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"26402": 0.417115718126297, "26520": 0.1718502640724182, "26651": 0.0797421783208847, "26773": 0.06795065850019455, "27006": 0.9417452812194824, "27144": 0.29473719000816345, "27295": 0.304147332906723, "27854": 0.4158279001712799, "27881": 0.7105726003646851, "28207": 0.53589928150177, "28286": 1.0437490940093994, "28309": 0.03360854089260101, "28327": 0.7656494975090027, "28522": 0.14939609169960022, "28691": 0.1693800985813141, "28728": 0.1011524572968483, "28756": 0.056018441915512085, "28873": 0.040196798741817474, "29290": 0.45994341373443604, "29720": 0.7445381283760071, "29721": 0.6160298585891724, "29726": 0.630689799785614} | 23078022 | Nuclear factor-κB (NF-κB) is constitutively activated in diverse human malignancies by mechanisms that are not understood. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and, similarly to NF-κB, blocks apoptosis and induces transformation. This study demonstrates that overexpression of MUC1 in human carcinoma cells is associated with constitutive activation of NF-κB p65. We show that MUC1 interacts with the high-molecular-weight IκB kinase (IKK) complex in vivo and that the MUC1 cytoplasmic domain binds directly to IKKβ and IKKγ. Interaction of MUC1 with both IKKβ and IKKγ is necessary for IKKβ activation, resulting in phosphorylation and degradation of IκBα. Studies in non-malignant epithelial cells show that MUC1 is recruited to the TNF-R1 complex and interacts with IKKβ–IKKγ in response to TNFα stimulation. TNFα-induced recruitment of MUC1 is dependent on TRADD and TRAF2, but not the death-domain kinase RIP1. In addition, MUC1-mediated activation of IKKβ is dependent on TAK1 and TAB2. These findings indicate that MUC1 is important for physiological activation of IKKβ and that overexpression of MUC1, as found in human cancers, confers sustained induction of the IKKβ–NF-κB p65 pathway. | MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling |
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0.09850110858678818} | 23100220 | Trihydroxytetraenes, a novel series of oxygenated derivatives formed from arachidonic acid in human leukocytes, were recently isolated [Serhan, C. N., Hamberg, M. & Samuelsson, B. (1984) Biochem. Biophys. Res. Commun. 118, 943-949]. The structure of the major compound was established--i.e., 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid. The present study reports the structure of a second member of the trihydroxytetraene series of compounds--i.e., 5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoic acid. When added to human neutrophils, 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid stimulated superoxide anion generation and degranulation at submicromolar concentrations without provoking a substantial aggregation response. With respect to superoxide anion generation, 5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid proved to be as potent as leukotriene B4. In contrast, the compound was approximately 2 orders of magnitude less potent than either leukotriene B4 or fMet-Leu-Phe at provoking degranulation. The results indicate that interaction(s) between the 5- and 15-lipoxygenase pathways of human leukocytes leads to formation of a new series of oxygenated derivatives of arachidonic acid that may be involved in regulating specific cellular responses. The trivial names lipoxin A (5,6,15L-trihydroxy-7,9,11,13-icosatetraenoic acid) and lipoxin B (5D,14,15L-trihydroxy-6,8,10,12-icosatetraenoic acid) are proposed for the new compounds. | Lipoxins: novel series of biologically active compounds formed from arachidonic acid in human leukocytes. |
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By using electron paramagnetic resonance spin-trapping techniques, we monitored NO and .O2- formation in nNOS-transfected human kidney 293 cells. In control transfected cells, the Ca2+ ionophore A23187 triggered NO generation but no .O2- was seen. With cells in L-Arg-free medium, we observed .O2- formation that increased as the cytosolic L-Arg levels decreased, while NO generation declined. .O2- formation was virtually abolished by the specific NOS blocker, N-nitro-L-arginine methyl ester (L-NAME). Nitrotyrosine, a specific nitration product of peroxynitrite, accumulated in L-Arg-depleted cells but not in control cells. Activation by A23187 was cytotoxic to L-Arg-depleted, but not to control cells, with marked lactate dehydrogenase release. The cytotoxicity was largely prevented by either superoxide dismutase or L-NAME. Thus, with reduced L-Arg availability NOS elicits cytotoxicity by generating .O2- and NO that interact to form the potent oxidant peroxynitrite. Regulating arginine levels may provide a therapeutic approach to disorders involving .O2-/NO-mediated cellular injury. | Nitric oxide synthase generates superoxide and nitric oxide in arginine-depleted cells leading to peroxynitrite-mediated cellular injury. |
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During the following 15 years, an enormous amount of additional information has emerged, justifying additional refinement of the definition of SIDS to incorporate epidemiologic features, risk factors, pathologic features, and ancillary test findings. An expert panel of pediatric and forensic pathologists and pediatricians considered these issues and developed a new general definition of SIDS for administrative and vital statistics purposes. The new definition was then stratified to facilitate research into sudden infant death. Another category, defined as unclassified sudden infant deaths, was introduced for cases that do not meet the criteria for a diagnosis of SIDS and for which alternative diagnoses of natural or unnatural conditions were equivocal. It is anticipated that these new definitions will be modified in the future to accommodate new understanding of SIDS and sudden infant death. | Sudden infant death syndrome and unclassified sudden infant deaths: a definitional and diagnostic approach. |
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0.14179791510105133, "25194": 0.020300358533859253, "25357": 0.44753631949424744, "25456": 0.03266380727291107, "25714": 0.2223619967699051, "25876": 0.052318159490823746, "25969": 1.072225570678711, "26013": 0.4794800877571106, "26083": 0.0606246218085289, "26305": 0.04767346754670143, "26402": 0.23633737862110138, "26754": 0.42416930198669434, "26835": 0.5629584193229675, "27152": 0.7305257320404053, "27491": 0.129004567861557, "27788": 0.7818660736083984, "27806": 0.1332872211933136, "27895": 0.021256839856505394, "28024": 0.3519764244556427, "28573": 0.47158926725387573, "28976": 0.1510767638683319, "29021": 0.22937409579753876, "29160": 0.28155985474586487, "29290": 0.5822374224662781} | 23117928 | Infection of Sulfolobus islandicus REY15A with mixtures of different Sulfolobus viruses, including STSV2, did not induce spacer acquisition by the host CRISPR immune system. However, coinfection with the tailed fusiform viruses SMV1 and STSV2 generated hyperactive spacer acquisition in both CRISPR loci, exclusively from STSV2, with the resultant loss of STSV2 but not SMV1. SMV1 was shown to activate adaptation while itself being resistant to CRISPR-mediated adaptation and DNA interference. Exceptionally, a single clone S-1 isolated from an SMV1 + STSV2-infected culture, that carried STSV2-specific spacers and had lost STSV2 but not SMV1, acquired spacers from SMV1. This effect was also reproducible on reinfecting wild-type host cells with a variant SMV1 isolated from the S-1 culture. The SMV1 variant lacked a virion protein ORF114 that was shown to bind DNA. This study also provided evidence for: (i) limits on the maximum sizes of CRISPR loci; (ii) spacer uptake strongly retarding growth of infected cultures; (iii) protospacer selection being essentially random and non-directional, and (iv) the reversible uptake of spacers from STSV2 and SMV1. A hypothesis is presented to explain the interactive conflicts between SMV1 and the host CRISPR immune system. | Inter-viral conflicts that exploit host CRISPR immune systems of Sulfolobus. |
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"28345": 1.3439046144485474, "28479": 1.4450790882110596, "28835": 0.3547199070453644, "28884": 0.848413348197937, "29090": 0.13925230503082275, "29191": 0.08871890604496002, "29290": 0.5701626539230347, "29607": 0.11430477350950241} | 23122306 | In an experiment to clarify the involvement of oxygen radicals in lung carcinogenesis induced by diesel exhaust particles (DEP), we found that there is a strong relation between lung tumor response and formation of 8-hydroxydeoxyguanosine (8-OHdG) in lung DNA of mice administered DEP by repeated intratracheal instillation. Repeated intratracheal instillation of DEP also induced the activity of cytochrome P-450 reductase in the lungs as a representative enzyme of superoxide generation, and two types of nitric oxide (NO) synthase, cNOS and iNOS, in the lungs. On the other hand, activities of CuZn-superoxide dismutase (SOD) and Mn-SOD antioxidant enzymes were depressed by the instillation of DEP. These results suggest that generation of superoxide, hydroxyI radical, and nitric oxide are increased in epithelial cells in airways, and that the increased superoxide and nitric oxide react very easily to produce peroxynitrite (ONOO(-)). The peroxynitrite also produce hydroxyI radical. The hydroxyl radical may play an important role in carcinogenesis by DEP. | Lung Carcinogenesis by Diesel Exhaust Particles and the Carcinogenic Mechanism Via Active Oxygens. |
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investigated extraneural manifestations in scrapie-infected transgenic mice expressing prion protein lacking the glycophosphatydylinositol membrane anchor. In the brain, blood, and heart, both abnormal protease-resistant prion protein (PrPres) and prion infectivity were readily detected by immunoblot and by inoculation into nontransgenic recipients. The titer of infectious scrapie in blood plasma exceeded 10(7) 50% infectious doses per milliliter. The hearts of these transgenic mice contained PrPres-positive amyloid deposits that led to myocardial stiffness and cardiac disease. | Prion-induced amyloid heart disease with high blood infectivity in transgenic mice. |
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0.18654440343379974, "27906": 0.7647408246994019, "28207": 0.11256109178066254, "28436": 0.10291612148284912, "28472": 0.07884006202220917, "28756": 0.7220231294631958, "28848": 0.6999598741531372, "28873": 0.14433705806732178, "29490": 0.401551216840744, "29533": 0.23556606471538544} | 23126677 | BACKGROUND MicroRNAs (miRNAs) are small non-coding RNA molecules. Reduced or increased levels of specific miRNAs are observed in colon and other cancers, supporting their role in carcinogenesis. Detection of colorectal polyps is the cornerstone of the Bowel Cancer Screening Programme in the UK. However, uptake of screening nationally remains under 60%. We aimed to see whether circulating plasma miRNAs can be used to screen for patients with colorectal polyps, adenomas, or both. METHODS Blood samples were taken from patients from the Bowel Cancer Screening Programme (asymptomatic but faecal occult blood testing [FOBt] positive). Plasma RNA was extracted, target miRNAs (19a, 98, 146b, 186, 191, 222*, 331-5p, 452, 625, 664, 1247) were identified on pooled case miRNA assay cards, and miRNA fraction was quantified by quantitative RT-PCR assay. Results were compared with endoscopy reports and with histology of any polyps identified and removed. Analysis was done with Excel (2011) and SPSS (version 20) software. FINDINGS 210 patients were included (117 with polyps, 12 with cancer, 81 healthy controls [FOBt positive]). The miRNA panel showed significant differences in expression (on t testing) for patients compared with controls for those with polyps, cancer, or both (miR-19a, p=0·0184; miR-98, p=0·0206; miR-146b, p=0·0029; miR-186, p=0·0006; miR-62,5 p=0·0008), polyps (miR-19a, p=0·0233; miR-98, p=0·0224; miR-146b, p=0·003; miR-186, p=0·0004; miR-625, p=0·001), adenomas (miR-19a, p=0·0339; miR-98, p=0·0266; miR-146b, p=0·0045; miR-186, p=0·0008; miR-625, p=0·0049), multiple adenomas (both sides of colon; miR-146b, p=0·0194; miR-186, p=0·0226; miR-625, p=0·0013), and right-sided adenomas (miR-98, p=0·031; miR-146b, p=0·0076; miR-186, p=0·0041; miR-331-5p, p=0·0142; miR-625, p=0·0049). Receiver operating characteristic analysis showed sensitivity of 60% or more, and specificity of 86% or more for men with polyps, men with adenomas, all patients with haemorrhoids or diverticulosis and polyps, and all patients with haemorrhoids or diverticulosis and adenomas. INTERPRETATION The target miRNAs that we identified showed significant differences in expression levels for patients with polyps and patients with adenomas from controls. Use of this panel has potential as a screening test. FUNDING Bowel Disease Research Foundation. | Circulating plasma microRNAs as a screening method for detection of colorectal adenomas. |
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0.0317181795835495, "28711": 1.4321038722991943, "28794": 0.022212404757738113, "28873": 0.3177432417869568, "29107": 0.11430477350950241, "29264": 0.06703783571720123, "29458": 0.6420594453811646, "29486": 0.7047978043556213} | 23136735 | OBJECTIVE To evaluate the cumulative incidence of cervical intraepithelial neoplasia II or worse (grade II+) or cervical intraepithelial neoplasia grade III+ after short term persistence of prevalently detected carcinogenic human papillomavirus (HPV). DESIGN Population based cohort study. SETTING Guanacaste, Costa Rica. PARTICIPANTS 2282 sexually active women actively followed after enrolment. MAIN OUTCOME MEASURES Primary end points: three year and five year cumulative incidence of histologically confirmed cervical intraepithelial neoplasia grade II+ (n=70). Cervical specimens collected at each visit tested for more than 40 HPV genotypes. HPV 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82 were considered the primary carcinogenic genotypes. RESULTS Women who tested positive for a carcinogenic HPV at enrolment and after about one year (9-21 months) (positive/positive) had a three year cumulative incidence of cervical intraepithelial neoplasia grade II+ of 17.0% (95% confidence interval 12.1% to 22.0%). Those who tested negative/positive (3.4%, 0.1% to 6.8%), positive/negative (1.2%, -0.2% to 2.5%), and negative/negative (0.5%, 0.1% to 0.9%) were at a significantly lower risk. There was little difference in the cumulative incidence of cervical intraepithelial neoplasia grade II+ between testing positive twice for any carcinogenic HPV genotype (same genotype or different genotypes) v testing positive twice for the same carcinogenic genotype (17.0% v 21.3%, respectively). Short term persistence of HPV 16 strongly predicted cervical intraepithelial neoplasia grade II+, with a three year cumulative incidence of 40.8% (26.4% to 55.1%). Similar patterns were observed for the five year cumulative incidence of grade II+ and for three year and five year cumulative incidence of grade III+. CONCLUSIONS Short term persistence of a prevalently detected carcinogenic HPV infection, especially HPV 16, strongly predicts a subsequent diagnosis of cervical intraepithelial neoplasia II+ over the next few years. | Short term persistence of human papillomavirus and risk of cervical precancer and cancer: population based cohort study |
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"28086": 1.3828705549240112, "28228": 0.8212929964065552, "28309": 0.24171993136405945, "28436": 0.5341835021972656, "28664": 0.3423145115375519, "28892": 1.1653456687927246, "28991": 1.151856780052185, "29129": 0.15693697333335876, "29197": 1.2198615074157715} | 23141360 | The morphogenesis of developing embryos and organs relies on the ability of cells to remodel their contacts with neighbouring cells. Using quantitative modelling and laser nano-dissection, we probed the mechanics of a morphogenetic process, the elongation of Drosophila melanogaster embryos, which results from polarized cell neighbour exchanges. We show that anisotropy of cortical tension at apical cell junctions is sufficient to drive tissue elongation. We estimated its value through comparisons between in silico and in vivo data using various tissue descriptors. Nano-dissection of the actomyosin network indicates that tension is anisotropically distributed and depends on myosin II accumulation. Junction relaxation after nano-dissection also suggests that cortical elastic forces are dominant in this process. Interestingly, fluctuations in vertex position (points where three or more cells meet) facilitate neighbour exchanges. We delineate the contribution of subcellular tensile activity polarizing junction remodelling, and the permissive role of vertex fluctuations during tissue elongation. | Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis |
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"27854": 0.11865071207284927, "28156": 0.4770587682723999, "28518": 0.015504186972975731, "28741": 0.040196798741817474, "28788": 0.1946154683828354, "28976": 0.3464667797088623, "28987": 0.09761575609445572} | 23148978 | The action of different metabolic inhibitors on phagocytosis by macrophages from mouse peritoneal exudate cultured in vitro was studied. The following metabolic inhibitors were tested: sodium iodoacetate, sodium fluoride, sodium fluoroacetate, sodium malonate, 2-4-dinitrophenol, sodium azide, ouabain and cycloheximide, all at the concentration of 10(-3) M. Iodoacetate caused a strong inhibitory effect on phagocytosis; this observation confirms that glycolysis is the main source of energy for the phagocytic process. On the contrary, fluoride, although it is an effective inhibitor of glycolysis, did not exert any effect. This difference may be explained by the fact that sodium fluoride blocks anaerobic glycolysis only in vitro at an unphysiological temperature (0 degrees C). Fluoroacetate and malonate, two compounds which interfere with the Krebs cycle, did not inhibit phagocytosis, but it is known that the Krebs cycle activity is poorly developed in the macrophagic cells. Sodium azide and 2-4-dinitrophenol, two inhibitors of oxidative phosphorylation, showed an effect on phagocytosis only after 3 h of contact with the cell cultures. Ouabain blocks Na+ and K+ transport across the plasma membrane and, probably, it inhibited phagocytosis by interfering with the movements of the cell membrane. Finally, the mode of action of cycloheximide on phagocytosis is uncertain. This compound inhibits the protein synthesis and, perhaps, it can act by preventing the renewal of the cell membrane. | The influence of some metabolic inhibitors on phagocytic activity of mouse macrophages in vitro. |
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0.08244366943836212, "26228": 0.021256839856505394, "26243": 0.09938567131757736, "26396": 0.02412080205976963, "26633": 0.12384103983640671, "26651": 0.176772341132164, "27080": 0.2652147710323334, "27108": 0.15275461971759796, "27169": 0.006812678650021553, "27295": 0.15359249711036682, "27354": 0.11951763927936554, "27400": 0.012615402229130268, "27598": 0.5410289764404297, "27633": 0.1064341589808464, "27697": 0.09317722171545029, "27790": 0.07884006202220917, "27846": 0.23787821829319, "27854": 0.018384648486971855, "27965": 0.08154398202896118, "28041": 0.2105647772550583, "28228": 0.01934296265244484, "28353": 1.2134976387023926, "28636": 0.46486347913742065, "28715": 0.05694137513637543, "28820": 0.24018502235412598, "28991": 0.22626367211341858, "29105": 0.8715548515319824, "29477": 0.056018441915512085, "29494": 0.11778303235769272, "29497": 0.7220231294631958} | 23160444 | Neuronal growth cones move forward by dynamically connecting actin-based motility to substrate adhesion, but the mechanisms at the individual molecular level remain unclear. We cultured primary neurons on N-cadherin-coated micropatterned substrates, and imaged adhesion and cytoskeletal proteins at the ventral surface of growth cones using single particle tracking combined to photoactivated localization microscopy (sptPALM). We demonstrate transient interactions in the second time scale between flowing actin filaments and immobilized N-cadherin/catenin complexes, translating into a local reduction of the actin retrograde flow. Normal actin flow on micropatterns was rescued by expression of a dominant negative N-cadherin construct competing for the coupling between actin and endogenous N-cadherin. Fluorescence recovery after photobleaching (FRAP) experiments confirmed the differential kinetics of actin and N-cadherin, and further revealed a 20% actin population confined at N-cadherin micropatterns, contributing to local actin accumulation. Computer simulations with relevant kinetic parameters modeled N-cadherin and actin turnover well, validating this mechanism. Such a combination of short- and long-lived interactions between the motile actin network and spatially restricted adhesive complexes represents a two-tiered clutch mechanism likely to sustain dynamic environment sensing and provide the force necessary for growth cone migration. | Two-tiered coupling between flowing actin and immobilized N-cadherin/catenin complexes in neuronal growth cones. |
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Adrenal and gonadal strategies for P450scc gene transcription are essentially identical and depend on the orphan nuclear receptor steroidogenic factor-1, but the placental strategy for transcription of P450scc employs cis-acting elements different from those used in the adrenal strategy and is independent of steroidogenic factor-1. Because placental expression of P450scc is required for human pregnancy, we sought factors that bind to the -155/-131 region of the human P450scc promoter, which participates in its placental but not adrenal or gonadal transcription. A yeast one-hybrid screen of 2.4 x 10(6) cDNA clones from human placental JEG-3 cells yielded two unique clones; one is the previously described transcription factor LBP-1b, which is induced by HIV, type I infection of lymphocytes, and the other is a new factor, termed LBP-9, that shares 83% amino acid sequence identity with LBP-1b. When expressed in transfected yeast, both factors bound specifically to the -155/-131 DNA; antisera to LBP proteins supershifted the LBP-9.DNA complex and inhibited formation of the LBP-1b. DNA complex. Reverse transcriptase-polymerase chain reaction detected LBP-1b in human placental JEG-3, adrenal NCI-H295A, liver HepG2, cervical HeLa, and monkey kidney COS-1 cells, but LBP-9 was detected only in JEG-3 cells. When the -155/-131 fragment was linked to a minimal promoter, co-expression of LBP-1b increased transcription 21-fold in a dose-dependent fashion, but addition of LBP-9 suppressed the stimulatory effect of LBP-1b. The roles of LBP transcription factors in normal human physiology have been unclear. Their modulation of placental but not adrenal P450scc transcription underscores the distinctiveness of placental strategies for steroidogenic enzyme gene transcription. | Cloning of factors related to HIV-inducible LBP proteins that regulate steroidogenic factor-1-independent human placental transcription of the cholesterol side-chain cleavage enzyme, P450scc. |
