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0.8788808584213257, "29037": 0.8298473954200745, "29206": 0.1602703034877777} | 16217855 | The product of the gene mutated in Bloom's syndrome, BLM, is a 3′–5′ DNA helicase belonging to the highly conserved RecQ family. In addition to a conventional DNA strand separation activity, BLM catalyzes both the disruption of non-B-form DNA, such as G-quadruplexes, and the branch migration of Holliday junctions. Here, we have characterized a new activity for BLM: the promotion of single-stranded DNA (ssDNA) annealing. This activity does not require Mg2+, is inhibited by ssDNA binding proteins and ATP, and is dependent on DNA length. Through analysis of various truncation mutants of BLM, we show that the C-terminal domain is essential for strand annealing and identify a 60 amino acid stretch of this domain as being important for both ssDNA binding and strand annealing. We present a model in which the ssDNA annealing activity of BLM facilitates its role in the processing of DNA intermediates that arise during repair of damaged replication forks. | The Bloom's syndrome helicase promotes the annealing of complementary single-stranded DNA |
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0.018384648486971855, "25986": 0.854249119758606, "26126": 0.07431721687316895, "26237": 0.16359257698059082, "26266": 0.18248429894447327, "26282": 0.41840189695358276, "26305": 0.24631060659885406, "26397": 0.04207121208310127, "26591": 0.29400965571403503, "26601": 1.0828639268875122, "26633": 0.5472630262374878, "26686": 0.02316705882549286, "26835": 0.32129061222076416, "27152": 0.7220231294631958, "27354": 0.0317181795835495, "27356": 0.1011524572968483, "27691": 0.2749055027961731, "27774": 1.1153976917266846, "27946": 0.07250232994556427, "27965": 0.12038381397724152, "28003": 1.360575795173645, "28086": 0.15610189735889435, "28252": 0.19381128251552582, "28436": 0.1994270235300064, "28561": 0.0038986403960734606, "28759": 0.06337817758321762, "28788": 0.6244332790374756, "28848": 0.35745587944984436, "28937": 0.129004567861557, "29021": 0.5220900774002075, "29107": 1.1941591501235962, "29458": 0.35745587944984436} | 16232581 | We develop a reversible jump Markov chain Monte Carlo approach to estimating the posterior distribution of phylogenies based on aligned DNA/RNA sequences under several hierarchical evolutionary models. Using a proper, yet nontruncated and uninformative prior, we demonstrate the advantages of the Bayesian approach to hypothesis testing and estimation in phylogenetics by comparing different models for the infinitesimal rates of change among nucleotides, for the number of rate classes, and for the relationships among branch lengths. We compare the relative probabilities of these models and the appropriateness of a molecular clock using Bayes factors. Our most general model, first proposed by Tamura and Nei, parameterizes the infinitesimal change probabilities among nucleotides (A, G, C, T/U) into six parameters, consisting of three parameters for the nucleotide stationary distribution, two rate parameters for nucleotide transitions, and another parameter for nucleotide transversions. Nested models include the Hasegawa, Kishino, and Yano model with equal transition rates and the Kimura model with a uniform stationary distribution and equal transition rates. To illustrate our methods, we examine simulated data, 16S rRNA sequences from 15 contemporary eubacteria, halobacteria, eocytes, and eukaryotes, 9 primates, and the entire HIV genome of 11 isolates. We find that the Kimura model is too restrictive, that the Hasegawa, Kishino, and Yano model can be rejected for some data sets, that there is evidence for more than one rate class and a molecular clock among similar taxa, and that a molecular clock can be rejected for more distantly related taxa. | Bayesian selection of continuous-time Markov chain evolutionary models. |
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0.07884006202220917, "25870": 0.15943801403045654, "26226": 0.5562619566917419, "26462": 1.072225570678711, "26524": 0.3615458607673645, "26773": 0.8143964409828186, "26906": 0.6260011196136475, "28093": 0.4891071021556854, "28353": 0.6027565002441406, "28767": 0.09672962874174118, "28964": 0.0752234235405922, "29024": 0.371698260307312, "29166": 0.18816383183002472, "29494": 0.32129061222076416} | 16233471 | The average lifespan of humans is increasing, and with it the percentage of people entering the 65 and older age group is growing rapidly and will continue to do so in the next 20 years. Within this age group, cardiovascular disease will remain the leading cause of death, and the cost associated with treatment will continue to increase. Aging is an inevitable part of life and unfortunately poses the largest risk factor for cardiovascular disease. Although numerous studies in the cardiovascular field have considered both young and aged humans, there are still many unanswered questions as to how the genetic pathways that regulate aging in model organisms influence cardiovascular aging. Likewise, in the molecular biology of aging field, few studies fully assess the role of these aging pathways in cardiovascular health. Fortunately, this gap is beginning to close, and these two fields are merging together. We provide an overview of some of the key genes involved in regulating lifespan and health span, including sirtuins, AMP-activated protein kinase, mammalian target of rapamycin, and insulin-like growth factor 1 and their roles regulating cardiovascular health. We then discuss a series of review articles that will appear in succession and provide a more comprehensive analysis of studies carried out linking genes of aging and cardiovascular health, and perspectives of future directions of these two intimately linked fields. | The intersection between aging and cardiovascular disease. |
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| Proper execution of transcriptional programs is a key requirement of gene expression regulation, demanding accurate control of timing and amplitude. How precisely the transcription machinery fulfills this task is not known. Using an in situ hybridization approach that detects single mRNA molecules, we measured mRNA abundance and transcriptional activity within single Saccharomyces cerevisiae cells. We found that expression levels for particular genes are higher than initially reported and can vary substantially among cells. However, variability for most constitutively expressed genes is unexpectedly small. Combining single-transcript measurements with computational modeling indicates that low expression variation is achieved by transcribing genes using single transcription-initiation events that are clearly separated in time, rather than by transcriptional bursts. In contrast, PDR5, a gene regulated by the transcription coactivator complex SAGA, is expressed using transcription bursts, resulting in larger variation. These data directly demonstrate the existence of multiple expression modes used to modulate the transcriptome. | Single-RNA counting reveals alternative modes of gene expression in yeast |
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"27112": 0.07793712615966797, "27152": 0.35060185194015503, "27642": 0.03266380727291107, "27777": 0.0752234235405922, "28024": 0.1477125883102417, "28699": 0.3106105625629425, "28774": 0.3005385100841522, "29226": 0.9907892942428589, "29458": 0.5629584193229675} | 16242975 | In mammalian mitochondria, 22 species of tRNAs encoded in mitochondrial DNA play crucial roles in the translation of 13 essential subunits of the respiratory chain complexes involved in oxidative phosphorylation. Following transcription, mitochondrial tRNAs are modified by nuclear-encoded tRNA-modifying enzymes. These modifications are required for the proper functioning of mitochondrial tRNAs (mt tRNAs), and the absence of these modifications can cause pathological consequences. To date, however, the information available about these modifications has been incomplete. To address this issue, we isolated all 22 species of mt tRNAs from bovine liver and comprehensively determined the post-transcriptional modifications in each tRNA by mass spectrometry. Here, we describe the primary structures with post-transcriptional modifications of seven species of mt tRNAs which were previously uncharacterized, and provide revised information regarding base modifications in five other mt tRNAs. In the complete set of bovine mt tRNAs, we found 15 species of modified nucleosides at 118 positions (7.48% of total bases). This result provides insight into the molecular mechanisms underlying the decoding system in mammalian mitochondria and enables prediction of candidate tRNA-modifying enzymes responsible for each modification of mt tRNAs. | A complete landscape of post-transcriptional modifications in mammalian mitochondrial tRNAs |
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"26745": 0.5398913025856018, "26780": 0.3027053773403168, "27024": 0.46117570996284485, "27118": 0.6892333030700684, "27321": 0.29109421372413635, "27753": 0.812664806842804, "27833": 0.987156867980957, "28093": 0.42416930198669434, "28173": 0.5551415085792542, "28268": 0.055094651877880096, "28353": 0.3784096837043762, "28403": 0.2822965085506439, "28689": 0.0009760859538801014, "28828": 0.6233867406845093, "28915": 0.1913948506116867, "29048": 0.554580807685852, "29166": 0.42225050926208496, "29167": 0.010684899985790253, "29336": 0.19782574474811554, "29491": 0.2689530849456787} | 16252863 | The list of preventable and reversible risk factors for atherosclerotic cardiovascular disease continues to grow. Cigarette smoking, high blood pressure, physical inactivity, elevated cholesterol, underlying lipoprotein abnormalities, lipoprotein(a), diabetes, overweight, male gender, and age are well-established risk factors. During the 1990s, there have been many reports associating elevated plasma homocysteine levels with arteriosclerotic cardiovascular disease and consistent evidence that dietary and supplemental folic acid can reduce homocysteine levels.1 2 The article by Robinson and colleagues3 in this issue of Circulation presents further evidence of the importance of homocysteine and suggestive evidence that plasma folate and plasma pyrixodal-l-phosphate (vitamin B6) are protective factors. Their study is part of the European Concerted Action Project,4 which examined 750 patients younger than age 60 with diagnoses within the previous 12 months of coronary, cerebrovascular, or peripheral vascular disease and 800 healthy control subjects. The patient groups were young (47 years for cases and 44 years for control subjects) and heterogeneous, with nonfatal clinical events or symptoms of arteriosclerotic cardiovascular disease supported by ECG, angiographic, or Doppler evidence; the study involved 19 centers in nine European countries. Men in the highest quintile for fasting total homocysteine (tHcy), compared with the remainder of the population, had an estimated relative risk of 2.2 (95% confidence interval [CI], 1.6 to 2.9), with a striking dose-response relationship and a more-than-multiplicative interaction with cigarette smoking and high blood pressure on vascular disease risk4 ; the corresponding estimated relative risk for coronary heart disease was similar (2.0; 95% CI 1.6 to 2.8). (tHcy is the sum of homocysteine and homocysteinyl moieties of oxidized disulfides, homocystine, and cysteine- homocysteine. ) Robinson and colleagues3 examined three B vitamins in detail to determine their effects on fasting and post–methionine-loading tHcy levels and any independent effects on cardiovascular disease … | Preventing coronary heart disease: B vitamins and homocysteine. |
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"21447": 0.23092569410800934, "21453": 0.39696553349494934, "21497": 0.31489628553390503, "22096": 0.37304413318634033, "22154": 0.015504186972975731, "22537": 0.0842406153678894, "22943": 0.5662899017333984, "23444": 0.07612881064414978, "23569": 0.3995884954929352, "23613": 0.450652539730072, "24081": 0.3127557039260864, "24110": 0.4002431631088257, "24668": 0.36697331070899963, "24734": 0.43875885009765625, "24798": 0.0038986403960734606, "24936": 0.31560876965522766, "24983": 0.010684899985790253, "25654": 0.5607312321662903, "26780": 0.23324857652187347, "27197": 0.7182208299636841, "28268": 0.1930064558982849, "28403": 0.9531047344207764, "28559": 0.176772341132164, "28591": 0.6327666640281677, "28696": 0.9820492267608643, "29610": 0.5778634548187256} | 16256507 | CONTEXT Adequate vitamin D status for optimum bone health has received increased recognition in recent years; however, the ideal intake is not known. Serum 25-hydroxyvitamin D is the generally accepted indicator of vitamin D status, but no universal reference level has been reached. OBJECTIVE To investigate the relative importance of high calcium intake and serum 25-hydroxyvitamin D for calcium homeostasis, as determined by serum intact parathyroid hormone (PTH). DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of 2310 healthy Icelandic adults who were divided equally into 3 age groups (30-45 years, 50-65 years, or 70-85 years) and recruited from February 2001 to January 2003. They were administered a semi-quantitative food frequency questionnaire, which assessed vitamin D and calcium intake. Participants were further divided into groups according to calcium intake (<800 mg/d, 800-1200 mg/d, and >1200 mg/d) and serum 25-hydroxyvitamin D level (<10 ng/mL, 10-18 ng/mL, and >18 ng/mL). MAIN OUTCOME MEASURE Serum intact PTH as determined by calcium intake and vitamin D. RESULTS A total of 944 healthy participants completed all parts of the study. After adjusting for relevant factors, serum PTH was lowest in the group with a serum 25-hydroxyvitamin D level of more than 18 ng/mL but highest in the group with a serum 25-hydroxyvitamin D level of less than 10 ng/mL. At the low serum 25-hydroxyvitamin D level (<10 ng/mL), calcium intake of less than 800 mg/d vs more than 1200 mg/d was significantly associated with higher serum PTH (P = .04); and at a calcium intake of more than 1200 mg/d, there was a significant difference between the lowest and highest vitamin D groups (P = .04). CONCLUSIONS As long as vitamin D status is ensured, calcium intake levels of more than 800 mg/d may be unnecessary for maintaining calcium metabolism. Vitamin D supplements are necessary for adequate vitamin D status in northern climates. | Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. |
