pregnancy. DATA SYNTHESIS Results summarised as relative risks for dichotomous data and mean differences for continuous data. RESULTS We identified 44 relevant randomised controlled trials (7278 women) evaluating three categories of interventions: diet, physical activity, and a mixed approach. Overall, there was 1.42 kg reduction (95% confidence interval 0.95 to 1.89 kg) in gestational weight gain with any intervention compared with control. With all interventions combined, there were no significant differences in birth weight (mean difference -50 g, -100 to 0 g) and the incidence of large for gestational age (relative risk 0.85, 0.66 to 1.09) or small for gestational age (1.00, 0.78 to 1.28) babies between the groups, though by itself physical activity was associated with reduced birth weight (mean difference -60 g, -120 to -10 g). Interventions were associated with a reduced the risk of pre-eclampsia (0.74, 0.60 to 0.92) and shoulder dystocia (0.39, 0.22 to 0.70), with no significant effect on other critically important outcomes. Dietary intervention resulted in the largest reduction in maternal gestational weight gain (3.84 kg, 2.45 to 5.22 kg), with improved pregnancy outcomes compared with other interventions. The overall evidence rating was low to very low for important outcomes such as pre-eclampsia, gestational diabetes, gestational hypertension, and preterm delivery. CONCLUSIONS Dietary and lifestyle interventions in pregnancy can reduce maternal gestational weight gain and improve outcomes for both mother and baby. Among the interventions, those based on diet are the most effective and are associated with reductions in maternal gestational weight gain and improved obstetric outcomes. | Effects of interventions in pregnancy on maternal weight and obstetric outcomes: meta-analysis of randomised evidence |
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0.029824240133166313, "28829": 0.02887592278420925, "28848": 0.4487839937210083, "29295": 0.15610189735889435} | 11369420 | Acute Myelogenous Leukemia (AML) is an aggressive cancer that strikes both adults and children and is frequently resistant to therapy. Thus, identifying signals needed for AML propagation is a critical step toward developing new approaches for treating this disease. Here, we show that Tetraspanin 3 is a target of the RNA binding protein Musashi 2, which plays a key role in AML. We generated Tspan3 knockout mice that were born without overt defects. However, Tspan3 deletion impaired leukemia stem cell self-renewal and disease propagation and markedly improved survival in mouse models of AML. Additionally, Tspan3 inhibition blocked growth of AML patient samples, suggesting that Tspan3 is also important in human disease. As part of the mechanism, we show that Tspan3 deficiency disabled responses to CXCL12/SDF-1 and led to defects in AML localization within the niche. These identify Tspan3 as an important regulator of aggressive leukemias and highlight a role for Tspan3 in oncogenesis. | Tetraspanin 3 Is Required for the Development and Propagation of Acute Myelogenous Leukemia. |
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Here, we demonstrate that transition between these two pluripotent states is associated with widespread Oct4 relocalization, mirrored by global rearrangement of enhancer chromatin landscapes. Our genomic and biochemical analyses identified candidate mediators of primed state-specific Oct4 binding, including Otx2 and Zic2/3. Even when differentiation cues are blocked, premature Otx2 overexpression is sufficient to exit the naive state, induce transcription of a substantial subset of primed pluripotency-associated genes, and redirect Oct4 to previously inaccessible enhancer sites. However, the ability of Otx2 to engage new enhancer regions is determined by its levels, cis-encoded properties of the sites, and the signaling environment. Our results illuminate regulatory mechanisms underlying pluripotency and suggest that the capacity of transcription factors such as Otx2 and Oct4 to pioneer new enhancer sites is highly context dependent. | Reorganization of enhancer patterns in transition from naive to primed pluripotency. |
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"28024": 1.02149498462677, "28406": 0.33675122261047363, "28691": 0.10818854719400406, "29025": 0.07431721687316895, "29046": 0.21530038118362427, "29107": 0.22548456490039825, "29206": 0.07884006202220917, "29320": 0.1212492436170578, "29537": 0.3297532796859741} | 11401602 | The effects of topoisomerases I and II on the replication of SV40 DNA were examined using an in vitro replication system of purified proteins that constitutes the monopolymerase system. In the presence of the two topoisomerases, two distinct nascent DNAs were formed. One product arising from the replication of the leading template strand was approximately half the size of the template DNA, whereas the other product derived from the lagging template strand consisted of short DNAs. These products were synthesized from both SV40 naked DNA and SV40 chromosomes. For the replication of SV40 naked DNA, either topoisomerase I or II maintained replication fork movement and supported complete leading strand synthesis. When SV40 chromosomes were replicated with the same proteins, reactions containing only topoisomerase I produced shorter leading strands. However, mature size DNA products accumulated in reactions supplemented with topoisomerase II, as well as in reactions containing only topoisomerase II. In the presence of crude extracts of HeLa cells, VP-16, a specific inhibitor of topoisomerase II, blocked elongation of the nascent DNA during the replication of SV40 chromosomes. These results indicate that topoisomerase II plays a crucial role as a swivelase in the late stage of SV40 chromosome replication in vitro. | Topoisomerase II plays an essential role as a swivelase in the late stage of SV40 chromosome replication in vitro. |
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0.013579257763922215, "29513": 0.053244512528181076} | 11411060 | Trypanosoma brucei, the causative agent of African sleeping sickness, is transmitted to its mammalian host by the tsetse. In the fly, the parasite's surface is covered with invariant procyclin, while in the mammal it resides extracellularly in its bloodstream form (BF) and is densely covered with highly immunogenic Variant Surface Glycoprotein (VSG). In the BF, the parasite varies this highly immunogenic surface VSG using a repertoire of ~2500 distinct VSG genes. Recent reports in mammalian systems point to a role for histone acetyl-lysine recognizing bromodomain proteins in the maintenance of stem cell fate, leading us to hypothesize that bromodomain proteins may maintain the BF cell fate in trypanosomes. Using small-molecule inhibitors and genetic mutants for individual bromodomain proteins, we performed RNA-seq experiments that revealed changes in the transcriptome similar to those seen in cells differentiating from the BF to the insect stage. This was recapitulated at the protein level by the appearance of insect-stage proteins on the cell surface. Furthermore, bromodomain inhibition disrupts two major BF-specific immune evasion mechanisms that trypanosomes harness to evade mammalian host antibody responses. First, monoallelic expression of the antigenically varied VSG is disrupted. Second, rapid internalization of antibodies bound to VSG on the surface of the trypanosome is blocked. Thus, our studies reveal a role for trypanosome bromodomain proteins in maintaining bloodstream stage identity and immune evasion. Importantly, bromodomain inhibition leads to a decrease in virulence in a mouse model of infection, establishing these proteins as potential therapeutic drug targets for trypanosomiasis. Our 1.25Å resolution crystal structure of a trypanosome bromodomain in complex with I-BET151 reveals a novel binding mode of the inhibitor, which serves as a promising starting point for rational drug design. | Bromodomain Proteins Contribute to Maintenance of Bloodstream Form Stage Identity in the African Trypanosome |
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many organisms. Because of the fundamental importance of this system in animal physiology, we asked when during the animal's life it is required to regulate these different processes. We find that in Caenorhabditis elegans, the pathway acts during adulthood, to relatively advanced ages, to influence aging. In contrast, it regulates diapause during development. In addition, the pathway controls longevity and reproduction independently of one another. Together our findings show that life-span regulation can be dissociated temporally from phenotypes that might seem to decrease the quality of life. | Timing requirements for insulin/IGF-1 signaling in C. elegans. |
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0.6793810129165649, "27199": 0.18411032855510712, "27321": 0.03925827145576477, "27325": 0.23402166366577148, "27395": 0.6139179468154907, "27441": 0.47402387857437134, "27491": 0.7737906575202942, "27781": 0.05694137513637543, "27814": 0.025073638185858727, "28154": 0.1930064558982849, "28311": 0.10026945173740387, "28389": 0.02887592278420925, "28667": 0.9108069539070129, "28674": 0.5151132941246033, "28788": 0.7417513132095337, "28873": 0.38374659419059753, "29295": 0.0797421783208847, "29543": 0.8500841856002808, "29610": 0.151916041970253} | 11415809 | OBJECTIVES Non-celiac wheat sensitivity (NCWS) is defined as a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis is incompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients with well-defined NCWS. METHODS The prospective study included 22 patients with irritable bowel syndrome (IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. Eight IBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge was performed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughly characterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surface markers. RESULTS Rectal biopsies from wheat-challenged NCWS patients showed that a significant mucosal CD45(+) infiltrate consisted of CD3(+) and CD3(-) lymphocytes, with the latter spontaneously producing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45(+) cells were T-bet(+), CD56(-), NKP44(-), and CD117(-), defining them as a type-1 innate lymphoid cells (ILC1). IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed a wheat-free diet. CONCLUSIONS These data indicate that, in patients with active NCWS, IFN-γ-producing ILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in the pathogenesis of NCWS. | Predominance of Type 1 Innate Lymphoid Cells in the Rectal Mucosa of Patients With Non-Celiac Wheat Sensitivity: Reversal After a Wheat-Free Diet |
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"24710": 0.7737906575202942, "24774": 0.2231435477733612, "24972": 0.8592242002487183, "25060": 0.0058422754518687725, "25117": 1.1102628707885742, "25170": 0.36086538434028625, "25180": 0.45870962738990784, "25613": 0.2160874605178833, "25635": 0.2317005842924118, "25743": 1.207676887512207, "26089": 0.043007105588912964, "26244": 0.06703783571720123, "26261": 0.755608320236206, "26282": 0.25995752215385437, "26356": 0.0317181795835495, "26591": 0.34023189544677734, "26633": 0.06337817758321762, "26721": 0.5784112811088562, "26835": 0.22626367211341858, "27169": 0.13499516248703003, "27216": 0.12814582884311676, "27559": 0.2409527748823166, "27854": 0.21372433006763458, "27915": 0.12642613053321838, "28038": 0.022212404757738113, "28173": 0.9635916948318481, "28688": 0.11604541540145874, "28969": 0.20102575421333313, "29060": 0.2786078155040741, "29146": 0.10291612148284912, "29290": 1.024303913116455, "29300": 1.3118107318878174} | 11419230 | We propose a concept for the folding and self-assembly of the pore-forming TatA complex from the Twin-arginine translocase and of other membrane proteins based on electrostatic "charge zippers. " Each subunit of TatA consists of a transmembrane segment, an amphiphilic helix (APH), and a C-terminal densely charged region (DCR). The sequence of charges in the DCR is complementary to the charge pattern on the APH, suggesting that the protein can be "zipped up" by a ladder of seven salt bridges. The length of the resulting hairpin matches the lipid bilayer thickness, hence a transmembrane pore could self-assemble via intra- and intermolecular salt bridges. The steric feasibility was rationalized by molecular dynamics simulations, and experimental evidence was obtained by monitoring the monomer-oligomer equilibrium of specific charge mutants. Similar "charge zippers" are proposed for other membrane-associated proteins, e.g., the biofilm-inducing peptide TisB, the human antimicrobial peptide dermcidin, and the pestiviral E(RNS) protein. | Folding and Self-Assembly of the TatA Translocation Pore Based on a Charge Zipper Mechanism |
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0.2637155055999756, "26244": 0.11951763927936554, "26402": 0.17431432008743286, "26512": 1.0907690525054932, "26520": 0.006812678650021553, "26534": 0.23247487843036652, "26601": 0.0913962796330452, "26773": 0.9371650815010071, "26775": 0.3554046154022217, "26832": 1.1115491390228271, "26874": 0.5506471395492554, "27169": 0.1011524572968483, "27226": 0.4400174915790558, "27295": 0.04860413447022438, "27642": 1.0229004621505737, "27777": 0.03925827145576477, "27854": 0.151916041970253, "28691": 0.0019512200960889459, "28848": 0.13157635927200317, "29297": 1.2829933166503906, "29458": 0.05970508232712746} | 11420613 | The 137 ribosomal protein genes (RPGs) of Saccharomyces provide a model for gene coregulation. We examined the positional and functional organization of their regulators (Rap1 [repressor activator protein 1], Fhl1, Ifh1, Sfp1, and Hmo1), the transcription machinery (TFIIB, TFIID, and RNA polymerase II), and chromatin at near-base-pair resolution using ChIP-exo, as RPGs are coordinately reprogrammed. Where Hmo1 is enriched, Fhl1, Ifh1, Sfp1, and Hmo1 cross-linked broadly to promoter DNA in an RPG-specific manner and demarcated by general minor groove widening. Importantly, Hmo1 extended 20-50 base pairs (bp) downstream from Fhl1. Upon RPG repression, Fhl1 remained in place. Hmo1 dissociated, which was coupled to an upstream shift of the +1 nucleosome, as reflected by the Hmo1 extension and core promoter region. Fhl1 and Hmo1 may create two regulatable and positionally distinct barriers, against which chromatin remodelers position the +1 nucleosome into either an activating or a repressive state. Consistent with in vitro studies, we found that specific TFIID subunits, in addition to cross-linking at the core promoter, made precise cross-links at Rap1 sites, which we interpret to reflect native Rap1-TFIID interactions. Our findings suggest how sequence-specific DNA binding regulates nucleosome positioning and transcription complex assembly >300 bp away and how coregulation coevolved with coding sequences. | Molecular mechanisms of ribosomal protein gene coregulation. |
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"26524": 0.17922431230545044, "26534": 0.0009760859538801014, "26741": 0.00875066313892603, "26773": 0.4770587682723999, "27133": 1.5809098482131958, "27321": 0.6327666640281677, "27564": 0.5045560002326965, "27753": 0.2830325961112976, "27854": 0.045809537172317505, "28086": 0.036437395960092545, "28156": 0.38574060797691345, "28466": 0.7592713832855225, "28517": 0.34922540187835693, "28667": 0.0752234235405922, "28689": 0.09584271162748337, "28691": 0.009718249551951885, "28696": 0.9500881433486938, "28817": 0.15860503911972046, "28873": 0.05046287178993225, "28964": 0.1808556467294693, "29533": 0.02887592278420925, "29720": 0.07068414986133575, "29721": 0.9060825705528259} | 11428884 | Adipose tissue is an important metabolic organ, the dysfunction of which is associated with the development of obesity, diabetes mellitus, and cardiovascular disease. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered the master regulator of adipocyte differentiation and function. Although its cell-autonomous role in adipogenesis has been clearly demonstrated in cell culture, previous fat-specific knockouts of the murine PPARγ gene did not demonstrate a dramatic phenotype in vivo. Here, using Adipoq-Cre mice to drive adipose-specific recombination, we report a unique fat-specific PPARγ knockout (PPARγ FKO) mouse model with almost no visible brown and white adipose tissue at age 3 mo. As a consequence, PPARγ FKO mice had hugely enlarged pancreatic islets, massive fatty livers, and dramatically elevated levels of blood glucose and serum insulin accompanied by extreme insulin resistance. PPARγ FKO mice also exhibited delayed hair coat formation associated with absence of dermal fat, disrupted mammary gland development with loss of mammary fat pads, and high bone mass with loss of bone marrow fat, indicating the critical roles of adipose PPARγ in these tissues. Together, our data reveal the necessity of fat PPARγ in adipose formation, whole-body metabolic homeostasis, and normal development of fat-containing tissues. | Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARγ. |
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"26835": 0.13670019805431366, "27046": 0.3723714053630829, "27166": 0.040196798741817474, "27177": 0.01934296265244484, "27467": 1.2910817861557007, "27480": 0.0038986403960734606, "27631": 0.025073638185858727, "27815": 0.9463045597076416, "27969": 0.35128939151763916, "28046": 0.016465263441205025, "28079": 1.1437997817993164, "28225": 0.11256109178066254, "28413": 0.011650617234408855, "28621": 0.083342544734478, "28804": 0.06612417846918106, "29172": 0.07159364968538284, "29342": 0.0009760859538801014, "29516": 0.0058422754518687725, "29598": 0.8731874823570251} | 11441172 | PURPOSE OF REVIEW Owing to the high mortality, risk of neurodevelopmental impairment and end-organ involvement with fungal infections in the neonate, prevention of invasive Candida infections in extremely preterm infants should be a priority for each neonatal ICU. RECENT FINDINGS Even with prompt or empiric treatment, mortality and neurodevelopmental impairment is high (57%) in infants <1000 g. Multiple studies have been performed with fluconazole prophylaxis, including a recent multicenter randomized controlled trial. All of the studies have demonstrated efficacy and safety with no increase or emergence of fungal resistance. Analysis of these studies demonstrates that fluconazole prophylaxis decreased the incidence of invasive Candida infections in high-risk infants <1000 g by 91% (P = 0.0004) and all infants <1500 g by 85% (P < 0.0001). The mortality rate from all causes was 25% lower (P = 0.029). Furthermore, studies have demonstrated that all Candida-related mortality can be eliminated in an entire neonatal ICU by targeting fluconazole prophylaxis in infants <1000 g. SUMMARY Targeting fluconazole prophylaxis to infants who are either <1000 g or < or =27 weeks is highly effective, safe and inexpensive, and can eliminate these infections as a cause of neurodevelopmental impairment and mortality. | Fluconazole prophylaxis: can we eliminate invasive Candida infections in the neonatal ICU? |