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1.1249549388885498, "27321": 0.7417513132095337, "27642": 0.016465263441205025, "27710": 0.23787821829319, "27881": 0.01934296265244484, "28024": 0.10291612148284912, "28064": 0.8332487344741821, "28184": 0.25845035910606384, "28327": 0.8109301924705505, "28788": 0.37640097737312317, "28828": 0.28082266449928284, "28829": 0.23324857652187347, "28873": 0.06977381557226181, "29107": 0.0174254160374403} | 23190392 | Polyploidization is a natural process that frequently accompanies differentiation; its deregulation is linked to genomic instability and cancer. Despite its relevance, why cells select different polyploidization mechanisms is unknown. Here we report a systematic genetic analysis of endomitosis, a process in which megakaryocytes become polyploid by entering mitosis but aborting anaphase. Whereas ablation of the APC/C cofactor Cdc20 results in mitotic arrest and severe thrombocytopenia, lack of the kinases Aurora-B, Cdk1, or Cdk2 does not affect megakaryocyte polyploidization or platelet levels. Ablation of Cdk1 forces a switch to endocycles without mitosis, whereas polyploidization in the absence of Cdk1 and Cdk2 occurs in the presence of aberrant re-replication events. Importantly, ablation of these kinases rescues the defects in Cdc20 null megakaryocytes. These findings suggest that endomitosis can be functionally replaced by alternative polyploidization mechanisms in vivo and provide the cellular basis for therapeutic approaches aimed to discriminate mitotic and polyploid cells. | Functional reprogramming of polyploidization in megakaryocytes. |
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23195302 | Enhancer of Zeste [E(z)] is a Polycomb-group transcriptional repressor and one of the founding members of the family of SET domain-containing proteins. Several SET-domain proteins possess intrinsic histone methyltransferase (HMT) activity. However, recombinant E(z) protein was found to be inactive in a HMT assay. Here we report the isolation of a multiprotein E(z) complex that contains extra sex combs, suppressor of zeste-12 [Su(z)12], and the histone binding proteins RbAp46/RbAp48. This complex, which we termed Polycomb repressive complex (PRC) 2, possesses HMT activity with specificity for Lys 9 (K9) and Lys 27 (K27) of histone H3. The HMT activity of PRC2 is dependent on an intact SET domain in the E(z) protein. We hypothesize that transcriptional repression by the E(z) protein involves methylation-dependent recruitment of PRC1. The presence of Su(z)12, a strong suppressor of position effect variegation, in PRC2 suggests that PRC2 may play a widespread role in heterochromatin-mediated silencing. | Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. |
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evaluate the relationship between CD40/CD40L system and increased thrombogenesis in AF, and to test the effects of simvastatin treatment. METHODS In vitro study using human tissue, University Hospital (tertiary referral center). Experiments on right atrial segments obtained before the onset of cardiopulmonary bypass were done in either presence or absence of 5 microM simvastatin. Two groups of patients in either chronic atrial fibrillation or sinus rhythm at the time of cardiac surgery. The endocardial expression of CD40, the release of CD40L, and adhesion of platelets to endocardium. Additionally, the thickness of platelet aggregates and the platelet distribution on the endocardium were also evaluated. RESULTS Atrial fibrillation was associated with a significant increase of endocardial CD40 expression (293.1+/-55.1 pg/ml vs. 230.9+/-53.3 pg/ml, p<0.01), and platelet-endocardial adhesion compared with sinus rhythm atria (10.8+/-2.2 vs. 5.2+/-1.3 platelet CD41 AU p<0.01). At immunofluorescence about 62% of fibrillating endocardium was covered by platelets, compared with 12% of not sinus rhythm atria. Addition of simvastatin significantly reduced CD40 expression as well as platelet adhesion to fibrillating atria; its efficacy was not reversed by the addition of mevalonic acid. CONCLUSIONS Chronic atrial fibrillation acutely upregulates CD40 expression as well as platelet adhesion to the endocardium. Simvastatin is effective in modulating this expression, thus it may potentially contribute to reduce the risk of intra-atrial thrombus formation. | Simvastatin reduces platelet-endocardium adhesion in atrial fibrillation. |
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0.5784112811088562, "27247": 0.4093637466430664, "27282": 0.009718249551951885, "27480": 0.0354953333735466, "27491": 0.2637155055999756, "27894": 0.05417001247406006, "28389": 0.34577593207359314, "28418": 0.02316705882549286, "28436": 0.11430477350950241, "28444": 0.13925230503082275, "28582": 0.007782140281051397, "28739": 0.9045027494430542, "28828": 0.007782140281051397, "28989": 0.1685553640127182, "29145": 0.1693800985813141, "29248": 0.14264501631259918, "29264": 0.255429208278656, "29458": 0.03266380727291107} | 23203102 | BACKGROUND The occurrence of transfusion transmissions of variant Creutzfeldt-Jakob disease (CJD) cases has reawakened attention to the possible similar risk posed by other forms of CJD. STUDY DESIGN AND METHODS CJD with a definite or probable diagnosis (sporadic CJD, n = 741; genetic CJD, n = 175) and no-CJD patients with definite alternative diagnosis (n = 482) with available blood transfusion history were included in the study. The risk of exposure to blood transfusion occurring more than 10 years before disease onset and for some possible confounding factors was evaluated by calculating crude odds ratios (ORs). Variables with significant ORs in univariate analyses were included in multivariate logistic regression analyses. RESULTS In the univariate model, blood transfusion occurring more than 10 years before clinical onset is 4.1-fold more frequent in sporadic CJD than in other neurologic disorders. This significance is lost when the 10-year lag time was not considered. Multivariate analyses show that the risk of developing sporadic CJD after transfusion increases (OR, 5.05) after adjusting for possible confounding factors. Analysis conducted on patients with genetic CJD did not reveal any significant risk factor associated with transfusion. CONCLUSION This is the first case-control study showing a significant risk of transfusion occurring more than 10 years before clinical onset in sporadic CJD patients. It remains questionable whether the significance of these data is biologically plausible or the consequence of biases in the design of the study, but they counterbalance previous epidemiologic negative reports that might have overestimated the assessment of blood safety in sporadic CJD. | Transmission of sporadic Creutzfeldt-Jakob disease by blood transfusion: risk factor or possible biases. |
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1.1076855659484863, "26886": 0.0913962796330452, "26989": 0.2394166737794876, "27354": 0.012615402229130268, "27605": 0.22626367211341858, "27651": 0.04953393340110779, "27953": 0.953857421875, "28093": 0.022212404757738113, "28177": 0.20739519596099854, "28329": 0.3127557039260864, "28436": 0.16276304423809052, "28648": 0.7163142561912537, "28696": 1.0828639268875122, "28833": 0.34370049834251404, "29125": 0.10731173306703568, "29299": 0.8893690705299377, "29458": 0.31845372915267944, "29490": 0.09050461649894714} | 23206239 | The efficient diagnosis and accurate monitoring of diabetic patients are cornerstones for reducing the risk of diabetic complications. The current diagnostic and prognostic strategies in diabetes are mainly based on two tests, plasma (or capillary) glucose and glycated hemoglobin (HbA1c). Nevertheless, these measures are not foolproof, and their clinical usefulness is biased by a number of clinical and analytical factors. The introduction of other indices of glucose homeostasis in clinical practice such as fructosamine and glycated albumin (GA) may be regarded as an attractive alternative, especially in patients in whom the measurement of HbA1c may be biased or even unreliable. These include patients with rapid changes of glucose homeostasis and larger glycemic excursions, and patients with red blood cell disorders and renal disease. According to available evidence, the overall diagnostic efficiency of GA seems superior to that of fructosamine throughout a broad range of clinical settings. The current method for measuring GA is also better standardized and less vulnerable to preanalytical variables than those used for assessing fructosamine. Additional advantages of GA over HbA1c are represented by lower reagent cost and being able to automate the GA analysis on many conventional laboratory instruments. Although further studies are needed to definitely establish that GA can complement or even replace conventional measures of glycemic control such as HbA1c, GA may help the clinical management of patients with diabetes in whom HbA1c values might be unreliable. | Advantages and pitfalls of fructosamine and glycated albumin in the diagnosis and treatment of diabetes. |
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promote enhancer formation. The mechanism by which pioneer TFs gain access to chromatin remains an important unanswered question. Here we show that PARP-1, a nucleosome-binding protein, cooperates with intrinsic properties of the pioneer TF Sox2 to facilitate its binding to intractable genomic loci in embryonic stem cells. These actions of PARP-1 occur independently of its poly(ADP-ribosyl) transferase activity. PARP-1-dependent Sox2-binding sites reside in euchromatic regions of the genome with relatively high nucleosome occupancy and low co-occupancy by other transcription factors. PARP-1 stabilizes Sox2 binding to nucleosomes at suboptimal sites through cooperative interactions on DNA. Our results define intrinsic and extrinsic features that determine Sox2 pioneer activity. The conditional pioneer activity observed with Sox2 at a subset of binding sites may be a key feature of other pioneer TFs operating at intractable genomic loci. | Catalytic-Independent Functions of PARP-1 Determine Sox2 Pioneer Activity at Intractable Genomic Loci. |
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"29514": 0.8829278349876404, "29610": 0.5151132941246033} | 23237995 | Hormones play a critical role in driving major stage transitions and developmental timing events in many species. In the nematode C. elegans the steroid hormone receptor, DAF-12, works at the confluence of pathways regulating developmental timing, stage specification, and longevity. DAF-12 couples environmental and physiologic signals to life history regulation, and it is embedded in a rich architecture governing diverse processes. Here, we highlight the molecular insights, extraordinary circuitry, and signaling pathways governing life stage transitions in the worm and how they have yielded fundamental insights into steroid regulation of biological time. | Steroid regulation of C. elegans diapause, developmental timing, and longevity. |
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"22552": 0.08513788133859634, "22851": 0.05786345899105072, "22863": 0.7463917136192322, "23150": 0.007782140281051397, "23216": 0.043007105588912964, "23237": 0.3012613356113434, "23247": 0.12986256182193756, "23586": 0.5601736903190613, "23807": 0.9994535446166992, "23915": 0.16524957120418549, "23959": 0.1011524572968483, "24054": 0.630689799785614, "24558": 0.20660123229026794, "24879": 1.0073304176330566, "24908": 0.02887592278420925, "25086": 0.11430477350950241, "25177": 0.8013357520103455, "25206": 0.19541899859905243, "25324": 0.0752234235405922, "25456": 0.46117570996284485, "25524": 0.0797421783208847, "25705": 0.3883931338787079, "26083": 1.2192846536636353, "26141": 0.9021284580230713, "26242": 0.10026945173740387, "26244": 0.018384648486971855, "26402": 1.1153976917266846, "26408": 0.11343330889940262, "26572": 1.094698429107666, "26874": 0.1212492436170578, "27019": 0.4002431631088257, "27263": 0.00875066313892603, "27642": 0.018384648486971855, "27749": 0.35813871026039124, "28691": 0.05139094591140747, "28736": 0.5272908806800842, "29060": 0.6327666640281677, "29226": 0.6931471824645996, "29458": 0.4574742913246155} | 23244529 | Polycomb Group (PcG) proteins mediate heritable gene silencing by modifying chromatin structure. An essential PcG complex, PRC1, compacts chromatin and inhibits chromatin remodeling. In Drosophila melanogaster, the intrinsically disordered C-terminal region of PSC (PSC-CTR) mediates these noncovalent effects on chromatin, and is essential for viability. Because the PSC-CTR sequence is poorly conserved, the significance of its effects on chromatin outside of Drosophila was unclear. The absence of folded domains also made it difficult to understand how the sequence of PSC-CTR encodes its function. To determine the mechanistic basis and extent of conservation of PSC-CTR activity, we identified 17 metazoan PSC-CTRs spanning chordates to arthropods, and examined their sequence features and biochemical properties. PSC-CTR sequences are poorly conserved, but are all highly charged and structurally disordered. We show that active PSC-CTRs--which bind DNA tightly and inhibit chromatin remodeling efficiently--are distinguished from less active ones by the absence of extended negatively charged stretches. PSC-CTR activity can be increased by dispersing its contiguous negative charge, confirming the importance of this property. Using the sequence properties defined as important for PSC-CTR activity, we predicted the presence of active PSC-CTRs in additional diverse genomes. Our analysis reveals broad conservation of PSC-CTR activity across metazoans. This conclusion could not have been determined from sequence alignments. We further find that plants that lack active PSC-CTRs instead possess a functionally analogous PcG protein, EMF1. Thus, our study suggests that a disordered domain with dispersed negative charges underlies PRC1 activity, and is conserved across metazoans and plants. | A core subunit of Polycomb repressive complex 1 is broadly conserved in function but not primary sequence. |
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was evaluated in eight highly trained female cyclists. Each cyclist kept a 3-day weighed food record. Diets were analyzed for nutrient content using a computerized software package. Blood was also obtained and evaluated for hemoglobin, hematocrit, and albumin. For an athletic group, the cyclists' diets were found to be low in energy (85% RDA) and carbohydrate (4.4 gm/kg body weight per day). Mean daily dietary intakes were well below the RDAs for folacin (76% RDA), magnesium (81%), iron (59%), and zinc (48%). In addition, more than one-third of the cyclists failed to consume 67% of the RDA for the following micronutrients: pyridoxine, folacin, cobalamin, vitamin E, magnesium, iron, and zinc. Hemoglobin (135 gm/L), hematocrit (0.39), and albumin (45 gm/L) values were all normal, although most hemoglobin values were in the lower 50% of normal range. Foods such as meats, poultry, fish, beans, peas, and nuts were low or absent from the diets of most athletes. Dietary quality in this group of female cyclists could have been greatly improved with the addition of more of those foods. These athletes could benefit from nutrition education and diet counseling. | Dietary status of trained female cyclists. |
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A number of transcription factors containing a paired domain (Pax proteins) are expressed in the segmented mesoderm during embryogenesis. These include Pax-3 and a closely related gene, Pax-7, both of which are expressed in the segmental plate and in the dermomyotome. In this paper, we show that signals from the notochord pattern the expression of Pax-3, Pax-7 and Pax-9 in somites and the subsequent differentiation of cell types that arise from the somitic mesoderm. We directly assess the role of the Pax-3 gene in the differentiation of cell types derived from the dermomyotome by analyzing the development of muscle in splotch mouse embryos which lack a functional Pax-3 gene. A population of Pax-3-expressing cells derived from the dermomyotome that normally migrate into the limb are absent in homozygous splotch embryos and, as a result, limb muscles are lost. No abnormalities were detected in the trunk musculature of splotch embryos indicating that Pax-3 is necessary for the development of the limb but not trunk muscle. | Regulation of Pax-3 expression in the dermomyotome and its role in muscle development. |
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0.5145297050476074, "28032": 0.6223390698432922, "28086": 0.07612881064414978, "28348": 0.28670501708984375, "28636": 0.07068414986133575, "29237": 0.16110190749168396, "29290": 0.25694093108177185} | 23260700 | Angiopoietin 2 (Ang2) was originally shown to be a competitive antagonist for Ang1 of the receptor tyrosine kinase Tie2 in endothelial cells (ECs). Since then, reports have conflicted on whether Ang2 is an agonist or antagonist of Tie2. Here we show that Ang2 functions as an agonist when Ang1 is absent but as a dose-dependent antagonist when Ang1 is present. Exogenous Ang2 activates Tie2 and the promigratory, prosurvival PI3K/Akt pathway in ECs but with less potency and lower affinity than exogenous Ang1. ECs produce Ang2 but not Ang1. This endogenous Ang2 maintains Tie2, phosphatidylinositol 3-kinase, and Akt activities, and it promotes EC survival, migration, and tube formation. However, when ECs are stimulated with Ang1 and Ang2, Ang2 dose-dependently inhibits Ang1-induced Tie2 phosphorylation, Akt activation, and EC survival. We conclude that Ang2 is both an agonist and an antagonist of Tie2. Although Ang2 is a weaker agonist than Ang1, endogenous Ang2 maintains a level of Tie2 activation that is critical to a spectrum of EC functions. These findings may reconcile disparate reports of Ang2's effect on Tie2, impact our understanding of endogenous receptor tyrosine kinase signal transduction mechanisms, and affect how Ang2 and Tie2 are targeted under conditions such as sepsis and cancer. | Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. |
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Seven isolates were part of a mixed flora [corrected]. One strain was isolated in pure culture from the blood of a patient with peritonitis of appendicular origin. According to the 16S rRNA gene sequences, this strain was close to Desulfovibrio fairfieldensis. The present report describes the fourth isolate of this recently described species to be isolated in pure culture or as a predominant part of the flora and to be associated with infectious processes. Thus, D. fairfieldensis may possess a higher pathogenic potential than other Desulfovibrio species. | Bacteremia caused by a strain of Desulfovibrio related to the provisionally named Desulfovibrio fairfieldensis. |
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23267371 | Vitamin D insufficiency affects almost 50% of the population worldwide. An estimated 1 billion people worldwide, across all ethnicities and age groups, have a vitamin D deficiency (VDD). This pandemic of hypovitaminosis D can mainly be attributed to lifestyle (for example, reduced outdoor activities) and environmental (for example, air pollution) factors that reduce exposure to sunlight, which is required for ultraviolet-B (UVB)-induced vitamin D production in the skin. High prevalence of vitamin D insufficiency is a particularly important public health issue because hypovitaminosis D is an independent risk factor for total mortality in the general population. Current studies suggest that we may need more vitamin D than presently recommended to prevent chronic disease. As the number of people with VDD continues to increase, the importance of this hormone in overall health and the prevention of chronic diseases are at the forefront of research. VDD is very common in all age groups. As few foods contain vitamin D, guidelines recommended supplementation at suggested daily intake and tolerable upper limit levels. It is also suggested to measure the serum 25-hydroxyvitamin D level as the initial diagnostic test in patients at risk for deficiency. Treatment with either vitamin D2 or vitamin D3 is recommended for deficient patients. A meta-analysis published in 2007 showed that vitamin D supplementation was associated with significantly reduced mortality. In this review, we will summarize the mechanisms that are presumed to underlie the relationship between vitamin D and understand its biology and clinical implications. | Vitamin D: The "sunshine" vitamin. |
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0.10467668622732162, "29107": 0.24325250089168549} | 23269537 | Cyclin D1 expression is deregulated by chromosome translocation in mantle cell lymphoma and a subset of multiple myeloma. The molecular mechanisms involved in long-distance gene deregulation remain obscure, although changes in acetylated histones and methylated CpG dinucleotides may be important. The patterns of DNA methylation and histone acetylation were determined at the cyclin D1 locus on chromosome 11q13 in B-cell malignancies. The cyclin D1 promoter was hypomethylated and hyperacetylated in expressing cell lines and patient samples, and methylated and hypoacetylated in nonexpressing cell lines. Domains of hyperacetylated histones and hypomethylated DNA extended over 120 kb upstream of the cyclin D1 gene. Interestingly, hypomethylated DNA and hyperacetylated histones were also located at the cyclin D1 promoter but not the upstream major translocation cluster region in cyclin D1-nonexpressing, nontumorigenic B and T cells. RNA polymerase II binding was demonstrated both at the cyclin D1 promoter and 3' immunoglobulin heavy-chain regulatory regions only in malignant B-cell lines with deregulated cyclin D1 expression. Our results suggest a model where RNA polymerase II bound at IgH regulatory sequences can activate the cyclin D1 promoter by either long-range polymerase transfer or tracking. | Cyclin D1 activation in B-cell malignancy: association with changes in histone acetylation, DNA methylation, and RNA polymerase II binding to both promoter and distal sequences. |