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These are likely to result, in part, from sex differences in endocrinology. In the nematode Caenorhabditis elegans, males are the longer-lived sex. Here we explore the possibility that sex differences in insulin/insulin-like growth factor 1 (IGF-1) and steroid endocrinology contribute to this sex difference in aging by studying C. elegans populations in liquid culture. We report that in hermaphrodite populations, mutational loss of the DAF-12 steroid receptor affected life span as in previous plate-culture studies: mutant longevity is suppressed in a weak daf-2 insulin/IGF-1 receptor mutant but enhanced in a stronger daf-2 mutant. However, in males, mutation of daf-12 had little effect on aging in either weak or strong daf-2 mutants. Moreover, while mutation of daf-12 marginally reduced life span in daf-2(+) hermaphrodites, as in plate-cultured populations, it did not in daf-2(+) males. These results could imply that in C. elegans, as in mammals, sex differences in steroid endocrinology contribute to sex differences in aging. | Sex-specific effects of the DAF-12 steroid receptor on aging in Caenorhabditis elegans. |
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To elucidate the basis of this unusual specificity, we expressed and crystallized a soluble form of M3 with a formylated nonamer peptide, fMYFINILTL, and determined the structure by X-ray crystallography. M3, refined at 2.1 A resolution, resembles class la MHC molecules in its overall structure, but differs in the peptide-binding groove. The A pocket, which usually accommodates the free N-terminus of a bound peptide, is closed, and the peptide is shifted one residue, such that the P1 side chain is lodged in the B pocket. The formyl group is coordinated by His-9 and a bound water on the floor of the groove. | Nonclassical binding of formylated peptide in crystal structure of the MHC class lb molecule H2-M3 |
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"25202": 0.5033760666847229, "25238": 0.42544642090797424, "25293": 0.055094651877880096, "25357": 0.20977331697940826, "25409": 0.5590575933456421, "25505": 0.1808556467294693, "25714": 0.04674193635582924, "26061": 0.0752234235405922, "26072": 0.06337817758321762, "26131": 0.3656192123889923, "26394": 0.014542185701429844, "26548": 0.018384648486971855, "26723": 1.223315715789795, "26795": 0.02412080205976963, "27169": 0.009718249551951885, "27178": 0.08961215615272522, "27226": 0.3547199070453644, "27598": 0.42353010177612305, "27633": 1.4478377103805542, "27642": 0.7295845746994019, "27697": 0.7701805830001831, "27777": 0.4679262638092041, "27790": 0.5596157908439636, "27854": 0.2659635543823242, "28041": 0.1510767638683319, "28086": 0.13157635927200317, "28691": 0.3810817003250122, "28715": 0.39367714524269104, "28765": 0.8349450826644897, "29111": 0.07341018319129944, "29489": 0.16442140936851501} | 16280642 | Podosomes (also termed invadopodia in cancer cells) are actin-rich adhesion structures with matrix degradation activity that develop in various cell types. Despite their significant physiological importance, the molecular mechanism of podosome formation is largely unknown. In this study, we investigated the molecular mechanisms of podosome formation. The expression of various phosphoinositide-binding domains revealed that the podosomes in Src-transformed NIH3T3 (NIH-src) cells are enriched with PtdIns(3,4)P2, suggesting an important role of this phosphoinositide in podosome formation. Live-cell imaging analysis revealed that Src-expression stimulated podosome formation at focal adhesions of NIH3T3 cells after PtdIns(3,4)P2 accumulation. The adaptor protein Tks5/FISH, which is essential for podosome formation, was found to form a complex with Grb2 at adhesion sites in an Src-dependent manner. Further, it was found that N-WASP bound all SH3 domains of Tks5/FISH, which facilitated circular podosome formation. These results indicate that augmentation of the N-WASP-Arp2/3 signal was accomplished on the platform of Tks5/FISH-Grb2 complex at focal adhesions, which is stabilized by PtdIns(3,4)P2. | Sequential signals toward podosome formation in NIH-src cells |
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"28788": 0.4311734735965729, "29076": 0.15275461971759796, "29125": 0.4311734735965729, "29222": 0.14433705806732178, "29320": 0.030771657824516296} | 16284655 | Human astrocytes are larger and more complex than those of infraprimate mammals, suggesting that their role in neural processing has expanded with evolution. To assess the cell-autonomous and species-selective properties of human glia, we engrafted human glial progenitor cells (GPCs) into neonatal immunodeficient mice. Upon maturation, the recipient brains exhibited large numbers and high proportions of both human glial progenitors and astrocytes. The engrafted human glia were gap-junction-coupled to host astroglia, yet retained the size and pleomorphism of hominid astroglia, and propagated Ca2+ signals 3-fold faster than their hosts. Long-term potentiation (LTP) was sharply enhanced in the human glial chimeric mice, as was their learning, as assessed by Barnes maze navigation, object-location memory, and both contextual and tone fear conditioning. Mice allografted with murine GPCs showed no enhancement of either LTP or learning. These findings indicate that human glia differentially enhance both activity-dependent plasticity and learning in mice. | Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. |
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However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to accomplish this replacement. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency. | Reprogramming of human fibroblasts to pluripotency with lineage specifiers. |
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Here, we review what is known about mammalian endocytic mechanisms, with focus on the cellular proteins that control these events. We discuss the well-studied clathrin-mediated endocytic mechanisms and dissect endocytic pathways that proceed independently of clathrin. These clathrin-independent pathways include the CLIC/GEEC endocytic pathway, arf6-dependent endocytosis, flotillin-dependent endocytosis, macropinocytosis, circular doral ruffles, phagocytosis, and trans-endocytosis. We also critically review the role of caveolae and caveolin1 in endocytosis. We highlight the roles of lipids, membrane curvature-modulating proteins, small G proteins, actin, and dynamin in endocytic pathways. We discuss the functional relevance of distinct endocytic pathways and emphasize the importance of studying these pathways to understand human disease processes. | Mechanisms of endocytosis. |
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0.21214580535888672, "28436": 0.34300774335861206, "28578": 0.7710843086242676, "28648": 0.02412080205976963, "29101": 0.23247487843036652, "29107": 0.020300358533859253, "29212": 0.058784693479537964, "29458": 0.7881022095680237, "29477": 0.6603899002075195} | 16322674 | BACKGROUND Birth size, perhaps a proxy for prenatal environment, might be a correlate of subsequent breast cancer risk, but findings from epidemiological studies have been inconsistent. We re-analysed individual participant data from published and unpublished studies to obtain more precise estimates of the magnitude and shape of the birth size-breast cancer association. METHODS AND FINDINGS Studies were identified through computer-assisted and manual searches, and personal communication with investigators. Individual participant data from 32 studies, comprising 22,058 breast cancer cases, were obtained. Random effect models were used, if appropriate, to combine study-specific estimates of effect. Birth weight was positively associated with breast cancer risk in studies based on birth records (pooled relative risk [RR] per one standard deviation [SD] [= 0.5 kg] increment in birth weight: 1.06; 95% confidence interval [CI] 1.02-1.09) and parental recall when the participants were children (1.02; 95% CI 0.99-1.05), but not in those based on adult self-reports, or maternal recall during the woman's adulthood (0.98; 95% CI 0.95-1.01) (p for heterogeneity between data sources = 0.003). Relative to women who weighed 3.000-3.499 kg, the risk was 0.96 (CI 0.80-1.16) in those who weighed < 2.500 kg, and 1.12 (95% CI 1.00-1.25) in those who weighed > or = 4.000 kg (p for linear trend = 0.001) in birth record data. Birth length and head circumference from birth records were also positively associated with breast cancer risk (pooled RR per one SD increment: 1.06 [95% CI 1.03-1.10] and 1.09 [95% CI 1.03-1.15], respectively). Simultaneous adjustment for these three birth size variables showed that length was the strongest independent predictor of risk. The birth size effects did not appear to be confounded or mediated by established breast cancer risk factors and were not modified by age or menopausal status. The cumulative incidence of breast cancer per 100 women by age 80 y in the study populations was estimated to be 10.0, 10.0, 10.4, and 11.5 in those who were, respectively, in the bottom, second, third, and top fourths of the birth length distribution. CONCLUSIONS This pooled analysis of individual participant data is consistent with birth size, and in particular birth length, being an independent correlate of breast cancer risk in adulthood. | Birth Size and Breast Cancer Risk: Re-analysis of Individual Participant Data from 32 Studies |
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0.07793712615966797, "25714": 0.20739519596099854, "25778": 0.043007105588912964, "25950": 1.117316484451294, "26163": 0.36426326632499695, "26187": 0.16359257698059082, "26402": 1.1115491390228271, "26435": 0.15860503911972046, "26512": 0.01934296265244484, "26520": 0.07068414986133575, "26633": 0.16690383851528168, "26773": 0.6872705817222595, "26835": 0.8525851964950562, "26986": 0.31132611632347107, "27144": 0.1619328260421753, "27216": 0.2105647772550583, "27295": 0.4330752193927765, "27854": 0.11865071207284927, "27881": 0.058784693479537964, "28024": 0.36494144797325134, "28327": 0.7009293437004089, "28427": 0.25995752215385437, "28774": 0.0029254043474793434, "28848": 0.757441520690918, "29034": 0.05694137513637543, "29458": 0.5805994272232056, "29490": 0.2741633653640747} | 16346504 | BACKGROUND Growth arrest-specific 5 (GAS5) was reported to be implicated and aberrantly express in multiple cancers. However, the expression and mechanism of action of GAS5 were largely poor understood in endometrial carcinoma. RESULTS According to the result of real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and flow cytometry analysis, we identified that GAS5 was down-regulated in endometrial cancer cells and stimulated the apoptosis of endometrial cancer cells. To investigate the expression of GAS5, PTEN and miR-103, RT-PCR was performed. And we found that the expression of PTEN was up-regulated when endometrial cancer cells overexpressed GAS5. The prediction of bioinformatics online revealed that GAS5 could bind to miR-103, which was further found to be regulated by GAS5. Finally, we found that miR-103 mimic could decrease the mRNA and protein levels of PTEN through luciferase reporter assay and western blotting, and GAS5 plasmid may reverse this regulation effect in endometrial cancer cells. CONCLUSION In summary, we demonstrate that GAS5 acts as an tumor suppressor lncRNA in endometrial cancer. Through inhibiting the expression of miR-103, GAS5 significantly enhanced the expression of PTEN to promote cancer cell apoptosis, and, thus, could be an important mediator in the pathogenesis of endometrial cancer. | LncRNA-GAS5 induces PTEN expression through inhibiting miR-103 in endometrial cancer cells |
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"26402": 0.27564704418182373, "26616": 0.11865071207284927, "26629": 1.1185935735702515, "26651": 0.055094651877880096, "26657": 0.055094651877880096, "26723": 0.9621002674102783, "26773": 0.5033760666847229, "27295": 0.08154398202896118, "27321": 0.2711893916130066, "27633": 0.7647408246994019, "27703": 1.2250384092330933, "27854": 0.2223619967699051, "27989": 0.4926934838294983, "28156": 0.5718178153038025, "28227": 0.0038986403960734606, "28466": 1.013020396232605, "28593": 0.04113444685935974, "28696": 0.05786345899105072, "28788": 0.9598589539527893, "28828": 0.08961215615272522, "28927": 0.08692999184131622, "29107": 0.11951763927936554, "29290": 0.5197699069976807, "29720": 0.7445381283760071} | 16355392 | Podocyte dysfunction, represented by foot process effacement and proteinuria, is often the starting point for progressive kidney disease. Therapies aimed at the cellular level of the disease are currently not available. Here we show that induction of urokinase receptor (uPAR) signaling in podocytes leads to foot process effacement and urinary protein loss via a mechanism that includes lipid-dependent activation of αvβ3 integrin. Mice lacking uPAR (Plaur−/−) are protected from lipopolysaccharide (LPS)-mediated proteinuria but develop disease after expression of a constitutively active β3 integrin. Gene transfer studies reveal a prerequisite for uPAR expression in podocytes, but not in endothelial cells, for the development of LPS-mediated proteinuria. Mechanistically, uPAR is required to activate αvβ3 integrin in podocytes, promoting cell motility and activation of the small GTPases Cdc42 and Rac1. Blockade of αvβ3 integrin reduces podocyte motility in vitro and lowers proteinuria in mice. Our findings show a physiological role for uPAR signaling in the regulation of kidney permeability. | Modification of kidney barrier function by the urokinase receptor |