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"26208": 0.09850110858678818, "26218": 0.01934296265244484, "26290": 0.07793712615966797, "26305": 0.3027053773403168, "26419": 0.12470348179340363, "26741": 0.18573370575904846, "26787": 0.07068414986133575, "26877": 0.0174254160374403, "26947": 0.841701865196228, "27268": 0.8475768566131592, "27480": 0.34577593207359314, "27572": 0.2786078155040741, "27651": 0.09317722171545029, "27678": 0.8349450826644897, "27703": 0.13499516248703003, "28225": 1.5178706645965576, "28227": 0.9115922451019287, "28290": 1.269914150238037, "28403": 0.040196798741817474, "28450": 0.02412080205976963, "28466": 0.009718249551951885, "28616": 0.04113444685935974, "28685": 0.2674594223499298, "28689": 0.3560888469219208, "28828": 0.2852376699447632, "28829": 0.39893341064453125, "28835": 0.42735910415649414, "28927": 0.07250232994556427, "29125": 0.7389566898345947, "29238": 0.22157983481884003, "29301": 0.09228714555501938, "29339": 0.27934664487838745, "29481": 0.14095009863376617} | 11457219 | Fumarase deficiency is a rare autosomal recessive inborn error of metabolism of the Krebs Tricarboxylic Acid cycle. A heavy neurological disease burden is imparted by fumarase deficiency, commonly manifesting as microcephaly, dystonia, global developmental delay, seizures, and lethality in the infantile period. Heterozygous carriers also carry an increased risk of developing hereditary leiomyomatosis and renal cell carcinoma. We describe a non-consanguineous family in whom a dichorionic diamniotic twin pregnancy resulted in twin boys with fumarase deficiency proven at the biochemical, enzymatic, and molecular levels. Their clinical phenotype included hepatic involvement. A novel mutation in the fumarate hydratase gene was identified in this family. | Fumarase deficiency in dichorionic diamniotic twins. |
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"28873": 0.16690383851528168, "29107": 0.175953671336174, "29324": 0.52266925573349, "29490": 0.020300358533859253, "29513": 0.0317181795835495} | 11459139 | INTRODUCTION Angiopoietin-2 (ang-2), an angiogenic peptide released by endothelial cell Weibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability. Ang-2 is raised in severe sepsis but the mechanisms underlying this are not known. Nitric oxide (NO) inhibits WPB exocytosis, and bioavailability of endothelial NO is decreased in sepsis. We hypothesized that endothelial NO bioavailability would be inversely correlated with ang-2 concentrations in sepsis. METHODS Plasma ang-2, vascular endothelial growth factor (VEGF) and endothelial-active cytokines were assessed in 83 patients with early sepsis and 41 hospital controls, and related to reactive hyperaemia-peripheral arterial tonometry, RH-PAT, a measure of endothelial NO bioavailability. RESULTS Plasma Ang-2 was elevated in sepsis (median [interquartile range (IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4], sepsis without organ failure 6.1 [5.0-10.4], controls 2.7 [2.2-3.6], P < 0.0001). It correlated inversely with RH-PAT (r = -0.38, P < 0.0001) and positively with IL-6 (r = 0.57, P < 0.0001) and degree of organ failure (sequential organ function assessment score) (r = 0.58, P < 0.0001). The correlation of ang-2 with RH-PAT persisted after controlling for sepsis severity. In a longitudinal mixed-effects model, recovery of RH-PAT over time was associated with decline in ang-2. CONCLUSIONS Ang-2 is elevated in proportion to sepsis severity, and inversely correlated with NO-dependent microvascular reactivity. Impaired endothelial NO bioavailability may contribute to increased endothelial cell release of ang-2, endothelial activation and capillary leak. Agents that increase endothelial NO bioavailability or inhibit WPB exocytosis and/or Ang-2 activity may have therapeutic potential in sepsis. | Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity |
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0.1970241367816925, "26597": 0.5033760666847229, "27179": 1.0305955410003662, "27605": 0.0913962796330452, "27694": 0.20102575421333313, "28041": 1.2471669912338257, "28436": 0.5734702348709106, "28488": 0.6043586730957031, "28739": 0.23864774405956268, "28797": 0.2822965085506439, "28892": 0.036437395960092545, "28937": 0.2478361576795578, "29458": 0.21765978634357452} | 11469078 | A number of authors have attempted to defend ecologic (aggregate) studies by claiming that the goal of those studies is estimation of ecologic (contextual or group-level) effects rather than individual-level effects. Critics of these attempts point out that ecologic effect estimates are inevitably used as estimates of individual effects, despite disclaimers. A more subtle problem is that ecologic variation in the distribution of individual effects can bias ecologic estimates of contextual effects. The conditions leading to this bias are plausible and perhaps even common in studies of ecosocial factors and health outcomes because social context is not randomized across typical analysis units (administrative regions). By definition, ecologic data contain only marginal observations on the joint distribution of individually defined confounders and outcomes, and so identify neither contextual nor individual-level effects. While ecologic studies can still be useful given appropriate caveats, their problems are better addressed by multilevel study designs, which obtain and use individual as well as group-level data. Nonetheless, such studies often share certain special problems with ecologic studies, including problems due to inappropriate aggregation and problems due to temporal changes in covariate distributions. | Ecologic versus individual-level sources of bias in ecologic estimates of contextual health effects. |
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These asymmetries are established during embryogenesis by complex epigenetic and genetic cascades. Recent studies in a range of model organisms have made important progress in understanding how this laterality information is generated and conveyed to large regions of the embryo. Both commonalities and divergences are emerging in the mechanisms that different vertebrates use in left–right axis specification. Recent evidence also provides intriguing links between the establishment of left–right asymmetries and the symmetrical elongation of the anterior–posterior axis. | Left–right asymmetry in the vertebrate embryo: from early information to higher-level integration |
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Insulin resistance, hyperinsulinemia, increased levels of IGF, elevated levels of steroid and peptide hormones, and inflammatory markers appear to play a role in the connection between these different diseases. Medications, such as metformin and exogenous insulin, used to treat T2D may affect the risk of cancer and cancer-related mortality. Newer therapies targeting the insulin and IGF1 systems are being developed for use in cancer therapy. | Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. |
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This non-coding transcriptome has challenged the notion of the central dogma and its involvement in transcriptional and post-transcriptional regulation of gene expression is well established. Interestingly, several ncRNAs are dysregulated in cancer and current non-coding transcriptome research aims to use our increasing knowledge of these ncRNAs for the development of cancer biomarkers and anti-cancer drugs. In endocrine-related cancers, for which survival rates can be relatively low, there is a need for such advancements. In this review, we aimed to summarize the roles and clinical implications of recently discovered ncRNAs, including long ncRNAs, PIWI-interacting RNAs, tRNA- and Y RNA-derived ncRNAs, and small nucleolar RNAs, in endocrine-related cancers affecting both sexes. We focus on recent studies highlighting discoveries in ncRNA biology and expression in cancer, and conclude with a discussion on the challenges and future directions, including clinical application. ncRNAs show great promise as diagnostic tools and therapeutic targets, but further work is necessary to realize the potential of these unconventional transcripts. | Non-coding RNAs: Functions and applications in endocrine-related cancer. |
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"28309": 0.23402166366577148, "28488": 0.22937409579753876, "28699": 0.6128603219985962, "28820": 0.21922965347766876, "28911": 0.21530038118362427, "28991": 0.08064348995685577, "29060": 0.0009760859538801014, "29237": 0.17759032547473907, "29494": 0.6338034868240356} | 11498670 | Nonspecific protein-DNA interactions are inherently dynamic and involve both diffusion of the protein along the DNA and hopping of the protein from one DNA molecule or segment to another. Understanding how gene regulatory proteins interact nonspecifically with DNA in terms of both structure and dynamics is challenging because the experimental observables are an ensemble average of many rapidly exchanging states. By using a variety of NMR spectroscopic techniques, including relaxation analysis, paramagnetic relaxation enhancement, and residual dipolar couplings, we have characterized structural and kinetic aspects of the interaction of the HoxD9 homeodomain with a nonspecific, 24-bp DNA duplex in a system in which the protein is not constrained to any particular site. The data reveal that HoxD9 binds to nonspecific DNA with the same binding mode and orientation as that observed in the specific complex. The mobility, however, of Arg side-chains contacting the DNA is increased in the nonspecific complex relative to the specific one. The kinetics of intermolecular translocation between two different nonspecific DNA molecules have also been analyzed and reveal that at high DNA concentrations (such as those present in vivo) direct transfer from one nonspecific complex to another nonspecific DNA molecule occurs without going through the intermediary of free protein. This finding provides a simple mechanism for accelerating the target search in vivo for the specific site in a sea of nonspecific sites by permitting more effective sampling of available DNA sites as the protein jumps from one segment to another. | NMR structural and kinetic characterization of a homeodomain diffusing and hopping on nonspecific DNA. |
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"27159": 0.16607704758644104, "27354": 0.1710275560617447, "27398": 0.17922431230545044, "27528": 0.1930064558982849, "27781": 0.36086538434028625, "28086": 0.12470348179340363, "28290": 0.14686977863311768, "28389": 0.053244512528181076, "28788": 0.6139179468154907, "28873": 1.2533208131790161} | 11527199 | Background Current criteria for the selection of unrelated donors for hematopoietic cell transplantation (HCT) include matching for the alleles of each human leukocyte antigen (HLA) locus within the major histocompatibility complex (MHC). Graft-versus-host disease (GVHD), however, remains a significant and potentially life-threatening complication even after HLA-identical unrelated HCT. The MHC harbors more than 400 genes, but the total number of transplantation antigens is unknown. Genes that influence transplantation outcome could be identified by using linkage disequilibrium (LD)-mapping approaches, if the extended MHC haplotypes of the unrelated donor and recipient could be defined. | MHC Haplotype Matching for Unrelated Hematopoietic Cell Transplantation |
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Here we show that life span regulation by the Sir proteins is independent of their role in nonhomologous end joining. The short life span of a sir3 or sir4 mutant is due to the simultaneous expression of a and alpha mating-type information, which indirectly causes an increase in rDNA recombination and likely increases the production of extrachromosomal rDNA circles. The short life span of a sir2 mutant also reveals a direct failure to repress recombination generated by the Fob1p-mediated replication block in the rDNA. Sir2p is a limiting component in promoting yeast longevity, and increasing the gene dosage extends the life span in wild-type cells. A possible role of the conserved SIR2 in mammalian aging is discussed. | The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 13 |
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"22026": 0.3388410806655884, "22107": 0.10906458646059036, "22466": 0.45994341373443604, "22907": 0.5080875158309937, "23192": 0.053244512528181076, "23368": 0.5313173532485962, "23399": 0.19220098853111267, "23767": 0.026976587250828743, "23900": 0.5139457583427429, "23983": 0.5398913025856018, "24004": 0.1994270235300064, "24552": 1.5280922651290894, "24558": 0.20421554148197174, "24576": 0.7934166193008423, "25022": 0.05786345899105072, "25206": 0.6000806093215942, "25331": 0.3134697377681732, "25469": 0.1485546976327896, "25524": 0.34577593207359314, "26305": 0.5450005531311035, "26601": 0.14179791510105133, "26741": 0.5341835021972656, "26874": 0.25088030099868774, "27019": 0.9209672808647156, "27133": 0.19381128251552582, "27204": 0.14433705806732178, "27974": 0.18411032855510712, "28024": 0.2223619967699051, "28290": 0.06795065850019455, "28321": 0.23247487843036652, "28637": 0.09050461649894714, "29206": 0.09938567131757736, "29299": 0.5404602885246277} | 11532028 | Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations. | Meta-analysis identifies common variants associated with body mass index in East Asians |
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Post-translational modifications (PTMs) of the histone proteins within nucleosomes regulate these DNA processes. Histone H3(T118) is a site of phosphorylation [H3(T118ph)] and is implicated in regulation of transcription and DNA repair. We prepared H3(T118ph) by expressed protein ligation and determined its influence on nucleosome dynamics. We find H3(T118ph) reduces DNA-histone binding by 2 kcal/mol, increases nucleosome mobility by 28-fold and increases DNA accessibility near the dyad region by 6-fold. Moreover, H3(T118ph) increases the rate of hMSH2-hMSH6 nucleosome disassembly and enables nucleosome disassembly by the SWI/SNF chromatin remodeler. These studies suggest that H3(T118ph) directly enhances and may reprogram chromatin remodeling reactions. | Phosphorylation of histone H3(T118) alters nucleosome dynamics and remodeling |
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However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis. | Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. |
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0.4356052577495575, "29290": 0.4673144817352295} | 11557602 | LXR alpha is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a role for this transcription factor in the control of cellular cholesterol efflux. We demonstrate that retroviral expression of LXR alpha in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding the putative cholesterol/phospholipid transporter ATP-binding cassette (ABC)A1. In contrast, induction of ABCA1 mRNA in response to oxysterols is attenuated in cells that constitutively express dominant-negative forms of LXR alpha or LXR beta that lack the AF2 transcriptional activation domain. We further demonstrate that expression of LXR alpha in NIH 3T3 fibroblasts and/or treatment of these cells with oxysterols is sufficient to stimulate cholesterol efflux to extracellular apolipoprotein AI. The ability of oxysterol ligands of LXR to stimulate efflux is dramatically reduced in Tangier fibroblasts, which carry a loss of function mutation in the ABCA1 gene. Taken together, these results indicate that cellular cholesterol efflux is controlled, at least in part, at the level of transcription by a nuclear receptor-signaling pathway. They suggest a model in which activation of LXRs by oxysterols in response to cellular sterol loading leads to induction of the ABCA1 transporter and the stimulation of lipid efflux to extracellular acceptors. These findings have important implications for our understanding of mammalian cholesterol homeostasis and suggest new opportunities for pharmacological regulation of cellular lipid metabolism. | Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. |
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communication, the principle of which is largely unknown. Here we show that the amount of RGS16 (regulator of G protein signalling 16), a protein known to inactivate Gαi, increases at a selective circadian time to allow time-dependent activation of intracellular cyclic AMP signalling in the SCN. Gene ablation of Rgs16 leads to the loss of circadian production of cAMP and as a result lengthens circadian period of behavioural rhythm. The temporally precise regulation of the cAMP signal by clock-controlled RGS16 is needed for the dorsomedial SCN to maintain a normal phase-relationship to the ventrolateral SCN. Thus, RGS16-dependent temporal regulation of intracellular G protein signalling coordinates the intercellular synchrony of SCN pacemaker neurons and thereby defines the 24 h rhythm in behaviour. | Circadian regulation of intracellular G-protein signalling mediates intercellular synchrony and rhythmicity in the suprachiasmatic nucleus |
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In this study, we identified MDC1, a key checkpoint protein involved in the cellular response to DNA double-strand breaks, as a TopBP1-associated protein. The specific TopBP1-MDC1 interaction is mediated by the fifth BRCT domain of TopBP1 and the Ser-Asp-Thr (SDT) repeats of MDC1. In addition, we demonstrated that TopBP1 accumulation at stalled replication forks is promoted by the H2AX/MDC1 signaling cascade. Moreover, MDC1 is important for ATR-dependent Chk1 activation in response to replication stress. Collectively, our data suggest that MDC1 facilitates several important steps in both cellular DNA damage response and the DNA replication checkpoint. | MDC1 collaborates with TopBP1 in DNA replication checkpoint control |
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polymerase β (Pol β) is an error-prone enzyme which has been found to be overexpressed in several human tumors. By using a couple of recombinant CHO cells differing only from the exogenous expression of Pol β, we showed here that cells overexpressing Pol β are much more sensitive to IR treatments by increasing apoptosis. We also found that the surviving cells displayed an hypermutator phenotype which could be explained by different pathways involving Pol β, such as (i) an increased capacity to incorporate into DNA the mutagenic dGTP analog, 8-oxo-dGTP, one of the most abundant purine-derived nucleotides exposed to γ-irradiation, (ii) the induction of IR-induced DNA breaks and (iii) accumulation of chromosome aberrations induced by radiation. Alteration of Pol β expression in irradiated cells thus appears to strengthen both cell death and genetic changes associated with a malignant phenotype. These data provide new insights into the cellular response to radiations and the associated carcinogenic consequences. | Deregulated DNA polymerase β strengthens ionizing radiation-induced nucleotidic and chromosomal instabilities |