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0.13670019805431366, "28873": 0.822151780128479, "29610": 0.3850763738155365} | 23273454 | Eleven mammalian toll-like receptors (TLRs 1-11) have been identified to date and are known to play a crucial role in the regulation of immune responses; however, the factors that regulate TLR expression and function in vivo are poorly understood. Therefore, in the present study, we investigated the physiological regulation of TLR expression and function in humans. To examine the influence of diurnal rhythmicity on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers (n = 8) at time points coinciding with the peak and nadir in the endogenous circulating cortisol concentration. While no diurnal rhythmicity in the expression of TLRs 1, 2, 4 or 9 was observed, the upregulation of costimulatory (CD80 and CD86) and antigen-presenting (MHC class II) molecules on CD14(+) monocytes following activation with specific TLR ligands was greater (P < 0.05) in samples obtained in the evening compared with the morning. To examine the influence of physical stress on TLR expression and function, peripheral venous blood samples were collected from healthy volunteers (n = 11) at rest and following 1.5 h of strenuous exercise in the heat (34 degrees C). Strenuous exercise resulted in a decrease (P < 0.005) in the expression of TLRs 1, 2 and 4 on CD14(+) monocytes. Furthermore, the upregulation of CD80, CD86, MHC class II and interleukin-6 by CD14(+) monocytes following activation with specific TLR ligands was decreased (P < 0.05) in samples obtained following exercise compared with at rest. These results demonstrate that TLR function is subject to modulation under physiological conditions in vivo and provide evidence for the role of immunomodulatory hormones in the regulation of TLR function. | The physiological regulation of toll-like receptor expression and function in humans. |
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0.053244512528181076, "29192": 0.052318159490823746, "29477": 0.47036975622177124} | 23284774 | AIM To identify the psychosocial needs of breast-cancer patients and their relatives along with factors affecting these needs and to develop a tentative model to guide further research and need assessments in clinical practice. BACKGROUND Women experiencing breast cancer must deal with the diagnosis of a life-threatening illness. Treatment and the recovery process can be demanding for patients and their relatives. Need assessment may help clinicians focus on providing appropriate help. DESIGN Literature review. METHOD Undertaken using electronic databases and specific research terms; 20 articles were identified and analysed. RESULTS The needs identified by patients involve (1) treatment-related physical and social impairment like fatigue, menopausal symptoms and a changed body image and (2) emotional distress like fear of recurrence, anxiety and depression. Partners need help to protect themselves and the patient from different threats. Women need information to maintain control and manage their illness. Partners want information concerning the patient's condition and both of them about the prognosis and perspectives. There is a lack of knowledge of relatives' needs. Mutual familial support, women's and partners' health and emotional distress may affect the interaction between the patients and their partners. CONCLUSIONS A tentative family-based model to guide further research and clinical support is proposed. Further research is needed to determine precisely which psychosocial factors may influence fulfilment of the patients' and relatives' needs. RELEVANCE TO CLINICAL PRACTICE The proposed model may provide a framework for healthcare professionals to evaluate the patients' and relatives' met and unmet needs and the real demand for help, to guide care planning, counselling and education. | A review of psychosocial needs of breast-cancer patients and their relatives. |
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receptors that play a central role in reverse cholesterol transport through up-regulation of ATP-binding cassette transporters (ABCA1 and ABCG1) that mediate cellular cholesterol efflux. Mouse models of atherosclerosis exhibit reduced atherosclerosis and enhanced regression of established plaques upon LXR activation. However, the coregulatory factors that affect LXR-dependent gene activation in macrophages remain to be elucidated. To identify novel regulators of LXR that modulate its activity, we used affinity purification and mass spectrometry to analyze nuclear LXRα complexes and identified poly(ADP-ribose) polymerase-1 (PARP-1) as an LXR-associated factor. In fact, PARP-1 interacted with both LXRα and LXRβ. Both depletion of PARP-1 and inhibition of PARP-1 activity augmented LXR ligand-induced ABCA1 expression in the RAW 264.7 macrophage line and primary bone marrow-derived macrophages but did not affect LXR-dependent expression of other target genes, ABCG1 and SREBP-1c. Chromatin immunoprecipitation experiments confirmed PARP-1 recruitment at the LXR response element in the promoter of the ABCA1 gene. Further, we demonstrated that LXR is poly(ADP-ribosyl)ated by PARP-1, a potential mechanism by which PARP-1 influences LXR function. Importantly, the PARP inhibitor 3-aminobenzamide enhanced macrophage ABCA1-mediated cholesterol efflux to the lipid-poor apolipoprotein AI. These findings shed light on the important role of PARP-1 on LXR-regulated lipid homeostasis. Understanding the interplay between PARP-1 and LXR may provide insights into developing novel therapeutics for treating atherosclerosis. | Poly(ADP-ribose) Polymerase 1 Represses Liver X Receptor-mediated ABCA1 Expression and Cholesterol Efflux in Macrophages. |
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"24555": 0.175953671336174, "24608": 0.03266380727291107, "24755": 0.13670019805431366, "25088": 0.0606246218085289, "25612": 0.37102460861206055, "25947": 0.129004567861557, "26319": 0.08782484382390976, "26360": 0.37102460861206055, "26557": 0.6872705817222595, "26877": 0.20739519596099854, "27155": 0.04860413447022438, "27204": 0.1332872211933136, "27354": 0.007782140281051397, "27794": 0.1619328260421753, "27891": 0.004870930220931768, "28093": 0.04394211992621422, "28687": 1.1864371299743652, "28711": 0.3956514894962311, "29031": 0.1994270235300064, "29094": 0.5104349255561829, "29172": 0.17922431230545044, "29234": 0.058784693479537964, "29251": 0.03266380727291107} | 23294314 | OBJECTIVE To assess whether advance provision of emergency contraception increases its use and whether it has secondary effects on regular contraceptive use. METHODS We conducted a controlled trial of female clients, aged 16-24 years, who attended a publicly funded family planning clinic. Women were systematically assigned to receive an advance provision of emergency contraception and education (treatment) or education only (control). Among 263 participants enrolled (133 treatment, 130 control), follow-up was completed in 213 (111 treatment, 102 control). The main outcome measures were emergency contraception knowledge and use, frequency of unprotected sex, and pattern of contraceptive use in the past 4 months. RESULTS Participants were aware of emergency contraception at follow-up, but the treatment group was three times as likely to use it (P =.006). Although the treatment group did not report higher frequencies of unprotected sex than the control group, women in the treatment group (28%) were more likely than those in the control group (17%) to report using less effective contraception at follow-up compared with enrollment (P =.05). The proportion of women in both groups who reported consistent pill use increased from enrollment to follow-up (34% versus 45%); however, the control group (58%) was more likely than the treatment group (32%) to report consistent pill use at follow-up (P =.03). CONCLUSION Use of emergency contraception was increased by providing it in advance, but not by education alone. Changes to less effective contraceptive methods and patterns of pill use were potentially negative effects that need to be explored in relation to observed benefits. | Emergency contraception: advance provision in a young, high-risk clinic population. |
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"26419": 0.09584271162748337, "26520": 0.2918238639831543, "26563": 0.009718249551951885, "26646": 1.2387138605117798, "26745": 0.7038320899009705, "26775": 0.7737906575202942, "26786": 0.05417001247406006, "26835": 0.22782009840011597, "27009": 0.1808556467294693, "27144": 0.28082266449928284, "27354": 0.28670501708984375, "27512": 0.9922385215759277, "27781": 0.28597161173820496, "28032": 0.5540198087692261, "28105": 1.2682671546936035, "28775": 0.6573580503463745, "28788": 0.5278670787811279, "28873": 0.5562619566917419, "29290": 0.03925827145576477, "29299": 0.53589928150177, "29458": 0.822151780128479, "29491": 0.2741633653640747} | 23304931 | PURPOSE Diffuse large B-cell lymphoma (DLBCL) represents a clinically heterogeneous disease. Models based on immunohistochemistry predict clinical outcome. These include subdivision into germinal center (GC) versus non-GC subtypes; proliferation index (measured by expression of Ki-67), and expression of BCL-2, FOXP1, or B-lymphocyte-induced maturation protein (Blimp-1)/PRDM1. We sought to determine whether immunohistochemical analyses of biopsies from patients with DLBCL having HIV infection are similarly relevant for prognosis. PATIENTS AND METHODS We examined 81 DLBCLs from patients with AIDS in AMC010 (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] v CHOP-rituximab) and AMC034 (etoposide, doxorubicin, vincristine, prednisone, and dose-adjusted cyclophosphamide plus rituximab concurrent v sequential) clinical trials and compared the immunophenotype with survival data, Epstein-Barr virus (EBV) positivity, and CD4 counts. RESULTS The GC and non-GC subtypes of DLBCL did not differ significantly with respect to overall survival or CD4 count at cancer presentation. EBV could be found in both subtypes of DLBCL, although less frequently in the GC subtype, and did not affect survival. Expression of FOXP1, Blimp-1/PRDM1, or BCL-2 was not correlated with the outcome in patients with AIDS-related DLBCL. CONCLUSION These data indicate that with current treatment strategies for lymphoma and control of HIV infection, commonly used immunohistochemical markers may not be clinically relevant in HIV-infected patients with DLBCL. The only predictive immunohistochemical marker was found to be Ki-67, where a higher proliferation index was associated with better survival, suggesting a better response to therapy in patients whose tumors had higher proliferation rates. | Immunophenotypic analysis of AIDS-related diffuse large B-cell lymphoma and clinical implications in patients from AIDS malignancies consortium clinical trials 010 and 034 |
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"25353": 0.020300358533859253, "25520": 1.498855471611023, "25950": 0.06154331564903259, "26287": 0.09495500475168228, "26534": 0.0913962796330452, "26616": 0.17840765416622162, "26835": 0.7791815400123596, "26927": 1.533164143562317, "27734": 0.151916041970253, "27989": 0.06977381557226181, "28041": 1.0073304176330566, "28173": 0.7389566898345947, "28327": 0.8829278349876404, "28466": 0.015504186972975731, "28616": 1.0151457786560059, "28767": 0.5450005531311035, "28927": 0.151916041970253, "28947": 0.1734936386346817, "29090": 0.5086748600006104, "29477": 1.190008521080017, "29532": 0.4356052577495575} | 23305547 | Neurodegenerative diseases belong to a larger group of protein misfolding disorders, known as proteinopathies. There is increasing experimental evidence implicating prion-like mechanisms in many common neurodegenerative disorders, including Alzheimer disease, Parkinson disease, the tauopathies, and amyotrophic lateral sclerosis (ALS), all of which feature the aberrant misfolding and aggregation of specific proteins. The prion paradigm provides a mechanism by which a mutant or wild-type protein can dominate pathogenesis through the initiation of self-propagating protein misfolding. ALS, a lethal disease characterized by progressive degeneration of motor neurons is understood as a classical proteinopathy; the disease is typified by the formation of inclusions consisting of aggregated protein within and around motor neurons that can contribute to neurotoxicity. It is well established that misfolded/oxidized SOD1 protein is highly toxic to motor neurons and plays a prominent role in the pathology of ALS. Recent work has identified propagated protein misfolding properties in both mutant and wild-type SOD1, which may provide the molecular basis for the clinically observed contiguous spread of the disease through the neuroaxis. In this review we examine the current state of knowledge regarding the prion-like properties of SOD1 and comment on its proposed mechanisms of intercellular transmission. | Prion-like activity of Cu/Zn superoxide dismutase: implications for amyotrophic lateral sclerosis. |
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"28024": 0.21765978634357452, "28389": 0.2954642176628113, "28788": 0.0752234235405922, "28848": 0.7305257320404053, "28873": 0.3269403576850891, "29090": 0.19622190296649933, "29215": 1.0458102226257324, "29295": 0.083342544734478, "29491": 0.03831886500120163} | 23305884 | Epstein-Barr virus (EBV) is an oncogenic human herpesvirus that dramatically reorganizes host gene expression to immortalize primary B cells. In this study, we analyzed EBV-regulated host gene expression changes following primary B-cell infection, both during initial proliferation and through transformation into lymphoblastoid cell lines (LCLs). While most EBV-regulated mRNAs were changed during the transition from resting, uninfected B cells through initial B-cell proliferation, a substantial number of mRNAs changed uniquely from early proliferation through LCL outgrowth. We identified constitutively and dynamically EBV-regulated biological processes, protein classes, and targets of specific transcription factors. Early after infection, genes associated with proliferation, stress responses, and the p53 pathway were highly enriched. However, the transition from early to long-term outgrowth was characterized by genes involved in the inhibition of apoptosis, the actin cytoskeleton, and NF-κB activity. It was previously thought that the major viral protein responsible for NF-κB activation, latent membrane protein 1 (LMP1), is expressed within 2 days after infection. Our data indicate that while this is true, LCL-level LMP1 expression and NF-κB activity are not evident until 3 weeks after primary B-cell infection. Furthermore, heterologous NF-κB activation during the first week after infection increased the transformation efficiency, while early NF-κB inhibition had no effect on transformation. Rather, inhibition of NF-κB was not toxic to EBV-infected cells until LMP1 levels and NF-κB activity were high. These data collectively highlight the dynamic nature of EBV-regulated host gene expression and support the notion that early EBV-infected proliferating B cells have a fundamentally distinct growth and survival phenotype from that of LCLs. | Analysis of Epstein-Barr virus-regulated host gene expression changes through primary B-cell outgrowth reveals delayed kinetics of latent membrane protein 1-mediated NF-κB activation. |
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0.052318159490823746, "26023": 0.2954642176628113, "26164": 0.5979346632957458, "26236": 0.09584271162748337, "26279": 0.16442140936851501, "26305": 0.1401015669107437, "26419": 0.5489565134048462, "26462": 0.27342069149017334, "26651": 0.08871890604496002, "26728": 0.5180262327194214, "26745": 0.630689799785614, "26835": 0.23247487843036652, "26957": 0.055094651877880096, "27144": 0.9732321500778198, "27438": 0.22859740257263184, "27695": 0.7124901413917542, "27793": 0.026025565341114998, "28689": 0.18654440343379974, "28723": 0.175953671336174, "28788": 0.24631060659885406, "28873": 0.10203468054533005, "29107": 0.32553088665008545, "29153": 0.03925827145576477, "29365": 0.5551415085792542, "29401": 0.056018441915512085, "29486": 0.07068414986133575} | 23326722 | We describe the clinical and pathological features of 23 Afro-Caribbean patients with adult T-cell leukaemia/lymphoma admitted to the Queen Elizabeth Hospital, Barbados over a 5 year period. There were 9 males and 14 females, with a median age of 38 years (range 14-84). Twelve had acute leukaemia, 10 lymphoma (including 4 with solitary extra nodal lesions) and 1 smouldering subtype. Two patients had a past history of tropical spastic paraparesis/HTLV I associated myelopathy (TSP/HAM). The prognosis was poor, with only 3 complete responses to chemotherapy (CHOP) lasting from 9 to 36 months. We conclude that ATLL in Barbados is similar to the disease in the other Caribbean islands and Japan, except that in Barbados the age of onset is over a decade younger than in Japan. | Clinical and laboratory features of adult T-cell leukaemia lymphoma in Barbados. |
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0.9037119746208191, "29577": 0.15359249711036682} | 23331269 | A growing body of research suggests that intrinsic neuronal slow (<10 Hz) oscillations in auditory cortex appear to track incoming speech and other spectro-temporally complex auditory signals. Within this framework, several recent studies have identified critical-band temporal envelopes as the specific acoustic feature being reflected by the phase of these oscillations. However, how this alignment between speech acoustics and neural oscillations might underpin intelligibility is unclear. Here we test the hypothesis that the 'sharpness' of temporal fluctuations in the critical band envelope acts as a temporal cue to speech syllabic rate, driving delta-theta rhythms to track the stimulus and facilitate intelligibility. We interpret our findings as evidence that sharp events in the stimulus cause cortical rhythms to re-align and parse the stimulus into syllable-sized chunks for further decoding. Using magnetoencephalographic recordings, we show that by removing temporal fluctuations that occur at the syllabic rate, envelope-tracking activity is reduced. By artificially reinstating these temporal fluctuations, envelope-tracking activity is regained. These changes in tracking correlate with intelligibility of the stimulus. Together, the results suggest that the sharpness of fluctuations in the stimulus, as reflected in the cochlear output, drive oscillatory activity to track and entrain to the stimulus, at its syllabic rate. This process likely facilitates parsing of the stimulus into meaningful chunks appropriate for subsequent decoding, enhancing perception and intelligibility. | Acoustic landmarks drive delta-theta oscillations to enable speech comprehension by facilitating perceptual parsing. |
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"23735": 0.6533012986183167, "23737": 0.06337817758321762, "23758": 0.9440274834632874, "23777": 0.06886265426874161, "24054": 1.310231328010559, "24203": 0.7314660549163818, "24229": 0.09761575609445572, "24312": 1.4283655881881714, "24628": 0.2674594223499298, "24829": 0.1619328260421753, "24879": 0.00875066313892603, "25269": 0.23247487843036652, "25456": 1.117316484451294, "25458": 0.12470348179340363, "25505": 0.055094651877880096, "26228": 0.8091925978660583, "26244": 0.21687394380569458, "26402": 1.094698429107666, "26534": 0.1619328260421753, "26616": 0.6808650493621826, "26721": 0.04767346754670143, "26773": 0.04953393340110779, "26874": 0.306306391954422, "27208": 0.1710275560617447, "27321": 0.25845035910606384, "27642": 1.1394343376159668, "27854": 0.22704219818115234, "28433": 0.10203468054533005, "28550": 0.272677481174469, "28603": 0.058784693479537964, "28691": 0.2696990668773651, "29060": 0.20501139760017395, "29290": 0.20739519596099854} | 23342686 | The small ribosomal subunit is responsible for the decoding of genetic information and plays a key role in the initiation of protein synthesis. We analyzed by X-ray crystallography the structures of three different complexes of the small ribosomal subunit of Thermus thermophilus with the A-site inhibitor tetracycline, the universal initiation inhibitor edeine and the C-terminal domain of the translation initiation factor IF3. The crystal structure analysis of the complex with tetracycline revealed the functionally important site responsible for the blockage of the A-site. Five additional tetracycline sites resolve most of the controversial biochemical data on the location of tetracycline. The interaction of edeine with the small subunit indicates its role in inhibiting initiation and shows its involvement with P-site tRNA. The location of the C-terminal domain of IF3, at the solvent side of the platform, sheds light on the formation of the initiation complex, and implies that the anti-association activity of IF3 is due to its influence on the conformational dynamics of the small ribosomal subunit. | Crystal structures of complexes of the small ribosomal subunit with tetracycline, edeine and IF3. |
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0.35060185194015503, "26721": 0.650757372379303, "26745": 0.14686977863311768, "26835": 0.1734936386346817, "26953": 0.42353010177612305, "27144": 0.16359257698059082, "27292": 0.15610189735889435, "27697": 0.0174254160374403, "27781": 0.417115718126297, "27790": 0.03831886500120163, "28696": 0.11865071207284927, "28788": 0.29255300760269165, "28848": 0.01934296265244484, "28873": 0.9936857223510742, "28896": 0.0354953333735466, "29003": 0.08244366943836212, "29327": 0.2918238639831543, "29361": 0.02792670577764511, "29490": 0.20818853378295898, "29610": 0.21922965347766876} | 23342845 | In type 1 diabetes (T1D), there is an intense inflammatory response that destroys the β cells in the pancreatic islets of Langerhans, the site where insulin is produced and released. A therapy for T1D that targets the specific autoimmune response in this disease while leaving the remainder of the immune system intact, has long been sought. Proinsulin is a major target of the adaptive immune response in T1D. We hypothesized that an engineered DNA plasmid encoding proinsulin (BHT-3021) would preserve β cell function in T1D patients through reduction of insulin-specific CD8⁺ T cells. We studied 80 subjects over 18 years of age who were diagnosed with T1D within the past 5 years. Subjects were randomized 2:1 to receive intramuscular injections of BHT-3021 or BHT-placebo, weekly for 12 weeks, and then monitored for safety and immune responses in a blinded fashion. Four dose levels of BHT-3021 were evaluated: 0.3, 1.0, 3.0, and 6.0 mg. C-peptide was used both as an exploratory efficacy measure and as a safety measure. Islet-specific CD8⁺ T cell frequencies were assessed with multimers of monomeric human leukocyte antigen class I molecules loaded with peptides from pancreatic and unrelated antigens. No serious adverse events related to BHT-3021 were observed. C-peptide levels improved relative to placebo at all doses, at 1 mg at the 15-week time point (+19.5% BHT-3021 versus -8.8% BHT-placebo, P < 0.026). Proinsulin-reactive CD8⁺ T cells, but not T cells against unrelated islet or foreign molecules, declined in the BHT-3021 arm (P < 0.006). No significant changes were noted in interferon-γ, interleukin-4 (IL-4), or IL-10 production in CD4 T cells. Thus, we demonstrate that a plasmid encoding proinsulin reduces the frequency of CD8⁺ T cells reactive to proinsulin while preserving C-peptide over the course of dosing. | Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8⁺ T cells in type 1 diabetes. |