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and thereby control cell fate decisions and survival. We recently demonstrated that Notch signaling is involved in proliferation and survival of B cell-derived tumor cells of classic Hodgkin disease and described a novel mechanism for the oncogenic capacity of Notch. In this study we investigated whether Notch signaling is involved in the tight interactions between neoplastic plasma cells and their bone marrow microenvironment, which are essential for tumor cell growth in multiple myeloma (MM). Here we demonstrate that Notch receptors and their ligand Jagged1 are highly expressed in cultured and primary MM cells, whereas nonneoplastic counterparts show low to undetectable levels of Notch. Functional data indicate that ligand-induced Notch signaling is a growth factor for MM cells and suggest that these interactions contribute to myelomagenesis in vivo. | Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. |
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"26512": 0.1212492436170578, "26520": 0.12470348179340363, "26534": 0.08154398202896118, "26616": 0.4248080551624298, "26773": 0.9225212931632996, "26944": 0.2918238639831543, "27144": 0.05694137513637543, "27339": 0.13925230503082275, "27354": 0.3656192123889923, "27524": 0.09050461649894714, "27528": 0.09495500475168228, "27854": 0.004870930220931768, "27881": 0.06612417846918106, "28014": 0.8459017872810364, "28086": 0.36697331070899963, "28093": 0.7314660549163818, "28207": 0.06429435312747955, "28436": 0.8264343738555908, "28522": 1.1598494052886963, "28625": 0.3012613356113434, "28774": 0.011650617234408855, "29206": 0.16524957120418549, "29290": 0.012615402229130268, "29458": 0.5811457633972168, "29480": 0.6430866718292236} | 16364639 | By analyzing gene expression data in glioblastoma in combination with matched microRNA profiles, we have uncovered a posttranscriptional regulation layer of surprising magnitude, comprising more than 248,000 microRNA (miR)-mediated interactions. These include ∼7,000 genes whose transcripts act as miR "sponges" and 148 genes that act through alternative, nonsponge interactions. Biochemical analyses in cell lines confirmed that this network regulates established drivers of tumor initiation and subtype implementation, including PTEN, PDGFRA, RB1, VEGFA, STAT3, and RUNX1, suggesting that these interactions mediate crosstalk between canonical oncogenic pathways. siRNA silencing of 13 miR-mediated PTEN regulators, whose locus deletions are predictive of PTEN expression variability, was sufficient to downregulate PTEN in a 3'UTR-dependent manner and to increase tumor cell growth rates. Thus, miR-mediated interactions provide a mechanistic, experimentally validated rationale for the loss of PTEN expression in a large number of glioma samples with an intact PTEN locus. | An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma |
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0.18329764902591705, "28405": 0.22392450273036957, "28522": 0.9060825705528259, "28788": 0.10818854719400406, "29226": 0.17759032547473907, "29290": 0.8600510358810425, "29320": 0.14349138736724854} | 16375102 | The simple yet powerful technique of induced pluripotency may eventually supply a wide range of differentiated cells for cell therapy and drug development. However, making the appropriate cells via induced pluripotent stem cells (iPSCs) requires reprogramming of somatic cells and subsequent redifferentiation. Given how arduous and lengthy this process can be, we sought to determine whether it might be possible to convert somatic cells into lineage-specific stem/progenitor cells of another germ layer in one step, bypassing the intermediate pluripotent stage. Here we show that transient induction of the four reprogramming factors (Oct4, Sox2, Klf4, and c-Myc) can efficiently transdifferentiate fibroblasts into functional neural stem/progenitor cells (NPCs) with appropriate signaling inputs. Compared with induced neurons (or iN cells, which are directly converted from fibroblasts), transdifferentiated NPCs have the distinct advantage of being expandable in vitro and retaining the ability to give rise to multiple neuronal subtypes and glial cells. Our results provide a unique paradigm for iPSC-factor-based reprogramming by demonstrating that it can be readily modified to serve as a general platform for transdifferentiation. | Direct reprogramming of mouse fibroblasts to neural progenitors. |
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To determine whether insulin signaling has a functional role in the beta cell we have used the Cre-loxP system to specifically inactivate the insulin receptor gene in the beta cells. The resultant mice exhibit a selective loss of insulin secretion in response to glucose and a progressive impairment of glucose tolerance. These data indicate an important functional role for the insulin receptor in glucose sensing by the pancreatic beta cell and suggest that defects in insulin signaling at the level of the beta cell may contribute to the observed alterations in insulin secretion in type 2 diabetes. | Tissue-Specific Knockout of the Insulin Receptor in Pancreatic β Cells Creates an Insulin Secretory Defect Similar to that in Type 2 Diabetes |
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admission (emergency compared with elective) and surgical procedure varied by socioeconomic circumstances, age, sex, and year of admission for colorectal, breast, and lung cancer. DESIGN Repeated cross sectional study with data from individual patients, 1 April 1999 to 31 March 2006. SETTING Hospital episode statistics (HES) dataset. PARTICIPANTS 564 821 patients aged 50 and over admitted with a diagnosis of colorectal, breast, or lung cancer. MAIN OUTCOME MEASURES Proportion of patients admitted as emergencies, and the proportion receiving the recommended surgical treatment. RESULTS Patients from deprived areas, older people, and women were more likely to be admitted as emergencies. For example, the adjusted odds ratio for patients with breast cancer in the least compared with most deprived fifth of deprivation was 0.63 (95% confidence interval 0.60 to 0.66) and the adjusted odds ratio for patients with lung cancer aged 80-89 compared with those aged 50-59 was 3.13 (2.93 to 3.34). There were some improvements in disparities between age groups but not for patients living in deprived areas over time. Patients from deprived areas were less likely to receive preferred procedures for rectal, breast, and lung cancer. These findings did not improve with time. For example, 67.4% (3529/5237) of patients in the most deprived fifth of deprivation had anterior resection for rectal cancer compared with 75.5% (4497/5959) of patients in the least deprived fifth (1.34, 1.22 to 1.47). Over half (54.0%, 11 256/20 849) of patients in the most deprived fifth of deprivation had breast conserving surgery compared with 63.7% (18 445/28 960) of patients in the least deprived fifth (1.21, 1.16 to 1.26). Men were less likely than women to undergo anterior resection and lung cancer resection and older people were less likely to receive breast conserving surgery and lung cancer resection. For example, the adjusted odds ratio for lung cancer patients aged 80-89 compared with those aged 50-59 was 0.52 (0.46 to 0.59). Conclusions Despite the implementation of the NHS Cancer Plan, social factors still strongly influence access to and the provision of care. | Social variations in access to hospital care for patients with colorectal, breast, and lung cancer between 1999 and 2006: retrospective analysis of hospital episode statistics |
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non-randomly in the 3D space of the cell nucleus. Here, we have developed HIPMap, a high-precision, high-throughput, automated fluorescent in situ hybridization imaging pipeline, for mapping of the spatial location of genome regions at large scale. High-throughput imaging position mapping (HIPMap) enabled an unbiased siRNA screen for factors involved in genome organization in human cells. We identify 50 cellular factors required for proper positioning of a set of functionally diverse genomic loci. Positioning factors include chromatin remodelers, histone modifiers, and nuclear envelope and pore proteins. Components of the replication and post-replication chromatin re-assembly machinery are prominently represented among positioning factors, and timely progression of cells through replication, but not mitosis, is required for correct gene positioning. Our results establish a method for the large-scale mapping of genome locations and have led to the identification of a compendium of cellular factors involved in spatial genome organization. | Identification of Gene Positioning Factors Using High-Throughput Imaging Mapping |
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Using combined electrophysiology, caged molecule photolysis, and Ca(2+) imaging, we describe a plasticity in which the recruitment of astrocytes in response to afferent activity causes a fast and feed-forward, yet distributed increase in the amplitude of quantal synaptic currents at multiple glutamate synapses on magnocellular neurosecretory cells in the hypothalamic paraventricular nucleus. The plasticity is largely multiplicative, consistent with a proportional increase or "scaling" in the strength of all synapses on the neuron. This effect requires a metabotropic glutamate receptor-mediated rise in Ca(2+) in the astrocyte processes surrounding the neuron and the release of the gliotransmitter ATP, which acts on postsynaptic purinergic receptors. These data provide evidence for a form of distributed synaptic plasticity that is feed-forward, expressed quickly, and mediated by the synaptic activation of neighboring astrocytes. | Astrocyte-Mediated Distributed Plasticity at Hypothalamic Glutamate Synapses |
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0.09050461649894714, "29134": 0.06154331564903259, "29172": 0.02792670577764511, "29458": 0.026025565341114998, "29486": 0.08603433519601822} | 16422880 | CONTEXT Many smokers are unable or unwilling to completely quit smoking. A proposed means of harm reduction is to reduce the number of cigarettes smoked per day. However, it is not clear whether this strategy decreases the risk for tobacco-related diseases. OBJECTIVE To assess the effects of smoking reduction on lung cancer incidence. DESIGN, SETTING, AND PARTICIPANTS Observational population-based cohort study with up to 31 years of follow-up from the Copenhagen Centre for Prospective Population Studies, which administrates data from 3 longitudinal studies conducted in Copenhagen and suburbs, the Copenhagen City Heart Study, the Copenhagen Male Study, and the Glostrup Population Studies, Denmark. Participants were 11,151 men and 8563 women (N = 19,714) aged 20 to 93 years, who attended 2 consecutive examinations with a 5- to 10-year interval between 1964 and 1988. Participants underwent a physical examination and completed self-filled questionnaires about lifestyle habits. The study population was divided into 6 groups according to smoking habits: continued heavy smokers (> or =15 cigarettes/d), reducers (reduced from > or =15 cigarettes/d by minimum of 50% without quitting), continued light smokers (1-14 cigarettes/d), quitters (stopped between first and second examination), stable ex-smokers, and never smokers. MAIN OUTCOME MEASURE Incident primary lung cancer cases assessed by record linkage with the National Cancer Registry until December 31, 2003. RESULTS There were 864 incident lung cancers during follow-up. Using Cox regression, the adjusted hazard ratio (HR) for lung cancer in reducers was 0.73 (95% confidence interval [CI], 0.54-0.98) compared with persistent heavy smokers. The HR for light smokers was 0.44 (95% CI, 0.35-0.56); for quitters, HR 0.50 (95% CI, 0.36-0.69), for stable ex-smokers, HR 0.17 (95% CI, 0.13-0.23), and for never smokers, HR 0.09 (95% CI, 0.06-0.13). CONCLUSION Among individuals who smoke 15 or more cigarettes per day, smoking reduction by 50% significantly reduces the risk of lung cancer. | Effect of smoking reduction on lung cancer risk. |