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0.7978238463401794} | 11578459 | BACKGROUND HOX genes are a family of developmental genes that are expressed neither in the developing forebrain nor in the normal brain. Aberrant expression of a HOX-gene dominated stem-cell signature in glioblastoma has been linked with increased resistance to chemo-radiotherapy and sustained proliferation of glioma initiating cells. Here we describe the epigenetic and genetic alterations and their interactions associated with the expression of this signature in glioblastoma. RESULTS We observe prominent hypermethylation of the HOXA locus 7p15.2 in glioblastoma in contrast to non-tumoral brain. Hypermethylation is associated with a gain of chromosome 7, a hallmark of glioblastoma, and may compensate for tumor-driven enhanced gene dosage as a rescue mechanism by preventing undue gene expression. We identify the CpG island of the HOXA10 alternative promoter that appears to escape hypermethylation in the HOX-high glioblastoma. An additive effect of gene copy gain at 7p15.2 and DNA methylation at key regulatory CpGs in HOXA10 is significantly associated with HOX-signature expression. Additionally, we show concordance between methylation status and presence of active or inactive chromatin marks in glioblastoma-derived spheres that are HOX-high or HOX-low, respectively. CONCLUSIONS Based on these findings, we propose co-evolution and interaction between gene copy gain, associated with a gain of chromosome 7, and additional epigenetic alterations as key mechanisms triggering a coordinated, but inappropriate, HOX transcriptional program in glioblastoma. | Chromosome 7 gain and DNA hypermethylation at the HOXA10 locus are associated with expression of a stem cell related HOX-signature in glioblastoma |
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0.0029254043474793434, "29206": 1.013020396232605, "29222": 0.27342069149017334, "29228": 0.06886265426874161} | 11581157 | The invertebrate's innate immune system was reported to show some form of adaptive features, termed trained immunity. However, the memory characteristics of innate immune system and the mechanisms behind such phenomena remain unclear. Using the invertebrate model Artemia, we verified the possibility or impossibility of trained immunity, examining the presence or absence of enduring memory against homologous and heterologous antigens (Vibrio spp.) during a transgenerational study. We also determined the mechanisms behind such phenomenon. Our results showed the occurrence of memory and partial discrimination in Artemia's immune system, as manifested by increased resistance, for three successive generations, of the progenies of Vibrio-exposed ancestors towards a homologous bacterial strain, rather than to a heterologous strain. This increased resistance phenotype was associated with elevated levels of hsp70 and hmgb1 signaling molecules and alteration in the expression of key innate immunity-related genes. Our results also showed stochastic pattern in the acetylation and methylation levels of H4 and H3K4me3 histones, respectively, in the progenies whose ancestors were challenged. Overall results suggest that innate immune responses in invertebrates have the capacity to be trained, and epigenetic reprogramming of (selected) innate immune effectors is likely to have central place in the mechanisms leading to trained immunity. | Probing the phenomenon of trained immunity in invertebrates during a transgenerational study, using brine shrimp Artemia as a model system |
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"26520": 0.31132611632347107, "26591": 0.19220098853111267, "26651": 0.1602703034877777, "26702": 1.0587663650512695, "26773": 0.2231435477733612, "26835": 0.10203468054533005, "27144": 0.6813592314720154, "27854": 0.18978065252304077, "28014": 1.0087559223175049, "28283": 0.7047978043556213, "28691": 0.009718249551951885, "28901": 0.11343330889940262, "28938": 0.25239890813827515, "29076": 0.14602625370025635} | 11603066 | Two-component signal transduction pathways comprising histidine protein kinases (HPKs) and their response regulators (RRs) are widely used to control bacterial responses to environmental challenges. Some bacteria have over 150 different two-component pathways, and the specificity of the phosphotransfer reactions within these systems is tightly controlled to prevent unwanted crosstalk. One of the best understood two-component signalling pathways is the chemotaxis pathway. Here, we present the 1.40 A crystal structure of the histidine-containing phosphotransfer domain of the chemotaxis HPK, CheA(3), in complex with its cognate RR, CheY(6). A methionine finger on CheY(6) that nestles in a hydrophobic pocket in CheA(3) was shown to be important for the interaction and was found to only occur in the cognate RRs of CheA(3), CheY(6), and CheB(2). Site-directed mutagenesis of this methionine in combination with two adjacent residues abolished binding, as shown by surface plasmon resonance studies, and phosphotransfer from CheA(3)-P to CheY(6). Introduction of this methionine and an adjacent alanine residue into a range of noncognate CheYs, dramatically changed their specificity, allowing protein interaction and rapid phosphotransfer from CheA(3)-P. The structure presented here has allowed us to identify specificity determinants for the CheA-CheY interaction and subsequently to successfully reengineer phosphotransfer signalling. In summary, our results provide valuable insight into how cells mediate specificity in one of the most abundant signalling pathways in biology, two-component signal transduction. | Using Structural Information to Change the Phosphotransfer Specificity of a Two-Component Chemotaxis Signalling Complex |
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0.11778303235769272, "28155": 0.0354953333735466, "28297": 0.08064348995685577, "28879": 0.2652147710323334, "29207": 0.1889725625514984, "29235": 0.025073638185858727, "29336": 0.14433705806732178, "29486": 0.06337817758321762, "29513": 0.04860413447022438} | 11614737 | IMPORTANCE Combining pharmacotherapies for tobacco-dependence treatment may increase smoking abstinence. OBJECTIVE To determine efficacy and safety of varenicline and bupropion sustained-release (SR; combination therapy) compared with varenicline (monotherapy) in cigarette smokers. DESIGN, SETTING, AND PARTICIPANTS Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and follow-up through week 52 conducted between October 2009 and April 2013 at 3 midwestern clinical research sites. Five hundred six adult (≥18 years) cigarette smokers were randomly assigned and 315 (62%) completed the study. INTERVENTIONS Twelve weeks of varenicline and bupropion SR or varenicline and placebo. MAIN OUTCOMES AND MEASURES Primary outcome was abstinence rates at week 12, defined as prolonged (no smoking from 2 weeks after the target quit date) abstinence and 7-day point-prevalence (no smoking past 7 days) abstinence. Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52. Outcomes were biochemically confirmed. RESULTS At 12 weeks, 53.0% of the combination therapy group achieved prolonged smoking abstinence and 56.2% achieved 7-day point-prevalence smoking abstinence compared with 43.2% and 48.6% in varenicline monotherapy (odds ratio [OR], 1.49; 95% CI, 1.05-2.12; P = .03 and OR, 1.36; 95% CI, 0.95-1.93; P = .09, respectively). At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence compared with 27.6% and 31.9% in varenicline monotherapy (OR, 1.52; 95% CI, 1.04-2.22; P = .03 and OR, 1.32; 95% CI, 0.91-1.91; P = .14, respectively). At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence compared with 24.5% and 29.2% in varenicline monotherapy (OR, 1.39; 95% CI, 0.93-2.07; P = .11 and OR, 1.40; 95% CI, 0.96-2.05; P = .08, respectively). Participants receiving combination therapy reported more anxiety (7.2% vs 3.1%; P = .04) and depressive symptoms (3.6% vs 0.8%; P = .03). CONCLUSIONS AND RELEVANCE Among cigarette smokers, combined use of varenicline and bupropion, compared with varenicline alone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks. Neither outcome was significantly different at 52 weeks. Further research is required to determine the role of combination therapy in smoking cessation. TRIAL REGISTRATION clinicaltrials.gov Identifier: http://clinicaltrials.gov/show/NCT00935818. | Combination varenicline and bupropion SR for tobacco-dependence treatment in cigarette smokers: a randomized trial. |
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"26773": 0.176772341132164, "26906": 0.2539152204990387, "27133": 1.1217793226242065, "27226": 0.6369074583053589, "27295": 0.22157983481884003, "27598": 0.7124901413917542, "27651": 0.14349138736724854, "27753": 0.2223619967699051, "27833": 0.37974658608436584, "27854": 0.1485546976327896, "28156": 0.637939989566803, "28173": 0.32553088665008545, "28194": 1.3505052328109741, "28728": 0.36697331070899963} | 11615242 | CCAAT/enhancer-binding proteins, C/EBPalpha and C/EBPbeta, are required for fat cell differentiation and maturation. Previous studies showed that replacement of C/EBPalpha with C/EBPbeta, generating the beta/beta alleles in the mouse genome, prevents lipid accumulation in white adipose tissue (WAT). In this study, beta/beta mice lived longer and had higher energy expenditure than their control littermates due to increased WAT energy oxidation. The WAT of beta/beta mice was enriched with metabolically active, thermogenic mitochondria known for energy burning. The beta/beta allele exerted its effect through the elevated expression of the G protein alpha stimulatory subunit (Galphas) in WAT. Galphas, when overexpressed in fat-laden 3T3-L1 cells, stimulated mitochondrial biogenesis similar to that seen in the WAT of beta/beta mice, and effectively diminished the stored lipid pool. | Effect of a C/EBP gene replacement on mitochondrial biogenesis in fat cells. |
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"28290": 0.1064341589808464, "28309": 0.23710809648036957, "28424": 0.2822965085506439, "28498": 0.0058422754518687725, "28685": 0.26146242022514343, "28691": 0.09050461649894714, "28723": 1.061472773551941, "28828": 0.7809720039367676, "28939": 0.17020416259765625, "29248": 0.6902132034301758, "29292": 1.0001721382141113, "29458": 0.6989894509315491} | 11615422 | The search for target genes involved in unbalanced acquired chromosomal abnormalities has been largely unsuccessful, because the breakpoints of these rearrangements are too variable. Here, we use the example of dicentric chromosomes in B cell precursor acute lymphoblastic leukemia to show that, despite this heterogeneity, single genes are targeted through a variety of mechanisms. FISH showed that, although they were heterogeneous, breakpoints on 9p resulted in the partial or complete deletion of PAX5. Molecular copy number counting further delineated the breakpoints and facilitated cloning with long-distance inverse PCR. This approach identified 5 fusion gene partners with PAX5: LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1 (20q11.1), KIF3B (20q11.21), and C20orf112 (20q11.1). In each predicted fusion protein, the DNA-binding paired domain of PAX5 was present. Using quantitative PCR, we demonstrated that both the deletion and gene fusion events resulted in the same underexpression of PAX5, which extended to the differential expression of the PAX5 target genes, EBF1, ALDH1A1, ATP9A, and FLT3. Further molecular analysis showed deletion and mutation of the homologous PAX5 allele, providing further support for the key role of PAX5. Here, we show that specific gene loci may be the target of heterogeneous translocation breakpoints in human cancer, acting through a variety of mechanisms. This approach indicates an application for the identification of cancer genes in solid tumours, where unbalanced chromosomal rearrangements are particularly prevalent and few genes have been identified. It can be extrapolated that this strategy will reveal that the same mechanisms operate in cancer pathogenesis in general. | Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. |
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0.26446542143821716, "25950": 0.2231435477733612, "25999": 0.1212492436170578, "26402": 0.06703783571720123, "26524": 0.13670019805431366, "26632": 1.2460440397262573, "26651": 0.40481385588645935, "26807": 0.06703783571720123, "27295": 0.8057082891464233, "27321": 0.18329764902591705, "27891": 0.06703783571720123, "28086": 0.12642613053321838, "28696": 0.07884006202220917, "28788": 0.1970241367816925, "28848": 0.7426811456680298, "29021": 0.13071982562541962, "29160": 0.10203468054533005, "29290": 0.03360854089260101, "29494": 0.5718178153038025} | 11616424 | Hypoglycemia is among the most injurious metabolic disorders caused by endotoxemia. In experimental endotoxemia with lipopolysaccharide (LPS) in animals, a marked glucose consumption is observed in macrophage-rich organs. However, the direct effect of LPS on the uptake of glucose by macrophages has not been fully understood, and the present study was undertaken to shed light on this point. The consumption and uptake of glucose, as measured with 2-deoxy-D-[3H]glucose, by murine peritoneal exudate macrophages in culture were accelerated two- to threefold by stimulation with 3 ng of LPS per ml. The rate of glucose uptake reached a plateau after 20 min of stimulation and remained at the maximum as long as LPS was present. Northern (RNA) blot analysis with cDNA probes for five known isoforms of glucose transporter (GLUT) revealed that the expression of GLUT by macrophages was restricted to the GLUT1 isoform during LPS stimulation and the amount of GLUT1 mRNA was increased by the stimulation. These results suggest that macrophage responses to LPS are supported by a rapid and sustained glucose influx via GLUT1 and that this is a participating factor in the development of systemic hypoglycemia when endotoxemia is prolonged. | Copyright � 1996, American Society for Microbiology Endotoxin-Induced Enhancement of Glucose Influx into |
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"19824": 0.8425432443618774, "19909": 0.29473719000816345, "19960": 0.6512666940689087, "19968": 0.12384103983640671, "19993": 0.14939609169960022, "20118": 1.0519683361053467, "20576": 0.06429435312747955, "20936": 0.0029254043474793434, "21419": 0.02316705882549286, "21673": 0.3963087201118469, "21778": 0.07068414986133575, "21784": 0.0770333781838417, "21877": 0.176772341132164, "21879": 0.7370892763137817, "22496": 0.4437839686870575, "22522": 0.3656192123889923, "22861": 0.16110190749168396, "22963": 0.03925827145576477, "23368": 0.2976420819759369, "23614": 0.8433839678764343, "23744": 0.22001366317272186, "24174": 0.1229778528213501, "24665": 0.11865071207284927, "24807": 0.3191637098789215, "24965": 0.034552380442619324, "25022": 0.4374985992908478, "25344": 0.08154398202896118, "25778": 0.5472630262374878, "26237": 0.9500881433486938, "27312": 0.39762192964553833, "27352": 0.026025565341114998, "27421": 0.2561853528022766, "27794": 0.8315495252609253, "27885": 1.15000319480896, "27937": 0.02792670577764511, "28031": 0.27786844968795776, "28321": 0.6410312056541443, "28774": 0.7201237678527832, "28994": 0.5313173532485962, "29031": 0.2539152204990387, "29300": 0.09317722171545029, "29392": 0.8731874823570251, "29477": 0.07068414986133575} | 11624482 | CONTEXT Certification by an American Board of Medical Specialties (ABMS) member board is emerging as a measure of physician quality. OBJECTIVE To identify demographic and educational factors associated with ABMS member board certification of US medical school graduates. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of a national cohort of 1997-2000 US medical school graduates, grouped by specialty choice at graduation and followed up through March 2, 2009. In separate multivariable logistic regression models for each specialty category, factors associated with ABMS member board certification were identified. MAIN OUTCOME MEASURE ABMS member board certification. RESULTS Of 42,440 graduates in the study sample, 37,054 (87.3%) were board certified. Graduates in all specialty categories with first-attempt passing scores in the highest tertile (vs first-attempt failing scores) on US Medical Licensing Examination Step 2 Clinical Knowledge were more likely to be board certified; adjusted odds ratios (AORs) varied by specialty category, with the lowest odds for emergency medicine (87.4% vs 73.6%; AOR, 1.82; 95% CI, 1.03-3.20) and highest odds for radiology (98.1% vs 74.9%; AOR, 13.19; 95% CI, 5.55-31.32). In each specialty category except family medicine, graduates self-identified as underrepresented racial/ethnic minorities (vs white) were less likely to be board certified, ranging from 83.5% vs 95.6% in the pediatrics category (AOR, 0.44; 95% CI, 0.33-0.58) to 71.5% vs 83.7% in the other nongeneralist specialties category (AOR, 0.79; 95% CI, 0.64-0.96). With each $50,000 unit increase in debt (vs no debt), graduates choosing obstetrics/gynecology were less likely to be board certified (AOR, 0.89; 95% CI, 0.83-0.96), and graduates choosing family medicine were more likely to be board certified (AOR, 1.13; 95% CI, 1.01-1.26). CONCLUSION Demographic and educational factors were associated with board certification among US medical school graduates in every specialty category examined; findings varied among specialty categories. | Factors associated with American Board of Medical Specialties member board certification among US medical school graduates. |
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0.2969166338443756, "24915": 0.14602625370025635, "25121": 0.1221139207482338, "25135": 0.1221139207482338, "25409": 0.6291293501853943, "25613": 0.06429435312747955, "26070": 0.04394211992621422, "26163": 0.684319257736206, "26180": 0.05970508232712746, "26226": 0.09050461649894714, "26451": 0.18816383183002472, "26462": 0.38441169261932373, "26906": 0.15777134895324707, "27204": 0.07068414986133575, "27794": 0.8459017872810364, "27833": 0.20022670924663544, "27954": 0.2184450328350067, "28093": 0.13157635927200317, "29166": 0.6598852276802063, "29299": 0.10555581003427505, "29308": 0.03360854089260101} | 11630388 | BACKGROUND Obesity is associated with diverse health risks, but the role of body weight as a risk factor for death remains controversial. METHODS We examined the association between body weight and the risk of death in a 12-year prospective cohort study of 1,213,829 Koreans between the ages of 30 and 95 years. We examined 82,372 deaths from any cause and 48,731 deaths from specific diseases (including 29,123 from cancer, 16,426 from atherosclerotic cardiovascular disease, and 3362 from respiratory disease) in relation to the body-mass index (BMI) (the weight in kilograms divided by the square of the height in meters). RESULTS In both sexes, the average baseline BMI was 23.2, and the rate of death from any cause had a J-shaped association with the BMI, regardless of cigarette-smoking history. The risk of death from any cause was lowest among patients with a BMI of 23.0 to 24.9. In all groups, the risk of death from respiratory causes was higher among subjects with a lower BMI, and the risk of death from atherosclerotic cardiovascular disease or cancer was higher among subjects with a higher BMI. The relative risk of death associated with BMI declined with increasing age. CONCLUSIONS Underweight, overweight, and obese men and women had higher rates of death than men and women of normal weight. The association of BMI with death varied according to the cause of death and was modified by age, sex, and smoking history. | Body-mass index and mortality in Korean men and women. |