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1.1063944101333618, "23971": 0.10203468054533005, "24479": 0.40285754203796387, "24780": 1.0960047245025635, "24979": 0.34922540187835693, "25022": 0.3676496744155884, "25344": 1.0382318496704102, "25604": 0.23015019297599792, "25775": 0.058784693479537964, "25918": 1.013020396232605, "26243": 0.06703783571720123, "26261": 0.42225050926208496, "26363": 0.18816383183002472, "26557": 0.21135559678077698, "26708": 0.11604541540145874, "26721": 0.5723689198493958, "27108": 0.0752234235405922, "27211": 0.23324857652187347, "27572": 0.12384103983640671, "27698": 0.02887592278420925, "28144": 0.02412080205976963, "29278": 0.06520967930555344, "29290": 0.20421554148197174, "29361": 0.1221139207482338, "29454": 0.23787821829319} | 23349986 | CONTEXT Dexamethasone is widely used to prevent postoperative nausea and vomiting (PONV) in pediatric tonsillectomy. OBJECTIVE To assess whether dexamethasone dose-dependently reduces the risk of PONV at 24 hours after tonsillectomy. DESIGN, SETTING, AND PATIENTS Randomized placebo-controlled trial conducted among 215 children undergoing elective tonsillectomy at a major public teaching hospital in Switzerland from February 2005 to December 2007. INTERVENTIONS Children were randomly assigned to receive dexamethasone (0.05, 0.15, or 0.5 mg/kg) or placebo intravenously after induction of anesthesia. Acetaminophen-codeine and ibuprofen were given as postoperative analgesia. Follow-up continued until the 10th postoperative day. MAIN OUTCOME MEASURES The primary end point was prevention of PONV at 24 hours; secondary end points were decrease in the need for ibuprofen at 24 hours and evaluation of adverse effects. RESULTS At 24 hours, 24 of 54 participants who received placebo (44%; 95% confidence interval [CI], 31%-59%) had experienced PONV compared with 20 of 53 (38%; 95% CI, 25%-52%), 13 of 54 (24%; 95% CI, 13%-38%), and 6 of 52 (12%; 95% CI, 4%-23%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P<.001 for linear trend). Children who received dexamethasone received significantly less ibuprofen. There were 26 postoperative bleeding episodes in 22 children. Two of 53 (4%; 95% CI, 0.5%-13%) children who received placebo had bleeding compared with 6 of 53 (11%; 95% CI, 4%-23%), 2 of 51 (4%; 95% CI, 0.5%-13%), and 12 of 50 (24%; 95% CI, 13%-38%) who received dexamethasone at 0.05, 0.15, and 0.5 mg/kg, respectively (P = .003). Dexamethasone, 0.5 mg/kg, was associated with the highest bleeding risk (adjusted relative risk, 6.80; 95% CI, 1.77-16.5). Eight children had to undergo emergency reoperation because of bleeding, all of whom had received dexamethasone. The trial was stopped early for safety reasons. CONCLUSION In this study of children undergoing tonsillectomy, dexamethasone decreased the risk of PONV dose dependently but was associated with an increased risk of postoperative bleeding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00403806. | Dexamethasone and risk of nausea and vomiting and postoperative bleeding after tonsillectomy in children: a randomized trial. |
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Molecular genetics and heterologous expression implicate T1r2 plus T1r3 as a sweet-responsive receptor,and T1r1 plus T1r3,as well as a truncated form of the type 4 metabotropic glutamate receptor (taste-mGluR4),as umami-responsive receptors. Here,we show that mice lacking T1r3 showed no preference for artificial sweeteners and had diminished but not abolished behavioral and nerve responses to sugars and umami compounds. These results indicate that T1r3-independent sweet- and umami-responsive receptors and/or pathways exist in taste cells. | Detection of sweet and umami taste in the absence of taste receptor T1r3. |
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members, cyclin A1 (encoded by Ccna1) and cyclin A2 (encoded by Ccna2). Cyclin A2 promotes both G1/S and G2/M transitions, and targeted deletion of Ccna2 in mouse is embryonic lethal. Cyclin A1 is expressed in mice exclusively in the germ cell lineage and is expressed in humans at highest levels in the testis and certain myeloid leukaemia cells. To investigate the role of cyclin A1 and possible redundancy among the cyclins in vivo, we generated mice bearing a null mutation of Ccna1. Ccna1-/- males were sterile due to a block of spermatogenesis before the first meiotic division, whereas females were normal. Meiosis arrest in Ccna1–/– males was associated with increased germ cell apoptosis, desynapsis abnormalities and reduction of Cdc2 kinase activation at the end of meiotic prophase. Cyclin A1 is therefore essential for spermatocyte passage into the first meiotic division in male mice, a function that cannot be complemented by the concurrently expressed B-type cyclins. | Cyclin A1 is required for meiosis in the male mouse |
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"25524": 0.07159364968538284, "26062": 0.006812678650021553, "26731": 0.10203468054533005, "26780": 0.09672962874174118, "27074": 0.08961215615272522, "27133": 0.16359257698059082, "27204": 0.07341018319129944, "27749": 0.09228714555501938, "27753": 0.06246116757392883, "28134": 1.417065978050232, "28268": 0.3683255612850189, "28436": 0.38041436672210693, "28550": 0.010684899985790253, "28794": 0.04860413447022438, "28892": 0.011650617234408855, "29050": 0.12642613053321838, "29180": 0.12814582884311676} | 23369842 | Twenty-four hour whole body indirect calorimetry has been used to study the effects of feeding, during a sedentary test day, isoenergetic diets which varied in fat (3 or 40 per cent of total energy) and carbohydrate (82 or 45 per cent) content. Three groups of women were studied: lean, obese and 'post-obese' after slimming. Energy expenditure was greater in absolute terms in the obese women. Twenty-four hour energy expenditure was lower by only 3-7 per cent when fasting compared to that when fed to achieve energy balance. There were no large differences in energy expenditure between the two diets or between the groups but the thermogenic effect of the high carbohydrate diet was significantly greater than that of the high fat diet (5.8 vs 3.5 per cent of energy expenditure: P less than 0.01). The post-obese tended to have lower energy expenditure per kg FFM than controls when fasting and when high-fat fed, but this pattern was not shown by the obese. Sleeping energy expenditure was particularly low in the post-obese group when high-fat fed. Dirunal variations in RQ appear to show more marked rise in morning RQ from the nocturnal minimum in the obese and post-obese, which might be evidence for an energy-saving mechanism through greater availability of stored dietary carbohydrate. | Metabolic effects of isoenergetic nutrient exchange over 24 hours in relation to obesity in women. |
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"26651": 0.04487626627087593, "26745": 0.16690383851528168, "27196": 0.012615402229130268, "27343": 0.037378571927547455, "27491": 0.011650617234408855, "27622": 0.2184450328350067, "27673": 0.1229778528213501, "27697": 0.11778303235769272, "27703": 0.08692999184131622, "27755": 0.06886265426874161, "27857": 0.23864774405956268, "27989": 0.16524957120418549, "28212": 0.14095009863376617, "28227": 0.053244512528181076, "28450": 0.10291612148284912, "28466": 0.23402166366577148, "28657": 0.040196798741817474, "28927": 0.17267228662967682, "28935": 0.9915141463279724, "29003": 0.10379679501056671, "29125": 0.812664806842804, "29166": 0.05694137513637543, "29347": 0.10203468054533005, "29458": 0.7380234599113464} | 23377475 | The previous conventional wisdom that survivors of acute kidney injury (AKI) tend to do well and fully recover renal function appears to be flawed. AKI can cause end-stage renal disease (ESRD) directly, and increase the risk of developing incident chronic kidney disease (CKD) and worsening of underlying CKD. In addition, severity, duration, and frequency of AKI appear to be important predictors of poor patient outcomes. CKD is an important risk factor for the development and ascertainment of AKI. Experimental data support the clinical observations and the bidirectional nature of the relationships between AKI and CKD. Reductions in renal mass and nephron number, vascular insufficiency, cell cycle disruption, and maladaptive repair mechanisms appear to be important modulators of progression in patients with and without coexistent CKD. Distinction between AKI and CKD may be artificial. Consideration should be given to the integrated clinical syndrome of diminished GFR, with acute and chronic stages, where spectrum of disease state and outcome is determined by host factors, including the balance of adaptive and maladaptive repair mechanisms over time. Physicians must provide long-term follow-up to patients with first episodes of AKI, even if they presented with normal renal function. | Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. |
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"25502": 0.32905077934265137, "25605": 0.010684899985790253, "25654": 0.24401791393756866, "25714": 0.4311734735965729, "25969": 0.0174254160374403, "26180": 1.0464962720870972, "26378": 0.026976587250828743, "26651": 0.24248650670051575, "26835": 0.083342544734478, "26992": 1.0641717910766602, "27641": 1.1356772184371948, "27753": 0.12470348179340363, "27781": 0.0842406153678894, "27833": 0.12642613053321838, "28144": 0.3622259199619293, "28873": 0.1064341589808464, "28896": 0.11430477350950241, "29490": 0.18411032855510712} | 23388442 | Research describing fatty acids as modulators of inflammation and immune responses abounds. Many of these studies have focused on one particular group of fatty acids, omega-3. The data from animal studies have shown that these fatty acids can have powerful anti-inflammatory and immunomodulatory activities in a wide array of diseases (e.g., autoimmunity, arthritis, and infection). However, the evidence from human trials is more equivocal. In this review, a historical framework for understanding how and why fatty acids may affect the immune system is provided. Second, highlights of two recent landmark reports from the Agency for Healthcare Research and Quality are presented. These reports critically evaluate the evidence from human clinical trials of omega-3 fatty acids and rheumatoid arthritis, asthma, and a few other immune-mediated diseases. Third, the data from human clinical trials investigating the impact of various bioactive fatty acids on ex vivo and in vivo immune response are reviewed. Limitations in experimental design and immune assays commonly used are discussed. The discordance between expectation and evidence in this field has been a disappointment. Recommendations for improving both animal-based and human studies are provided. | Fatty acids as modulators of the immune response. |
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"25206": 0.1401015669107437, "25426": 0.0913962796330452, "25437": 0.22937409579753876, "25524": 0.417115718126297, "25870": 0.3499138653278351, "25952": 0.03925827145576477, "26305": 0.2822965085506439, "26741": 0.14433705806732178, "26745": 0.27934664487838745, "26835": 0.16690383851528168, "26944": 0.17759032547473907, "26994": 0.006812678650021553, "27000": 0.17840765416622162, "27800": 0.11951763927936554, "28102": 0.9271688461303711, "28199": 0.015504186972975731, "28290": 0.19381128251552582, "28637": 0.19622190296649933, "29206": 0.06795065850019455, "29458": 0.06612417846918106} | 23389795 | Here, we give a historical overview of the search for genetic variants that influence the susceptibility of an individual to a chronic disease, from RA Fisher's seminal work to the current excitement of whole-genome association studies (WGAS). We then discuss the concepts behind the identification of common variants as disease causal factors and contrast them to the basic ideas that underlie the rare variant hypothesis. The identification of rare variants involves the careful selection of candidate genes to examine, the availability of highly efficient resequencing techniques and the appropriate assessment of the functional consequences of the implicated variant. We believe that this strategy can be successfully applied at present in order to unravel the contribution of rare variants to the multifactorial inheritance of common diseases, which could lead to the implementation of much needed preventative screening schemes. | Common and rare variants in multifactorial susceptibility to common diseases |
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Particularly exciting is the interplay between adherens junctions, activation of Rho proteins and the dynamics of microtubule, actin and intermediate filaments. This interplay has important implications for functional regulation of cell-cell adhesion, and points to a more integrated view of signalling processes. | Cell-cell adhesion and signalling. |
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"23632": 0.176772341132164, "23737": 0.890972912311554, "24054": 0.06246116757392883, "24171": 0.01934296265244484, "24269": 0.12814582884311676, "24278": 0.7610978484153748, "24552": 1.1959327459335327, "24848": 0.11168810725212097, "24952": 0.1693800985813141, "25117": 0.07884006202220917, "25194": 0.36290550231933594, "25519": 0.34715715050697327, "25708": 1.5005991458892822, "25971": 0.15526613593101501, "26402": 0.0009760859538801014, "26534": 0.04767346754670143, "26651": 0.0606246218085289, "26773": 0.8117979168891907, "26775": 0.7210738658905029, "26952": 0.04207121208310127, "27133": 0.9886114001274109, "27295": 0.2659635543823242, "27321": 0.6684301495552063, "27373": 0.2763880789279938, "27975": 0.20580662786960602, "28156": 0.3547199070453644, "28522": 1.02149498462677, "28667": 0.35677260160446167, "28915": 0.4752389192581177, "28939": 0.037378571927547455, "29107": 0.2800849378108978, "29721": 0.02316705882549286} | 23397658 | Fibroblast growth factor 21 (FGF21), a metabolic hormone predominantly produced by the liver, is also expressed in adipocytes and the pancreas. It regulates glucose and lipid metabolism through pleiotropic actions in these tissues and the brain. In mice, fasting leads to increased PPAR-α mediated expression of FGF21 in the liver where it stimulates gluconeogenesis, fatty acid oxidation, and ketogenesis, as an adaptive response to fasting and starvation. In the fed state, FGF21 acts as an autocrine factor in adipocytes, regulating the activity of PPAR-γ through a feed-forward loop mechanism. Administration of recombinant FGF21 has been shown to confer multiple metabolic benefits on insulin sensitivity, blood glucose, lipid profile and body weight in obese mice and diabetic monkeys, without mitogenic or other side effects. Such findings highlight the potential role of FGF21 as a therapeutic agent for obesity-related medical conditions. However, in human studies, high circulating FGF21 levels are found in obesity and its related cardiometabolic disorders including the metabolic syndrome, type 2 diabetes, non-alcoholic fatty liver disease and coronary artery disease. These findings may indicate the presence of FGF21 resistance or compensatory responses to the underlying metabolic stress, and imply the need for supraphysiological doses of FGF21 to achieve therapeutic efficacy. On the other hand, serum FGF21 has been implicated as a potential biomarker for the early detection of these cardiometabolic disorders. This review summarizes recent developments in the understanding of FGF21, from physiological and clinical perspectives. | Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. |
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"28155": 1.524696707725525, "28436": 0.016465263441205025, "28915": 0.5027855634689331, "29048": 0.10379679501056671, "29248": 0.08154398202896118} | 23400191 | AIMS There is a fivefold increase in the frequency of intracranial aneurysm (IA) in adults with coarctation of the aorta (CoA). Current guidelines for management of adults with CoA recommend computed tomography angiography (CTA) or magnetic resonance imaging of the intracranial vessels. However, this recommendation has not been universally accepted. The purpose of our study was to prospectively perform CTA of the intracranial vessels in adults with CoA to evaluate the prevalence and identify high-risk features of this complication. METHODS AND RESULTS From January 2008 to February 2011, adults ≥18 years of age with CoA were prospectively enrolled in a screening program with CTA of the intracranial vessels. Analyses of prognostic variables were performed with both Fisher's exact and two sample t-test. Forty-three patients (58% female, 33.55 ± 10.21 years) with CoA completed CTA of the intracranial vessels. Five patients (11%) were found to have IA. Patients with IA were older than those without (45.6 ± 8.17 vs. 30.89 ± 7.89, P = 0.0003). There were no statistically significant differences detected between measurements of fasting lipid profiles, C-reactive protein, brain natriuretic peptide, and homocysteine levels among CoA patients with and without IA (P = not significant). CONCLUSION Prospective screening of adults with CoA confirmed the increased prevalence of IA but also identified increased age as the sole risk factor. These data suggested that screening is justified particularly in the fourth and fifth decades of life. Further studies are required that focus on the development, natural history, and treatment of IA. | Assessment of the cerebral circulation in adults with coarctation of the aorta. |
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| 23403754 | In this review I summarize interrelations between bioenergetic processes and such programmed death phenomena as cell suicide (apoptosis and necrosis) and mitochondrial suicide (mitoptosis). The following conclusions are made. (I) ATP and rather often mitochondrial hyperpolarization (i.e. an increase in membrane potential, ΔΨ) are required for certain steps of apoptosis and necrosis. (II) Apoptosis, even if it is accompanied by ΔΨ and [ATP] increases at its early stage, finally results in a ΔΨ collapse and ATP decrease. (III) Moderate (about three-fold) lowering of [ATP] for short and long periods of time induces apoptosis and necrosis, respectively. In some types of apoptosis and necrosis, the cell death is mediated by a ΔΨ-dependent overproduction of ROS by the initial (Complex I) and the middle (Complex III) spans of the respiratory chain. ROS initiate mitoptosis which is postulated to rid the intracellular population of mitochondria from those that are ROS overproducing. Massive mitoptosis can result in cell death due to release to cytosol of the cell death proteins normally hidden in the mitochondrial intermembrane space. | Bioenergetic aspects of apoptosis, necrosis and mitoptosis |
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In the naive state of ESCs, the genome has an unusual open conformation and possesses a minimum of repressive epigenetic marks. In contrast, EpiSCs have activated the epigenetic machinery that supports differentiation towards the embryonic cell types. The transition from naive to primed pluripotency therefore represents a pivotal event in cellular differentiation. But the signals that control this fundamental differentiation step remain unclear. We show here that paracrine and autocrine Wnt signals are essential self-renewal factors for ESCs, and are required to inhibit their differentiation into EpiSCs. Moreover, we find that Wnt proteins in combination with the cytokine LIF are sufficient to support ESC self-renewal in the absence of any undefined factors, and support the derivation of new ESC lines, including ones from non-permissive mouse strains. Our results not only demonstrate that Wnt signals regulate the naive-to-primed pluripotency transition, but also identify Wnt as an essential and limiting ESC self-renewal factor. | Embryonic stem cells require Wnt proteins to prevent differentiation to epiblast stem cells |
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Nova proteins regulate neuronal pre-messenger RNA splicing by directly binding to RNA. To identify Nova RNA targets, we developed a method to purify protein-RNA complexes from mouse brain with the use of ultraviolet cross-linking and immunoprecipitation (CLIP).Thirty-four transcripts were identified multiple times by Nova CLIP.Three-quarters of these encode proteins that function at the neuronal synapse, and one-third are involved in neuronal inhibition. Splicing targets confirmed in Nova-/- mice include c-Jun N-terminal kinase 2, neogenin, and gephyrin; the latter encodes a protein that clusters inhibitory gamma-aminobutyric acid and glycine receptors, two previously identified Nova splicing targets. Thus, CLIP reveals that Nova coordinately regulates a biologically coherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that may relate to the cause of abnormal motor inhibition in POMA. | CLIP identifies Nova-regulated RNA networks in the brain. |
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0.040196798741817474, "28696": 0.029824240133166313, "28794": 0.01934296265244484, "28817": 0.777387797832489, "28976": 0.29036402702331543, "28987": 1.068206787109375, "29107": 0.1751343309879303, "29206": 0.12986256182193756, "29237": 0.25088030099868774, "29290": 0.034552380442619324, "29295": 0.0174254160374403, "29490": 0.4374985992908478} | 23420807 | Angiogenesis, the formation of new blood vessels from an existing vasculature, is requisite for tumor growth. It entails intercellular coordination of endothelial and tumor cells through angiogenic growth factor signaling. Interruption of these events has implications in the suppression of tumor growth. PD166285, a broad-spectrum receptor tyrosine kinase (RTK) inhibitor, and PD173074, a selective FGFR1TK inhibitor, were evaluated for their anti-angiogenic activity and anti-tumor efficacy in combination with photodynamic therapy (PDT). To evaluate the anti-angiogenic and anti-tumor activities of these compounds, RTK assays, in vitro tumor cell growth and microcapillary formation assays, in vivo murine angiogenesis and anti-tumor efficacy studies utilizing RTK inhibitors in combination with photodynamic therapy were performed. PD166285 inhibited PDGFR-β-, EGFR-, and FGFR1TKs and c-src TK by 50% (IC50) at concentrations between 7−85nM. PD173074 displayed selective inhibitory activity towards FGFR1TK at 26nM. PD173074 demonstrated (>100 fold) selective growth inhibitory action towards human umbilical vein endothelial cells compared with a panel of tumor cell lines. Both PD166285 and PD173074 (at 10nM) inhibited the formation of microcapillaries on Matrigel-coated plastic. In vivo anti-angiogenesis studies in mice revealed that oral administration (p.o.) of either PD166285 (1−25 mg/kg) or PD173074 (25−100 mg/kg) generated dose dependent inhibition of angiogenesis. Against a murine mammary 16c tumor, significantly prolonged tumor regressions were achieved with daily p.o. doses of PD166285 (5−10 mg/kg) or PD173074 (30−60 mg/kg) following PDT compared with PDT alone (p<0.001). Many long-term survivors were also noted in combination treatment groups. PD166285 and PD173074 displayed potent anti-angiogenic and anti-tumor activity and prolonged the duration of anti-tumor response to PDT. Interference in membrane signal transduction by inhibitors of specific RTKs (e.g. FGFR1TK) should result in new chemotherapeutic agents having the ability to limit tumor angiogenesis and regrowth following cytoreductive treatments such as PDT. | Anti-Angiogenic Activity of Selected Receptor Tyrosine Kinase Inhibitors, PD166285 and PD173074: Implications for Combination Treatment with Photodynamic Therapy |