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"28381": 0.347847044467926, "28406": 0.011650617234408855, "28691": 0.2711893916130066, "29093": 0.04860413447022438, "29105": 0.259204238653183, "29263": 0.40089741349220276, "29490": 0.12384103983640671} | 16427454 | Three macromolecular crystallography (MX) beamlines at the Helmholtz-Zentrum Berlin (HZB) are available for the regional, national and international structural biology user community. The state-of-the-art synchrotron beamlines for MX BL14.1, BL14.2 and BL14.3 are located within the low-β section of the BESSY II electron storage ring. All beamlines are fed from a superconducting 7 T wavelength-shifter insertion device. BL14.1 and BL14.2 are energy tunable in the range 5-16 keV, while BL14.3 is a fixed-energy side station operated at 13.8 keV. All three beamlines are equipped with CCD detectors. BL14.1 and BL14.2 are in regular user operation providing about 200 beam days per year and about 600 user shifts to approximately 50 research groups across Europe. BL14.3 has initially been used as a test facility and was brought into regular user mode operation during the year 2010. BL14.1 has recently been upgraded with a microdiffractometer including a mini-κ goniometer and an automated sample changer. Additional user facilities include office space adjacent to the beamlines, a sample preparation laboratory, a biology laboratory (safety level 1) and high-end computing resources. In this article the instrumentation of the beamlines is described, and a summary of the experimental possibilities of the beamlines and the provided ancillary equipment for the user community is given. | Facilities for macromolecular crystallography at the Helmholtz-Zentrum Berlin |
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However, significant time and effort are still required to solve and complete many of these structures because of the need for manual interpretation of complex numerical data using many software packages and the repeated use of interactive three-dimensional graphics. PHENIX has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on the automation of all procedures. This has relied on the development of algorithms that minimize or eliminate subjective input, the development of algorithms that automate procedures that are traditionally performed by hand and, finally, the development of a framework that allows a tight integration between the algorithms. | PHENIX: a comprehensive Python-based system for macromolecular structure solution |
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0.9754437208175659, "25476": 0.39367714524269104, "25644": 0.13499516248703003, "25662": 0.11951763927936554, "26067": 0.19862671196460724, "26402": 0.12728634476661682, "26433": 0.04953393340110779, "26514": 0.09938567131757736, "26524": 0.8625272512435913, "26601": 0.05046287178993225, "26616": 0.15610189735889435, "26657": 0.036437395960092545, "26773": 0.4855078160762787, "26874": 0.6165571808815002, "26982": 0.10818854719400406, "26994": 0.2561853528022766, "27169": 0.026976587250828743, "27642": 0.2470736801624298, "27777": 0.043007105588912964, "27854": 0.03925827145576477, "28024": 0.13499516248703003, "28086": 0.04860413447022438, "28156": 0.44753631949424744, "28691": 0.5162794589996338, "28751": 0.12384103983640671, "28805": 0.015504186972975731, "28964": 0.13157635927200317} | 16465895 | A 3' overhang is critical for the protection and maintenance of mammalian telomeres, but its synthesis must be regulated to avoid excessive resection of the 5' end, which could cause telomere shortening. How this balance is achieved in mammals has not been resolved. Here, we determine the mechanism for 3' overhang synthesis in mouse cells by evaluating changes in telomeric overhangs throughout the cell cycle and at leading- and lagging-end telomeres. Apollo, a nuclease bound to the shelterin subunit TRF2, initiates formation of the 3' overhang at leading-, but not lagging-end telomeres. Hyperresection by Apollo is blocked at both ends by the shelterin protein POT1b. Exo1 extensively resects both telomere ends, generating transient long 3' overhangs in S/G2. CST/AAF, a DNA polα.primase accessory factor, binds POT1b and shortens the extended overhangs produced by Exo1, likely through fill-in synthesis. 3' overhang formation is thus a multistep, shelterin-controlled process, ensuring functional telomeric overhangs at chromosome ends. | Telomeric 3′ Overhangs Derive from Resection by Exo1 and Apollo and Fill-In by POT1b-Associated CST |
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Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition. | Targeting BRCA1 and BRCA2 Deficiencies with G-Quadruplex-Interacting Compounds |
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"27461": 0.12556517124176025, "27651": 0.055094651877880096, "27895": 0.06703783571720123, "27944": 0.7728893756866455, "28233": 0.2231435477733612, "28286": 1.1319060325622559, "28428": 1.1160377264022827, "28472": 0.46853771805763245, "28674": 0.09761575609445572, "28696": 0.04207121208310127, "28788": 0.8143964409828186, "28848": 0.6451379656791687, "28873": 0.22937409579753876, "29160": 0.0354953333735466, "29166": 0.8973627090454102, "29290": 0.5197699069976807, "29720": 0.6054253578186035} | 16488405 | Physical activity induces a subclinical inflammatory response, mediated in part by leukocytes, and manifested by elevated concentrations of circulating proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α). However, the source of the cytokines that appear during exercise remains unknown. In this study, we examined exercise-induced changes in plasma cytokine concentrations and their corresponding mRNA expression in peripheral blood mononuclear cells. Ten healthy [peak oxygen uptake = 48.8 ± 6.5 (SD) ml · kg−1 · min−1] but untrained men [age = 25 ± 5 (SD) yr] undertook 3 h of exercise (cycling and inclined walking) at 60–65% peak oxygen uptake. Circulating leukocyte subset counts were elevated during and 2 h postexercise but returned to normal within 24 h. Plasma concentrations of IL-1β, IL-6, and TNF-α peaked at the end of exercise and remained elevated at 2 h (IL-6) and up to 24 h (IL-1β and TNF-α) postexercise. Cytokine gene expression in circulating mononucl... | Downloaded from |
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It is now generally accepted that receptor tyrosine kinase signaling occurs intracellularly and on the plasma membrane, although many important details remain to be worked out. Endocytosis and subsequent intracellular trafficking spatiotemporally regulate receptor tyrosine kinase signaling, whereas signaling endosomes provide a platform for the compartmentalization of signaling events. This review summarizes recent advances in our understanding of endothelial receptor tyrosine kinase endocytosis and signaling using vascular endothelial growth factor receptor-2 as a paradigm. | Receptor tyrosine kinases endocytosis in endothelium: biology and signaling. |
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0.10731173306703568, "29300": 0.3923587501049042, "29361": 0.09850110858678818, "29411": 0.18492233753204346, "29592": 0.10026945173740387} | 16495649 | OBJECTIVES To determine the incidence and clinical importance of errors in the preparation and administration of intravenous drugs and the stages of the process in which errors occur. DESIGN Prospective ethnographic study using disguised observation. PARTICIPANTS Nurses who prepared and administered intravenous drugs. SETTING 10 wards in a teaching and non-teaching hospital in the United Kingdom. MAIN OUTCOME MEASURES Number, type, and clinical importance of errors. RESULTS 249 errors were identified. At least one error occurred in 212 out of 430 intravenous drug doses (49%, 95% confidence interval 45% to 54%). Three doses (1%) had potentially severe errors, 126 (29%) potentially moderate errors, and 83 (19%) potentially minor errors. Most errors occurred when giving bolus doses or making up drugs that required multiple step preparation. CONCLUSIONS The rate of intravenous drug errors was high. Although most errors would cause only short term adverse effects, a few could have been serious. A combination of reducing the amount of preparation on the ward, training, and technology to administer slow bolus doses would probably have the greatest effect on error rates. | Ethnographic study of incidence and severity of intravenous drug errors. |
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0.37974658608436584} | 16510361 | This article describes a R package Boruta, implementing a novel feature selection algorithm for finding emph{all relevant variables}. The algorithm is designed as a wrapper around a Random Forest classification algorithm. It iteratively removes the features which are proved by a statistical test to be less relevant than random probes. The Boruta package provides a convenient interface to the algorithm. The short description of the algorithm and examples of its application are presented. | Feature Selection with the Boruta Package |
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"26244": 0.00875066313892603, "26305": 0.13499516248703003, "26402": 0.08961215615272522, "26520": 0.0317181795835495, "26629": 0.8633513450622559, "26651": 0.053244512528181076, "26721": 0.3601844012737274, "26773": 0.5069117546081543, "27009": 0.34370049834251404, "27208": 0.6921701431274414, "27295": 0.040196798741817474, "27321": 0.0770333781838417, "27480": 0.9005423784255981, "27854": 0.09495500475168228, "27989": 0.8074519634246826, "28156": 0.26446542143821716, "28287": 0.175953671336174, "28353": 0.2741633653640747, "29097": 0.8152611255645752, "29258": 0.950843095779419} | 16511863 | BACKGROUND Although numerous signaling pathways are known to be activated in experimental cardiac hypertrophy, the molecular basis of the hypertrophic response inherent in human heart diseases remains largely unknown. Integrin-linked kinase (ILK) is a multifunctional protein kinase that physically links beta-integrins with the actin cytoskeleton, suggesting a potential mechanoreceptor role. METHODS AND RESULTS Here, we show a marked increase in ILK protein levels in hypertrophic ventricles of patients with congenital and acquired outflow tract obstruction. This increase in ILK was associated with activation of the Rho family guanine triphosphatases, Rac1 and Cdc42, and known hypertrophic signaling kinases, including extracellular signal-related kinases (ERK1/2) and p70 S6 kinase. Transgenic mice with cardiac-specific expression of a constitutively active ILK (ILK(S343D)) or wild-type ILK (ILK(WT)) exhibited a compensated ventricular hypertrophic phenotype and displayed an activation profile of guanine triphosphatases and downstream protein kinases concordant with that seen in human hypertrophy. In contrast, transgenic mice with cardiomyocyte-restricted expression of a kinase-inactive ILK (ILK(R211A)) were unable to mount a compensatory hypertrophic response to angiotensin II in vivo. CONCLUSIONS Taken together, these results identify ILK-regulated signaling as a broadly adaptive hypertrophic response mechanism relevant to a wide range of clinical heart disease. | Integrin-linked kinase expression is elevated in human cardiac hypertrophy and induces hypertrophy in transgenic mice. |
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"24623": 0.3084607720375061, "24720": 0.009718249551951885, "24821": 0.004870930220931768, "24840": 0.13414156436920166, "25006": 0.1221139207482338, "25117": 0.020300358533859253, "25172": 0.9958525896072388, "25194": 1.0409941673278809, "25320": 0.021256839856505394, "25643": 0.056018441915512085, "25761": 0.13499516248703003, "26014": 0.8366385698318481, "26089": 0.040196798741817474, "26243": 0.19541899859905243, "26402": 0.38374659419059753, "26534": 0.15610189735889435, "26786": 0.19541899859905243, "27152": 0.5186077356338501, "27295": 0.6674286723136902, "28227": 0.06429435312747955, "28282": 0.12470348179340363, "28353": 1.005902886390686, "28466": 0.18411032855510712, "28828": 0.18167030811309814, "28829": 0.2034190446138382, "28848": 0.817850649356842, "29172": 0.010684899985790253, "29295": 0.5968599319458008, "29336": 0.9842413663864136, "29393": 0.18492233753204346, "29516": 0.16607704758644104, "29521": 1.0979610681533813} | 16527698 | To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy. | Functional and molecular defects of pancreatic islets in human type 2 diabetes. |
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1.3144375085830688, "28327": 0.9005423784255981, "28353": 0.7153595685958862, "28621": 0.06520967930555344, "28636": 0.33605360984802246, "28736": 0.5278670787811279, "28991": 1.3565597534179688, "29191": 0.06337817758321762, "29206": 0.9929623603820801, "29290": 0.4431571960449219, "29458": 0.7314660549163818} | 16532419 | BACKGROUND Carbon nanotubes (CNT) hold great promise to create new and better products for commercial and biomedical applications, but their long-term adverse health effects are a major concern. The objective of this study was to address human lung cancer risks associated with chronic pulmonary exposure to single-walled (SW) CNT through the fundamental understanding of cellular and molecular processes leading to carcinogenesis. We hypothesized that the acquisition of cancer stem cells (CSC), a subpopulation that drive tumor initiation and progression, may contribute to CNT carcinogenesis. METHODS Non-tumorigenic human lung epithelial cells were chronically exposed to well-dispersed SWCNT for a period of 6 months at the physiologically relevant concentration of 0.02 μg/cm2 surface area dose. Chronic SWCNT-exposed cells were evaluated for the presence of CSC-like cells under CSC-selective conditions of tumor spheres and side population (SP). CSC-like cells were isolated using fluorescence-activated cell sorting and were assessed for aggressive behaviors, including acquired apoptosis resistance and increased cell migration and invasion in vitro, and tumor-initiating capability in vivo. Non-small cell lung cancer cells served as a positive control. RESULTS We demonstrated for the first time the existence of CSC-like cells in all clones of chronic SWCNT-exposed lung epithelial cells. These CSC-like cells, in contrary to their non-CSC counterpart, possessed all biological features of lung CSC that are central to irreversible malignant transformation, self-renewal, aggressive cancer behaviors, and in vivo tumorigenesis. These cells also displayed aberrant stem cell markers, notably Nanog, SOX-2, SOX-17 and E-cadherin. Restored expression of tumor suppressor p53 abrogated CSC properties of CSC-like cells. Furthermore, we identified specific stem cell surface markers CD24low and CD133high that are associated with SWCNT-induced CSC formation and tumorigenesis. CONCLUSIONS Our findings provide new and compelling evidence for the acquisition of CSC-like cells induced by chronic SWCNT exposure, which are likely to be a major driving force for SWCNT tumorigenesis. Thus, our study supports prudent adoption of prevention strategies and implementation of exposure control for SWCNT. We also suggest that the detection of CSC and associated surface markers may provide an effective screening tool for prediction of the carcinogenic potential of SWCNT and related nanoparticles. | Induction of stem-like cells with malignant properties by chronic exposure of human lung epithelial cells to single-walled carbon nanotubes |