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In this study, we describe a strategy for inducing aging-related features in human iPSC-derived lineages and apply it to the modeling of Parkinson's disease (PD). Our approach involves expression of progerin, a truncated form of lamin A associated with premature aging. We found that expression of progerin in iPSC-derived fibroblasts and neurons induces multiple aging-related markers and characteristics, including dopamine-specific phenotypes such as neuromelanin accumulation. Induced aging in PD iPSC-derived dopamine neurons revealed disease phenotypes that require both aging and genetic susceptibility, such as pronounced dendrite degeneration, progressive loss of tyrosine hydroxylase (TH) expression, and enlarged mitochondria or Lewy-body-precursor inclusions. Thus, our study suggests that progerin-induced aging can be used to reveal late-onset age-related disease features in hiPSC-based disease models. | Human iPSC-based modeling of late-onset disease via progerin-induced aging. |
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drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging. | SNAREs — engines for membrane fusion |
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"28873": 0.9980146884918213, "29091": 0.025073638185858727, "29222": 0.26820653676986694, "29486": 0.678390383720398, "29610": 0.26446542143821716} | 11666252 | The persistence of naive and memory T cells has long been of interest to immunologists, but the factors that influence the survival and homeostasis of these subsets have remained obscure. In recent years, it has become evident that the homeostasis of both naive and memory T-cell pools is highly dynamic and tightly regulated by internal stimuli, including cytokines and self-peptide–MHC ligands for the T-cell receptor. These homeostatic mechanisms might have a vital influence on the capacity of the T-cell pool to respond to both foreign and self-antigens. | Maintaining the norm: T-cell homeostasis |
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It remains unclear whether iPSCs generated from different cell types are molecularly and functionally similar. Here we show that iPSCs obtained from mouse fibroblasts, hematopoietic and myogenic cells exhibit distinct transcriptional and epigenetic patterns. Moreover, we demonstrate that cellular origin influences the in vitro differentiation potentials of iPSCs into embryoid bodies and different hematopoietic cell types. Notably, continuous passaging of iPSCs largely attenuates these differences. Our results suggest that early-passage iPSCs retain a transient epigenetic memory of their somatic cells of origin, which manifests as differential gene expression and altered differentiation capacity. These observations may influence ongoing attempts to use iPSCs for disease modeling and could also be exploited in potential therapeutic applications to enhance differentiation into desired cell lineages. | Cell type of origin influences the molecular and functional properties of mouse induced pluripotent stem cells |
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"26874": 0.952351450920105, "27226": 1.2041680812835693, "27642": 0.503966212272644, "27777": 0.22626367211341858, "27822": 0.9340999722480774, "28251": 0.8600510358810425, "28935": 0.05417001247406006, "29320": 0.11256109178066254} | 11674596 | A putative spindle matrix has been hypothesized to mediate chromosome motion, but its existence and functionality remain controversial. In this report, we show that Megator (Mtor), the Drosophila melanogaster counterpart of the human nuclear pore complex protein translocated promoter region (Tpr), and the spindle assembly checkpoint (SAC) protein Mad2 form a conserved complex that localizes to a nuclear derived spindle matrix in living cells. Fluorescence recovery after photobleaching experiments supports that Mtor is retained around spindle microtubules, where it shows distinct dynamic properties. Mtor/Tpr promotes the recruitment of Mad2 and Mps1 but not Mad1 to unattached kinetochores (KTs), mediating normal mitotic duration and SAC response. At anaphase, Mtor plays a role in spindle elongation, thereby affecting normal chromosome movement. We propose that Mtor/Tpr functions as a spatial regulator of the SAC, which ensures the efficient recruitment of Mad2 to unattached KTs at the onset of mitosis and proper spindle maturation, whereas enrichment of Mad2 in a spindle matrix helps confine the action of a diffusible "wait anaphase" signal to the vicinity of the spindle. | Spatiotemporal control of mitosis by the conserved spindle matrix protein Megator |
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ischemic heart disease. Homocysteine reduction is known to be maximal at a folic acid dosage of 1 mg/d, but the effect of lower doses (relevant to food fortification) is unclear. METHODS We randomized 151 patients with ischemic heart disease to 1 of 5 dosages of folic acid (0.2, 0.4, 0.6, 0.8, and 1.0 mg/d) or placebo. Fasting blood samples for serum homocysteine and serum folate analysis were taken initially, after 3 months of supplementation, and 3 months after folic acid use was discontinued. RESULTS Median serum homocysteine level decreased with increasing folic acid dosage, to a maximum at 0.8 mg of folic acid per day, when the homocysteine reduction (placebo adjusted) was 2.7 micromol/L (23%), similar to the known effect of folic acid dosages of 1 mg/d and above. The higher a person's initial serum homocysteine level, the greater was the response to folic acid, but there were statistically significant reductions regardless of the initial level. Serum folate level increased approximately linearly (5.5 nmol/L for every 0.1 mg of folic acid). Within-person fluctuations over time in serum homocysteine levels, measured in the placebo group, were large compared with the effect of folic acid, indicating that monitoring of the reduction in an individual is impractical. CONCLUSIONS A dosage of folic acid of 0.8 mg/d appears necessary to achieve the maximum reduction in serum homocysteine level across the range of homocysteine levels in the population. Current US food fortification levels will achieve only a small proportion of the achievable homocysteine reduction. | Randomized trial of folic acid supplementation and serum homocysteine levels. |
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Although the significance of cadherins in development is generally accepted, the mechanisms regulating adherens junction function during morphogenesis remain a subject of intense research. Adherens junctions are involved in the organization of simple cellular patterns, and more complex cell shape changes and cell movements that depend on the dynamic modulation of adherens junctions. | Adherens junctions in Drosophila retinal morphogenesis. |
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factor (VEGF) in skeletal morphogenesis, speculates on the future directions of research in this area, and describes some of the challenges in the field. VEGF regulates osteoclastic differentiation, migration, and activity. VEGF is, therefore, a key coordinator of the entire process. VEGF is necessary for osteoclastic activity both at the stage when the primary ossification center is established and later during bone growth. A number of studies have led to the identification of VEGF as a critical factor for the survival of chondrocytes. Several factors with important roles in regulating bone formation also induce the expression of VEGF by osteoblasts. Prostaglandins E1 and E2, BMP-4, BMP-6, BMP-7, FGF-2, TGF-β, endothelin-1, IGF-1, and vitamin D3 can all induce VEGF expression in osteoblasts by activating a variety of signaling pathways. Bone fractures can heal in two divergent ways, similar to the two ways of forming bone during embryonic development. Stabilized fractures heal by intramembranous ossification, and unstable fractures undergo endochondral ossification. The similarity between the embryonic bone development and repair of fractured bones, coupled with the finding that VEGF is expressed at sites of bone fracture, suggests that VEGF is involved in bone repair as it is in bone development. | Multiple roles of vascular endothelial growth factor (VEGF) in skeletal development, growth, and repair. |
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0.4673144817352295, "25384": 0.1011524572968483, "25455": 0.24018502235412598, "25608": 0.04674193635582924, "25719": 0.0174254160374403, "25775": 0.030771657824516296, "25918": 0.02412080205976963, "26163": 0.30558720231056213, "26226": 0.0038986403960734606, "26290": 0.06612417846918106, "26412": 1.187628984451294, "26535": 0.12038381397724152, "26677": 0.01934296265244484, "26777": 0.1693800985813141, "26785": 0.6244332790374756, "27065": 0.034552380442619324, "27312": 0.9827804565429688, "27339": 0.4537591338157654, "27633": 0.04674193635582924, "27718": 0.3784096837043762, "28177": 0.4617912769317627, "28281": 0.11168810725212097, "28317": 0.04487626627087593, "28407": 0.4450363218784332, "28817": 0.06612417846918106, "28879": 0.3464667797088623, "29166": 0.9425065517425537, "29329": 0.41001203656196594, "29361": 0.08603433519601822} | 11718220 | BACKGROUND Deep vein thrombosis (DVT) and pulmonary embolism are common after stroke. In small trials of patients undergoing surgery, graduated compression stockings (GCS) reduce the risk of DVT. National stroke guidelines extrapolating from these trials recommend their use in patients with stroke despite insufficient evidence. We assessed the effectiveness of thigh-length GCS to reduce DVT after stroke. METHODS In this outcome-blinded, randomised controlled trial, 2518 patients who were admitted to hospital within 1 week of an acute stroke and who were immobile were enrolled from 64 centres in the UK, Italy, and Australia. Patients were allocated via a central randomisation system to routine care plus thigh-length GCS (n=1256) or to routine care plus avoidance of GCS (n=1262). A technician who was blinded to treatment allocation undertook compression Doppler ultrasound of both legs at about 7-10 days and, when practical, again at 25-30 days after enrolment. The primary outcome was the occurrence of symptomatic or asymptomatic DVT in the popliteal or femoral veins. Analyses were by intention to treat. This study is registered, number ISRCTN28163533. FINDINGS All patients were included in the analyses. The primary outcome occurred in 126 (10.0%) patients allocated to thigh-length GCS and in 133 (10.5%) allocated to avoid GCS, resulting in a non-significant absolute reduction in risk of 0.5% (95% CI -1.9% to 2.9%). Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patients allocated to GCS than in those allocated to avoid their use (64 [5%] vs 16 [1%]; odds ratio 4.18, 95% CI 2.40-7.27). INTERPRETATION These data do not lend support to the use of thigh-length GCS in patients admitted to hospital with acute stroke. National guidelines for stroke might need to be revised on the basis of these results. FUNDING Medical Research Council (UK), Chief Scientist Office of Scottish Government, Chest Heart and Stroke Scotland, Tyco Healthcare (Covidien) USA, and UK Stroke Research Network. | Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial |
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0.0058422754518687725, "28154": 0.052318159490823746, "28155": 0.0606246218085289, "28691": 0.1477125883102417, "28696": 0.007782140281051397, "28756": 0.13243216276168823, "29175": 0.9798521995544434} | 11721286 | BACKGROUND Streptococcus pneumoniae infection starts from colonization of the host respiratory tract where interaction with host respiratory tract epithelial cells occurs. To investigate pneumococcal genes that are involved in the early stage of interaction with host epithelial cells, transcriptional responses of an encapsulated pathogenic pneumococcal strain TIGR4 upon exposure to human lung epithelial cells A549 for 0.5 h and 1 h time periods were investigated by using TIGR (JCVI) microarray technology. Gene expression changes were validated by quantitative real-time PCR (qRT-PCR) analysis. FINDINGS We observed different transcriptional profiles at two incubation time periods in which most gene expressions were down-regulated at 0.5 h but up-regulated at 1 h. Many genes associated with ribonucleotide biosynthesis were down-regulated at both time points, whereas the genes associated with cell envelope, energy metabolism, transport and protein synthesis were mostly up-regulated at 1 h. Furthermore, these profiles were compared to the transcriptomes of a TIGR4-derived strain in response to human macrophages for the same time periods. We found one set of genes that exhibited similar expression changes upon exposure to both types of host cells, including cell envelope-associated bgaA (SP0648) and nanA (SP1693), and uncharacterized gene clusters such as SP1677-SP1680 and SP1688-SP1690. CONCLUSION These data indicate that at the early stage of interaction with host epithelial cells, a complex gene regulation and expression change occur in bacteria. Some of them might play an essential role during pathogen-host interactions and for the establishment of infection. | Streptococcus pneumoniae early response genes to human lung epithelial cells |
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0.19862671196460724, "23820": 0.2822965085506439, "24396": 0.6275664567947388, "24454": 0.1994270235300064, "24551": 0.02792670577764511, "24879": 0.175953671336174, "25194": 0.259204238653183, "25284": 0.5069117546081543, "25370": 0.29981520771980286, "25449": 1.0742288827896118, "25517": 0.259204238653183, "25524": 0.5668440461158752, "25952": 0.04953393340110779, "26243": 0.20421554148197174, "26288": 0.2160874605178833, "26305": 0.08782484382390976, "26651": 0.09761575609445572, "26944": 0.6970458030700684, "27223": 0.018384648486971855, "27287": 0.004870930220931768, "27373": 0.02792670577764511, "27419": 0.4337083101272583, "27532": 0.03266380727291107, "27642": 0.08154398202896118, "27781": 0.6989894509315491, "27963": 0.15693697333335876, "28156": 0.23092569410800934, "28424": 0.45870962738990784, "28550": 0.11691460013389587, "28667": 0.016465263441205025, "28873": 0.06703783571720123, "29021": 0.35060185194015503} | 11721676 | Primary afferent fibers are originated from pseudounipolar sensory cells in dorsal root ganglia (DRG) and transmit external stimuli received in the skin to the spinal cord. Here we undertook a proteomic approach to uncover the polarity of primary afferent fibers. Lumbar spinal nerve segments, peripheral and central to DRG, were dissected from 5-wk-old Wistar rats and the lysates were subjected to large-sized 2-DE at pH 5-6. Among approximately 800 protein spots detected in the central and peripheral fractions, one of the unique spots in the peripheral fraction with MW of 60 kDa and pI of 5.6 was identified as an isoform of collapsin response mediator protein-2 (CRMP-2) by MALDI-TOF MS and Western blots with anti-CRMP-2 antibodies that recognize 1-17 and 486-528 residues. Since this novel spot was detected only in the peripheral fraction, but not in the central fraction, DRG, and other regions of the brain, it was named periCRMP-2. The C-terminal fragment of CRMP-2 was not detected in periCRMP-2 by MS analyses. Expression of periCRMP-2 decreased following sciatic nerve injury. These results suggest that periCRMP-2 is a C-terminal truncated isoform polarized in the peripheral side of spinal nerves and may be involved in nerve degeneration and regeneration. | Proteomic identification of a novel isoform of collapsin response mediator protein-2 in spinal nerves peripheral to dorsal root ganglia. |
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0.7370892763137817, "25206": 0.08871890604496002, "25524": 0.5398913025856018, "26237": 1.0207915306091309, "26264": 0.2983669638633728, "26305": 0.0913962796330452, "26319": 0.7028654217720032, "26601": 0.23710809648036957, "26874": 0.040196798741817474, "26886": 0.0842406153678894, "27009": 0.1485546976327896, "27354": 0.15275461971759796, "27605": 0.08871890604496002, "27859": 0.9635916948318481, "28032": 1.0326838493347168, "28093": 0.5168620347976685, "28426": 0.29328158497810364, "28436": 0.14095009863376617, "28911": 0.129004567861557, "29280": 0.0058422754518687725, "29296": 0.2447827309370041, "29458": 0.1889725625514984, "29490": 0.026976587250828743} | 11728637 | The FASTA package of sequence comparison programs has been modified to provide accurate statistical estimates for local sequence similarity scores with gaps. These estimates are derived using the extreme value distribution from the mean and variance of the local similarity scores of unrelated sequences after the scores have been corrected for the expected effect of library sequence length. This approach allows accurate estimates to be calculated for both FASTA and Smith-Waterman similarity scores for protein/protein, DNA/DNA, and protein/translated-DNA comparisons. The accuracy of the statistical estimates is summarized for 54 protein families using FASTA and Smith-Waterman scores. Probability estimates calculated from the distribution of similarity scores are generally conservative, as are probabilities calculated using the Altschul-Gish lambda, kappa, and eta parameters. The performance of several alternative methods for correcting similarity scores for library-sequence length was evaluated using 54 protein superfamilies from the PIR39 database and 110 protein families from the Prosite/SwissProt rel. 34 database. Both regression-scaled and Altschul-Gish scaled scores perform significantly better than unscaled Smith-Waterman or FASTA similarity scores. When the Prosite/ SwissProt test set is used, regression-scaled scores perform slightly better; when the PIR database is used, Altschul-Gish scaled scores perform best. Thus, length-corrected similarity scores improve the sensitivity of database searches. Statistical parameters that are derived from the distribution of similarity scores from the thousands of unrelated sequences typically encountered in a database search provide accurate estimates of statistical significance that can be used to infer sequence homology. | Empirical statistical estimates for sequence similarity searches |