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"29282": 0.04394211992621422, "29336": 0.757441520690918} | 23423230 | Bartonella henselae is an arthropod-borne zoonotic pathogen causing intraerythrocytic bacteraemia in the feline reservoir host and a broad range of clinical manifestations in incidentally infected humans. Remarkably, B. henselae can specifically colonize the human vascular endothelium, resulting in inflammation and the formation of vasoproliferative lesions known as bacillary angiomatosis and bacillary peliosis. Cultured human endothelial cells provide an in vitro system to study this intimate interaction of B. henselae with the vascular endothelium. However, little is known about the bacterial virulence factors required for this pathogenic process. Recently, we identified the type IV secretion system (T4SS) VirB as an essential pathogenicity factor in Bartonella, required to establish intraerythrocytic infection in the mammalian reservoir. Here, we demonstrate that the VirB T4SS also mediates most of the virulence attributes associated with the interaction of B. henselae during the interaction with human endothelial cells. These include: (i) massive rearrangements of the actin cytoskeleton, resulting in the formation of bacterial aggregates and their internalization by the invasome structure; (ii) nuclear factor kappaB-dependent proinflammatory activation, leading to cell adhesion molecule expression and chemokine secretion, and (iii) inhibition of apoptotic cell death, resulting in enhanced endothelial cell survival. Moreover, we show that the VirB system mediates cytostatic and cytotoxic effects at high bacterial titres, which interfere with a potent VirB-independent mitogenic activity. We conclude that the VirB T4SS is a major virulence determinant of B. henselae, required for targeting multiple endothelial cell functions exploited by this vasculotropic pathogen. | The VirB type IV secretion system of Bartonella henselae mediates invasion, proinflammatory activation and antiapoptotic protection of endothelial cells. |
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0.17840765416622162, "24353": 0.29328158497810364, "24936": 0.04953393340110779, "25022": 0.347847044467926, "25523": 0.669430673122406, "25543": 1.020087480545044, "25604": 0.8289952278137207, "25643": 0.9225212931632996, "25708": 0.1212492436170578, "25937": 0.44753631949424744, "26163": 0.052318159490823746, "26206": 0.11168810725212097, "26226": 0.07250232994556427, "26237": 1.1512393951416016, "26651": 0.3177432417869568, "26953": 0.04767346754670143, "27204": 0.0029254043474793434, "27354": 0.04860413447022438, "27502": 0.7610978484153748, "27651": 0.10026945173740387, "27743": 0.011650617234408855, "27833": 0.2105647772550583, "28048": 0.7836518287658691, "28400": 1.2318994998931885, "28436": 0.2478361576795578, "28739": 0.14518201351165771, "28751": 0.15777134895324707, "28915": 0.5963221788406372, "29458": 0.49923527240753174, "29567": 0.2231435477733612} | 23439808 | We hypothesized that serum cystatin C can be a more predictable marker of arterial stiffness than serum creatinine and creatinine-based glomerular filtration rate (GFR). The aim of this study is to evaluate whether serum cystatin C is related to arterial stiffness independently of serum creatinine in subjects for whom serum creatinine is normal. A total of 2,018 individuals (1,120 males, 898 females) were enrolled. Mean brachial-ankle pulse wave velocity (baPWV) was used as a marker of arterial stiffness and sex-specific analysis was performed. A positive relationship between baPWV and serum cystatin C (Y=1109.0548+329.9102X, r2=0.056, p<0.001) was found in males. Stepwise multivariate regression analysis in males showed that age, waist circumference, heart rate, cystatin C level, triglyceride level, and fasting glucose were independent contributors to baPWV. In females, a positive relationship between baPWV and serum cystatin C (Y=1035.7828+402.2970X, r2=0.090, p<0.001) was found. Stepwise multivariate regression analysis showed that age, heart rate, cystatin C level, fasting glucose and insulin level were independent contributors to baPWV. Age, heart rate, fasting glucose and serum cystatin C were the significant variables in both genders that contributed to baPWV. In conclusion, this study confirmed that serum cystatin C was related to pulse wave velocity even in subjects with normal serum creatinine. This finding suggested that cystatin C could be a more predictable marker of arterial stiffness than serum creatinine and creatinine-based GFR. | Serum Cystatin C Is Related to Pulse Wave Velocity Even in Subjects with Normal Serum Creatinine |
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"24529": 0.48008447885513306, "24761": 0.2018241584300995, "24848": 1.04512357711792, "24862": 0.15275461971759796, "25117": 0.10993985831737518, "25320": 0.13414156436920166, "25456": 0.8161250352859497, "25562": 0.030771657824516296, "25714": 0.19782574474811554, "25761": 0.2317005842924118, "25916": 1.1147572994232178, "25961": 0.45870962738990784, "25969": 0.02792670577764511, "26131": 0.4437839686870575, "26282": 0.3547199070453644, "26402": 1.068206787109375, "26591": 0.4462870955467224, "26755": 0.0317181795835495, "26835": 0.48008447885513306, "27854": 0.04860413447022438, "28024": 0.26146242022514343, "28041": 0.16442140936851501, "28332": 0.8674615025520325, "28406": 0.3325583338737488, "28436": 0.7836518287658691, "28498": 0.18492233753204346, "28691": 0.06246116757392883, "28731": 0.5244048833847046, "28873": 0.2317005842924118, "29090": 0.036437395960092545, "29390": 0.5336109399795532, "29458": 0.28670501708984375, "29490": 0.48670899868011475, "29535": 0.8666408061981201} | 23440856 | The type VI secretion system (T6SS) is the most prevalent bacterial secretion system and an important virulence mechanism utilized by Gram-negative bacteria, either to target eukaryotic cells or to combat other microbes. The components show much variability, but some appear essential for the function, and two homologues, denoted VipA and VipB in Vibrio cholerae, have been identified in all T6SSs described so far. Secretion is dependent on binding of an α-helical region of VipA to VipB, and in the absence of this binding, both components are degraded within minutes and secretion is ceased. The aim of the study was to investigate if this interaction could be blocked, and we hypothesized that such inhibition would lead to abrogation of T6S. A library of 9,600 small-molecule compounds was screened for their ability to block the binding of VipA-VipB in a bacterial two-hybrid system (B2H). After excluding compounds that showed cytotoxicity toward eukaryotic cells, that inhibited growth of Vibrio, or that inhibited an unrelated B2H interaction, 34 compounds were further investigated for effects on the T6SS-dependent secretion of hemolysin-coregulated protein (Hcp) or of phospholipase A1 activity. Two compounds, KS100 and KS200, showed intermediate or strong effects in both assays. Analogues were obtained, and compounds with potent inhibitory effects in the assays and desirable physicochemical properties as predicted by in silico analysis were identified. Since the compounds specifically target a virulence mechanism without affecting bacterial replication, they have the potential to mitigate the virulence with minimal risk for development of resistance. | Screening for inhibition of Vibrio cholerae VipA-VipB interaction identifies small-molecule compounds active against type VI secretion. |
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"24587": 0.27786844968795776, "24759": 0.5495203733444214, "24848": 1.02149498462677, "25194": 0.8161250352859497, "25605": 0.42608439922332764, "25665": 0.10026945173740387, "25722": 0.04860413447022438, "25761": 0.09050461649894714, "26179": 1.0920805931091309, "26243": 0.20501139760017395, "26402": 0.034552380442619324, "26462": 0.3683255612850189, "26651": 0.4002431631088257, "26773": 0.3325583338737488, "26835": 0.2247048318386078, "26838": 0.15693697333335876, "27199": 0.2105647772550583, "27295": 0.31560876965522766, "27321": 0.18573370575904846, "27444": 0.8780695199966431, "27781": 0.18004031479358673, "27998": 0.08961215615272522, "28086": 0.304147332906723, "28156": 0.3897167444229126, "28295": 0.04767346754670143, "28696": 0.2976420819759369, "28788": 0.42990362644195557, "28873": 0.9209672808647156, "28896": 0.32553088665008545, "29031": 0.04953393340110779, "29610": 0.12470348179340363} | 23460562 | It is unclear how the immune response in early life becomes appropriately stimulated to provide protection while also avoiding excessive activation as a result of diverse new antigens. T cells are integral to adaptive immunity; mouse studies indicate that tissue localization of T cell subsets is important for both protective immunity and immunoregulation. In humans, however, the early development and function of T cells in tissues remain unexplored. We present here an analysis of lymphoid and mucosal tissue T cells derived from pediatric organ donors in the first two years of life, as compared to adult organ donors, revealing early compartmentalization of T cell differentiation and regulation. Whereas adult tissues contain a predominance of memory T cells, in pediatric blood and tissues the main subset consists of naive recent thymic emigrants, with effector memory T cells (T(EM)) found only in the lungs and small intestine. Additionally, regulatory T (T(reg)) cells comprise a high proportion (30-40%) of CD4(+) T cells in pediatric tissues but are present at much lower frequencies (1-10%) in adult tissues. Pediatric tissue T(reg) cells suppress endogenous T cell activation, and early T cell functionality is confined to the mucosal sites that have the lowest T(reg):T(EM) cell ratios, which suggests control in situ of immune responses in early life. | Early life compartmentalization of human T cell differentiation and regulatory function in mucosal and lymphoid tissues |
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"24051": 0.03360854089260101, "24110": 0.46608972549438477, "24328": 0.2652147710323334, "24374": 0.45499902963638306, "24395": 0.022212404757738113, "24759": 0.04394211992621422, "24840": 0.14349138736724854, "24952": 0.5751199722290039, "25025": 0.37974658608436584, "25086": 0.3012613356113434, "25117": 0.11951763927936554, "25175": 0.10203468054533005, "25226": 0.35060185194015503, "25229": 0.1970241367816925, "25409": 0.41840189695358276, "25468": 0.06612417846918106, "25708": 0.17267228662967682, "25714": 0.16442140936851501, "25926": 0.20102575421333313, "25937": 0.010684899985790253, "26033": 0.1913948506116867, "26163": 0.17020416259765625, "26268": 0.07793712615966797, "26358": 1.1166772842407227, "26520": 0.23864774405956268, "26534": 0.12986256182193756, "26651": 0.21530038118362427, "26745": 0.013579257763922215, "26886": 0.07341018319129944, "26953": 0.11778303235769272, "27144": 0.1693800985813141, "27152": 0.4041621685028076, "27343": 0.30917787551879883, "27354": 0.052318159490823746, "27781": 0.37371641397476196, "27833": 0.27044451236724854, "27881": 0.07250232994556427, "28207": 0.2026219218969345, "28327": 0.8109301924705505, "28329": 0.25239890813827515, "28389": 0.5618454217910767, "28591": 0.22859740257263184, "28697": 0.1510767638683319, "28848": 0.07884006202220917, "28873": 0.5512100458145142, "29295": 0.10993985831737518, "29458": 0.791648268699646, "29477": 0.08782484382390976, "29490": 0.3464667797088623} | 23471400 | GOALS We investigated whether measurement of serum levels of the microRNAs (miRNAs) miR-16, miR-195, and miR-199a, alone or in combination with conventional serum markers, can help to differentiate hepatocellular carcinoma (HCC) from chronic liver diseases (CLDs). BACKGROUND Recent reports suggest a link between aberrant expression of miRNA, and HCC. STUDY This retrospective analysis was conducted using sera from 105 HCC patients, 107 CLD patients, and 71 normal control subjects. The miRNAs were measured using real-time reverse transcription-polymerase chain reaction. The conventional HCC markers α-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3%), and des-γ-carboxyprothrombin (DCP) were measured with commercial kits. RESULTS Serum levels of miR-16 and miR-199a were significantly lower in HCC than in CLD patients or control subjects (P<0.01). As a single marker, miR-16 had the highest sensitivity for HCC, followed by miR-199a, AFP, DCP, AFP-L3%, and miR-195. The combination of miR-16, AFP, AFP-L3%, and DCP yielded the optimal combination of sensitivity (92.4%) and specificity (78.5%) for HCC, overall and when analysis was restricted to patients with tumors size smaller than 3 cm. As a second-line HCC marker, miR-16 yielded positive HCC predictions in 18 of the 26 (69.2%) HCC patients with negative results on all 3 conventional markers, most of whom had tumors size smaller than 3 cm; miR-16 was falsely positive in only 12 of 96 (12.5%) CLD patients. CONCLUSIONS The addition of miR-16 to conventional serum markers improved sensitivity and specificity for HCC. Use of miR-16 for second-line testing in cases considered negative on the basis of conventional HCC markers should be explored in larger, prospective studies. | Circulating microRNAs as biomarkers for hepatocellular carcinoma. |
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However, no study has examined the relationship between major mitochondrial DNA (mtDNA) haplogroups and SZ in the Chinese population. The aim of this study was to assess the association between mtDNA haplogroups and SZ genesis in the Chinese Han population. We used a case-control study and sequenced the mtDNA hypervariable regions (HVR1, HVR2, and HVR3) in the Han population. We analyzed mtDNA haplogroups and HVR polymorphisms in 298 SZ patients and 298 controls. The haplotypes were classified into 10 major haplogroups: A, B, CZ, D, F, G, M, N, N9a, and R. Statistical analysis revealed that only N9a showed a nominally significant association with protection from SZ [1.68% vs. 6.38%, p=0.004, OR=0.251 (0.092-0.680); after adjustment for age and sex: p=0.006, OR=0.246 (0.090-0.669)]. Three HVR polymorphisms were found to be nominally significantly different between subjects with SZ and controls, and all except one (m.204T>C) are linked to the N9a haplogroup. Our results indicate that mtDNA haplogroup N9a might be a protective factor for SZ. | Mitochondrial haplogroups and hypervariable region polymorphisms in schizophrenia: a case-control study. |
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So too is its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators, specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung. | Resolution of acute inflammation in the lung. |
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"25456": 0.3241194784641266, "25502": 0.35813871026039124, "25644": 0.7220231294631958, "25714": 0.08244366943836212, "25937": 0.5701626539230347, "26163": 0.45994341373443604, "26244": 0.1221139207482338, "26402": 0.8559102416038513, "26512": 1.0037577152252197, "26534": 0.7827593088150024, "26651": 0.15275461971759796, "26721": 0.9005423784255981, "26773": 0.6921701431274414, "27226": 0.6734226942062378, "27448": 0.14433705806732178, "27854": 0.18978065252304077, "28086": 0.04207121208310127, "28378": 0.8731874823570251, "28696": 0.12470348179340363, "29290": 0.6011518239974976, "29393": 0.28450319170951843, "29494": 0.056018441915512085} | 23509593 | BACKGROUND Prostate development and maintenance in the adult results from an interaction of stromal and glandular components. Androgens can drive this process by direct action on the stroma. We investigated whether there was a direct link between androgens and another key regulator of stromal cells, intracellular Ca2+ ([Ca2+ ]i ). METHODS Prostate stromal cells were freshly obtained and cultures derived from patients with benign prostatic hyperplasia. Gene expression in dihydrotestosterone treated and untreated cells was compared using Affymetrix gene expression arrays and Ca2+ regulated features were identified by Gene Ontology (GO). Changes in [Ca2+]i were determined in Fluo-4 loaded cells. Androgen regulation was confirmed by chromatin immunoprecipitaion. RESULTS Stromal cell cultures were sorted for expression of integrin α1 β1 , which enriched for cells expressing the androgen receptor (AR). We identified key functional categories, within the androgen-induced gene expression signature, focusing on genes involved in calcium signaling. From this analysis, stromal interaction molecule-1 (STIM1) was identified as a significantly differentially expressed gene with four relevant associated GO terms. DNA sequence analysis showed that the promoter region of STIM1 contained putative androgen response element sequences in which AR binding ability of STIM1 was confirmed. Androgens directly regulated STIM1 expression and STIM1 effects on store-operated calcium entry were inhibited by STIM1 knock-down. Reduced STIM1 expression in prostate stromal cells led to a reduction in basal Ca2+ levels, the amount of Ca2+ released by thapsigargin and a reduction in store filling following TG-induced store depletion. CONCLUSIONS These results indicate that androgens modulate [Ca2+]i through the direct regulation of the STIM1 gene by AR binding to the STIM1 promoter. | The calcium sensor STIM1 is regulated by androgens in prostate stromal cells. |
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1.076228141784668, "26651": 0.37304413318634033, "26721": 0.07341018319129944, "27065": 0.6813592314720154, "27099": 0.021256839856505394, "27295": 0.4286321699619293, "27325": 0.11951763927936554, "27427": 0.41195443272590637, "27532": 1.0137293338775635, "27651": 0.025073638185858727, "27854": 0.2659635543823242, "28228": 0.30989447236061096, "28282": 0.11343330889940262, "28517": 0.011650617234408855, "28696": 0.14349138736724854, "28815": 0.1064341589808464, "28835": 0.06429435312747955, "28915": 0.3346569836139679, "29111": 0.19622190296649933, "29290": 0.02412080205976963, "29358": 0.8649974465370178, "29454": 1.1018621921539307, "29598": 0.5021947622299194, "29607": 0.24859806895256042} | 23513718 | Responses of cerebral blood vessels to nitric oxide (NO) are mediated by soluble guanylate cyclase (sGC)-dependent and potentially by sGC-independent mechanisms. One sGC-independent mechanism by which NO may produce vasodilatation is inhibition of formation of a vasoconstrictor metabolite produced through the cytochrome P450 pathway. In these experiments, we examined the hypothesis that dilatation of cerebral microvessels in response to NO is dependent on activation of sGC. Diameters of cerebral arterioles (baseline diameter=94+/-5 micrometers, mean+/-S.E.) were measured using a closed cranial window in anesthetized rabbits. Under control conditions, YC-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole], an NO-independent activator of sGC, produced vasodilation that was blocked by ODQ (1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one)(10 microM), an inhibitor of sGC. These findings indicate that sGC is functionally important in cerebral arterioles. In addition, acetylcholine (which stimulates endogenous production of NO by endothelium) produced dilatation of cerebral arterioles that was inhibited by ODQ. For example, 1 microM acetylcholine dilated cerebral arterioles by 34+/-7 and 5+/-1% in the absence and presence of ODQ (10 microM), respectively. Increases in arteriolar diameter in response to sodium nitroprusside (1 microM, an NO donor) were inhibited by approximately 80% by ODQ, but were not affected by 17-ODYA (10 microM) or clotrimazole (10 microM), inhibitors of the cytochrome P450 pathway. Thus, dilatation of the cerebral microcirculation in response to exogenously applied and endogenously produced NO is dependent, in large part, on activation of sGC. | Role of soluble guanylate cyclase in dilator responses of the cerebral microcirculation. |
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"25761": 0.23787821829319, "26118": 0.19622190296649933, "26131": 0.7925328612327576, "26147": 0.05786345899105072, "26394": 0.3163207769393921, "26402": 0.3554046154022217, "26520": 0.04394211992621422, "26534": 0.07068414986133575, "26572": 0.6102113127708435, "26773": 0.6714286804199219, "26972": 0.10993985831737518, "27058": 1.004473328590393, "27099": 0.7500885725021362, "27642": 0.10467668622732162, "27790": 0.025073638185858727, "27846": 0.24171993136405945, "27895": 0.009718249551951885, "27989": 0.07341018319129944, "27998": 0.5784112811088562, "28155": 0.04394211992621422, "28184": 0.0797421783208847, "28691": 0.3388410806655884, "28696": 0.10203468054533005, "28976": 0.07884006202220917, "29170": 0.3683255612850189, "29206": 0.06977381557226181, "29290": 0.37371641397476196} | 23513818 | The level of the Mcl-1 pro-survival protein is highly regulated, and the down-regulation of Mcl-1 expression favors the apoptotic process. Mcl-1 physically interacts with different BH3-only proteins; particularly, Noxa is involved in the modulation of Mcl-1 expression. In this study, we demonstrated that Noxa triggers the degradation of Mcl-1 at the mitochondria according to the exclusive location of Noxa at this compartment. The Noxa-induced degradation of Mcl-1 required the E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Because the USP9X deubiquitinase was recently demonstrated to be involved in Mcl-1 protein turnover by preventing its degradation through the removal of conjugated ubiquitin, we investigated whether Noxa affected the deubiquitination process. Interestingly, Noxa over-expression caused a decrease in the USP9X/Mcl-1 interaction associated with an increase in the Mcl-1 polyubiquitinated forms. Additionally, Noxa over-expression triggered an increase in the Mule/Mcl-1 interaction in parallel with the decrease in Mule/USP9X complex formation. Taken together, these modifications result in the degradation of Mcl-1 by the proteasome machinery. The implication of Noxa in the regulation of Mcl-1 proteasomal degradation adds complexity to this process, which is governed by multiple interactions. | Noxa controls Mule-dependent Mcl-1 ubiquitination through the regulation of the Mcl-1/USP9X interaction. |
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Intervention strategies have been planned and in some instances already started. A timely and cost-effective strategy needs to take into account that most HIV-1 infected individuals reside in developing countries. Further studies are needed on immunological and virological factors affecting HIV-1 transmission from mother to child, on differential disease progression in affected children, and on transient infection. | Paediatric HIV infection. |