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"29206": 1.1524739265441895, "29290": 0.10906458646059036, "29390": 0.0029254043474793434} | 16541762 | We compared two genetically highly defined transgenic systems to identify parameters affecting reprogramming of somatic cells to a pluripotent state. Our results demonstrate that the level and stoichiometry of reprogramming factors during the reprogramming process strongly influence the resulting pluripotency of iPS cells. High expression of Oct4 and Klf4 combined with lower expression of c-Myc and Sox2 produced iPS cells that efficiently generated "all-iPSC mice" by tetraploid (4n) complementation, maintained normal imprinting at the Dlk1-Dio3 locus, and did not create mice with tumors. Loss of imprinting (LOI) at the Dlk1-Dio3 locus did not strictly correlate with reduced pluripotency though the efficiency of generating "all-iPSC mice" was diminished. Our data indicate that stoichiometry of reprogramming factors can influence epigenetic and biological properties of iPS cells. This concept complicates efforts to define a "generic" epigenetic state of iPSCs and ESCs and should be considered when comparing different iPS and ES cell lines. | Reprogramming factor stoichiometry influences the epigenetic state and biological properties of induced pluripotent stem cells. |
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0.16359257698059082} | 16546131 | Hydroxyurea is a potent teratogen; free radical scavengers or antioxidants reduce its teratogenicity. Activator Protein-1 (AP-1) and NF-kappaB are redox-sensitive transcription factors with important roles in normal development and the stress response. This study was designed to determine if exposure to teratogenic doses of hydroxyurea induces oxidative stress and alters gene expression by activating these transcription factors. Pregnant mice were treated with saline or hydroxyurea (400, 500, or 600 mg/kg) on gestation day 9 (GD 9) and killed either on GD 9, 0.5, 3, or 6 h after treatment, to assess oxidative stress and transcription factor activities, or on GD 18, to assess fetal development. Exposure to 400 mg/kg hydroxyurea did not affect the progeny, whereas exposure to 500 or 600 mg/kg resulted in dose-dependent increases in fetal resorptions and malformations, including curly tails, abnormal limbs (oligodactyly, hemimelia, and amelia), and short ribs. Hydroxyurea did not induce oxidative stress, as assessed by the ratio of oxidized to reduced glutathione, nor did it alter NF-kappaB DNA binding activity in the GD 9 conceptus. In contrast, exposure to hydroxyurea at any dose increased AP-1 DNA binding activity in embryos and yolk sacs 0.5 or 3 h after treatment. Hydroxyurea-induced c-Fos heterodimer activity in the embryo peaked 3-4-fold above control at 3 h and remained elevated by 6 h; in contrast, the activity of c-Jun dimers was not altered by drug exposure. A dramatic and region-specific increase in c-Fos immunoreactivity was found in hydroxyurea-treated embryos. The induction of AP-1 DNA binding activity by hydroxyurea represents an early, sensitive marker of the embryonic response to insult. | Activator protein-1 (AP-1) DNA binding activity is induced by hydroxyurea in organogenesis stage mouse embryos |
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"25449": 0.13670019805431366, "25456": 0.9052929878234863, "25468": 0.37707099318504333, "25502": 0.4794800877571106, "25644": 0.18004031479358673, "25761": 0.19381128251552582, "25932": 0.5756692886352539, "26402": 0.8143964409828186, "26520": 0.22157983481884003, "26534": 0.151916041970253, "26616": 0.053244512528181076, "26651": 0.02887592278420925, "26773": 0.8433839678764343, "27144": 0.8534175157546997, "27321": 0.5773153901100159, "27512": 1.162295937538147, "27854": 0.38308101892471313, "27881": 0.8117979168891907, "28086": 0.11951763927936554, "28788": 0.31845372915267944, "28873": 0.17840765416622162} | 16550075 | BCL-6, a transcriptional repressor frequently translocated in lymphomas, regulates germinal center B cell differentiation and inflammation. DNA microarray screening identified genes repressed by BCL-6, including many lymphocyte activation genes, suggesting that BCL-6 modulates B cell receptor signals. BCL-6 repression of two chemokine genes, MIP-1alpha and IP-10, may also attenuate inflammatory responses. Blimp-1, another BCL-6 target, is important for plasmacytic differentiation. Since BCL-6 expression is silenced in plasma cells, repression of blimp-1 by BCL-6 may control plasmacytic differentiation. Indeed, inhibition of BCL-6 function initiated changes indicative of plasmacytic differentiation, including decreased expression of c-Myc and increased expression of the cell cycle inhibitor p27kip1. These data suggest that malignant transformation by BCL-6 involves inhibition of differentiation and enhanced proliferation. | BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. |
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"24374": 0.4349733293056488, "24388": 0.8691008687019348, "24394": 0.030771657824516296, "24714": 0.010684899985790253, "24759": 0.06337817758321762, "24766": 0.24325250089168549, "25070": 0.5968599319458008, "25078": 0.23247487843036652, "25148": 1.0933903455734253, "25357": 0.5528968572616577, "25486": 0.15693697333335876, "25700": 0.15860503911972046, "25731": 0.9754437208175659, "25855": 0.006812678650021553, "26039": 0.1358480453491211, "26083": 0.21765978634357452, "26166": 0.4132472574710846, "26786": 0.5255602598190308, "26838": 0.034552380442619324, "26927": 1.3238370418548584, "27915": 0.11604541540145874, "28086": 0.562402069568634, "28228": 0.1602703034877777, "28424": 0.1485546976327896, "29129": 0.5827828645706177, "29197": 0.06520967930555344, "29273": 0.0174254160374403} | 16557565 | Plants, compared to animals, exhibit an amazing adaptability and plasticity in their development. This is largely dependent on the ability of plants to form new organs, such as lateral roots, leaves, and flowers during postembryonic development. Organ primordia develop from founder cell populations into organs by coordinated cell division and differentiation. Here, we show that organ formation in Arabidopsis involves dynamic gradients of the signaling molecule auxin with maxima at the primordia tips. These gradients are mediated by cellular efflux requiring asymmetrically localized PIN proteins, which represent a functionally redundant network for auxin distribution in both aerial and underground organs. PIN1 polar localization undergoes a dynamic rearrangement, which correlates with establishment of auxin gradients and primordium development. Our results suggest that PIN-dependent, local auxin gradients represent a common module for formation of all plant organs, regardless of their mature morphology or developmental origin. | Local, Efflux-Dependent Auxin Gradients as a Common Module for Plant Organ Formation |
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"26356": 0.00875066313892603, "26402": 0.007782140281051397, "26601": 0.1212492436170578, "26702": 1.1941591501235962, "27094": 0.34577593207359314, "27169": 1.2432310581207275, "27512": 0.17759032547473907, "27598": 0.5893046259880066, "28283": 0.7389566898345947, "28467": 0.3464667797088623, "28685": 0.12038381397724152, "28691": 0.012615402229130268, "28828": 0.5232481360435486, "28835": 0.8885661959648132, "28848": 0.1734936386346817, "28976": 0.19622190296649933, "29060": 0.3656192123889923, "29295": 0.012615402229130268} | 16562534 | The overall size and structure of a synaptic terminal is an important determinant of its function. In a large-scale mutagenesis screen, designed to identify Drosophila mutants with abnormally structured neuromuscular junctions (NMJs), we discovered mutations in Drosophila mical, a conserved gene encoding a multi-domain protein with a N-terminal monooxygenase domain. In mical mutants, synaptic boutons do not sprout normally over the muscle surface and tend to form clusters along synaptic branches and at nerve entry sites. Consistent with high expression of MICAL in somatic muscles, immunohistochemical stainings reveal that the subcellular localization and architecture of contractile muscle filaments are dramatically disturbed in mical mutants. Instead of being integrated into a regular sarcomeric pattern, actin and myosin filaments are disorganized and accumulate beneath the plasmamembrane. Whereas contractile elements are strongly deranged, the proposed organizer of sarcomeric structure, D-Titin, is much less affected. Transgenic expression of interfering RNA molecules demonstrates that MICAL is required in muscles for the higher order arrangement of myofilaments. Ultrastructural analysis confirms that myosin-rich thick filaments enter submembranous regions and interfere with synaptic development, indicating that the disorganized myofilaments may cause the synaptic growth phenotype. As a model, we suggest that the filamentous network around synaptic boutons restrains the spreading of synaptic branches. | Drosophila MICAL regulates myofilament organization and synaptic structure |
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"25817": 0.09672962874174118, "25962": 0.32764431834220886, "25969": 0.8534175157546997, "26013": 0.9333322048187256, "26226": 1.0458102226257324, "26419": 0.10379679501056671, "26422": 0.13670019805431366, "26524": 0.036437395960092545, "26651": 0.07612881064414978, "26835": 1.033379077911377, "27099": 0.7096124291419983, "27159": 0.25995752215385437, "27295": 0.3601844012737274, "27528": 0.3241194784641266, "27989": 0.08782484382390976, "28102": 0.7105726003646851, "28156": 0.8143964409828186, "28436": 0.01934296265244484, "28466": 0.7791815400123596, "28788": 0.18978065252304077, "28848": 0.10203468054533005, "28879": 0.05139094591140747, "29170": 0.08513788133859634, "29290": 0.3757305145263672, "29304": 0.15359249711036682, "29308": 0.2470736801624298, "29720": 0.19220098853111267} | 16572581 | Type 1 diabetes (T1D) is characterized by the destruction of the insulin-producing β-cells of pancreatic islets. Genetic and environmental factors both contribute to T1D development. Viral infection with enteroviruses is a suspected trigger for T1D, but a causal role remains unproven and controversial. Studies in animals are problematic because of species-specific differences in host cell susceptibility and immune responses to candidate viral pathogens such as coxsackievirus B (CVB). In order to resolve the controversial role of viruses in human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts. Hyperglycemia was induced in mice by specific ablation of native β-cells. Human islets, which are naturally susceptible to CVB infection, were transplanted to restore normoglycemia. Transplanted mice were infected with CVB4 and monitored for hyperglycemia. Forty-seven percent of CVB4-infected mice developed hyperglycemia. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and had reduced insulin levels compared with grafts from uninfected mice. Human-specific gene expression profiles in grafts from infected mice revealed the induction of multiple interferon-stimulated genes. Thus, human islets can become severely dysfunctional with diminished insulin production after CVB infection of β-cells, resulting in diabetes. | Viral Infection of Engrafted Human Islets Leads to Diabetes |