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"26187": 0.07793712615966797, "26261": 1.0478670597076416, "26462": 1.1573970317840576, "26534": 0.29255300760269165, "26615": 0.0354953333735466, "26651": 0.7889899015426636, "26709": 0.3499138653278351, "26718": 0.20102575421333313, "26773": 0.2674594223499298, "26780": 0.8366385698318481, "26906": 1.2238903045654297, "26996": 0.43053874373435974, "27108": 0.09228714555501938, "27142": 0.4067663550376892, "27570": 0.0606246218085289, "27754": 0.32553088665008545, "27768": 0.07884006202220917, "27854": 0.045809537172317505, "28054": 0.02792670577764511, "28064": 0.021256839856505394, "28144": 0.08871890604496002, "28228": 0.05694137513637543, "28268": 0.3499138653278351, "28283": 0.05694137513637543, "28369": 0.11343330889940262, "28550": 0.04953393340110779, "28696": 0.05417001247406006, "29172": 0.06429435312747955, "29514": 0.7398891448974609, "29516": 1.2012346982955933, "29610": 0.5133614540100098} | 11738716 | Dietary restriction (DR) increases healthspan and longevity in many species, including primates, but it is often accompanied by impaired reproductive function. Whether signals associated with the reproductive system contribute to or are required for DR effects on lifespan has not been established. Here we show that expression of the cytochrome P450 DAF-9/CYP450 and production of the steroid hormone Δ(7)-dafachronic acid (DA) are increased in C. elegans subjected to DR. DA signalling through the non-canonical nuclear hormone receptor NHR-8/NHR and the nutrient-responsive kinase let-363/mTOR is essential for DR-mediated longevity. Steroid signalling also affects germline plasticity in response to nutrient deprivation and this is required to achieve lifespan extension. These data demonstrate that steroid signalling links germline physiology to lifespan when nutrients are limited, and establish a central role for let-363/mTOR in integrating signals derived from nutrients and steroid hormones. | Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans. |
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0.9994535446166992, "26243": 0.12642613053321838, "26402": 0.3269403576850891, "26651": 0.2184450328350067, "26773": 0.21687394380569458, "26780": 0.5330380201339722, "27108": 0.12642613053321838, "27183": 0.013579257763922215, "27295": 0.5404602885246277, "27833": 0.10555581003427505, "27891": 0.6583697199821472, "27989": 0.11951763927936554, "28156": 0.495672345161438, "28228": 0.7565253376960754, "28268": 0.3381449282169342, "28696": 1.0519683361053467, "28935": 0.0842406153678894, "29273": 0.0354953333735466, "29290": 0.025073638185858727, "29516": 1.0229004621505737} | 11742219 | Galanin (GAL) is known to stimulate feeding behavior. This peptide has different properties and functions from other feeding stimulants, e.g., neuropeptide Y and agouti-related protein. Hypothalamic GAL is relatively unresponsive to food deprivation and to changes in corticosterone, glucose utilization, dietary carbohydrate and leptin. This indicates that this peptide is not essential under conditions when food is scarce or low-energy, high-carbohydrate diets are being consumed. In contrast, recent evidence suggests that GAL in the paraventricular nucleus (PVN) functions in close relation to dietary fat and alcohol. In particular, it mediates functions that allow animals to adapt to conditions of positive energy balance involving excess consumption of these nutrients. This peptide in the PVN is stimulated by a high-fat diet and also by alcohol. It is stimulated by an increase in circulating lipids caused by a fat-rich meal or alcohol consumption, and it rises during the middle of the active feeding cycle, when fat consumption and triglycerides naturally rise. When centrally injected, GAL in the PVN increases the consumption of food and alcohol. Moreover, it produces a significantly stronger feeding response in rats maintained on a fat-rich diet, which also promotes alcohol intake. This evidence supports the existence of non-homeostatic, positive feedback circuits between GAL and both dietary fat and alcohol. These circuits are believed to contribute to the large meal size, over-consumption of alcohol, and obesity which are generally associated with fat-rich foods. | Regulation and effects of hypothalamic galanin: relation to dietary fat, alcohol ingestion, circulating lipids and energy homeostasis. |
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Progress has been made with many interventions implemented at scale and the evidence for effectiveness of nutrition interventions and delivery strategies has grown since The Lancet Series on Maternal and Child Undernutrition in 2008. We did a comprehensive update of interventions to address undernutrition and micronutrient deficiencies in women and children and used standard methods to assess emerging new evidence for delivery platforms. We modelled the effect on lives saved and cost of these interventions in the 34 countries that have 90% of the world's children with stunted growth. We also examined the effect of various delivery platforms and delivery options using community health workers to engage poor populations and promote behaviour change, access and uptake of interventions. Our analysis suggests the current total of deaths in children younger than 5 years can be reduced by 15% if populations can access ten evidence-based nutrition interventions at 90% coverage. Additionally, access to and uptake of iodised salt can alleviate iodine deficiency and improve health outcomes. Accelerated gains are possible and about a fifth of the existing burden of stunting can be averted using these approaches, if access is improved in this way. The estimated total additional annual cost involved for scaling up access to these ten direct nutrition interventions in the 34 focus countries is Int$9·6 billion per year. Continued investments in nutrition-specific interventions to avert maternal and child undernutrition and micronutrient deficiencies through community engagement and delivery strategies that can reach poor segments of the population at greatest risk can make a great difference. If this improved access is linked to nutrition-sensitive approaches--ie, women's empowerment, agriculture, food systems, education, employment, social protection, and safety nets--they can greatly accelerate progress in countries with the highest burden of maternal and child undernutrition and mortality. | Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? |
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In this study, we show that disruption of baseline fibroblast growth factor (FGF) signaling to the endothelium leads to a dramatic reduction in let-7 miRNA levels that, in turn, increases expression of transforming growth factor (TGF)-β ligands and receptors and activation of TGF-β signaling, leading to endothelial-to-mesenchymal transition (Endo-MT). We also find that Endo-MT is an important driver of neointima formation in a murine transplant arteriopathy model and in rejection of human transplant lesions. The decline in endothelial FGF signaling input is due to the appearance of an FGF resistance state that is characterized by inflammation-dependent reduction in expression and activation of key components of the FGF signaling cascade. These results establish FGF signaling as a critical factor in maintenance of endothelial homeostasis and point to an unexpected role of Endo-MT in vascular pathology. | FGF regulates TGF-β signaling and endothelial-to-mesenchymal transition via control of let-7 miRNA expression. |
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"28712": 0.35403475165367126, "29060": 0.1751343309879303, "29110": 0.7872136831283569, "29300": 0.025073638185858727, "29514": 0.9878844022750854, "29610": 1.0485517978668213} | 11774598 | Isolation of genes encoding the receptors for steroids, retinoids, vitamin D, and thyroid hormone and their structural and functional analysis revealed an evolutionarily conserved template for nuclear hormone receptors. This discovery sparked identification of numerous genes encoding related proteins, termed orphan receptors. Characterization of these orphan receptors and, in particular, of the retinoid X receptor (RXR) positioned nuclear receptors at the epicenter of the "Big Bang" of molecular endocrinology. This Review provides a personal perspective on nuclear receptors and explores their integrated and coordinated signaling networks that are essential for multicellular life, highlighting the RXR heterodimer and its associated ligands and transcriptional mechanism. | Nuclear Receptors, RXR, and the Big Bang |
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"26835": 0.23402166366577148, "26953": 1.3921366930007935, "26986": 0.0770333781838417, "27054": 0.16276304423809052, "27118": 0.058784693479537964, "27200": 0.1751343309879303, "27502": 0.0029254043474793434, "28024": 0.8152611255645752, "28409": 0.255429208278656, "28467": 0.20660123229026794, "28489": 0.05694137513637543, "28731": 0.20660123229026794, "28848": 1.12432062625885, "28976": 0.36967599391937256, "28977": 0.04674193635582924, "29300": 0.20022670924663544, "29490": 0.33675122261047363, "29577": 0.009718249551951885} | 11784947 | Short interfering RNAs (siRNAs) have been used to inhibit HIV-1 replication. The durable inhibition of HIV-1 replication by RNA interference has been impeded, however, by a high mutation rate when viral sequences are targeted and by cytotoxicity when cellular genes are knocked down. To identify cellular proteins that contribute to HIV-1 replication that can be chronically silenced without significant cytotoxicity, we employed a shRNA library that targets 54,509 human transcripts. We used this library to select a comprehensive population of Jurkat T-cell clones, each expressing a single discrete shRNA. The Jurkat clones were then infected with HIV-1. Clones that survived viral infection represent moieties silenced for a human mRNA needed for virus replication, but whose chronic knockdown did not cause cytotoxicity. Overall, 252 individual Jurkat mRNAs were identified. Twenty-two of these mRNAs were secondarily verified for their contributions to HIV-1 replication. Five mRNAs, NRF1, STXBP2, NCOA3, PRDM2, and EXOSC5, were studied for their effect on steps of the HIV-1 life cycle. We discuss the similarities and differences between our shRNA findings for HIV-1 using a spreading infection assay in human Jurkat T-cells and results from other investigators who used siRNA-based screenings in HeLa or 293T cells. | A genome-wide short hairpin RNA screening of jurkat T-cells for human proteins contributing to productive HIV-1 replication. |
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"26475": 0.9209672808647156, "26520": 0.20421554148197174, "26534": 0.6358738541603088, "26641": 0.16690383851528168, "26657": 0.4177590310573578, "26741": 0.1332872211933136, "26773": 0.6181373596191406, "26874": 0.8821197748184204, "27642": 0.9348671436309814, "27776": 0.11256109178066254, "27777": 0.2822965085506439, "27918": 0.22626367211341858, "28086": 0.06429435312747955, "28712": 0.04207121208310127, "28848": 0.5336109399795532, "28935": 0.37371641397476196, "29091": 0.058784693479537964, "29258": 1.0802149772644043, "29427": 0.08244366943836212} | 11822354 | Dosage compensation is a regulatory process that balances the expression of X-chromosomal genes between males (XY) and females (XX). In Drosophila, this requires non-coding RNAs and RNA-binding proteins (RBPs) whose specific functions remain elusive. Here we show that the Drosophila RBP UNR promotes the targeting of the activating male-specific-lethal complex to the X-chromosome by facilitating the interaction of two crucial subunits: the RNA helicase MLE and the long non-coding RNA roX2. | UNR facilitates the interaction of MLE with the lncRNA roX2 during Drosophila dosage compensation. |
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"25456": 0.21372433006763458, "25634": 0.04860413447022438, "25700": 0.06612417846918106, "25708": 1.020087480545044, "25714": 0.7537717819213867, "25761": 0.6492279767990112, "25932": 0.09850110858678818, "26083": 0.37640097737312317, "26163": 0.08961215615272522, "26243": 0.037378571927547455, "26402": 0.77198725938797, "26520": 0.09050461649894714, "26524": 0.20660123229026794, "26651": 0.05786345899105072, "26819": 0.3423145115375519, "26886": 0.6186635494232178, "27852": 0.8057082891464233, "27854": 0.0174254160374403, "27965": 0.38441169261932373, "28086": 1.2353124618530273, "28228": 0.12556517124176025, "28309": 0.04860413447022438, "28699": 0.0752234235405922, "29101": 0.026025565341114998} | 11831598 | Bistability in developmental pathways refers to the generation of binary outputs from graded or noisy inputs. Signaling thresholds are critical for bistability. Specification of the left/right (LR) axis in vertebrate embryos involves bistable expression of transforming growth factor beta (TGFbeta) member NODAL in the left lateral plate mesoderm (LPM) controlled by feed-forward and feedback loops. Here we provide evidence that bone morphogenetic protein (BMP)/SMAD1 signaling sets a repressive threshold in the LPM essential for the integrity of LR signaling. Conditional deletion of Smad1 in the LPM led to precocious and bilateral pathway activation. NODAL expression from both the left and right sides of the node contributed to bilateral activation, indicating sensitivity of mutant LPM to noisy input from the LR system. In vitro, BMP signaling inhibited NODAL pathway activation and formation of its downstream SMAD2/4-FOXH1 transcriptional complex. Activity was restored by overexpression of SMAD4 and in embryos, elevated SMAD4 in the right LPM robustly activated LR gene expression, an effect reversed by superactivated BMP signaling. We conclude that BMP/SMAD1 signaling sets a bilateral, repressive threshold for NODAL-dependent Nodal activation in LPM, limiting availability of SMAD4. This repressive threshold is essential for bistable output of the LR system. | BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4. |
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"25950": 1.0775588750839233, "25969": 0.9317949414253235, "26013": 0.016465263441205025, "26242": 0.45623743534088135, "26282": 0.4349733293056488, "26402": 0.06703783571720123, "26419": 1.207676887512207, "26591": 0.1946154683828354, "26632": 1.133164644241333, "26646": 0.2800849378108978, "26651": 0.014542185701429844, "26721": 0.6833335757255554, "26775": 0.6265231370925903, "26785": 1.1647365093231201, "26835": 1.0101795196533203, "26872": 0.619189441204071, "27293": 1.0257055759429932, "27321": 0.2822965085506439, "28024": 0.5438674688339233, "28424": 1.0802149772644043, "28518": 0.9100211262702942, "28691": 0.129004567861557, "28776": 1.102510929107666, "28788": 0.22626367211341858, "28935": 0.06886265426874161, "29090": 0.08603433519601822, "29166": 1.004473328590393, "29211": 0.006812678650021553, "29290": 0.440646231174469, "29308": 0.11691460013389587, "29720": 0.6882523894309998} | 11837657 | Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasome in macrophages, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis. These are mediated through caspase-1 and cathepsin-B, respectively. Human monocyte-derived macrophages were infected with virulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in strongly enhanced release of IL-1β, while a low MOI gave no IL-1β response. The infected macrophages were collected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane was determined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensive DNA fragmentation, loss of mitochondrial membrane potential, loss of plasma membrane integrity, and HMGB1 release. Although we observed plasma membrane permeabilization and IL-1β release from infected cells, the cell death induced by Mtb was not dependent on caspase-1 or cathepsin B. It was, however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches a threshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process. | Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1- and Cathepsin B-Independent Necrosis |
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0.29400965571403503, "28406": 0.6684301495552063, "28436": 0.12384103983640671, "28516": 0.05786345899105072, "28530": 0.09406650811433792, "28636": 0.18492233753204346, "28691": 0.020300358533859253, "28723": 0.11951763927936554, "28788": 0.1011524572968483, "28848": 0.47584590315818787, "29090": 0.5092619061470032, "29109": 0.029824240133166313, "29125": 0.38574060797691345, "29237": 0.014542185701429844, "29290": 0.4349733293056488} | 11840194 | Conventional protocols for differentiating human induced-pluripotent stem cells (hiPSCs) into smooth-muscle cells (SMCs) can be inefficient and generally fail to yield cells with a specific SMC phenotype (i.e., contractile or synthetic SMCs). Here, we present two novel hiPSC-SMC differentiation protocols that yield SMCs with predominantly contractile or synthetic phenotypes. Flow cytometry analyses of smooth-muscle actin (SMA) expression indicated that ~45% of the cells obtained with each protocol assumed an SMC phenotype, and that the populations could be purified to ~95% via metabolic selection. Assessments of cellular mRNA and/or protein levels indicated that SMA, myosin heavy chain II, collagen 1, calponin, transgelin, connexin 43, and vimentin expression in the SMCs obtained via the Contractile SMC protocol and in SMCs differentiated via a traditional protocol were similar, while SMCs produced via the Sythetic SMC protocol expressed less calponin, more collagen 1, and more connexin 43. Differences were also observed in functional assessments of the two SMC populations: the two-dimensional surface area of Contractile SMCs declined more extensively (to 12% versus 44% of original size) in response to carbachol treatment, while quantification of cell migration and proliferation were greater in Synthetic SMCs. Collectively, these data demonstrate that our novel differentiation protocols can efficiently generate SMCs from hiPSCs. | Differentiation of Human Induced-Pluripotent Stem Cells into Smooth-Muscle Cells: Two Novel Protocols |
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Histone variant H2A.Z (Htz1 in yeast) replaces conventional H2A in many nucleosomes. Microarray analysis revealed that HTZ1-activated genes cluster near telomeres. The reduced expression of most of these genes in htz1Delta cells was reversed by the deletion of SIR2 (sir2Delta) suggesting that H2A.Z antagonizes telomeric silencing. Other Htz1-activated genes flank the silent HMR mating-type locus. Their requirement for Htz1 can be bypassed by sir2Delta or by a deletion encompassing the silencing nucleation sites in HMR. In htz1Delta cells, Sir2 and Sir3 spread into flanking euchromatic regions, producing changes in histone H4 acetylation and H3 4-methylation indicative of ectopic heterochromatin formation. Htz1 is enriched in these euchromatic regions and acts synergistically with a boundary element to prevent the spread of heterochromatin. Thus, euchromatin and heterochromatin each contains components that antagonize switching to the opposite chromatin state. | Conserved Histone Variant H2A.Z Protects Euchromatin from the Ectopic Spread of Silent Heterochromatin |
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0.24631060659885406, "26775": 0.04767346754670143, "26876": 0.7863243818283081, "27781": 0.1401015669107437, "27854": 0.13414156436920166, "27989": 0.9591107368469238, "28466": 0.08244366943836212, "28873": 0.045809537172317505, "29060": 0.006812678650021553, "29339": 0.02792670577764511} | 11844826 | MURR1 is a multifunctional protein that inhibits nuclear factor kappaB (NF-kappaB), a transcription factor with pleiotropic functions affecting innate and adaptive immunity, apoptosis, cell cycle regulation, and oncogenesis. Here we report the discovery of a new family of proteins with homology to MURR1. These proteins form multimeric complexes and were identified in a biochemical screen for MURR1-associated factors. The family is defined by the presence of a conserved and unique motif termed the COMM (copper metabolism gene MURR1) domain, which functions as an interface for protein-protein interactions. Like MURR1, several of these factors also associate with and inhibit NF-kappaB. The proteins designated as COMMD or COMM domain containing 1-10 are extensively conserved in multicellular eukaryotic organisms and define a novel family of structural and functional homologs of MURR1. The prototype of this family, MURR1/COMMD1, suppresses NF-kappaB not by affecting nuclear translocation or binding of NF-kappaB to cognate motifs; rather, it functions in the nucleus by affecting the association of NF-kappaB with chromatin. | COMMD proteins, a novel family of structural and functional homologs of MURR1. |