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"27427": 0.03925827145576477, "28086": 0.1718502640724182, "28636": 0.2983669638633728, "28691": 0.11517547070980072, "28788": 0.5080875158309937, "28901": 0.04207121208310127, "28991": 0.013579257763922215} | 23535770 | Neural stem cells are precursors of neurons and glial cells. During brain development, these cells proliferate, migrate and differentiate into specific lineages. Recently neural stem cells within the adult central nervous system were identified. Informations are now emerging about regulation of stem cell proliferation, migration and differentiation by numerous soluble factors such as chemokines and cytokines. However, the signal transduction mechanisms downstream of these factors are less clear. Here, we review potential evidences for a novel central role of the transcription factor nuclear factor kappa B (NF-kappaB) in these crucial signal transduction processes. NF-kappaB is an inducible transcription factor detected in neurons, glia and neural stem cells. NF-kappaB was discovered by David Baltimore's laboratory as a transcription factor in lymphocytes. NF-kappaB is involved in many biological processes such as inflammation and innate immunity, development, apoptosis and anti-apoptosis. It has been recently shown that members of the NF-kappaB family are widely expressed by neurons, glia and neural stem cells. In the nervous system, NF-kappaB plays a crucial role in neuronal plasticity, learning, memory consolidation, neuroprotection and neurodegeneration. Recent data suggest an important role of NF-kappaB on proliferation, migration and differentiation of neural stem cells. NF-kappaB is composed of three subunits: two DNA-binding and one inhibitory subunit. Activation of NF-kappaB takes place in the cytoplasm and results in degradation of the inhibitory subunit, thus enabling the nuclear import of the DNA-binding subunits. Within the nucleus, several target genes could be activated. In this review, we suggest a model explaining the multiple action of NF-kappaB on neural stem cells. Furthermore, we discuss the potential role of NF-kappaB within the so-called brain cancer stem cells. | Potential role of NF-kappaB in adult neural stem cells: the underrated steersman? |
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0.8869584798812866, "26994": 1.1230508089065552, "27144": 0.040196798741817474, "27162": 0.3916989266872406, "27360": 0.0770333781838417, "27453": 0.10291612148284912, "27480": 0.029824240133166313, "27642": 0.10555581003427505, "27678": 0.10026945173740387, "27815": 0.0770333781838417, "27833": 0.03360854089260101, "27881": 0.09317722171545029, "28086": 0.14179791510105133, "28102": 0.1485546976327896, "28159": 0.009718249551951885, "28207": 0.27044451236724854, "28436": 0.47463157773017883, "28687": 0.0797421783208847, "29101": 0.3034266233444214, "29206": 0.8682814836502075, "29242": 0.1946154683828354, "29361": 0.007782140281051397, "29598": 0.7482418417930603} | 23557241 | BACKGROUND Emerging evidence suggests an association between female prenatal experience and her subsequent risk of developing breast cancer. Potential underlying mechanisms include variation in amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formation of cancer stem-cells, and other genetic or epigenetic events. We reviewed and summarised quantitatively the available data on intrauterine exposures and risk of breast cancer. METHODS We systematically searched for studies that assessed association between perinatal factors and risk of breast cancer. We reviewed separately each of the perinatal factors, including birthweight, birth length, parental age at delivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternal pre-eclampsia or eclampsia, and other factors. FINDINGS We identified 57 studies published between Oct 1, 1980, and June 21, 2007. Increased risk of breast cancer was noted with increased birthweight (relative risk [RR] 1.15 [95% CI 1.09-1.21]), birth length (1.28 [1.11-1.48]), higher maternal age (1.13 [1.02-1.25]), and paternal age (1.12 [1.05-1.19]). Decreased risk of breast cancer was noted for maternal pre-eclampsia and eclampsia (0.48 [0.30-0.78]) and twin membership (0.93 [0.87-1.00]). No association was noted between risk of breast cancer and gestational age at birth (0.95 [0.71-1.26]) or maternal diethylstilbestrol treatment (1.40 [0.86-2.28]). INTERPRETATION The intrauterine environment contributes to the predisposition of women to breast cancer in adulthood. The in-utero mechanisms responsible for such predisposition need to be elucidated. | Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence. |
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0.22548456490039825, "26013": 0.018384648486971855, "26236": 0.14686977863311768, "26305": 0.15526613593101501, "26402": 0.1685553640127182, "26524": 0.02792670577764511, "26646": 0.24018502235412598, "26735": 0.052318159490823746, "26835": 0.8633513450622559, "27152": 0.6833335757255554, "27179": 0.5010119676589966, "27199": 0.15777134895324707, "27295": 0.021256839856505394, "27441": 1.3892197608947754, "27631": 0.11081436276435852, "27895": 0.0174254160374403, "28156": 0.7086513638496399, "28311": 0.6054253578186035, "28389": 1.1456648111343384, "28518": 0.04767346754670143, "28667": 0.5773153901100159, "28788": 0.09761575609445572, "28935": 0.053244512528181076, "29290": 0.638455867767334} | 23573229 | Helicobacter hepaticus has been reported to induce colitis, hepatitis, and hepatocellular carcinoma in several different murine models. The aim of this study was to determine if H. hepaticus will cause colitis in monoassociated mice lacking the interleukin-10 gene (IL-10(-/-) mice) and potentiate colitis in specific-pathogen-free (SPF) IL-10(-/-) mice. Germfree IL-10(-/-) mice on either a mixed (C57BL/6 x 129/Ola) or inbred (129/SvEv) genetic background were monoassociated with H. hepaticus ATCC 51448 by oral feeding and rectal enemas. In a second experiment, germfree IL-10(-/-) mice were colonized with stool from SPF mice that harbored or did not harbor endogenous H. hepaticus. After 7 to 9 weeks of colonization, weight loss and mortality were assessed, the colon was isolated for histology and IL-12 secretion, and mesenteric lymph node cells were assessed for T-cell activation markers. It was found that IL-10(-/-) mice monoassociated with H. hepaticus for up to 16 weeks showed almost no histologic colitis or increased IL-12 production. SPF IL-10-knockout mice had no significant difference in weight loss, mortality rate, histologic scores, colonic IL-12 secretion, or T-cell activation with or without H. hepaticus. We conclude that H. hepaticus does not induce or potentiate disease in our IL-10(-/-) mice and therefore is not required to induce colitis in genetically susceptible hosts. | Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice. |
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0.8500841856002808, "27998": 0.3485364317893982, "28177": 0.012615402229130268, "28389": 0.1212492436170578, "28527": 0.11256109178066254, "28613": 0.02792670577764511, "28835": 0.15860503911972046, "29347": 0.06612417846918106} | 23576165 | Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the "reverse Warburg effect". Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors. | Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication. |
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(hypoxia) during flooding is a key target for food security. In Arabidopsis thaliana (L.) Heynh., the N-end rule pathway of targeted proteolysis controls plant responses to hypoxia by regulating the stability of group VII ethylene response factor (ERFVII) transcription factors, controlled by the oxidation status of amino terminal (Nt)-cysteine (Cys). Here, we show that the barley (Hordeum vulgare L.) ERFVII BERF1 is a substrate of the N-end rule pathway in vitro. Furthermore, we show that Nt-Cys acts as a sensor for hypoxia in vivo, as the stability of the oxygen-sensor reporter protein MCGGAIL-GUS increased in waterlogged transgenic plants. Transgenic RNAi barley plants, with reduced expression of the N-end rule pathway N-recognin E3 ligase PROTEOLYSIS6 (HvPRT6), showed increased expression of hypoxia-associated genes and altered seed germination phenotypes. In addition, in response to waterlogging, transgenic plants showed sustained biomass, enhanced yield, retention of chlorophyll, and enhanced induction of hypoxia-related genes. HvPRT6 RNAi plants also showed reduced chlorophyll degradation in response to continued darkness, often associated with waterlogged conditions. Barley Targeting Induced Local Lesions IN Genomes (TILLING) lines, containing mutant alleles of HvPRT6, also showed increased expression of hypoxia-related genes and phenotypes similar to RNAi lines. We conclude that the N-end rule pathway represents an important target for plant breeding to enhance tolerance to waterlogging in barley and other cereals. | Enhanced waterlogging tolerance in barley by manipulation of expression of the N‐end rule pathway E3 ligase PROTEOLYSIS6 |
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"25580": 0.10731173306703568, "25644": 0.2969166338443756, "25714": 0.9186317324638367, "26083": 0.20660123229026794, "26244": 0.1693800985813141, "26285": 0.00875066313892603, "26351": 0.012615402229130268, "26402": 0.18492233753204346, "26520": 0.030771657824516296, "26576": 0.1477125883102417, "26773": 0.7086513638496399, "26874": 0.8925741910934448, "27642": 0.38041436672210693, "27777": 0.8315495252609253, "27854": 0.12986256182193756, "28041": 0.1905880719423294, "28193": 1.6371746063232422, "28691": 0.08154398202896118, "28788": 0.347847044467926, "29129": 0.6011518239974976, "29226": 0.0752234235405922} | 23577014 | During Caenorhabditis elegans oocyte meiosis, a multi-protein ring complex (RC) localized between homologous chromosomes, promotes chromosome congression through the action of the chromokinesin KLP-19. While some RC components are known, the mechanism of RC assembly has remained obscure. We show that SUMO E3 ligase GEI-17/PIAS is required for KLP-19 recruitment to the RC, and proteomic analysis identified KLP-19 as a SUMO substrate in vivo. In vitro analysis revealed that KLP-19 is efficiently sumoylated in a GEI-17-dependent manner, while GEI-17 undergoes extensive auto-sumoylation. GEI-17 and another RC component, the kinase BUB-1, contain functional SUMO interaction motifs (SIMs), allowing them to recruit SUMO modified proteins, including KLP-19, into the RC. Thus, dynamic SUMO modification and the presence of SIMs in RC components generate a SUMO-SIM network that facilitates assembly of the RC. Our results highlight the importance of SUMO-SIM networks in regulating the assembly of dynamic protein complexes. | A SUMO-Dependent Protein Network Regulates Chromosome Congression during Oocyte Meiosis |
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"27854": 0.03925827145576477, "27887": 0.006812678650021553, "28093": 0.27342069149017334, "28207": 0.04953393340110779, "28309": 0.09850110858678818, "28436": 0.0058422754518687725, "28689": 0.1889725625514984, "28873": 0.16110190749168396, "29107": 0.21214580535888672, "29494": 0.030771657824516296, "29610": 0.31845372915267944} | 23577867 | Conditions related to chronic hyperinsulinemia, such as obesity, noninsulin dependent diabetes mellitus and polycystic ovary syndrome, are associated with an increased risk of endometrial cancer. Elevated plasma IGF-I and decreased levels of IGF-binding proteins have been shown to be associated with increased risk of several cancer types that are frequent in affluent societies. We investigated for the first time in a prospective study the association of pre-diagnostic blood concentrations of C-peptide (a marker of pancreatic insulin production), IGF-I, IGFBP-1, -2 and -3 with endometrial cancer risk. A case-control study was nested within 3 cohorts in New York (USA), Umeå (Sweden) and Milan (Italy). It included 166 women with primary invasive endometrial cancer and 315 matched controls, of which 44 case and 78 control subjects were premenopausal at recruitment. Endometrial cancer risk increased with increasing levels of C-peptide (ptrend = 0.0002), up to an odds ratio (OR) of 4.76 [95% confidence interval (CI) = 1.91-11.8] for the highest quintile. This association remained after adjustment for BMI and other confounders [OR for the top quintile = 4.40 (1.65-11.7)]. IGFBP-1 levels were inversely related to endometrial cancer [ptrend = 0.002; OR in the upper quintile = 0.30 (0.15-0.62)], but the association was weakened and lost statistical significance after adjustment for confounders [ptrend = 0.06; OR in the upper quintile = 0.49 (0.22-1.07)]. Risk was unrelated to levels of IGF-I, IGFBP-2 and IGFBP-3. Chronic hyperinsulinemia, as reflected by increased circulating C-peptide, is associated with increased endometrial cancer risk. Decrease in the prevalence of chronic hyperinsulinemia, through changes in lifestyle or medication, is expected to prevent endometrial cancer. | Prediagnostic levels of C-peptide, IGF-I, IGFBP -1, -2 and -3 and risk of endometrial cancer. |
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"25937": 0.6773988008499146, "26261": 0.08692999184131622, "26305": 0.5116065740585327, "26402": 0.932563841342926, "26524": 0.8901712894439697, "26534": 0.36426326632499695, "26741": 0.18167030811309814, "26745": 0.06246116757392883, "26773": 0.2034190446138382, "26874": 0.952351450920105, "27000": 0.176772341132164, "27099": 0.045809537172317505, "27116": 0.40546512603759766, "27642": 0.4950772523880005, "27989": 0.0058422754518687725, "28086": 0.10906458646059036, "28227": 0.41065993905067444, "28228": 0.20580662786960602, "28290": 0.4500300884246826, "28873": 0.08961215615272522, "28901": 0.1808556467294693, "29024": 0.5261374711990356, "29206": 0.07793712615966797, "29242": 0.045809537172317505, "29458": 0.7934166193008423} | 23581096 | The SRY gene on the mammalian Y chromosome undoubtedly acts to determine testis, but it is still quite unclear how. It was originally supposed that SRY acts directly to activate other genes in the testis-determining pathway. This paper presents an alternative hypothesis that SRY functions indirectly, by interacting with related genes SOX3 (from which SRY evolved) and SOX9 (which appears to be intimately involved in vertebrate gonad differentiation). Specifically, I propose that in females SOX3 inhibits SOX9 function, but in males, SRY inhibits SOX3 and permits SOX9 to enact its testis-determining role. This hypothesis makes testable predictions of the phenotypes of XX and XY individuals with deficiencies or overproduction of any of the three genes, and is able to account for the difficult cases of XX(SRY-) males and transdifferentiation in the absence of SRY. The hypothesis also suggests a way that the dominant SRY sex-determining system of present-day mammals may have evolved from an ancient system relying on SOX3 dosage. | Interactions between SRY and SOX genes in mammalian sex determination. |
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"24198": 0.004870930220931768, "24269": 1.0271050930023193, "24494": 0.32270604372024536, "24558": 0.5925496220588684, "24848": 0.13670019805431366, "25095": 0.4093637466430664, "25202": 0.9958525896072388, "25307": 0.1930064558982849, "25458": 0.07341018319129944, "25524": 0.7683706283569336, "25714": 0.472198486328125, "25952": 0.11691460013389587, "26339": 0.12814582884311676, "26394": 0.48430517315864563, "26610": 0.175953671336174, "26691": 0.06520967930555344, "26872": 0.42416930198669434, "26986": 0.09761575609445572, "27226": 0.839173436164856, "27354": 0.0770333781838417, "27781": 0.040196798741817474, "28406": 0.8649974465370178, "28424": 0.9379299283027649, "28518": 0.0029254043474793434, "28727": 0.4349733293056488, "28820": 0.11343330889940262, "28847": 0.5876781344413757, "28911": 0.21530038118362427, "29490": 0.036437395960092545} | 23586085 | Genome-wide location analysis, also known as ChIP-Chip, combines chromatin immunoprecipitation and DNA microarray analysis to identify protein-DNA interactions that occur in living cells. Protein-DNA interactions are captured in vivo by chemical crosslinking. Cell lysis, DNA fragmentation and immunoaffinity purification of the desired protein will co-purify DNA fragments that are associated with that protein. The enriched DNA population is then labeled, combined with a differentially labeled reference sample and applied to DNA microarrays to detect enriched signals. Various computational and bioinformatic approaches are then applied to normalize the enriched and reference channels, to connect signals to the portions of the genome that are represented on the DNA microarrays, to provide confidence metrics and to generate maps of protein-genome occupancy. Here, we describe the experimental protocols that we use from crosslinking of cells to hybridization of labeled material, together with insights into the aspects of these protocols that influence the results. These protocols require approximately 1 week to complete once sufficient numbers of cells have been obtained, and have been used to produce robust, high-quality ChIP-chip results in many different cell and tissue types. | Chromatin immunoprecipitation and microarray-based analysis of protein location |
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0.22001366317272186, "25952": 0.030771657824516296, "26013": 0.6038249135017395, "26221": 0.12642613053321838, "26319": 0.46853771805763245, "26629": 0.22859740257263184, "26723": 0.11691460013389587, "26835": 0.5893046259880066, "26957": 0.47584590315818787, "27152": 0.5607312321662903, "27404": 0.5162794589996338, "27492": 0.22937409579753876, "27965": 0.06154331564903259, "28093": 0.6970458030700684, "28297": 0.04674193635582924, "28389": 0.06429435312747955, "28603": 0.020300358533859253, "28939": 1.4918501377105713, "29292": 0.6729245185852051, "29378": 1.2660669088363647, "29491": 0.2539152204990387} | 23594156 | OBJECTIVE To identify the spatial and temporal clusters of Barmah Forest virus (BFV) disease in Queensland in Australia, using geographical information systems and spatial scan statistic (SaTScan). METHODS We obtained BFV disease cases, population and statistical local areas (SLAs) boundary data from Queensland Health and Australian Bureau of Statistics, respectively, during 1992-2008 for Queensland. A retrospective Poisson-based analysis using SaTScan software and method was conducted to identify both purely spatial and space-time BFV disease high-rate clusters. A spatial cluster size of a proportion of the population and a 200 km radius and varying time windows from 1 to 12 months were chosen (for the space-time analysis). RESULTS The spatial scan statistic detected a most likely significant purely spatial cluster (including 23 SLAs) and a most likely significant space-time cluster (including 24 SLAs) in approximately the same location. Significant secondary clusters were also identified from both the analyses in several locations. CONCLUSIONS This study provides evidence of the existence of statistically significant BFV disease clusters in Queensland, Australia. The study also demonstrated the relevance and applicability of SaTScan in analysing ongoing surveillance data to identify clusters to facilitate the development of effective BFV disease prevention and control strategies in Queensland, Australia. | Spatial and temporal clusters of Barmah Forest virus disease in Queensland, Australia. |
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"26163": 0.08782484382390976, "26243": 0.04953393340110779, "26402": 0.23092569410800934, "26520": 0.06612417846918106, "26651": 0.18004031479358673, "26721": 0.6338034868240356, "26773": 0.5540198087692261, "26976": 0.06154331564903259, "27009": 1.0285027027130127, "27144": 0.6160298585891724, "27208": 0.12470348179340363, "27295": 0.36967599391937256, "27354": 0.021256839856505394, "27487": 0.12814582884311676, "27630": 0.5685047507286072, "27881": 0.018384648486971855, "28154": 0.06795065850019455, "28156": 0.3824150264263153, "28518": 0.02792670577764511, "28804": 0.016465263441205025, "29290": 0.22626367211341858, "29722": 0.29109421372413635} | 23599024 | Background/Aims: Radiotherapy is applied to patients with inoperable cancer types including advanced stage non-small cell lung cancer (NSCLC) and radioresistance functions as a critical obstacle in radiotherapy. This study was aimed to investigate the mechanism of radioresistance regulated by surfactant protein B (SP-B). Methods: To investigate the role of SP-B in radioresistance, ΔSFTPB A549 cell line was established and SP-B expression was analyzed. In response to ionizing radiation (IR), the change of SP-B expression was analyzed in A549 and NCI-H441 cell lines. Conditioned media (CM) from NSCLC cells were utilized to evaluate the downstream signaling pathway. The in vivo effects of SP-B were assessed through mouse xenograft model with intratumoral injection of CM. Results: In response to IR, NSCLC cell lines showed decreased SP-B regulated by the TGF-β signaling and decreased SP-B stimulated cell survival and epithelial-mesenchymal transition. Treatment with CM from irradiated cells activated sPLA2, enhanced protein kinase Cδ-MAPKs signaling pathway, and increased arachidonic acid production. We confirmed the in vivo roles of SP-B through mouse xenograft model. Conclusion: Our results revealed that down-regulation of SP-B was involved in the radiation-induced metastatic conversion of NSCLC and provided evidence that SP-B acted as a suppressor of NSCLC progression. | Surfactant Protein B Suppresses Lung Cancer Progression by Inhibiting Secretory Phospholipase A2 Activity and Arachidonic Acid Production |
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0.04207121208310127, "29172": 0.9425065517425537, "29181": 1.0546929836273193, "29222": 0.040196798741817474, "29290": 0.22079704701900482, "29295": 0.4145384132862091} | 23601616 | Objective:Consumption of high-fat diet exerts adverse effects on learning and memory formation, which is linked to impaired hippocampal function. Activation of glucagon-like peptide-1 (GLP-1) signalling ameliorates detrimental effects of obesity-diabetes on cognitive function; however, mechanisms underlying these beneficial actions remain unclear. This study examined effects of daily subcutaneous treatment with GLP-1 mimetic, Liraglutide, on synaptic plasticity, hippocampal gene expression and metabolic control in adult obese diabetic (ob/ob) mice. Results:Long-term potentiation (LTP) induced by area CA1 was completely abolished in ob/ob mice compared with lean controls. Deleterious effects on LTP were rescued (P<0.001) with Liraglutide. Indeed, Liraglutide-treated mice exhibited superior LTP profile compared with lean controls (P<0.01). Expression of hippocampal brain-derived neurotropic factor and neurotrophic tyrosine kinase receptor-type 2 were not significantly different, but synaptophysin and Mash1 were decreased in ob/ob mice. Treatment with Liraglutide over 21 days increased expression of Mash1 in ob/ob mice (2.0-fold; P<0.01). These changes were associated with significantly reduced plasma glucose (21% reduction; P<0.05) and markedly improved plasma insulin concentrations (2.1- to 3.3-fold; P<0.05 to P<0.01). Liraglutide also significantly reduced the glycaemic excursion following an intraperitonal glucose load (area under curve (AUC) values: 22%; P<0.05) and markedly enhanced the insulin response to glucose (AUC values: 1.6-fold; P<0.05). O2 consumption, CO2 production, respiratory exchange ratio and energy expenditure were not altered by Liraglutide therapy. On day 21, accumulated food intake (32% reduction; P<0.05) and number of feeding bouts (32% reduction; P<0.05) were significantly reduced but simple energy restriction was not responsible for the beneficial actions of Liraglutide. Conclusion:Liraglutide elicits beneficial effects on metabolic control and synaptic plasticity in mice with severe obesity and insulin resistance mediated in part through increased expression of Mash1 believed to improve hippocampal neurogenesis and cell survival. | Liraglutide improves hippocampal synaptic plasticity associated with increased expression of Mash1 in ob/ob mice |