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"26689": 0.04487626627087593, "26709": 0.450652539730072, "26773": 0.24401791393756866, "27009": 0.13243216276168823, "27011": 0.10291612148284912, "27144": 0.25694093108177185, "27427": 0.46363574266433716, "27598": 0.3416208028793335, "27641": 0.0009760859538801014, "27790": 0.0770333781838417, "27814": 0.20977331697940826, "27854": 0.25088030099868774, "27928": 0.14179791510105133, "27937": 0.5232481360435486, "27989": 0.026025565341114998, "28228": 0.6902132034301758, "28424": 0.3423145115375519, "28619": 0.0842406153678894, "28691": 0.02887592278420925, "28767": 0.77198725938797, "28848": 0.7592713832855225, "28964": 0.052318159490823746, "28994": 0.8022117614746094, "29068": 0.7201237678527832, "29076": 0.04207121208310127, "29458": 0.6512666940689087, "29494": 0.03266380727291107} | 16605494 | BACKGROUND Whereas many causes and mechanisms of neurodegenerative diseases have been identified, very few therapeutic strategies have emerged in parallel. One possible explanation is that successful treatment strategy may require simultaneous targeting of more than one molecule of pathway. A new therapeutic approach to have emerged recently is the engagement of microRNAs (miRNAs), which affords the opportunity to target multiple cellular pathways simultaneously using a single sequence. METHODOLOGY/PRINCIPAL FINDINGS We identified miR-22 as a potentially neuroprotective miRNA based on its predicted regulation of several targets implicated in Huntington's disease (histone deacetylase 4 (HDAC4), REST corepresor 1 (Rcor1) and regulator of G-protein signaling 2 (Rgs2)) and its diminished expression in Huntington's and Alzheimer's disease brains. We then tested the hypothesis that increasing cellular levels of miRNA-22 would achieve neuroprotection in in vitro models of neurodegeneration. As predicted, overexpression of miR-22 inhibited neurodegeneration in primary striatal and cortical cultures exposed to a mutated human huntingtin fragment (Htt171-82Q). Overexpression of miR-22 also decreased neurodegeneration in primary neuronal cultures exposed to 3-nitropropionic acid (3-NP), a mitochondrial complex II/III inhibitor. In addition, miR-22 improved neuronal viability in an in vitro model of brain aging. The mechanisms underlying the effects of miR-22 included a reduction in caspase activation, consistent with miR-22's targeting the pro-apoptotic activities of mitogen-activated protein kinase 14/p38 (MAPK14/p38) and tumor protein p53-inducible nuclear protein 1 (Tp53inp1). Moreover, HD-specific effects comprised not only targeting HDAC4, Rcor1 and Rgs2 mRNAs, but also decreasing focal accumulation of mutant Htt-positive foci, which occurred via an unknown mechanism. CONCLUSIONS These data show that miR-22 has multipartite anti-neurodegenerative activities including the inhibition of apoptosis and the targeting of mRNAs implicated in the etiology of HD. These results motivate additional studies to evaluate the feasibility and therapeutic efficacy of manipulating miR-22 in vivo. | MicroRNA-22 (miR-22) Overexpression Is Neuroprotective via General Anti-Apoptotic Effects and May also Target Specific Huntington’s Disease-Related Mechanisms |
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0.3903779089450836} | 16625620 | To deliver optimal patient care, evidence-based care is advocated and research is needed to support health care staff of all disciplines in deciding which options to use in their daily practice. Due to the increasing complexity of cardiac care across the life span of patients combined with the increasing opportunities and challenges in multidisciplinary research, the Science Committee of the Council on Cardiovascular Nursing and Allied Professionals (CCNAP) recognised the need for a position statement to guide researchers, policymakers and funding bodies to contribute to the advancement of the body of knowledge that is needed to further improve cardiovascular care. In this paper, knowledge gaps in current research related to cardiovascular patient care are identified, upcoming challenges are explored and recommendations for future research are given. | Research in cardiovascular care: a position statement of the Council on Cardiovascular Nursing and Allied Professionals of the European Society of Cardiology. |
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0.21922965347766876, "26773": 0.5220900774002075, "26775": 0.13755162060260773, "26786": 0.5800528526306152, "26874": 0.15943801403045654, "27146": 0.03925827145576477, "27642": 0.21135559678077698, "27777": 0.4770587682723999, "27790": 0.018384648486971855, "28079": 0.2409527748823166, "28406": 0.2837681770324707, "28570": 0.07431721687316895, "28691": 0.10291612148284912, "29206": 0.15526613593101501, "29226": 0.19622190296649933} | 16626264 | Histone variants help specialize chromatin regions; however, their impact on transcriptional regulation is largely unknown. Here, we determined the genome-wide localization and dynamics of Htz1, the yeast histone H2A variant. Htz1 localizes to hundreds of repressed/basal Pol II promoters and prefers TATA-less promoters. Specific Htz1 deposition requires the SWR1 complex, which largely colocalizes with Htz1. Htz1 occupancy correlates with particular histone modifications, and Htz1 deposition is partially reliant on Gcn5 (a histone acetyltransferase) and Bdf1, an SWR1 complex member that binds acetylated histones. Changes in growth conditions cause a striking redistribution of Htz1 from activated to repressed/basal promoters. Furthermore, Htz1 promotes full gene activation but does not generally impact repression. Importantly, Htz1 releases from purified chromatin in vitro under conditions where H2A and H3 remain associated. We suggest that Htz1-bearing nucleosomes are deposited at repressed/basal promoters but facilitate activation through their susceptibility to loss, thereby helping to expose promoter DNA. | Genome-Wide Dynamics of Htz1, a Histone H2A Variant that Poises Repressed/Basal Promoters for Activation through Histone Loss |
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"24558": 0.255429208278656, "24714": 1.3372600078582764, "24829": 1.3489859104156494, "25185": 0.06154331564903259, "25509": 0.1510767638683319, "25524": 0.6482070088386536, "25742": 0.1602703034877777, "25778": 0.04674193635582924, "26118": 0.35813871026039124, "26131": 0.7191727757453918, "26190": 1.117955207824707, "26282": 0.5506471395492554, "26427": 0.15693697333335876, "26591": 0.42225050926208496, "26835": 0.4926934838294983, "26888": 1.3305710554122925, "27144": 0.11951763927936554, "27417": 0.3019835948944092, "28148": 0.06795065850019455, "28173": 0.29255300760269165, "28596": 0.04767346754670143, "29090": 0.08871890604496002, "29228": 0.19782574474811554, "29389": 0.1229778528213501} | 16626846 | Crude oils can be major contaminants of the marine ecosystem and microorganisms play a significant role in the degradation of its main constituents. To increase our understanding of the microbial hydrocarbon degradation process in the marine ecosystem, we collected crude oil from an active seep area located in the Santa Barbara Channel (SBC) and generated a total of about 52 Gb of raw metagenomic sequence data. The assembled data comprised ~500 Mb, representing ~1.1 million genes derived primarily from chemolithoautotrophic bacteria. Members of Oceanospirillales, a bacterial order belonging to the Deltaproteobacteria, recruited less than 2% of the assembled genes within the SBC metagenome. In contrast, the microbial community associated with the oil plume that developed in the aftermath of the Deepwater Horizon (DWH) blowout in 2010, was dominated by Oceanospirillales, which comprised more than 60% of the metagenomic data generated from the DWH oil plume. This suggests that Oceanospirillales might play a less significant role in the microbially mediated hydrocarbon conversion within the SBC seep oil compared to the DWH plume oil. We hypothesize that this difference results from the SBC oil seep being mostly anaerobic, while the DWH oil plume is aerobic. Within the Archaea, the phylum Euryarchaeota, recruited more than 95% of the assembled archaeal sequences from the SBC oil seep metagenome, with more than 50% of the sequences assigned to members of the orders Methanomicrobiales and Methanosarcinales. These orders contain organisms capable of anaerobic methanogenesis and methane oxidation (AOM) and we hypothesize that these orders - and their metabolic capabilities - may be fundamental to the ecology of the SBC oil seep. | Metagenomic analysis of microbial consortium from natural crude oil that seeps into the marine ecosystem offshore Southern California |
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Self-renewal capacity declines with age, partly because of increasing expression of the tumor suppressor p16(Ink4a). We discovered that the Hmga2 transcriptional regulator is highly expressed in fetal neural stem cells but that expression declines with age. This decrease is partly caused by the increasing expression of let-7b microRNA, which is known to target HMGA2. Hmga2-deficient mice show reduced stem cell numbers and self-renewal throughout the central and peripheral nervous systems of fetal and young-adult mice but not old-adult mice. Furthermore, p16(Ink4a) and p19(Arf) expression were increased in Hmga2-deficient fetal and young-adult stem cells, and deletion of p16(Ink4a) and/or p19(Arf) partially restored self-renewal capacity. let-7b overexpression reduced Hmga2 and increased p16(Ink4a)/p19(Arf) expression. Hmga2 thus promotes fetal and young-adult stem cell self-renewal by decreasing p16(Ink4a)/p19(Arf) expression. Changes in let-7 and Hmga2 expression during aging contribute to the decline in neural stem cell function. | Hmga2 Promotes Neural Stem Cell Self-Renewal in Young but Not Old Mice by Reducing p16Ink4a and p19Arf Expression |
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"28927": 0.10291612148284912, "28964": 1.0382318496704102, "29046": 0.034552380442619324, "29172": 0.175953671336174, "29217": 0.020300358533859253, "29238": 0.10026945173740387, "29290": 0.36697331070899963, "29516": 0.4041621685028076, "29533": 0.8845420479774475} | 16630060 | Somatic stem cell depletion due to the accumulation of DNA damage has been implicated in the appearance of aging-related phenotypes. Hair graying, a typical sign of aging in mammals, is caused by the incomplete maintenance of melanocyte stem cells (MSCs) with age. Here, we report that irreparable DNA damage, as caused by ionizing radiation, abrogates renewal of MSCs in mice. Surprisingly, the DNA-damage response triggers MSC differentiation into mature melanocytes in the niche, rather than inducing their apoptosis or senescence. The resulting MSC depletion leads to irreversible hair graying. Furthermore, deficiency of Ataxia-telangiectasia mutated (ATM), a central transducer kinase of the DNA-damage response, sensitizes MSCs to ectopic differentiation, demonstrating that the kinase protects MSCs from their premature differentiation by functioning as a "stemness checkpoint" to maintain the stem cell quality and quantity. | Genotoxic Stress Abrogates Renewal of Melanocyte Stem Cells by Triggering Their Differentiation |
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"28848": 0.6553317308425903, "28873": 0.1212492436170578, "29458": 0.8442239761352539, "29490": 0.0770333781838417} | 16630996 | To identify predictive molecular markers for gemcitabine resistance, we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of pancreatic cancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR in various subclones during the development of acquired resistance to gemcitabine. Real-time light cycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increased during the development of gemcitabine resistance. Expression of dCK was slightly increased in cells resistant to lower concentrations of gemcitabine, but was decreased below the undetectable level in higher concentration-resistant subclones. Expression of hENT1 was increased in the development of gemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance of these four factors, we calculated the ratio of hENT1 × dCK/RRM1 × RRM2 gene expression in gemcitabine-resistant subclones. The ratio of gene expression decreased progressively with development of acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity. These results suggest that the sensitivity of pancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism. The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients. | Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells |
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Paradoxically, telomere function depends on checkpoint proteins such as ATM and ATR, but a molecular model explaining this seemingly contradictory relationship has been missing so far. Here we show that the DNA damage machinery acts on telomeres in at least two independent steps. First, the ATR-dependent machinery is recruited to telomeres before telomere replication is completed, likely in response to single-stranded DNA resulting from replication fork stalling. Second, after replication, telomeres attract ATM and the homologous recombination (HR) machinery. In vivo and in vitro results suggest that the HR machinery is required for formation of a telomere-specific structure at chromosome ends after replication. Our results suggest that telomere ends need to be recognized as DNA damage to complete end replication and to acquire a structure that is essential for function. | The DNA Damage Machinery and Homologous Recombination Pathway Act Consecutively to Protect Human Telomeres |
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1.2318994998931885, "29320": 0.10203468054533005} | 16660256 | Satellite cells are skeletal muscle stem cells capable of self-renewal and differentiation after transplantation, but whether they contribute to endogenous muscle fiber repair has been unclear. The transcription factor Pax7 marks satellite cells and is critical for establishing the adult satellite cell pool. By using a lineage tracing approach, we show that after injury, quiescent adult Pax7(+) cells enter the cell cycle; a subpopulation returns to quiescence to replenish the satellite cell compartment, while others contribute to muscle fiber formation. We demonstrate that Sprouty1 (Spry1), a receptor tyrosine kinase signaling inhibitor, is expressed in quiescent Pax7(+) satellite cells in uninjured muscle, downregulated in proliferating myogenic cells after injury, and reinduced as Pax7(+) cells re-enter quiescence. We show that Spry1 is required for the return to quiescence and homeostasis of the satellite cell pool during repair. Our results therefore define a role for Spry1 in adult muscle stem cell biology and tissue repair. | Sprouty1 Regulates Reversible Quiescence of a Self-Renewing Adult Muscle Stem Cell Pool during Regeneration |