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1.307593584060669, "26224": 0.13499516248703003, "26305": 0.5220900774002075, "26601": 0.15693697333335876, "26741": 0.10291612148284912, "26874": 0.9635916948318481, "26986": 0.05046287178993225, "27009": 0.49982786178588867, "27065": 0.010684899985790253, "27186": 0.08782484382390976, "27500": 0.2231435477733612, "27531": 0.19622190296649933, "27642": 0.791648268699646, "27703": 0.31132611632347107, "27814": 0.08513788133859634, "27881": 0.16690383851528168, "28472": 0.006812678650021553, "28518": 0.17431432008743286, "28522": 0.1221139207482338, "28696": 0.04953393340110779, "28774": 0.23556606471538544, "28828": 0.39762192964553833} | 11861374 | To define the genetic changes of flat urothelial lesions, carcinoma in situ (CIS) and moderate dysplasias (DII) were investigated for alterations in the two chromosomal regions most frequently involved in bladder cancer. Overall, 33 CIS and 16 DII from 21 patients were used to microdissect urothelium. Dual color fluorescence in situ hybridization (FISH) using gene locus probes of 9q22 (FACC), 9p21 (CDK), 17p13 (p53), and related centromeric probes was applied on interphase nuclei. In parallel, preamplified DNA of these samples was used for loss of heterozygosity (LOH) analyses with eight microsatellite markers on chromosomes 9p, 9q and 17p, and for sequencing of exons 5-9 of p53. Data indicated nearly identical deletion frequencies for chromosomes 9 and 17 for CIS (chromosome 9, 86%; p53, 84%). DII showed a lower deletion rate in comparison with CIS (chromosome 9, 75%; p53, 53%). A very high correlation between the results of FISH and LOH analyses was found. p53 mutations were detected in 12 of 15 patients (CIS, 72%; DII, 67%). In three of 16 patients with multifocal tumors, oligoclonal lesions were identified by LOH analyses, a finding further supported by sequencing of p53, by which two different p53 deletions were detected in two cases. In conclusion, data from microdissected flat urothelial lesions indicate that chromosome 9 deletions cannot be regarded as indicators of papillary growth, because they are found frequently in both types of flat lesions of the urothelium: those associated with papillary tumors and those that are not. The similar distribution and lower amount of genetic changes in DII render DII a possible precursor lesion of CIS. | Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder |
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"23943": 0.0019512200960889459, "24002": 0.2539152204990387, "24165": 0.1332872211933136, "24171": 0.35128939151763916, "24174": 0.00875066313892603, "24187": 0.8212929964065552, "24212": 0.8517522215843201, "24284": 0.12470348179340363, "24494": 0.27786844968795776, "24532": 0.08064348995685577, "24549": 0.07431721687316895, "24556": 0.22079704701900482, "24610": 0.6793810129165649, "24840": 0.2539152204990387, "25003": 0.26296505331993103, "25473": 0.5174443125724792, "25604": 0.06886265426874161, "25884": 0.6892333030700684, "26387": 0.21530038118362427, "26402": 0.0058422754518687725, "26514": 0.3963087201118469, "27589": 0.8600510358810425, "27947": 1.0051883459091187, "28268": 0.13071982562541962, "28596": 0.05046287178993225, "28613": 0.11691460013389587, "28667": 0.6394867897033691, "29167": 1.167778730392456, "29431": 0.08244366943836212, "29461": 0.12556517124176025, "29477": 1.1911962032318115} | 11862753 | Ractopamine hydrochloride (RAC) has consistently led to an advantage in carcass cutting yields of finishing pigs and remains a common feed additive in US finishing pig diets. Less is known about the effect of RAC on further processing characteristics. Some researchers have reported advantages in ultimate pH of the LM in pigs fed RAC. If a greater ultimate pH was also observed in hams, the increased pH could affect further processing characteristics and lead to better protein interaction and improved textural properties. The objective of this experiment was to determine if RAC-fed pigs yielded hams with a greater ultimate pH, and if so, whether or not that advantage improves textural properties and water retention of further processed hams. Two hundred hams from barrows and gilts fed RAC or control diets were selected based on HCW. Hams were fabricated into 5 separate pieces to determine cutting yields, and 6 muscles were evaluated for ultimate pH. Hams were processed to make cured and smoked hams. Ractopamine increased cutting yields of the whole ham (P < 0.0001), inside (P < 0.01), outside (P < 0.01), and knuckle (P < 0.01) when expressed as a percentage of chilled side weight. Ultimate pH of the rectus femoris, vastus lateralis, and semitendinosus were all 0.06 pH units greater (P < 0.05), the biceps femoris was 0.04 pH units greater (P = 0.02), and the semimembranosus and adductor muscles were 0.03 pH units greater in pigs fed 7.4 mg/kg of RAC when compared with control pigs. Cured hams from RAC-fed pigs were heavier at all stages of production. No differences were detected in binding strengths (P = 0.88) or protein fat-free values (P = 0.13) between RAC (9.06 kg and 20.37) and control hams (9.01 kg and 20.13). Ractopamine increased cutting yields, total weight of cured hams, and ultimate muscle pH. Ractopamine can be fed to pigs to achieve the desired growth characteristic advantages and cutting yields without affecting further processed ham characteristics. | Fresh meat and further processing characteristics of ham muscles from finishing pigs fed ractopamine hydrochloride. |
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"28685": 0.1751343309879303, "28788": 0.39696553349494934, "28828": 0.7629209756851196, "28873": 0.1905880719423294, "29090": 0.8600510358810425, "29267": 0.0317181795835495, "29290": 0.2447827309370041} | 11868606 | Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene codes of a chloride channel. The lungs of CF patients are chronically infected by several pathogens but bacteraemia have rarely been reported in this pathology. Besides that, circulating monocytes in CF patients exhibit a patent Endotoxin Tolerance (ET) state since they show a significant reduction of the inflammatory response to bacterial stimulus. Despite a previous description of this phenomenon, the direct cause of ET in CF patients remains unknown. In this study we have researched the possible role of microbial/endotoxin translocation from a localized infection to the bloodstream as a potential cause of ET induction in CF patients. Plasma analysis of fourteen CF patients revealed high levels of LPS compared to healthy volunteers and patients who suffer from Chronic Obstructive Pulmonary Disease. Experiments in vitro showed that endotoxin concentrations found in plasma of CF patients were enough to induce an ET phenotype in monocytes from healthy controls. In agreement with clinical data, we failed to detect bacterial DNA in CF plasma. Our results suggest that soluble endotoxin present in bloodstream of CF patients causes endotoxin tolerance in their circulating monocytes. | Translocated LPS Might Cause Endotoxin Tolerance in Circulating Monocytes of Cystic Fibrosis Patients |
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1.0828639268875122, "25409": 0.6853039860725403, "25437": 0.6223390698432922, "25719": 0.05417001247406006, "25819": 0.09228714555501938, "26163": 0.26146242022514343, "26179": 0.9271688461303711, "26264": 0.8383291959762573, "26462": 0.2576959431171417, "26745": 0.24631060659885406, "26914": 0.025073638185858727, "27159": 0.02316705882549286, "27312": 0.11951763927936554, "27794": 0.19622190296649933, "27813": 0.05694137513637543, "28093": 0.08603433519601822, "28207": 0.01934296265244484, "29458": 0.009718249551951885, "29492": 0.4126010537147522} | 11880289 | BACKGROUND Age-specific effects of mammographic screening, and the timing of such effects, are a matter of debate. The results of the UK Age trial, which compared the effect of invitation to annual mammographic screening from age 40 years with commencement of screening at age 50 years on breast cancer mortality, have been reported at 10 years of follow-up and showed no significant difference in mortality between the trial groups. Here, we report the results of the UK Age trial after 17 years of follow-up. METHODS Women aged 39-41 from 23 UK NHS Breast Screening Programme units years were randomly assigned by individual randomisation (1:2) to either an intervention group offered annual screening by mammography up to and including the calendar year of their 48th birthday or to a control group receiving usual medical care (invited for screening at age 50 years and every 3 years thereafter). Both groups were stratified by general practice. We compared breast cancer incidence and mortality by time since randomisation. Analyses included all women randomly assigned who could be traced with the National Health Service Central Register and who had not died or emigrated before entry. The primary outcome measures were mortality from breast cancer (defined as deaths with breast cancer coded as the underlying cause of death) and breast cancer incidence, including in-situ, invasive, and total incidence. Because there is an interest in the timing of the mortality effect, we analysed the results in different follow-up periods. This trial is registered, number ISRCTN24647151. FINDINGS Between Oct 14, 1990, and Sept 25, 1997, 160 921 participants were randomly assigned; 53 883 women in the intervention group and 106 953 assigned to usual medical care were included in this analysis. After a median follow-up of 17 years (IQR 16·8-18·8), the rate ratio (RR) for breast cancer mortality was 0·88 (95% CI 0·74-1·04) from tumours diagnosed during the intervention phase. A significant reduction in breast cancer mortality was noted in the intervention group compared with the control group in the first 10 years after diagnosis (RR 0·75, 0·58-0·97) but not thereafter (RR 1·02, 0·80-1·30) from tumours diagnosed during the intervention phase. The overall breast cancer incidence during 17 year follow-up was similar between the intervention group and the control group (RR 0·98, 0·93-1·04). INTERPRETATION Our results support an early reduction in mortality from breast cancer with annual mammography screening in women aged 40-49 years. Further data are needed to fully understand long-term effects. Cumulative incidence figures suggest at worst a small amount of overdiagnosis. FUNDING National Institute for Health Research Health Technology Assessment programme and the American Cancer Society. Past funding was received from the Medical Research Council, Cancer Research UK, the UK Department of Health, and the US National Cancer Institute. | Effect of mammographic screening from age 40 years on breast cancer mortality in the UK Age trial at 17 years' follow-up: a randomised controlled trial. |
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"28689": 0.016465263441205025, "28873": 0.3177432417869568, "28935": 0.0174254160374403, "29107": 0.46117570996284485, "29145": 0.16524957120418549, "29167": 0.8649974465370178, "29206": 0.15275461971759796, "29295": 0.10203468054533005, "29458": 0.30917787551879883, "29490": 0.040196798741817474} | 11884292 | BACKGROUND AND AIMS We adopted the twin method to disentangle the genetic and environmental components of susceptibility to coeliac disease (CD). We estimated disease concordance rate by zygosity and HLA genotypes, discordance times, progression rates to disease, and heritability. METHODS We crosslinked the Italian Twin Registry with the membership lists of the Italian Coeliac Disease Association and recruited 23 monozygotic (MZ) and 50 dizygotic (DZ) twin pairs with at least one affected member. Zygosity was assigned by DNA fingerprinting, and HLA-DQ and DR alleles were genotyped. Disease status was ascertained by antiendomysial, anti-human tissue transglutaminase antibodies, and bowel biopsy. RESULTS Concordance was significantly higher in MZ (83.3% probandwise, 71.4% pairwise) than in DZ (16.7% probandwise, 9.1% pairwise) pairs. Concordance was not affected by sex or HLA genotype of the co-twin and being MZ was significantly associated with the occurrence of CD (Cox adjusted hazard ratio 14.3 (95% confidence interval 4.0-50.3)). In 90% of concordant pairs the discordance time was <or=2 years. MZ and DZ co-twins had 70% and 9% cumulative probability of having symptomatic or silent forms of CD, respectively, within five years. Under ACE (additive genetic, common, and unshared environmental factors) models, with CD population prevalences of 1/91 and 1/1000, heritability estimates were 87% and 57%, respectively. CONCLUSION MZ pairs have a high probability of being concordant, regardless of sex or HLA genotype. Most of the affected co-twins receive a diagnosis within two years. A remarkable proportion of phenotypic variance is due to genetic factors. | Concordance, disease progression, and heritability of coeliac disease in Italian twins. |
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0.01934296265244484, "29361": 0.33953672647476196} | 11884867 | Electro-magnetic fields and wireless technology are part of modern life. The use of Magnetic Resonance Imaging (MRI) machines for clarification of internal human structures and function in healthcare is increasing. The rapid development of wireless devices, their miniaturization and their application as clinical tools creates an expanding intersection zone. Although safety standards for devices in MRI machines have been previously published, it is not clear that newer wireless technologies, including devices used in Medical Body Area Networks (MBAN) have been rigorously tested or disclosed. We undertook a review of the clinical scientific literature and the United States Food and Drug Administration adverse events database to discover whether this is a significant issue. There are currently no published studies specifically addressing the safety of wireless devices potentially used in MBAN in MRI machines. We suggest the addition of a research track to clarify the safety of MBAN devices in MRI machines. Informed design of current and future MBAN components, devices and systems can avoid potential patient adverse events due to the un-intended consequences of the concurrent use of these technologies in MRI machines. | A literature review of the safety of medical body area network devices in magnetic resonance imaging |
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0.1619328260421753, "24848": 0.9944084882736206, "25117": 0.11951763927936554, "25172": 0.6931471824645996, "25194": 0.04207121208310127, "25714": 0.5092619061470032, "25862": 0.12814582884311676, "26243": 0.1212492436170578, "26402": 0.32058215141296387, "26651": 0.09050461649894714, "26773": 0.23479416966438293, "27233": 0.823009729385376, "27830": 0.025073638185858727, "27833": 0.1510767638683319, "28156": 0.31845372915267944, "28228": 0.10467668622732162, "28282": 1.1506214141845703, "28287": 0.026976587250828743, "28466": 0.05139094591140747, "28696": 0.18816383183002472, "28829": 0.5898461937904358, "28848": 0.6764062643051147, "28879": 0.25467249751091003, "28927": 0.2539152204990387, "29290": 0.46117570996284485, "29536": 0.04860413447022438} | 11886686 | The importance of neuropeptides in the hypothalamus has been experimentally established. Due to difficulties in assessing function in vivo, the roles of the fast-acting neurotransmitters glutamate and GABA are largely unknown. Synaptic vesicular transporters (VGLUTs for glutamate and VGAT for GABA) are required for vesicular uptake and, consequently, synaptic release of neurotransmitters. Ventromedial hypothalamic (VMH) neurons are predominantly glutamatergic and express VGLUT2. To evaluate the role of glutamate release from VMH neurons, we generated mice lacking VGLUT2 selectively in SF1 neurons (a major subset of VMH neurons). These mice have hypoglycemia during fasting secondary to impaired fasting-induced increases in the glucose-raising pancreatic hormone glucagon and impaired induction in liver of mRNAs encoding PGC-1alpha and the gluconeogenic enzymes PEPCK and G6Pase. Similarly, these mice have defective counterregulatory responses to insulin-induced hypoglycemia and 2-deoxyglucose (an antimetabolite). Thus, glutamate release from VMH neurons is an important component of the neurocircuitry that functions to prevent hypoglycemia. | Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. |
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These observations have raised doubts about the involvement of c-src in the etiology of human tumors. However, recent studies have shown that c-Src, a non-receptor tyrosine kinase, exhibits elevated protein levels and activity in numerous types of human cancers. Furthermore, it has been found to be a critical component of multiple signaling pathways that regulate proliferation, survival, metastasis, and angiogenesis. Because of its important role in these oncogenic processes, it represents a therapeutic target ripe for exploitation. | c-Src and cooperating partners in human cancer. |
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Treg dysfunction could be a primary, causal event or may result from perturbations in the immune system during disease development. Polymorphisms in genes associated with Treg function, such as IL2RA, confer a higher risk of autoimmune disease. Although this suggests a primary role for defective Tregs in autoimmunity, a link between IL2RA gene polymorphisms and Treg function has not been examined. We addressed this by examining the impact of an IL2RA haplotype associated with type 1 diabetes on Treg fitness and suppressive function. Studies were conducted using healthy human subjects to avoid any confounding effects of disease. We demonstrated that the presence of an autoimmune disease-associated IL2RA haplotype correlates with diminished IL-2 responsiveness in Ag-experienced CD4(+) T cells, as measured by phosphorylation of STAT5a, and is associated with lower levels of FOXP3 expression by Tregs and a reduction in their ability to suppress proliferation of autologous effector T cells. These data offer a rationale that contributes to the molecular and cellular mechanisms through which polymorphisms in the IL-2RA gene affect immune regulation, and consequently upon susceptibility to autoimmune and inflammatory diseases. | Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. |