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"25652": 0.0797421783208847, "25714": 0.08064348995685577, "25761": 0.27342069149017334, "25874": 0.2852376699447632, "26042": 0.6497380137443542, "26223": 0.23710809648036957, "26402": 0.37371641397476196, "26512": 0.09228714555501938, "26534": 0.32129061222076416, "26616": 0.674915611743927, "26629": 0.812664806842804, "26773": 0.42799583077430725, "26775": 0.6778947114944458, "26780": 0.29473719000816345, "27099": 0.05970508232712746, "27118": 0.0842406153678894, "27295": 0.09850110858678818, "27710": 0.28155985474586487, "27777": 0.007782140281051397, "28215": 0.42735910415649414, "28427": 0.058784693479537964, "28616": 0.15860503911972046, "28848": 0.846739649772644, "29129": 0.05417001247406006, "29290": 0.7809720039367676, "29297": 1.2555493116378784, "29516": 0.4196864068508148} | 23604601 | The IME1 gene of Saccharomyces cerevisiae is required for initiation of meiosis. Transcription of IME1 is detected under conditions which are known to induce initiation of meiosis, namely starvation for nitrogen and glucose, and the presence of MATa1 and MAT alpha 2 gene products. In this paper we show that IME1 is also subject to translational regulation. Translation of IME1 mRNA is achieved either upon nitrogen starvation, or upon G1 arrest. In the presence of nutrients, constitutively elevated transcription of IME1 is also sufficient for the translation of IME1 RNA. Four different conditions were found to cause expression of Ime1 protein in vegetative cultures: elevated transcription levels due to the presence of IME1 on a multicopy plasmid; elevated transcription provided by a Gal-IME1 construct; G1 arrest due to alpha-factor treatment; G1 arrest following mild heat-shock treatment of cdc28 diploids. Using these conditions, we obtained evidence that starvation is required not only for transcription and efficient translation of IME1, but also for either the activation of Ime1 protein or for the induction/activation of another factor that, either alone or in combination with Ime1, induces meiosis. | Post-transcriptional regulation of IME1 determines initiation of meiosis in Saccharomyces cerevisiae. |
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0.022212404757738113, "28699": 0.77198725938797, "28731": 0.16110190749168396, "28846": 0.26446542143821716, "28849": 0.030771657824516296, "29237": 0.34922540187835693, "29336": 1.0695481300354004, "29494": 0.14602625370025635, "29516": 0.09938567131757736} | 23618826 | Construction and intracellular targeting of eukaryotic pre-ribosomal particles involve a multitude of diverse transiently associating trans-acting assembly factors, energy-consuming enzymes, and transport factors. The ability to rapidly and reliably measure co-enrichment of multiple factors with maturing pre-ribosomal particles presents a major biochemical bottleneck towards revealing their function and the precise contribution of >50 energy-consuming steps that drive ribosome assembly. Here, we devised a workflow that combines genetic trapping, affinity-capture, and selected reaction monitoring mass spectrometry (SRM-MS), to overcome this deficiency. We exploited this approach to interrogate the dynamic proteome of pre-60S particles after nuclear export. We uncovered assembly factors that travel with pre-60S particles to the cytoplasm, where they are released before initiating translation. Notably, we identified a novel shuttling factor that facilitates nuclear export of pre-60S particles. Capturing and quantitating protein interaction networks of trapped intermediates of macromolecular complexes by our workflow is a reliable discovery tool to unveil dynamic processes that contribute to their in vivo assembly and transport. | Targeted proteomics reveals compositional dynamics of 60S pre-ribosomes after nuclear export |
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OBJECTIVES To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea. METHODS Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke. MEASUREMENTS AND MAIN RESULTS A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25. CONCLUSIONS The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials. | Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. |
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1.19888174533844, "26992": 0.13157635927200317, "27011": 0.8517522215843201, "27019": 0.0354953333735466, "27312": 0.4673144817352295, "27354": 0.1685553640127182, "27404": 0.9546096324920654, "27605": 0.7683706283569336, "27833": 0.004870930220931768, "28093": 0.05417001247406006, "28141": 0.77198725938797, "28335": 0.27786844968795776, "28353": 0.026976587250828743, "28436": 1.3264323472976685, "28517": 0.1677299439907074, "28699": 0.20818853378295898, "28727": 0.10026945173740387, "28892": 0.05786345899105072, "28937": 0.820433497428894, "29237": 1.0868242979049683, "29304": 0.20501139760017395, "29378": 0.20102575421333313, "29490": 0.06337817758321762, "29610": 0.3084607720375061} | 23633726 | The purpose of this work was to take advantage of the new clinical field strength of 3 T to implement and optimize a chemical shift imaging (CSI) acquisition protocol to produce spectra of high quality with high specificity to the myocardium within a clinically feasible scan time. Further, an analysis method was implemented dependent purely on anatomical location of spectra, and as such free from any potential user bias caused by inference from spectral information. Twenty healthy male subjects were scanned on two separate occasions using the optimized CSI protocol at 3 T. Data were analyzed for intra- and inter-subject variability, as well as intra- and inter-observer variability. The average phosphocreatine (PCr)/adenosine triphosphate (ATP) value for scan 1 was 2.07 +/- 0.38 and for scan 2 was 2.14 +/- 0.46, showing no significant difference between scans. Intra-subject variability was 0.43 +/- 0.35 (percentage difference 20%) and the inter-subject coefficient of variation was 18%. The intra-observer variability, assessed as the absolute difference between analyses of the data by a single observer, was 0.14 +/- 0.24 with no significant difference between analyses. The inter-observer variability showed no significant differences between the PCr/ATP value measured by four different observers as demonstrated by an intra-class correlation coefficient of 0.763. The increased signal available at 3 T has improved spatial resolution and thereby increased myocardial specificity without any significant decrease in reproducibility over previous studies at 1.5 T. We present an acquisition protocol that routinely provides high quality spectra and a robust analysis method that is free from potential user bias. | Reproducibility of 31P cardiac magnetic resonance spectroscopy at 3 T. |
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proliferative signals, where it stabilizes or modulates the translation of target mRNAs. Here, we present evidence that HuR phosphorylation at S202 by the G2-phase kinase Cdk1 influences its subcellular distribution. HuR was specifically phosphorylated in synchronous G2-phase cultures; its cytoplasmic levels increased by Cdk1-inhibitory interventions and declined in response to Cdk1-activating interventions. In keeping with the prominently cytoplasmic location of the nonphosphorylatable point mutant HuR(S202A), phospho-HuR(S202) was shown to be predominantly nuclear using a novel anti-phospho-HuR(S202) antibody. The enhanced cytoplasmic presence of unphosphorylated HuR was linked to its decreased association with 14-3-3 and to its heightened binding to target mRNAs. Our findings suggest that Cdk1 phosphorylates HuR during G2, thereby helping to retain it in the nucleus in association with 14-3-3 and hindering its post-transcriptional function and anti-apoptotic influence. | Nuclear HuR accumulation through phosphorylation by Cdk1. |
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"28472": 0.20421554148197174, "28667": 0.5590575933456421, "29264": 0.3588210940361023, "29408": 0.06612417846918106, "29514": 0.6275664567947388} | 23639838 | Brain metastases occur in up to 40% of patients with cancer. Their management has been revolutionized in the last decade by three developments: improved imaging and detection of metastases, better treatment of systemic disease with the result that metastases occur more often; and improved surgical techniques including image-guided surgery to treat metastatic lesions. Class 1 data suggest that surgery is a better treatment for metastases than whole brain radiation. Other data suggest that metastases even in eloquent cortex can be removed safely. The complication rate is low and the recurrence rate is less than 10%. In general, indications for surgery include a mass with an unknown primary; a symptomatic mass including one in eloquent areas; a mass with considerable edema requiring high dose steroids; a mass greater than 3 cm; or patient preference when radiosurgery may also be an option. The question of radiosurgery or whole brain radiation as adjunct to surgical removal requires further evaluation. | Surgical Resection for Patients with Solid Brain Metastases: Current Status |
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"25473": 0.02792670577764511, "25665": 1.1198691129684448, "25957": 0.02316705882549286, "26243": 0.5069117546081543, "26282": 0.4002431631088257, "26572": 0.2317005842924118, "26591": 0.13414156436920166, "26721": 0.6931471824645996, "26745": 0.6064908504486084, "26871": 0.20102575421333313, "26994": 0.23710809648036957, "27144": 0.1485546976327896, "27165": 0.9820492267608643, "27381": 0.47766464948654175, "27395": 0.6317287683486938, "27441": 0.9798521995544434, "27711": 0.2247048318386078, "28228": 0.8357921838760376, "28528": 0.3027053773403168, "28616": 0.5957841277122498, "28646": 0.1913948506116867, "28685": 0.14179791510105133, "29251": 0.6970458030700684, "29451": 0.037378571927547455, "29514": 0.3810817003250122} | 23649163 | CONTEXT Peristomal pyoderma gangrenosum (PPG), an unusual variant of pyoderma gangrenosum, has been reported almost exclusively in patients with inflammatory bowel disease (IBD) and is frequently misdiagnosed. OBJECTIVE To better characterize the clinical manifestations, diagnosis, and management of PPG. DESIGN, SETTING, AND PATIENTS Retrospective analysis of 7 patients with PPG observed in a university-affiliated community setting between 1988 and December 1999. MAIN OUTCOME MEASURES Clinical and histopathologic features, associated disorders, and microbiologic findings. RESULTS Two patients had Crohn disease, 2 had ulcerative colitis, and 3 had abdominal cancer. Five patients had at least 1 relapse of PPG after initial healing. Although 3 of 4 patients with IBD had active bowel disease, a parallel course with PPG occurred in only 1 patient. Both patients whose stoma was relocated developed an ulcer at the new site. Effective therapies included topical superpotent corticosteroids; intralesional injection of triamcinolone acetonide at the ulcer margin; topical cromolyn sodium; oral dapsone, prednisone, cyclosporine, mycophenolate mofetil; and intravenous infliximab. CONCLUSION Our experiences demonstrate that although PPG has been most often reported in patients with IBD, it may occur in the absence of IBD. Biopsy of the skin lesion is not diagnostic but excludes other causes. Relocation of the stoma may be associated with a new ulceration and should be avoided. Trauma to the skin of a predisposed patient may elicit the pustules or ulcerations associated with pathergy. JAMA. 2000;284:1546-1548. | Clinical features and treatment of peristomal pyoderma gangrenosum. |
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Here we show, by both 2D gel analyses and chromatin immunoprecipitations (ChIP), that there exists a second level of global control mediated by the intra-S-phase checkpoint protein complex of Tof1p and Csm3p that protect stalled forks at Ter sites against the activity of the Rrm3p helicase ("sweepase"). The sweepase tends to release arrested forks presumably by the transient displacement of the Ter-bound Fob1p. Consistent with this mechanism, very few replication forks were arrested at the natural replication termini in the absence of the two checkpoint proteins. In the absence of the Rrm3p helicase, there was a slight enhancement of fork arrest at the Ter sites. Simultaneous deletions of the TOF1 (or CSM3), and the RRM3 genes restored fork arrest by removing both the fork-releasing and fork-protection activities. Other genes such as MRC1, WSS1, and PSY2 that are also involved in the MRC1 checkpoint pathway were not involved in this global control. This observation suggests that Tof1p-Csm3p function differently from MRC1 and the other above-mentioned genes. This mechanism is not restricted to the natural Ter sites but was also observed at fork arrest caused by the meeting of a replication fork with transcription approaching from the opposite direction. | The Tof1p-Csm3p protein complex counteracts the Rrm3p helicase to control replication termination of Saccharomyces cerevisiae. |
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"25409": 0.9680526852607727, "25468": 0.1011524572968483, "25604": 0.6907027959823608, "25610": 0.29328158497810364, "25937": 0.1685553640127182, "26236": 0.2026219218969345, "26305": 0.01934296265244484, "26678": 0.08692999184131622, "26874": 0.11343330889940262, "27216": 0.18654440343379974, "27321": 0.2881702482700348, "27509": 0.043007105588912964, "27881": 0.19541899859905243, "28207": 0.11865071207284927, "28227": 0.23864774405956268, "28436": 0.07250232994556427, "28498": 0.11430477350950241, "28788": 0.6482070088386536, "28828": 0.0058422754518687725, "28873": 0.23402166366577148, "28911": 0.4770587682723999, "29107": 0.12470348179340363, "29206": 0.07793712615966797, "29610": 0.4462870955467224} | 23665162 | Global DNA hypomethylation has been associated with increased risk for cancers of the colorectum, bladder, breast, head and neck, and testicular germ cells. The aim of this study was to examine whether global hypomethylation in blood leukocyte DNA is associated with the risk of hepatocellular carcinoma (HCC). A total of 315 HCC cases and 356 age-, sex- and HBsAg status-matched controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing long interspersed element-1 (LINE-1) repeats using bisulfite-polymerase chain reaction (PCR) and pyrosequencing. We observed that the median methylation level in HCC cases (percentage of 5-methylcytosine (5mC)=77.7%) was significantly lower than that in controls (79.5% 5mC) (P=0.004, Wilcoxon rank-sum test). The odds ratios (ORs) of HCC for individuals in the third, second, and first (lowest) quartiles of LINE-1 methylation were 1.1 (95% confidence interval (CI) 0.7–1.8), 1.4 (95% CI 0.8–2.2), and 2.6 (95% CI 1.7–4.1) (P for trend <0.001), respectively, compared to individuals in the fourth (highest) quartile. A 1.9-fold (95% CI 1.4–2.6) increased risk of HCC was observed among individuals with LINE-1 methylation below the median compared to individuals with higher (>median) LINE-1 methylation. Our results demonstrate for the first time that individuals with global hypomethylation measured in LINE-1 repeats in blood leukocyte DNA have an increased risk for HCC. Our data provide the evidence that global hypomethylation detected in the easily obtainable DNA source of blood leukocytes may help identify individuals at risk of HCC. | Association of hypomethylation of LINE-1 repetitive element in blood leukocyte DNA with an increased risk of hepatocellular carcinoma |
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0.5290185213088989, "26163": 0.5057345628738403, "26224": 0.0752234235405922, "26576": 0.2231435477733612, "26651": 0.23247487843036652, "26976": 0.02412080205976963, "27354": 0.02412080205976963, "27356": 0.14686977863311768, "27718": 0.3346569836139679, "28003": 0.06977381557226181, "28196": 0.1011524572968483, "29050": 0.17759032547473907, "29398": 0.0058422754518687725} | 23670644 | BACKGROUND The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial. METHODS 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915. FINDINGS 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62.0%vs 136.9%, 75% decrease, 95% CI 42.4-107.4%; p<0.0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0.0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger. INTERPRETATION The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy. FUNDING HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council. | The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial. |
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0.12038381397724152, "26835": 0.4002431631088257, "27142": 0.12038381397724152, "27152": 1.0179725885391235, "27491": 0.04860413447022438, "27559": 1.1756457090377808, "27570": 0.13499516248703003, "27617": 0.1889725625514984, "27788": 0.16359257698059082, "28024": 1.034073829650879, "28054": 0.11168810725212097, "28667": 0.15359249711036682, "28721": 0.8315495252609253, "28741": 0.9680526852607727, "29090": 0.8039615154266357, "29172": 0.39367714524269104, "29206": 0.22626367211341858} | 23686039 | As the field of synthetic biology develops, real-world applications are moving from the realms of ideas and laboratory-confined research towards implementation. A pressing concern, particularly with microbial systems, is that self-replicating re-engineered cells may produce undesired consequences if they escape or overwhelm their intended environment. To address this biosafety issue, multiple mechanisms for constraining microbial replication and horizontal gene transfer have been proposed. These include the use of host-construct dependencies such as toxin-antitoxin pairs, conditional plasmid replication or the requirement for a specific metabolite to be present for cellular function. While refactoring of the existing genetic code or tailoring of orthogonal systems, e.g. xeno nucleic acids, offers future promise of more stringent 'firewalls' between natural and synthetic cells, here we focus on what can be achieved using existing technology. The state-of-the-art in designing for biosafety is summarized and general recommendations are made (e.g. short environmental retention times) for current synthetic biology projects to better isolate themselves against potentially negative impacts. | Building-in biosafety for synthetic biology. |
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"27233": 0.14686977863311768, "27559": 1.020087480545044, "28024": 0.07250232994556427, "28247": 0.6833335757255554, "28361": 0.11865071207284927, "28424": 0.14939609169960022, "28829": 0.5364705324172974, "28927": 0.2089812457561493, "29060": 0.45623743534088135, "29728": 0.2231435477733612} | 23698769 | DNA polymerase μ (Pol μ) is the only template-dependent human DNA polymerase capable of repairing double-strand DNA breaks (DSBs) with unpaired 3′ ends in nonhomologous end joining (NHEJ). To probe this function, we structurally characterized Pol μ's catalytic cycle for single-nucleotide incorporation. These structures indicate that, unlike other template-dependent DNA polymerases, Pol μ shows no large-scale conformational changes in protein subdomains, amino acid side chains or DNA upon dNTP binding or catalysis. Instead, the only major conformational change is seen earlier in the catalytic cycle, when the flexible loop 1 region repositions upon DNA binding. Pol μ variants with changes in loop 1 have altered catalytic properties and are partially defective in NHEJ. The results indicate that specific loop 1 residues contribute to Pol μ's unique ability to catalyze template-dependent NHEJ of DSBs with unpaired 3′ ends. | Sustained active site rigidity during synthesis by human DNA polymerase μ |
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"28696": 0.2470736801624298, "28817": 0.857568621635437, "28848": 0.1994270235300064, "28976": 0.06612417846918106, "29090": 0.46117570996284485, "29290": 0.15860503911972046, "29324": 0.5778634548187256} | 23700330 | Angiopoietin-1 (Ang-1), a ligand of the endothelium-specific receptor Tie-2, inhibits permeability in the mature vasculature, but the mechanism remains unknown. Here we show that Ang-1 signals Rho family GTPases to organize the cytoskeleton into a junction-fortifying arrangement that enhances the permeability barrier function of the endothelium. Ang-1 phosphorylates Tie-2 and its downstream effector phosphatidylinositol 3-kinase. This induces activation of one endogenous GTPase, Rac1, and inhibition of another, RhoA. Loss of either part of this dual effect abrogates the cytoskeletal and anti-permeability actions of Ang-1, suggesting that coordinated GTPase regulation is necessary for the vessel-sealing effects of Ang-1. p190 RhoGAP, a GTPase regulatory protein, provides this coordinating function as it is phosphorylated by Ang-1 treatment, requires Rac1 activation, and is necessary for RhoA inhibition. Ang-1 prevents the cytoskeletal and pro-permeability effects of endotoxin but requires p190 RhoGAP to do so. Treatment with p190 RhoGAP small interfering RNA completely abolishes the ability of Ang-1 to rescue endotoxemia-induced pulmonary vascular leak and inflammation in mice. We conclude that Ang-1 prevents vascular permeability by regulating the endothelial cytoskeleton through coordinated and opposite effects on the Rho GTPases Rac1 and RhoA. By linking Rac1 activation and RhoA inhibition, p190 RhoGAP is critical to the protective effects of Ang-1 against endotoxin. These results provide mechanistic evidence that targeting the endothelium through Tie-2 may offer specific therapeutic strategies in life-threatening endotoxemic conditions such as sepsis and acute respiratory distress syndrome. | Angiopoietin-1 requires p190 RhoGAP to protect against vascular leakage in vivo. |