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0.1384023278951645, "27295": 0.18978065252304077, "27325": 0.4002431631088257, "27465": 0.11343330889940262, "27484": 0.5220900774002075, "27846": 0.7436100244522095, "27920": 0.5512100458145142, "27989": 0.5027855634689331, "28046": 0.03925827145576477, "28696": 0.0913962796330452, "29130": 0.8633513450622559, "29329": 0.32058215141296387, "29371": 0.026976587250828743} | 16669757 | The enteric nervous system (ENS) autonomously controls gut muscle activity. Mechanosensitive enteric neurons (MEN) initiate reflex activity by responding to mechanical deformation of the gastrointestinal wall. MEN throughout the gut primarily respond to compression or stretch rather than to shear force. Some MEN are multimodal as they respond to compression and stretch. Depending on the region up to 60% of the entire ENS population responds to mechanical stress. MEN fire action potentials after mechanical stimulation of processes or soma although they are more sensitive to process deformation. There are at least two populations of MEN based on their sensitivity to different modalities of mechanical stress and on their firing pattern. (1) Rapidly, slowly and ultra-slowly adapting neurons which encode compressive forces. (2) Ultra-slowly adapting stretch-sensitive neurons encoding tensile forces. Rapid adaptation of firing is typically observed after compressive force while slow adaptation or ongoing spike discharge occurs often during tensile stress (stretch). All MEN have some common properties: they receive synaptic input, are low fidelity mechanoreceptors and are multifunctional in that some serve interneuronal others even motor functions. Consequently, MEN possess processes with mechanosensitive as well as efferent functions. This raises the intriguing hypothesis that MEN sense and control muscle activity at the same time as servo-feedback loop. The mechanosensitive channel(s) or receptor(s) expressed by the different MEN populations are unknown. Future concepts have to incorporate compressive and tensile-sensitive MEN into neural circuits that controls muscle activity. They may interact to control various forms of a particular motor pattern or regulate different motor patterns independently from each other. | Mechanosensitivity in the enteric nervous system |
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"29297": 1.0278041362762451, "29490": 0.3191637098789215} | 16686383 | The centromeric histone H3 variant (CenH3) is essential for chromosome segregation in eukaryotes. We identify posttranslational modifications of Saccharomyces cerevisiae CenH3, Cse4. Functional characterization of cse4 phosphorylation mutants shows growth and chromosome segregation defects when combined with kinetochore mutants okp1 and ame1. Using a phosphoserine-specific antibody, we show that the association of phosphorylated Cse4 with centromeres increases in response to defective microtubule attachment or reduced cohesion. We determine that evolutionarily conserved Ipl1/Aurora B contributes to phosphorylation of Cse4, as levels of phosphorylated Cse4 are reduced at centromeres in ipl1 strains in vivo, and in vitro assays show phosphorylation of Cse4 by Ipl1. Consistent with these results, we observe that a phosphomimetic cse4-4SD mutant suppresses the temperature-sensitive growth of ipl1-2 and Ipl1 substrate mutants dam1 spc34 and ndc80, which are defective for chromosome biorientation. Furthermore, cell biology approaches using a green fluorescent protein-labeled chromosome show that cse4-4SD suppresses chromosome segregation defects in dam1 spc34 strains. On the basis of these results, we propose that phosphorylation of Cse4 destabilizes defective kinetochores to promote biorientation and ensure faithful chromosome segregation. Taken together, our results provide a detailed analysis, in vivo and in vitro, of Cse4 phosphorylation and its role in promoting faithful chromosome segregation. | Phosphorylation of centromeric histone H3 variant regulates chromosome segregation in Saccharomyces cerevisiae |
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We mapped all estrogen receptor and RNA polymerase II binding sites on a genome-wide scale, identifying the authentic cis binding sites and target genes, in breast cancer cells. Combining this unique resource with gene expression data demonstrates distinct temporal mechanisms of estrogen-mediated gene regulation, particularly in the case of estrogen-suppressed genes. Furthermore, this resource has allowed the identification of cis-regulatory sites in previously unexplored regions of the genome and the cooperating transcription factors underlying estrogen signaling in breast cancer. | Genome-wide analysis of estrogen receptor binding sites |
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0.5174443125724792, "23633": 0.2247048318386078, "23737": 0.29400965571403503, "23824": 0.006812678650021553, "23900": 0.14602625370025635, "24278": 0.05139094591140747, "24286": 0.10555581003427505, "24710": 0.13499516248703003, "25499": 0.0019512200960889459, "25502": 0.36358460783958435, "25613": 0.12038381397724152, "25644": 0.12384103983640671, "26462": 0.7755908370018005, "26524": 0.12038381397724152, "26906": 0.9271688461303711, "27467": 0.304147332906723, "27749": 0.037378571927547455, "27768": 0.04207121208310127, "28024": 0.5903874635696411, "28079": 0.07612881064414978, "28086": 0.055094651877880096, "28964": 0.29981520771980286, "29458": 0.03831886500120163, "29494": 0.3134697377681732} | 16693950 | Progress in aging research is now rapid, and surprisingly, studies in a single-celled eukaryote are a driving force. The genetic modulators of replicative life span in yeast are being identified, the molecular events that accompany aging are being discovered, and the extent to which longevity pathways are conserved between yeast and multicellular eukaryotes is being tested. In this review, we provide a brief retrospective view on the development of yeast as a model for aging and then turn to recent discoveries that have pushed aging research into novel directions and also linked aging in yeast to well-developed hypotheses in mammals. Although the question of what causes aging still cannot be answered definitively, that day may be rapidly approaching. | Replicative aging in yeast: the means to the end. |
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0.17431432008743286, "26236": 0.4624064862728119, "26237": 0.1905880719423294, "26319": 0.1401015669107437, "26563": 0.04207121208310127, "26877": 0.06612417846918106, "27753": 0.06337817758321762, "27833": 1.1923824548721313, "27896": 0.004870930220931768, "28093": 0.26820653676986694, "28207": 0.12986256182193756, "28344": 0.7417513132095337, "28436": 0.06886265426874161, "28498": 0.02412080205976963, "28687": 0.7934166193008423, "28739": 0.0174254160374403, "29048": 0.6160298585891724, "29299": 0.5461324453353882, "29458": 0.10906458646059036, "29477": 1.0298984050750732} | 16701509 | BACKGROUND The prevalence of metabolic syndrome (obesity, glucose intolerance, low serum high-density lipoprotein cholesterol [HDL-C], high serum triglycerides, hypertension) is high and increasing in parallel with an increasing breast cancer incidence worldwide. HDL-C represents an important aspect of the syndrome, yet its role in breast cancer is still undefined. METHODS In two population-based screening surveys during 1977-1983 and 1985-1987, serum HDL-C was assayed enzymatically among 38,823 Norwegian women aged 17-54 years at entry. Height, weight, blood pressure, serum lipids, fat and energy intake, physical activity, parity, oral contraceptive use, hormone therapy use, alcohol intake, and tobacco use were also assessed. We used Cox proportional hazards modeling to estimate the relative risk (RR) of breast cancer associated with serum HDL-C levels and to adjust for potential confounding variables. We performed stratified analyses to evaluate effect modification by body mass index (BMI) and menopausal status. All statistical tests were two-sided. RESULTS During a median follow-up of 17.2 years, we identified 708 cases of invasive breast cancer. In multivariable analysis, the risk of postmenopausal breast cancer was inversely related to quartile of HDL-C (P(trend) =.02). Among women with HDL-C above 1.64 mmol/L (highest quartile) versus below 1.20 mmol/L (lowest quartile), the relative risk was 0.75 (95% confidence interval [CI] = 0.58 to 0.97). The HDL-C association was confined to women in the heavier subgroup (BMI > or =25 kg/m2), for whom the relative risk of postmenopausal breast cancer in those with HDL-C above 1.64 mmol/L versus below 1.20 mmol/L was 0.43 (95% CI = 0.28 to 0.67; P(trend)<.001; P(interaction) =.001). CONCLUSION Low HDL-C, as part of the metabolic syndrome, is associated with increased postmenopausal breast cancer risk. | Serum high-density lipoprotein cholesterol, metabolic profile, and breast cancer risk. |
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However, large scale determination of CPI is a big challenge for in vitro or in vivo experiments, while in silico prediction shows great advantages due to low cost and high accuracy. On the basis of our previous drug-target interaction prediction via network-based inference (NBI) method, we further developed node- and edge-weighted NBI methods for CPI prediction here. Two comprehensive CPI bipartite networks extracted from ChEMBL database were used to evaluate the methods, one containing 17,111 CPI pairs between 4,741 compounds and 97 G protein-coupled receptors, the other including 13,648 CPI pairs between 2,827 compounds and 206 kinases. The range of the area under receiver operating characteristic curves was 0.73 to 0.83 for the external validation sets, which confirmed the reliability of the prediction. The weak-interaction hypothesis in CPI network was identified by the edge-weighted NBI method. Moreover, to validate the methods, several candidate targets were predicted for five approved drugs, namely imatinib, dasatinib, sertindole, olanzapine and ziprasidone. The molecular hypotheses and experimental evidence for these predictions were further provided. These results confirmed that our methods have potential values in understanding molecular basis of drug polypharmacology and would be helpful for drug repositioning. | Prediction of Chemical-Protein Interactions Network with Weighted Network-Based Inference Method |
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Whether stress arises from external insults or defects due to mutation and disease, cells must be able to respond precisely to mount the appropriate defenses. Multi-faceted stress responses are generally coupled with arrest of growth and cell-cycle progression, which both limits the transmission of damaged materials and serves to reallocate limited cellular resources toward defense. Therefore, stress defense versus rapid growth represent competing interests in the cell. How eukaryotic cells set the balance between defense versus proliferation, and in particular knowledge of the regulatory networks that control this decision, are poorly understood. In this perspective, we expand upon our recent work inferring the stress-activated signaling network in budding yeast, which captures pathways controlling stress defense and regulators of growth and cell-cycle progression. We highlight similarities between the yeast and mammalian stress responses and explore how stress-activated signaling networks in yeast can inform on signaling defects in human cancers. | Exploiting the yeast stress-activated signaling network to inform on stress biology and disease signaling |
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0.30917787551879883, "26906": 0.38174858689308167, "27854": 0.15275461971759796, "27881": 0.41065993905067444, "27998": 0.6624060273170471, "28086": 0.21293537318706512, "28166": 0.18248429894447327, "28848": 0.18654440343379974, "28964": 0.9878844022750854, "29147": 0.09495500475168228, "29206": 0.0752234235405922, "29290": 0.3499138653278351} | 16728949 | The forkhead O (FoxO) family of transcription factors participates in diverse physiologic processes, including induction of cell-cycle arrest, stress resistance, differentiation, apoptosis, and metabolism. Several recent studies indicate that FoxO-dependent signaling is required for long-term regenerative potential of the hematopoietic stem cell (HSC) compartment through regulation of HSC response to physiologic oxidative stress, quiescence, and survival. These observations link FoxO function in mammalian systems with the evolutionarily conserved role of FoxO in promotion of stress resistance and longevity in lower phylogenetic systems. Furthermore, these findings have implications for aging in higher organisms and in malignant stem cell biology, and suggest that FoxOs may play an important role in the maintenance and integrity of stem cell compartments in a broad spectrum of tissues. | Cell Stem Cell Review FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System |