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"29290": 0.7951818704605103, "29443": 0.043007105588912964, "29490": 0.3824150264263153} | 11900630 | Objective. Chemotherapeutic agents function by inducing apoptosis and their effectiveness depends on the balance of pro- and anti-apoptotic proteins in cells. Due to the complicated interactions of the many proteins involved, it has been difficult to determine in tumors whether overexpression of single genes is prognostic for increased resistance. Therefore, we studied the influence of bcl-2 overexpression on resistance to chemotherapeutics in a transgenic mouse system. This allowed us to study a wide variety of cells, including important but rare populations such as hematopoietic stem cells (HSC).Methods. H2K-bcl-2 transgenic and wild-type (WT) mice were treated with several agents(5-fluoruracil, cyclophosphamide, and busulfan) to determine the contribution of increased amounts of bcl-2 to the response to these chemotherapeutics in vivo. Populations were enumerated using flow cytometry. HSC were studied by FACS purification and long-term reconstitution assays in vivo and resistance was confirmed by short-term proliferation assays with different amounts of chemotherapeutics in vitro. Results. bcl-2 overexpression alone protects many cell types, though protection levels differ between populations and agents. However, even sensitive populations return to pretreatment levels faster in transgenic mice. bcl-2 overexpression also prevents the dramatic changes in HSC following 5-FU treatment (downregulation of c-kit, upregulation of Lin, less efficient long-term reconstitution). In vitro studies directly demonstrate increased resistance of bcl-2 overexpressing HSC to chemotherapeutic agents. Conclusions. Increased expression of bcl-2 in HSC and their progeny endows these cells with broad resistance to chemotherapeutic agents. The ability to (differentially) regulate sensitivity to apoptosis of bystander and tumor cells is clinically important. | Hematopoietic stem cells and other hematopoietic cells show broad resistance to chemotherapeutic agents in vivo when overexpressing bcl-2. |
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"28268": 0.4770587682723999, "28788": 0.2983669638633728} | 11902109 | The Drosophila lymph gland is a haematopoietic organ in which progenitor cells, which are most akin to the common myeloid progenitor in mammals, proliferate and differentiate into three types of mature cell--plasmatocytes, crystal cells and lamellocytes--the functions of which are reminiscent of mammalian myeloid cells. During the first and early second instars of larval development, the lymph gland contains only progenitors, whereas in the third instar, a medial region of the primary lobe of the lymph gland called the medullary zone contains these progenitors, and maturing blood cells are found juxtaposed in a peripheral region designated the cortical zone. A third group of cells referred to as the posterior signalling centre functions as a haematopoietic niche. Similarly to mammalian myeloid cells, Drosophila blood cells respond to multiple stresses including hypoxia, infection and oxidative stress. However, how systemic signals are sensed by myeloid progenitors to regulate cell-fate determination has not been well described. Here, we show that the haematopoietic progenitors of Drosophila are direct targets of systemic (insulin) and nutritional (essential amino acid) signals, and that these systemic signals maintain the progenitors by promoting Wingless (WNT in mammals) signalling. We expect that this study will promote investigation of such possible direct signal sensing mechanisms by mammalian myeloid progenitors. | Direct sensing of systemic and nutritional signals by hematopoietic progenitors in Drosophila |
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Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53−/− cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53. | Regulation of autophagy by cytoplasmic p53 |
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Molecularly, the circadian rhythm of sleep involves interlocking positive- and negative-feedback mechanisms of circadian genes and their protein products in cells of the suprachiasmatic nucleus that are entrained to ambient conditions by light. Circadian information is integrated with information on homeostatic sleep need in nuclei of the anterior hypothalamus. These nuclei interact with arousal systems in the posterior hypothalamus, basal forebrain and brainstem to control sleep onset. During sleep, an ultradian oscillator in the mesopontine junction controls the regular alternation of rapid eye movement (REM) and non-REM sleep. Sleep cycles are accompanied by neuromodulatory influences on forebrain structures that influence behaviour, consciousness and cognition. | The Neurobiology of Sleep: Genetics, cellular physiology and subcortical networks |
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"25761": 1.2353124618530273, "25978": 0.14602625370025635, "26305": 0.02412080205976963, "26396": 0.3982778787612915, "26402": 0.1619328260421753, "26520": 0.34922540187835693, "26601": 0.02792670577764511, "26632": 1.0285027027130127, "26702": 0.09938567131757736, "26709": 0.0029254043474793434, "26718": 0.20660123229026794, "26838": 0.06337817758321762, "26874": 0.11081436276435852, "26982": 0.9936857223510742, "27118": 0.8861536383628845, "27144": 0.17267228662967682, "27673": 0.3070250153541565, "27709": 0.9287132620811462, "27881": 0.13071982562541962, "28064": 0.3897167444229126, "28144": 0.06520967930555344, "28156": 0.3963087201118469, "28290": 0.12986256182193756, "28327": 1.0628231763839722, "28424": 0.04767346754670143, "28577": 0.40741631388664246, "29206": 0.034552380442619324, "29516": 0.14686977863311768} | 11915280 | Aberrant gene silencing accompanied by DNA methylation is associated with neoplastic progression in many tumors that also show global loss of DNA methylation. Using conditional inactivation of de novo methyltransferase Dnmt3b in Apc(Min/+) mice, we demonstrate that the loss of Dnmt3b has no impact on microadenoma formation, which is considered the earliest stage of intestinal tumor formation. Nevertheless, we observed a significant decrease in the formation of macroscopic colonic adenomas. Interestingly, many large adenomas showed regions with Dnmt3b inactivation, indicating that Dnmt3b is required for initial outgrowth of macroscopic adenomas but is not required for their maintenance. These results support a role for Dnmt3b in the transition stage between microadenoma formation and macroscopic colonic tumor growth and further suggest that Dnmt3b, and by extension de novo methylation, is not required for maintaining tumor growth after this transition stage has occurred. | Suppression of intestinal neoplasia by deletion of Dnmt3b |
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"26520": 0.08244366943836212, "26591": 0.24018502235412598, "26721": 0.9951307773590088, "26835": 1.1858406066894531, "26996": 0.3027053773403168, "27142": 0.4145384132862091, "27152": 0.42225050926208496, "27199": 0.4818955361843109, "27343": 0.24401791393756866, "27441": 0.06886265426874161, "27920": 0.4196864068508148, "28024": 0.9348671436309814, "28283": 0.14179791510105133, "28467": 0.176772341132164, "28518": 0.011650617234408855, "28644": 0.1734936386346817, "28788": 0.46853771805763245, "28873": 0.13243216276168823, "29477": 0.9248477816581726, "29494": 0.5069117546081543, "29516": 0.2493593990802765, "29543": 0.24018502235412598} | 11921405 | The gut mucosal epithelium separates the host from the microbiota, but enteropathogens such as Salmonella Typhimurium (S.Tm) can invade and breach this barrier. Defenses against such acute insults remain incompletely understood. Using a murine model of Salmonella enterocolitis, we analyzed mechanisms limiting pathogen loads in the epithelium during early infection. Although the epithelium-invading S.Tm replicate initially, this intraepithelial replicative niche is restricted by expulsion of infected enterocytes into the lumen. This mechanism is compromised if inflammasome components (NAIP1-6, NLRC4, caspase-1/-11) are deleted, or ablated specifically in the epithelium, resulting in ∼100-fold higher intraepithelial loads and accelerated lymph node colonization. Interestingly, the cytokines downstream of inflammasome activation, interleukin (IL)-1α/β and IL-18, appear dispensable for epithelial restriction of early infection. These data establish the role of an epithelium-intrinsic inflammasome, which drives expulsion of infected cells to restrict the pathogen's intraepithelial proliferation. This may represent a general defense mechanism against mucosal infections. | Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. |
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"26777": 0.056018441915512085, "26874": 0.6764062643051147, "27059": 0.34023189544677734, "27295": 0.40546512603759766, "27531": 0.11256109178066254, "27642": 1.039613962173462, "27777": 0.36358460783958435, "27854": 0.10555581003427505, "28024": 1.0312920808792114, "28086": 0.9783848524093628, "28765": 0.00875066313892603, "29172": 0.08513788133859634, "29290": 0.06977381557226181, "29349": 0.0317181795835495, "29516": 0.12384103983640671} | 11922370 | Many of the factors required for chromosomal DNA replication have been identified in unicellular eukaryotes. However, DNA replication is poorly understood in multicellular organisms. Here, we report the identification of GEMC1 (geminin coiled-coil containing protein 1), a novel vertebrate protein required for chromosomal DNA replication. GEMC1 is highly conserved in vertebrates and is preferentially expressed in proliferating cells. Using Xenopus laevis egg extract we show that Xenopus GEMC1 (xGEMC1) binds to the checkpoint and replication factor TopBP1, which promotes binding of xGEMC1 to chromatin during pre-replication complex (pre-RC) formation. We demonstrate that xGEMC1 interacts directly with replication factors such as Cdc45 and the kinase Cdk2-CyclinE, through which it is heavily phosphorylated. Phosphorylated xGEMC1 stimulates initiation of DNA replication, whereas depletion of xGEMC1 prevents the onset of DNA replication owing to the impairment of Cdc45 loading onto chromatin. Similarly, inhibition of GEMC1 expression with morpholino and siRNA oligos prevents DNA replication in embryonic and somatic vertebrate cells. These data suggest that GEMC1 promotes initiation of chromosomal DNA replication in multicellular organisms by mediating TopBP1- and Cdk2-dependent recruitment of Cdc45 onto replication origins. | GEMC1 is a TopBP1 interacting protein required for chromosomal DNA replication |
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0.052318159490823746, "27329": 0.020300358533859253, "27404": 0.10467668622732162, "27597": 0.0019512200960889459, "27651": 0.13670019805431366, "27790": 0.1229778528213501, "27989": 0.0797421783208847, "28024": 0.0842406153678894, "28715": 0.03266380727291107, "29251": 0.018384648486971855, "29458": 0.7248653769493103, "29600": 0.013579257763922215} | 11933721 | UNLABELLED Biomechanical studies suggest a suture bridge technique enhances rotator cuff tendon footprint contact area, holding strength, and mean contact pressure. Based on these studies, we asked whether (1) the suture bridge technique would provide a high rate of cuff integrity after surgery, (2) the status of the repaired cuff would change with time, (3) preoperative factors could predict postoperative cuff integrity, and (4) patients with retears had less favorable pain, functional scores, range of motion (ROM), and muscle strength compared with those with intact repairs. We prospectively followed 78 patients with arthroscopic repairs in whom we used the suture bridge technique. The integrity of the rotator cuff repair was determined using ultrasonographic evaluation at 4.5 and 12 months after surgery. Ultrasonography revealed intact cuffs in 91% at 4.5 months postoperatively, all of which were maintained at the 12-month followup. Failure rates were 17.6% (three of 17) for massive tears, 11.1% (two of 18) for large tears, 6.3% (two of 32) for medium tears, and no failures for small tears. Preoperative fatty degeneration of the supraspinatus muscle was a strong predictor of cuff integrity. We found no correlation between the integrity and clinical outcomes except for a temporary decrease of abduction strength at 6 months. Arthroscopic repair using suture bridge technique can achieve a low retear rate in shoulders treated for rotator cuff tears, but the occurrence of retear did not influence the outcome. LEVEL OF EVIDENCE Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. | Does an arthroscopic suture bridge technique maintain repair integrity?: a serial evaluation by ultrasonography. |
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It is not known whether this age-related DNA methylation phenomenon is specific to human tissues. We performed comprehensive DNA methylation profiling of promoter regions in aging mouse intestine using methylated CpG island amplification in combination with microarray analysis. By comparing C57BL/6 mice at 3-mo-old versus 35-mo-old for 3627 detectable autosomal genes, we found 774 (21%) that showed increased methylation and 466 (13%) that showed decreased methylation. We used pyrosequencing to quantitatively validate the microarray data and confirmed linear age-related methylation changes for all 12 genomic regions examined. We then examined 11 changed genomic loci for age-related methylation in other tissues. Of these, three of 11 showed similar changes in lung, seven of 11 changed in liver, and six of 11 changed in spleen, though to a lower degree than the changes seen in colon. There was partial conservation between age-related hypermethylation in human and mouse intestines, and Polycomb targets in embryonic stem cells were enriched among the hypermethylated genes. Our findings demonstrate a surprisingly high rate of hyper- and hypomethylation as a function of age in normal mouse small intestine tissues and a strong tissue-specificity to the process. We conclude that epigenetic deregulation is a common feature of aging in mammals. | Widespread and tissue specific age-related DNA methylation changes in mice. |
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During the last 40 years, nearly one-third of the world's arable land has been lost by erosion and continues to be lost at a rate of more than 10 million hectares per year. With the addition of a quarter of a million people each day, the world population's food demand is increasing at a time when per capita food productivity is beginning to decline. | Environmental and economic costs of soil erosion and conservation benefits. |
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0.09938567131757736, "26914": 0.02316705882549286, "27024": 0.1229778528213501, "27064": 1.0375399589538574, "27354": 0.10026945173740387, "27753": 0.9333322048187256, "28093": 0.6086184978485107, "28155": 0.0038986403960734606, "28353": 0.40546512603759766, "28696": 0.18248429894447327, "28896": 1.1005635261535645, "29048": 0.026976587250828743, "29166": 0.013579257763922215, "29207": 0.2184450328350067, "29361": 0.21293537318706512} | 11939159 | IMPORTANCE Among nontraditional cardiovascular risk factors, recent influenzalike infection is associated with fatal and nonfatal atherothrombotic events. OBJECTIVES To determine if influenza vaccination is associated with prevention of cardiovascular events. DATA SOURCES AND STUDY SELECTION A systematic review and meta-analysis of MEDLINE (1946-August 2013), EMBASE (1947-August 2013), and the Cochrane Library Central Register of Controlled Trials (inception-August 2013) for randomized clinical trials (RCTs) comparing influenza vaccine vs placebo or control in patients at high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safety events. DATA EXTRACTION AND SYNTHESIS Two investigators extracted data independently on trial design, baseline characteristics, outcomes, and safety events from published manuscripts and unpublished supplemental data. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. MAIN OUTCOMES AND MEASURES Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derived for composite cardiovascular events, cardiovascular mortality, all-cause mortality, and individual cardiovascular events. Analyses were stratified by subgroups of patients with and without a history of acute coronary syndrome (ACS) within 1 year of randomization. RESULTS Five published and 1 unpublished randomized clinical trials of 6735 patients (mean age, 67 years; 51.3% women; 36.2% with a cardiac history; mean follow-up time, 7.9 months) were included. Influenza vaccine was associated with a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P = .003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI, 0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Results were similar with the addition of unpublished data. CONCLUSIONS AND RELEVANCE In a meta-analysis of RCTs, the use of influenza vaccine was associated with a lower risk of major adverse cardiovascular events. The greatest treatment effect was seen among the highest-risk patients with more active coronary disease. A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular end points. | Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis. |
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0.4419025182723999, "25972": 0.08692999184131622, "26308": 0.05139094591140747, "26578": 0.06520967930555344, "26651": 0.09672962874174118, "26664": 0.7009293437004089, "26757": 0.025073638185858727, "26837": 0.020300358533859253, "27080": 0.2223619967699051, "27343": 0.1485546976327896, "27480": 0.0009760859538801014, "27574": 0.052318159490823746, "27754": 0.31132611632347107, "27815": 0.06703783571720123, "27846": 0.021256839856505394, "28042": 0.18492233753204346, "28086": 0.1332872211933136, "28255": 0.0797421783208847, "28329": 0.13071982562541962, "28498": 0.21214580535888672, "28618": 0.25694093108177185, "28684": 0.016465263441205025, "28699": 0.6744182109832764, "29088": 0.1064341589808464, "29325": 0.417115718126297, "29458": 0.5540198087692261, "29552": 0.16276304423809052} | 11943989 | The "ba, ba, ba" sound universal to babies' babbling around 7 months captures scientific attention because it provides insights into the mechanisms underlying language acquisition and vestiges of its evolutionary origins. Yet the prevailing mystery is what is the biological basis of babbling, with one hypothesis being that it is a non-linguistic motoric activity driven largely by the baby's emerging control over the mouth and jaw, and another being that it is a linguistic activity reflecting the babies' early sensitivity to specific phonetic-syllabic patterns. Two groups of hearing babies were studied over time (ages 6, 10, and 12 months), equal in all developmental respects except for the modality of language input (mouth versus hand): three hearing babies acquiring spoken language (group 1: "speech-exposed") and a rare group of three hearing babies acquiring sign language only, not speech (group 2: "sign-exposed"). Despite this latter group's exposure to sign, the motoric hypothesis would predict similar hand activity to that seen in speech-exposed hearing babies because language acquisition in sign-exposed babies does not involve the mouth. Using innovative quantitative Optotrak 3-D motion-tracking technology, applied here for the first time to study infant language acquisition, we obtained physical measurements similar to a speech spectrogram, but for the hands. Here we discovered that the specific rhythmic frequencies of the hands of the sign-exposed hearing babies differed depending on whether they were producing linguistic activity, which they produced at a low frequency of approximately 1 Hz, versus non-linguistic activity, which they produced at a higher frequency of approximately 2.5 Hz - the identical class of hand activity that the speech-exposed hearing babies produced nearly exclusively. Surprisingly, without benefit of the mouth, hearing sign-exposed babies alone babbled systematically on their hands. We conclude that babbling is fundamentally a linguistic activity and explain why the differentiation between linguistic and non-linguistic hand activity in a single manual modality (one distinct from the human mouth) could only have resulted if all babies are born with a sensitivity to specific rhythmic patterns at the heart of human language and the capacity to use them. | Baby hands that move to the rhythm of language: hearing babies acquiring sign languages babble silently on the hands |