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0.23092569410800934, "28086": 0.11865071207284927, "28228": 0.6420594453811646, "28251": 1.034073829650879, "28741": 1.240975022315979, "29290": 0.31845372915267944, "29494": 0.7047978043556213} | 23702805 | Secreted semaphorins act as guidance cues in the developing nervous system and may have additional functions in mature neurons. How semaphorins are transported and secreted by neurons is poorly understood. We find that endogenous semaphorin 3A (Sema3A) displays a punctate distribution in axons and dendrites of cultured cortical neurons. GFP-Sema3A shows a similar distribution and co-localizes with secretory vesicle cargo proteins. Live-cell imaging reveals highly dynamic trafficking of GFP-Sema3A vesicles with distinct properties in axons and dendrites regarding directionality, velocity, mobility and pausing time. In axons, most GFP-Sema3A vesicles move fast without interruption, almost exclusively in the anterograde direction, while in dendrites many GFP-Sema3A vesicles are stationary and move equally frequent in both directions. Disruption of microtubules, but not of actin filaments, significantly impairs GFP-Sema3A transport. Interestingly, depolarization induces a reversible arrest of axonal transport of GFP-Sema3A vesicles but has little effect on dendritic transport. Conversely, action potential blockade using tetrodotoxin (TTX) accelerates axonal transport, but not dendritic transport. These data indicate that axons and dendrites regulate trafficking of Sema3A and probably other secretory vesicles in distinct ways, with axons specializing in fast, uninterrupted, anterograde transport. Furthermore, neuronal activity regulates secretory vesicle trafficking in axons by a depolarization-evoked trafficking arrest. | Vesicular trafficking of semaphorin 3A is activity-dependent and differs between axons and dendrites. |
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0.19782574474811554, "26462": 0.3850763738155365, "26535": 1.0073304176330566, "26721": 0.7854343056678772, "26745": 0.5139457583427429, "26775": 0.2247048318386078, "26994": 0.2969166338443756, "27011": 0.757441520690918, "27065": 0.03831886500120163, "27109": 0.31132611632347107, "27144": 0.007782140281051397, "27208": 0.10026945173740387, "27312": 0.3547199070453644, "27480": 0.08244366943836212, "27532": 1.0158531665802002, "27989": 0.16442140936851501, "28062": 0.04394211992621422, "28155": 1.1413075923919678, "28228": 0.33115679025650024, "28466": 0.23633737862110138, "28697": 0.18167030811309814, "28817": 0.7105726003646851, "28828": 0.39367714524269104, "28915": 0.37371641397476196, "29048": 0.8893690705299377, "29561": 0.0770333781838417} | 23704559 | Coarctation of the aorta (CofA) has been associated with an increased risk of intracranial aneurysm (IA). This magnetic resonance angiography (MRA) study investigates the prevalence of IAs in 80 children treated in early life for CofA. MRA was performed at mean age of 15.7 ± 7.1 years, and surgical or endovascular treatment for CofA occurred at a mean age of 2.6 ± 4.4 years. No IA was found. In contrast with earlier findings in adult patients with late treatment for CofA, this first systematic study of very early treated patients for CofA failed to confirm the association between CofA and IAs. Our results call the abnormal developmental relation between CofA and IAs into question and suggest that modifiable risk factors like hypertension may be responsible for IA development in patients with CofA with adult diagnosis and treatment. In conclusion, our data suggest that early treatment of CofA can reduce the formation of IAs in children so as to make MRA screening less valuable in this young population. | Frequency of Intracranial Aneurysms Determined by Magnetic Resonance Angiography in Children (Mean Age 16) Having Operative or Endovascular Treatment of Coarctation of the Aorta (Mean Age 3). |
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0.8298473954200745, "28353": 0.5336109399795532, "28637": 0.15777134895324707, "28699": 0.18329764902591705, "29025": 0.026025565341114998, "29060": 0.12384103983640671, "29206": 0.02792670577764511} | 23716150 | Cardiac chamber-specific gene expression is critical for the normal development and function of the heart. To investigate the genetic basis of cardiac anatomical specialization, we have undertaken a nearly genome-wide transcriptional profiling of the four heart chambers and the interventricular septum. Rigorous statistical analysis has allowed the identification of known and novel members of gene families that are felt to be important in cardiac development and function, including LIM proteins, homeobox proteins, wnt and T-box pathway proteins, as well as structural proteins like actins and myosins. In addition, these studies have allowed the identification of thousands of additional differentially expressed genes, for which there is little structural or functional information. Clustering of genes with known and unknown functions provides insights into signaling pathways that are essential for development and maintenance of chamber-specific features. To facilitate future research in this area, a searchable internet database has been constructed that allows study of the chamber-specific expression of any gene represented on this comprehensive microarray. It is anticipated that further study of genes identified through this effort will provide insights into the specialization of heart chamber tissues, and their specific roles in cardiac development, aging, and disease. | Transcriptional profiling of the heart reveals chamber-specific gene expression patterns. |
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"27287": 0.5734702348709106, "27354": 0.3409265875816345, "27526": 0.5110208988189697, "27854": 0.07159364968538284, "28086": 0.17267228662967682, "28848": 1.0298984050750732, "28901": 0.1710275560617447, "29206": 1.013020396232605, "29458": 0.7314660549163818, "29533": 0.10026945173740387} | 23727313 | MicroRNAs (miRNAs) are a recently identified class of epigenetic elements consisting of small noncoding RNAs that bind to the 3' untranslated region of mRNAs and down-regulate their translation to protein. miRNAs play critical roles in many different cellular processes including metabolism, apoptosis, differentiation, and development. We found 33 miRNAs expressed in CD34+ hematopoietic stem-progenitor cells (HSPCs) from normal human bone marrow and mobilized human peripheral blood stem cell harvests. We then combined these data with human HSPC mRNA expression data and with miRNA-mRNA target predictions, into a previously undescribed miRNA:mRNA interaction database called the Transcriptome Interaction Database. The in silico predictions from the Transcriptome Interaction Database pointed to miRNA control of hematopoietic differentiation through translational control of mRNAs critical to hematopoiesis. From these predictions, we formulated a model for miRNA control of stages of hematopoiesis in which many of the genes specifying hematopoietic differentiation are expressed by HSPCs, but are held in check by miRNAs until differentiation occurs. We validated miRNA control of several of these target mRNAs by demonstrating that their translation in fact is decreased by miRNAs. Finally, we chose miRNA-155 for functional characterization in hematopoiesis, because we predicted that it would control both myelopoiesis and erythropoiesis. As predicted, miRNA-155 transduction greatly reduced both myeloid and erythroid colony formation of normal human HSPCs. | CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. |
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In Study 1, a group of rats (n=6) was run on the treadmill at 25 m/min, 5% grade, for 1 h or until exhaustion (Ex), and compared with a second group (n=6) injected with two doses of pyrrolidine dithiocarbamate (PDTC, 100 mg/kg, i.p.) 24 and 1 h prior to the acute exercise bout. Three additional groups of rats (n=6) were injected with either 8 mg/kg (i.p.) of lipopolysaccharide (LPS), 1 mmol/kg (i.p.) t-butylhydroperoxide (tBHP), or saline (C) and killed at resting condition. Ex rats showed higher levels of NF-kappaB binding and P50 protein content in muscle nuclear extracts compared with C rats. Cytosolic IkappaBalpha and IkappaB kinase (IKK) contents were decreased, whereas phospho-IkappaBalpha and phospho-IKK contents were increased, comparing Ex vs. C. The exercise-induced activation of NF-kappaB signaling cascade was partially abolished by PDTC treatment. LPS, but not tBHP, treatment mimicked and exaggerated the effects observed in Ex rats. In Study 2, the time course of exercise-induced NF-kappaB activation was examined. Highest levels of NF-kappaB binding were observed at 2 h postexercise. Decreased cytosolic IkappaBalpha and increased phosphor-IkappaBalpha content were found 0-1 h postexercise whereas P65 reached peak levels at 2-4 h. These data suggest that the NF-kappaB signaling pathway can be activated in a redox-sensitive manner during muscular contraction, presumably due to increased oxidant production. The cascade of intracellular events may be the overture to elevated gene expression of manganese superoxide dismutase reported earlier (Pfluegers Arch. 442, 426-434, 2001). | Acute exercise activates nuclear factor (NF)-kappaB signaling pathway in rat skeletal muscle. |
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0.05046287178993225, "29598": 0.8074519634246826} | 23746313 | Staphylococcus aureus RNAIII is one of the largest regulatory RNAs, which controls several virulence genes encoding exoproteins and cell-wall-associated proteins. One of the RNAIII effects is the repression of spa gene (coding for the surface protein A) expression. Here, we show that spa repression occurs not only at the transcriptional level but also by RNAIII-mediated inhibition of translation and degradation of the stable spa mRNA by the double-strand-specific endoribonuclease III (RNase III). The 3' end domain of RNAIII, partially complementary to the 5' part of spa mRNA, efficiently anneals to spa mRNA through an initial loop-loop interaction. Although this annealing is sufficient to inhibit in vitro the formation of the translation initiation complex, the coordinated action of RNase III is essential in vivo to degrade the mRNA and irreversibly arrest translation. Our results further suggest that RNase III is recruited for targeting the paired RNAs. These findings add further complexity to the expression of the S. aureus virulon. | Staphylococcus aureus RNAIII and the endoribonuclease III coordinately regulate spa gene expression. |
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1.0641717910766602, "27404": 0.684319257736206, "27559": 0.0354953333735466, "27651": 0.08244366943836212, "27774": 0.06703783571720123, "27854": 0.10818854719400406, "27969": 0.1358480453491211, "28215": 0.2223619967699051, "28228": 0.026976587250828743, "28332": 0.2607102394104004, "28432": 0.33115679025650024, "28570": 0.10906458646059036, "28688": 0.37907835841178894, "28793": 0.09050461649894714, "28815": 0.015504186972975731, "29090": 0.5444341897964478, "29237": 0.33115679025650024, "29248": 0.12814582884311676, "29311": 0.15860503911972046, "29494": 0.053244512528181076, "29607": 0.08513788133859634} | 23746332 | Slow changes in [Ca(2+)](i) reflect increased neuronal activity. Our study demonstrates that single-trial fast [Ca(2+)](i) imaging (≥200 Hz sampling rate) revealed peaks each of which are associated with single spike discharge recorded by consecutive voltage-sensitive dye (VSD) imaging in enteric neurones and nerve fibres. Fast [Ca(2+)](i) imaging also revealed subthreshold fast excitatory postsynaptic potentials. Nicotine-evoked [Ca(2+)](i) peaks were reduced by -conotoxin and blocked by ruthenium red or tetrodotoxin. Fast [Ca(2+)](i) imaging can be used to directly record single action potentials in enteric neurones. [Ca(2+)](i) peaks required opening of voltage-gated sodium and calcium channels as well as Ca(2+) release from intracellular stores. | Fast calcium and voltage-sensitive dye imaging in enteric neurones reveal calcium peaks associated with single action potential discharge. |
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"29598": 0.7182208299636841} | 23763738 | We have developed a rapid, sensitive, and inexpensive method for measuring the cellular protein content of adherent and suspension cultures in 96-well microtiter plates. The method is suitable for ordinary laboratory purposes and for very large-scale applications, such as the National Cancer Institute's disease-oriented in vitro anticancer-drug discovery screen, which requires the use of several million culture wells per year. Cultures fixed with trichloroacetic acid were stained for 30 minutes with 0.4% (wt/vol) sulforhodamine B (SRB) dissolved in 1% acetic acid. Unbound dye was removed by four washes with 1% acetic acid, and protein-bound dye was extracted with 10 mM unbuffered Tris base [tris (hydroxymethyl)aminomethane] for determination of optical density in a computer-interfaced, 96-well microtiter plate reader. The SRB assay results were linear with the number of cells and with values for cellular protein measured by both the Lowry and Bradford assays at densities ranging from sparse subconfluence to multilayered supraconfluence. The signal-to-noise ratio at 564 nm was approximately 1.5 with 1,000 cells per well. The sensitivity of the SRB assay compared favorably with sensitivities of several fluorescence assays and was superior to those of both the Lowry and Bradford assays and to those of 20 other visible dyes. The SRB assay provides a colorimetric end point that is nondestructive, indefinitely stable, and visible to the naked eye. It provides a sensitive measure of drug-induced cytotoxicity, is useful in quantitating clonogenicity, and is well suited to high-volume, automated drug screening. SRB fluoresces strongly with laser excitation at 488 nm and can be measured quantitatively at the single-cell level by static fluorescence cytometry. | New colorimetric cytotoxicity assay for anticancer-drug screening. |
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0.7201237678527832, "28723": 0.28450319170951843, "28788": 0.11778303235769272, "29109": 0.07612881064414978, "29290": 0.34300774335861206, "29458": 0.6659244894981384, "29477": 0.8649974465370178} | 23777820 | Myeloma causes a devastating and unique form of osteolytic bone disease. Although osteoclast activation is responsible for bone destruction, the precise mechanisms by which myeloma cells increase osteoclast activity have not been defined. An animal model of human myeloma bone disease would help in clarification of these mechanisms. Multiple myeloma occurs spontaneously in aging C57 BL/KaLwRij mice and has all of the features of the disease in humans, including the characteristic bone lesions. The disease can be induced in normal C57 BL/KaLwRij mice by inoculation of fresh marrow-derived cells from mice with myeloma, but this model is difficult to study because of variability in the number of myeloma cells in marrow-derived preparations. To develop a better animal model of human myeloma bone disease, we have established and subcloned a cell line from this murine myeloma and found that it causes osteolytic bone lesions in mice characteristic of human myeloma bone disease. The cell line produces interleukin-6, but grows independent of exogenous interleukin-6. Mice inoculated intravenously with the cultured cells predictably develop an identical disease to the mice injected intravenously with fresh bone-marrow-derived myeloma cells, including monoclonal gammopathy and radiologic bone lesions. We found that some of the mice became hypercalcemic, and the bone lesions are characterized by increased osteoclast activity. We found identical results when we inoculated Nu/Bg/XID mice with cultured murine myeloma cells. Because we can inoculate mice with precise numbers of cells and predict accurately when the mice will develop bone lesions, become hypercalcemic, and die, this should be a convenient model for determining the mechanisms by which the myeloma cells cause osteoclast activation in this model of human myeloma bone disease. | A murine model of human myeloma bone disease. |
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"27144": 0.036437395960092545, "27325": 0.06154331564903259, "27339": 0.2696990668773651, "27794": 0.9317949414253235, "28093": 0.25694093108177185, "28155": 0.1477125883102417, "28225": 0.14602625370025635, "28621": 0.14179791510105133, "28696": 0.16690383851528168} | 23783727 | AIMS patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control. METHODS AND RESULTS we analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76-1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66-1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36-1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81-1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70-0.91; HR: 0.78, 95% CI: 0.65-0.93; and HR: 0.62, 95% CI: 0.39-1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86-1.12). CONCLUSION ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events. | Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial |
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"24759": 0.0029254043474793434, "24848": 0.19862671196460724, "24901": 0.15860503911972046, "25032": 0.3134697377681732, "25070": 0.6674286723136902, "25222": 0.09317722171545029, "25344": 0.06337817758321762, "25353": 0.4512746334075928, "25519": 0.6212902665138245, "25613": 0.025073638185858727, "25937": 0.15275461971759796, "26033": 0.07250232994556427, "26163": 0.6048921346664429, "26226": 0.5104349255561829, "26236": 0.15610189735889435, "26266": 0.736154317855835, "26305": 0.27934664487838745, "26456": 1.309704303741455, "26462": 0.3170322775840759, "27204": 0.10291612148284912, "27339": 0.5301685929298401, "27833": 1.2353124618530273, "28093": 0.5016035437583923, "28353": 0.25995752215385437, "28687": 0.8583967685699463, "28697": 0.030771657824516296, "29048": 0.5517725944519043, "29166": 0.255429208278656, "29212": 0.4041621685028076, "29458": 0.055094651877880096, "29477": 0.2089812457561493} | 23785605 | BACKGROUND Migraine, particularly with aura, is a risk factor for early-onset ischemic stroke. The underlying mechanisms are unknown, but may in part be due to migraineurs having an increased risk profile for cardiovascular disease. In this study, the authors compare the cardiovascular risk profile of adult migraineurs to that of nonmigraineurs. METHODS Participants (n = 5,755, 48% men, age 20 to 65 years) are from the Genetic Epidemiology of Migraine (GEM) study, a population-based study in the Netherlands. A total of 620 current migraineurs were identified: 31% with aura (MA), 64% without aura (MO), and 5% unclassified. Controls were 5,135 individuals without lifetime migraine. Measured cardiovascular risk factors included blood pressure (BP), serum total and high-density lipoprotein cholesterol (TC, HDL), smoking, oral contraceptive use, and the Framingham risk score for myocardial infarction or coronary heart disease (CHD) death. RESULTS Compared to controls, migraineurs were more likely to smoke (OR = 1.43 [1.1 to 1.8]), less likely to consume alcohol (OR = 0.58 [0.5 to 0.7]), and more likely to report a parental history of early myocardial infarction. Migraineurs with aura were more likely to have an unfavorable cholesterol profile (TC > or = 240 mg/dL [OR = 1.43 (0.97 to 2.1)], TC:HDL ratio > 5.0 [OR = 1.64 (1.1 to 2.4)]), have elevated BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg [OR = 1.76 (1.04 to 3.0)]), and report a history of early onset CHD or stroke (OR = 3.96 [1.1 to 14.3]); female migraineurs with aura were more likely to be using oral contraceptives (OR = 2.06 [1.05 to 4.0]). The odds of having an elevated Framingham risk score for CHD were approximately doubled for the migraineurs with aura. CONCLUSIONS Migraineurs, particularly with aura, have a higher cardiovascular risk profile than individuals without migraine. | Cardiovascular risk factors and migraine: the GEM population-based study. |
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"26243": 0.1401015669107437, "26402": 0.10379679501056671, "26524": 0.16359257698059082, "26591": 0.09317722171545029, "26597": 0.1873544454574585, "26651": 0.40481385588645935, "26721": 0.03360854089260101, "26735": 0.08871890604496002, "26773": 0.5016035437583923, "26835": 0.35334911942481995, "27152": 0.020300358533859253, "27199": 0.021256839856505394, "27781": 0.812664806842804, "27854": 0.026976587250828743, "27998": 0.5573811531066895, "28156": 0.956112265586853, "28498": 0.07793712615966797, "28696": 0.2539152204990387, "28788": 0.6734226942062378, "28805": 0.1229778528213501, "28857": 0.05694137513637543, "28873": 0.22937409579753876, "28896": 0.22079704701900482, "29384": 0.010684899985790253} | 23801039 | Despite many years of study, relatively little is known about the effector mechanisms that operate against intestine-dwelling nematodes. Most of the current understanding comes from studies of laboratory model systems in rodents. It is clear that when an intestinal helminth infection takes place the immune system generates a strong Th2-mediated response, which regulates a variety of responses characteristic of helminth infections such as eosinophilia, intestinal mastocytosis and elevated IgE production. The ability to modulate the host's immune response in vivo with cytokine-specific monoclonal antibodies and recombinant cytokines, together with the use of animals with disruption of key genes involved in the immune response, have provided powerful tools with which to dissect the potential effector mechanisms operating. In the absence of a T-cell compartment the host is unable to expel the parasite. If a Th1-dominated response is generated, protective immunity is almost universally compromised. Thus, it it would appear that some aspect of a Th2-mediated response controls effector mechanisms. Although it is clear that for some infections the mast cell appears to be involved in protection, probably through the generation of a non-specific inflammatory response, how these cells become activated remains unclear. Data from infections in transgenic animals suggest that activation is not through the high-affinity receptor for IgE. Such studies also call into doubt the importance of conventional interactions between effector leucocytes and antibody. There is little evidence to support a protective role for eosinophilia in any system. New data also imply that, although interleukin 4 (IL-4) is generally important (and can exert effects independent of an adaptive immune response), it is not always sufficient to mediate protection; other Th2 cytokines (e.g. IL-13) may warrant closer investigation. It is apparent that a number of potential Th2-controlled effector mechanisms (some of which may be particularly important at mucosal surfaces) remain to be explored. Overall, it is likely that worm expulsion is the result of a combination of multiple mechanisms, some of which are more critical to some species of parasite than to others. | Th2-mediated host protective immunity to intestinal nematode infections. |
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