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"29598": 0.5381823778152466, "29610": 0.255429208278656} | 11951999 | Ten-Eleven Translocation-2 (TET2) inactivation through loss-of-function mutation, deletion and IDH1/2 (Isocitrate Dehydrogenase 1 and 2) gene mutation is a common event in myeloid and lymphoid malignancies. TET2 gene mutations similar to those observed in myeloid and lymphoid malignancies also accumulate with age in otherwise healthy subjects with clonal hematopoiesis. TET2 is one of the three proteins of the TET (Ten-Eleven Translocation) family, which are evolutionarily conserved dioxygenases that catalyze the conversion of 5-methyl-cytosine (5-mC) to 5-hydroxymethyl-cytosine (5-hmC) and promote DNA demethylation. TET dioxygenases require 2-oxoglutarate, oxygen and Fe(II) for their activity, which is enhanced in the presence of ascorbic acid. TET2 is the most expressed TET gene in the hematopoietic tissue, especially in hematopoietic stem cells. In addition to their hydroxylase activity, TET proteins recruit the O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) enzyme to chromatin, which promotes post-transcriptional modifications of histones and facilitates gene expression. The TET2 level is regulated by interaction with IDAX, originating from TET2 gene fission during evolution, and by the microRNA miR-22. TET2 has pleiotropic roles during hematopoiesis, including stem-cell self-renewal, lineage commitment and terminal differentiation of monocytes. Analysis of Tet2 knockout mice, which are viable and fertile, demonstrated that Tet2 functions as a tumor suppressor whose haploinsufficiency initiates myeloid and lymphoid transformations. This review summarizes the recently identified TET2 physiological and pathological functions and discusses how this knowledge influences our therapeutic approaches in hematological malignancies and possibly other tumor types. | The Ten-Eleven Translocation-2 (TET2) gene in hematopoiesis and hematopoietic diseases |
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0.7018978595733643, "29295": 0.13157635927200317, "29458": 0.06520967930555344, "29491": 0.011650617234408855} | 11953232 | OBJECTIVE To determine the prevalence and clinical associations of impaired awareness of hypoglycemia in a population-based sample of children and adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS A validated questionnaire was administered to 656 patients with type 1 diabetes over a 6-month period to determine hypoglycemia awareness status. Case ascertainment was 79% of the clinic population. The rate of severe hypoglycemia was determined by data collected prospectively in the preceding year. RESULTS Impaired awareness of hypoglycemia was present in 29% of patients. Patients with impaired awareness of hypoglycemia had an earlier onset of diabetes (P < 0.001), were younger (P < 0.001), and had lower mean levels of A1C since diabetes onset (P = 0.006) and at their last visit (P = 0.001). The overall rate of severe hypoglycemia was 24.5 episodes per 100 patient-years in the preceding year. The severe hypoglycemia rate was higher in those with impaired awareness of hypoglycemia (37.1 vs. 19.3 episodes per 100 patient-years, P < 0.001). Among patients aged <6 years (n = 46), 59% of care providers reported impaired awareness of hypoglycemia, and the rate of severe hypoglycemia was significantly higher in those reporting impaired awareness (33.3 vs. 52 episodes per 100 patient-years, P = 0.02). More patients with recurrent hypoglycemia reported impaired awareness of hypoglycemia (47 vs. 28%, P = 0.03). CONCLUSIONS A significant proportion of children and adolescents with type 1 diabetes have impaired awareness of hypoglycemia. Screening for impaired awareness is an important component of routine diabetes care and can identify patients at increased risk of a severe hypoglycemic event. | Impaired Awareness of Hypoglycemia in a Population-Based Sample of Children and Adolescents With Type 1 Diabetes |
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"26351": 0.052318159490823746, "26402": 0.42735910415649414, "26520": 0.1384023278951645, "26702": 0.052318159490823746, "26773": 0.09584271162748337, "26837": 0.22626367211341858, "26982": 0.2447827309370041, "27099": 0.33115679025650024, "27144": 0.5069117546081543, "27184": 0.2516399025917053, "27295": 0.3012613356113434, "27460": 0.08871890604496002, "27673": 0.09317722171545029, "27881": 0.41195443272590637, "28207": 0.09228714555501938, "28215": 0.619189441204071, "28300": 0.1718502640724182, "28466": 0.7445381283760071, "28561": 0.5860490798950195, "28696": 0.12642613053321838, "28927": 0.016465263441205025, "29170": 0.009718249551951885, "29290": 0.6338034868240356, "29378": 0.07068414986133575, "29491": 1.1281205415725708} | 11968641 | BACKGROUND Circadian clocks control cell cycle factors, and circadian disruption promotes cancer. To address whether enhancing circadian rhythmicity in tumor cells affects cell cycle progression and reduces proliferation, we compared growth and cell cycle events of B16 melanoma cells and tumors with either a functional or dysfunctional clock. RESULTS We found that clock genes were suppressed in B16 cells and tumors, but treatments inducing circadian rhythmicity, such as dexamethasone, forskolin and heat shock, triggered rhythmic clock and cell cycle gene expression, which resulted in fewer cells in S phase and more in G1 phase. Accordingly, B16 proliferation in vitro and tumor growth in vivo was slowed down. Similar effects were observed in human colon carcinoma HCT-116 cells. Notably, the effects of dexamethasone were not due to an increase in apoptosis nor to an enhancement of immune cell recruitment to the tumor. Knocking down the essential clock gene Bmal1 in B16 tumors prevented the effects of dexamethasone on tumor growth and cell cycle events. CONCLUSIONS Here we demonstrated that the effects of dexamethasone on cell cycle and tumor growth are mediated by the tumor-intrinsic circadian clock. Thus, our work reveals that enhancing circadian clock function might represent a novel strategy to control cancer progression. | Enhancing circadian clock function in cancer cells inhibits tumor growth |
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The motor domain of dynein contains six tandemly linked AAA (ATPases associated with diverse cellular activities) modules, with the first four containing predicted nucleotide-binding/hydrolysis sites (P1-P4). To dissect the functions of these multiple nucleotide-binding/hydrolysis sites, we expressed and purified Dictyostelium dynein motor domains in which mutations were introduced to block nucleotide binding at each of the four AAA modules, and then examined their detailed biochemical properties. The P1 mutant was trapped in a strong-binding state even in the presence of ATP and lost its motile activity. The P3 mutant also showed a high affinity for microtubules in the presence of ATP and lost most of the microtubule-activated ATPase activity, but retained microtubule sliding activity, although the sliding velocity of the mutant was more than 20-fold slower than that of the wild type. In contrast, mutation in the P2 or P4 site did not affect the apparent binding affinity of the mutant for microtubules in the presence of ATP, but reduced ATPase and microtubule sliding activities. These results indicate that ATP binding and its hydrolysis only at the P1 site are essential for the motor activities of cytoplasmic dynein, and suggest that the other nucleotide-binding/hydrolysis sites regulate the motor activities. Among them, nucleotide binding at the P3 site is not essential but is critical for microtubule-activated ATPase and motile activities of cytoplasmic dynein. | Distinct functions of nucleotide-binding/hydrolysis sites in the four AAA modules of cytoplasmic dynein. |
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Alterations affecting neurotransmission and signalling pathways that govern brain function are also evident. A large number of genes are simultaneously expressed at abnormal levels in DS; therefore, it is a challenge to determine which gene(s) contribute to specific abnormalities, and then identify the key molecular pathways involved. We generated RCAN1-TG mice to study the consequences of RCAN1 over-expression and investigate the contribution of RCAN1 to the brain phenotype of DS. RCAN1-TG mice exhibit structural brain abnormalities in those areas affected in DS. The volume and number of neurons within the hippocampus is reduced and this correlates with a defect in adult neurogenesis. The density of dendritic spines on RCAN1-TG hippocampal pyramidal neurons is also reduced. Deficits in hippocampal-dependent learning and short- and long-term memory are accompanied by a failure to maintain long-term potentiation (LTP) in hippocampal slices. In response to LTP induction, we observed diminished calcium transients and decreased phosphorylation of CaMKII and ERK1/2-proteins that are essential for the maintenance of LTP and formation of memory. Our data strongly suggest that RCAN1 plays an important role in normal brain development and function and its up-regulation likely contributes to the neural deficits associated with DS. | Over-expression of RCAN1 causes Down syndrome-like hippocampal deficits that alter learning and memory. |
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1.0144377946853638, "25468": 0.15610189735889435, "25654": 0.8492490649223328, "25778": 0.12814582884311676, "25937": 0.272677481174469, "26462": 0.15610189735889435, "26780": 0.25239890813827515, "27144": 0.11604541540145874, "27881": 0.1510767638683319, "27921": 0.11081436276435852, "28093": 0.1064341589808464, "28207": 0.3615458607673645, "28268": 0.16524957120418549, "28403": 0.4512746334075928, "29235": 0.6729245185852051, "29491": 0.030771657824516296} | 12009265 | CONTEXT Many individuals take vitamins in the hopes of preventing chronic diseases such as cancer, and vitamins E and C are among the most common individual supplements. A large-scale randomized trial suggested that vitamin E may reduce risk of prostate cancer; however, few trials have been powered to address this relationship. No previous trial in men at usual risk has examined vitamin C alone in the prevention of cancer. OBJECTIVE To evaluate whether long-term vitamin E or C supplementation decreases risk of prostate and total cancer events among men. DESIGN, SETTING, AND PARTICIPANTS The Physicians' Health Study II is a randomized, double-blind, placebo-controlled factorial trial of vitamins E and C that began in 1997 and continued until its scheduled completion on August 31, 2007. A total of 14,641 male physicians in the United States initially aged 50 years or older, including 1307 men with a history of prior cancer at randomization, were enrolled. INTERVENTION Individual supplements of 400 IU of vitamin E every other day and 500 mg of vitamin C daily. MAIN OUTCOME MEASURES Prostate and total cancer. RESULTS During a mean follow-up of 8.0 years, there were 1008 confirmed incident cases of prostate cancer and 1943 total cancers. Compared with placebo, vitamin E had no effect on the incidence of prostate cancer (active and placebo vitamin E groups, 9.1 and 9.5 events per 1000 person-years; hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.85-1.09; P = .58) or total cancer (active and placebo vitamin E groups, 17.8 and 17.3 cases per 1000 person-years; HR, 1.04; 95% CI, 0.95-1.13; P = .41). There was also no significant effect of vitamin C on total cancer (active and placebo vitamin C groups, 17.6 and 17.5 events per 1000 person-years; HR, 1.01; 95% CI, 0.92-1.10; P = .86) or prostate cancer (active and placebo vitamin C groups, 9.4 and 9.2 cases per 1000 person-years; HR, 1.02; 95% CI, 0.90-1.15; P = .80). Neither vitamin E nor vitamin C had a significant effect on colorectal, lung, or other site-specific cancers. Adjustment for adherence and exclusion of the first 4 or 6 years of follow-up did not alter the results. Stratification by various cancer risk factors demonstrated no significant modification of the effect of vitamin E on prostate cancer risk or either agent on total cancer risk. CONCLUSIONS In this large, long-term trial of male physicians, neither vitamin E nor C supplementation reduced the risk of prostate or total cancer. These data provide no support for the use of these supplements for the prevention of cancer in middle-aged and older men. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00270647. | Vitamins E and C in the prevention of prostate and total cancer in men: the Physicians' Health Study II randomized controlled trial. |
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For genes that should not be expressed in a particular cell type, protein output is lowered to inconsequential levels. For other genes, dosage is adjusted in a manner that allows for customized expression in different cell types while achieving a more uniform level within each cell type. In these ways, the microRNAs add an extensive layer of gene control that integrates with transcriptional and other regulatory processes to expand the complexity of metazoan gene expression. | Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs |
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multicellular. But in contrast to the developmental biology of plants and animals, the principles of morphogenesis and pattern formation in single cells remain largely unknown. Although all cells develop patterns, they are most obvious in ciliates; hence, we have turned to a classical unicellular model system, the giant ciliate Stentor coeruleus. Here we show that the RNA interference (RNAi) machinery is conserved in Stentor. Using RNAi, we identify the kinase coactivator Mob1--with conserved functions in cell division and morphogenesis from plants to humans-as an asymmetrically localized patterning protein required for global patterning during development and regeneration in Stentor. Our studies reopen the door for Stentor as a model regeneration system. | The Kinase Regulator Mob1 Acts as a Patterning Protein for Stentor Morphogenesis |
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"28873": 0.40546512603759766, "28911": 0.2561853528022766, "29237": 0.932563841342926, "29304": 0.15526613593101501, "29458": 0.05786345899105072} | 12030680 | The complex repertoire of immune receptors generated by B and T cells enables recognition of diverse threats to the host organism. In this work, we show that massively parallel DNA sequencing of rearranged immune receptor loci can provide direct detection and tracking of immune diversity and expanded clonal lymphocyte populations in physiological and pathological contexts. DNA was isolated from blood and tissue samples, a series of redundant primers was used to amplify diverse DNA rearrangements, and the resulting mixtures of barcoded amplicons were sequenced using long-read ultra deep sequencing. Individual DNA molecules were then characterized on the basis of DNA segments that had been joined to make a functional (or nonfunctional) immune effector. Current experimental designs can accommodate up to 150 samples in a single sequence run, with the depth of sequencing sufficient to identify stable and dynamic aspects of the immune repertoire in both normal and diseased circumstances. These data provide a high-resolution picture of immune spectra in normal individuals and in patients with hematological malignancies, illuminating, in the latter case, both the initial behavior of clonal tumor populations and the later suppression or re-emergence of such populations after treatment. | Measurement and clinical monitoring of human lymphocyte clonality by massively parallel VDJ pyrosequencing. |
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"27197": 0.7210738658905029, "27354": 0.0752234235405922, "27487": 0.27044451236724854, "27833": 0.7408206462860107, "27974": 0.5404602885246277, "28321": 0.2837681770324707, "28472": 0.0317181795835495, "28591": 0.4818955361843109, "28907": 0.010684899985790253, "29015": 0.10379679501056671, "29166": 0.03266380727291107, "29458": 0.19862671196460724} | 12030735 | OBJECTIVE Limited information is available about the metabolic syndrome in Asians. Furthermore, the definition of central obesity using waist circumference may not be appropriate for Asians. The objectives of this study were to determine the optimal waist circumference for diagnosing central obesity in Asians and to estimate the prevalence of the metabolic syndrome in an Asian population. RESEARCH DESIGN AND METHODS We used data from the 1998 Singapore National Health Survey, a cross-sectional survey involving 4,723 men and women of Chinese, Malay, and Asian-Indian ethnicity aged 18-69 years. Receiver operating characteristic analysis suggested that waist circumference >80 cm in women and >90 cm in men was a more appropriate definition of central obesity in this population. The prevalence of the metabolic syndrome was then determined using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria with and without the modified waist circumference criteria. RESULTS In Asians, decreasing waist circumference increased the crude prevalence of the metabolic syndrome from 12.2 to 17.9%. Using the modified Asian criteria, the prevalence of the metabolic syndrome increased from 2.9% in those aged 18-30 years to 31.0% in those aged 60-69 years. It was more common in men (prevalence 20.9% in men versus 15.5% in women; P < 0.001) and Asian Indians (prevalence 28.8% in Asian-Indians, 24.2% in Malays, and 14.8% in Chinese; P < 0.001). CONCLUSIONS NCEP ATP III criteria, applied to an Asian population, will underestimate the population at risk. With a lower waist circumference cutoff, the prevalence of the metabolic syndrome is comparable to that in Western populations. Ethnic differences are likely to exist between populations across Asia. | Can we apply the National Cholesterol Education Program Adult Treatment Panel definition of the metabolic syndrome to Asians? |
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