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"26601": 0.7898768186569214, "26633": 0.05786345899105072, "26702": 0.052318159490823746, "26741": 0.23247487843036652, "26773": 0.40481385588645935, "26874": 0.8989537954330444, "27144": 0.11343330889940262, "27642": 0.5540198087692261, "27881": 1.0920805931091309, "28024": 0.1946154683828354, "28086": 1.3998736143112183, "28156": 0.08064348995685577, "28207": 0.6482070088386536, "28472": 0.0019512200960889459, "28723": 0.037378571927547455, "28774": 1.0841858386993408, "28788": 0.00875066313892603, "28828": 0.44753631949424744, "29206": 0.036437395960092545, "29458": 0.04113444685935974} | 16732790 | The first Swiss human embryonic stem cell (hESC) line, CH-ES1, has shown features of a malignant cell line. It originated from the only single blastomere that survived cryopreservation of an embryo, and it more closely resembles teratocarcinoma lines than other hESC lines with respect to its abnormal karyotype and its formation of invasive tumors when injected into SCID mice. The aim of this study was to characterize the molecular basis of the oncogenicity of CH-ES1 cells, we looked for abnormal chromosomal copy number (by array Comparative Genomic Hybridization, aCGH) and single nucleotide polymorphisms (SNPs). To see how unique these changes were, we compared these results to data collected from the 2102Ep teratocarcinoma line and four hESC lines (H1, HS293, HS401 and SIVF-02) which displayed normal G-banding result. We identified genomic gains and losses in CH-ES1, including gains in areas containing several oncogenes. These features are similar to those observed in teratocarcinomas, and this explains the high malignancy. The CH-ES1 line was trisomic for chromosomes 1, 9, 12, 17, 19, 20 and X. Also the karyotypically (based on G-banding) normal hESC lines were also found to have several genomic changes that involved genes with known roles in cancer. The largest changes were found in the H1 line at passage number 56, when large 5 Mb duplications in chromosomes 1q32.2 and 22q12.2 were detected, but the losses and gains were seen already at passage 22. These changes found in the other lines highlight the importance of assessing the acquisition of genetic changes by hESCs before their use in regenerative medicine applications. They also point to the possibility that the acquisition of genetic changes by ESCs in culture may be used to explore certain aspects of the mechanisms regulating oncogenesis. | A Teratocarcinoma-Like Human Embryonic Stem Cell (hESC) Line and Four hESC Lines Reveal Potentially Oncogenic Genomic Changes |
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"26610": 0.4450363218784332, "26741": 0.6793810129165649, "27131": 0.016465263441205025, "27144": 0.15610189735889435, "27673": 0.09317722171545029, "27781": 0.08603433519601822, "27854": 0.23015019297599792, "27881": 0.05046287178993225, "28207": 0.7755908370018005, "28212": 0.026976587250828743, "28290": 1.06349778175354, "28873": 0.6170841455459595, "29107": 0.0752234235405922, "29206": 0.13670019805431366, "29490": 0.1873544454574585, "29610": 0.030771657824516296} | 16734530 | BACKGROUND Breast cancer is the most common malignancy in women. There is increasing evidence suggesting that ORAI1, components of store-operated calcium channel, play a pivotal role in breast cancer progression and metastasis. METHODS A total of 384 female patients with breast cancer were included in this study. We selected five representative tagging ORAI1 SNPs from HapMap database with minimum allele frequency (MAF) >10%. Genotyping was performed using TaqMan allelic discrimination assay. Chi-square (χ²) test was used to analyze statistical differences among control and patient groups in genotype and allelic frequencies. RESULTS Two of the ORAI1 SNPs (rs12320939 and rs12313273) were associated with estrogen receptors positive in breast cancer patients under the recessive model. When the Bonferroni correction was performed, the significance still existed. In addition, rs12320939 also associated with the lymph nodal involvement. CONCLUSION We showed that genetic polymorphisms of ORAI1 associated strongly with lymph nodal involvement and estrogen receptors (ERs) positive breast cancer patients in a Taiwanese population. | The Association between Single-Nucleotide Polymorphisms of ORAI1 Gene and Breast Cancer in a Taiwanese Population |
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"27725": 0.0752234235405922, "27830": 0.49030399322509766, "28086": 1.2221657037734985, "28302": 0.623910129070282, "28522": 0.5947071313858032, "29083": 0.304147332906723, "29097": 0.29981520771980286, "29105": 1.243794322013855, "29109": 0.03831886500120163, "29304": 0.29328158497810364} | 16736872 | Optical imaging of the dynamics of living specimens involves tradeoffs between spatial resolution, temporal resolution, and phototoxicity, made more difficult in three dimensions. Here, however, we report that rapid three-dimensional (3D) dynamics can be studied beyond the diffraction limit in thick or densely fluorescent living specimens over many time points by combining ultrathin planar illumination produced by scanned Bessel beams with super-resolution structured illumination microscopy. We demonstrate in vivo karyotyping of chromosomes during mitosis and identify different dynamics for the actin cytoskeleton at the dorsal and ventral surfaces of fibroblasts. Compared to spinning disk confocal microscopy, we demonstrate substantially reduced photodamage when imaging rapid morphological changes in D. discoideum cells, as well as improved contrast and resolution at depth within developing C. elegans embryos. Bessel beam structured plane illumination thus promises new insights into complex biological phenomena that require 4D subcellular spatiotemporal detail in either a single or multicellular context. | Noninvasive Imaging beyond the Diffraction Limit of 3D Dynamics in Thickly Fluorescent Specimens |
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Genetic, biochemical, and structural studies implicate the Ndc80 complex as a direct point of contact between kinetochores and microtubules, but these approaches provide only a static view. Here, using techniques for manipulating and tracking individual molecules in vitro, we demonstrate that the Ndc80 complex is capable of forming the dynamic, load-bearing attachments to assembling and disassembling tips required for coupling in vivo. We also establish that Ndc80-based coupling likely occurs through a biased diffusion mechanism and that this activity is conserved from yeast to humans. Our findings demonstrate how an ensemble of Ndc80 complexes may provide the combination of plasticity and strength that allows kinetochores to maintain load-bearing tip attachments during both microtubule assembly and disassembly. | The Ndc80 Kinetochore Complex Forms Load-Bearing Attachments to Dynamic Microtubule Tips via Biased Diffusion |
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"26972": 0.9037119746208191, "27011": 0.13925230503082275, "27152": 0.44753631949424744, "27321": 0.7144040465354919, "27354": 0.12642613053321838, "27391": 0.2576959431171417, "27480": 0.026976587250828743, "27781": 1.2533208131790161, "27793": 0.36290550231933594, "27794": 0.022212404757738113, "28032": 0.7537717819213867, "28352": 0.09495500475168228, "28788": 0.1064341589808464, "28873": 0.7144040465354919, "29458": 1.0648454427719116, "29490": 0.46055975556373596} | 16737163 | OBJECTIVE To determine whether myelin oligodendrocyte glycoprotein antibodies (MOG-Abs) were predictive of a demyelination phenotype in children presenting with acquired demyelinating syndrome (ADS). METHOD Sixty-five children with a first episode of ADS (12 acute disseminated encephalomyelitis, 24 optic neuritis, 18 transverse myelitis, 11 other clinically isolated syndrome) were identified from 2 national demyelination programs in the United Kingdom and France. Acute serum samples were tested for MOG-Abs by cell-based assay. Antibodies were used to predict diagnosis of multiple sclerosis (MS) at 1 year. RESULTS Twenty-three of 65 (35%) children had MOG-Abs. Antibody-positive and antibody-negative patients were not clinically different at presentation, but identification of MOG-Abs predicted a non-MS course at 1-year follow-up: only 2/23 (9%) MOG-Ab-positive patients were diagnosed with MS compared to 16/42 (38%) MOG-Ab-negative patients (p = 0.019, Fisher exact test). Antibody positivity at outset was a useful predictor for a non-MS disease course, with a positive predictive value of 91% (95% confidence interval [CI] 72-99), negative predictive value of 38% (95% CI 24-54), positive likelihood ratio of 4.02 (CI 1.0-15.4), and odds ratio of 6.5 (CI 1.3-31.3). CONCLUSIONS MOG-Abs are found at presentation in 35% of patients with childhood ADS, across a range of demyelinating disorders. Antibody positivity can be useful in predicting a non-MS disease course at onset. | Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children |
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"25613": 0.129004567861557, "25622": 0.151916041970253, "25714": 0.1332872211933136, "25837": 0.4624064862728119, "25876": 1.151856780052185, "26237": 0.010684899985790253, "26462": 0.12642613053321838, "26478": 0.0174254160374403, "26633": 0.9363996982574463, "26751": 0.06154331564903259, "26994": 0.026025565341114998, "27025": 0.0752234235405922, "27159": 0.23015019297599792, "27354": 0.07793712615966797, "27398": 0.1212492436170578, "27528": 0.2394166737794876, "27605": 0.678885817527771, "27615": 0.17922431230545044, "27694": 1.0802149772644043, "27894": 0.18816383183002472, "28024": 0.3930181860923767, "28032": 0.4400174915790558, "28120": 0.16110190749168396, "28155": 0.015504186972975731, "28400": 0.012615402229130268, "28616": 0.9980146884918213, "28873": 0.8764448165893555, "29458": 0.05786345899105072} | 16737210 | CONTEXT Blood type and crossmatch incompatibility will exclude at least one third of patients in need from receiving a live donor kidney transplant. Kidney paired donation (KPD) offers incompatible donor/recipient pairs the opportunity to match for compatible transplants. Despite its increasing popularity, very few transplants have resulted from KPD. OBJECTIVE To determine the potential impact of improved matching schemes on the number and quality of transplants achievable with KPD. DESIGN, SETTING, AND POPULATION We developed a model that simulates pools of incompatible donor/recipient pairs. We designed a mathematically verifiable optimized matching algorithm and compared it with the scheme currently used in some centers and regions. Simulated patients from the general community with characteristics drawn from distributions describing end-stage renal disease patients eligible for renal transplantation and their willing and eligible live donors. MAIN OUTCOME MEASURES Number of kidneys matched, HLA mismatch of matched kidneys, and number of grafts surviving 5 years after transplantation. RESULTS A national optimized matching algorithm would result in more transplants (47.7% vs 42.0%, P<.001), better HLA concordance (3.0 vs 4.5 mismatched antigens; P<.001), more grafts surviving at 5 years (34.9% vs 28.7%; P<.001), and a reduction in the number of pairs required to travel (2.9% vs 18.4%; P<.001) when compared with an extension of the currently used first-accept scheme to a national level. Furthermore, highly sensitized patients would benefit 6-fold from a national optimized scheme (2.3% vs 14.1% successfully matched; P<.001). Even if only 7% of patients awaiting kidney transplantation participated in an optimized national KPD program, the health care system could save as much as $750 million. CONCLUSIONS The combination of a national KPD program and a mathematically optimized matching algorithm yields more matches with lower HLA disparity. Optimized matching affords patients the flexibility of customizing their matching priorities and the security of knowing that the greatest number of high-quality matches will be found and distributed equitably. | Kidney paired donation and optimizing the use of live donor organs. |
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"27854": 0.23710809648036957, "27928": 0.3070250153541565, "28156": 0.5080875158309937, "28389": 0.10555581003427505, "28828": 0.2447827309370041, "28829": 0.19541899859905243, "28873": 0.18167030811309814, "29354": 0.0174254160374403} | 16745747 | Adult blood cell production or definitive hematopoiesis requires the transcription factor c-Myb. The closely related KAT3 histone acetyltransferases CBP (CREBBP) and p300 (EP300) bind c-Myb through their KIX domains and mice homozygous for a p300 KIX domain mutation exhibit multiple blood defects. Perplexingly, mice homozygous for the same KIX domain mutation in CBP have normal blood. Here we test the hypothesis that the CBP KIX domain contributes subordinately to hematopoiesis via a genetic interaction with c-Myb. We assessed hematopoiesis in mice bearing compound mutations of c-Myb and/or the KIX domains of CBP and p300, and measured the effect of KIX domain mutations on c-Myb-dependent gene expression. We found that in the context of a p300 KIX mutation, the CBP KIX domain mutation affects platelets, B cells, T cells, and red cells. Gene interaction (epistasis) analysis provides mechanistic evidence that blood defects in KIX mutant mice are consistent with reduced c-Myb and KIX interaction. Lastly, we demonstrated that the CBP and p300 KIX domains contribute to both c-Myb-dependent gene activation and repression. Together these results suggest that the KIX domains of CBP, and especially p300, are principal mediators of c-Myb-dependent gene activation and repression that is required for definitive hematopoiesis. | Genetic Interaction between Mutations in c-Myb and the KIX Domains of CBP and p300 Affects Multiple Blood Cell Lineages and Influences Both Gene Activation and Repression |
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0.14264501631259918, "27203": 0.3784096837043762, "27339": 0.6022219061851501, "27354": 0.1734936386346817, "27697": 0.1677299439907074, "27790": 0.22079704701900482, "28093": 0.30558720231056213, "28353": 0.45870962738990784, "28696": 0.20977331697940826, "28697": 0.1718502640724182, "28915": 0.6911921501159668, "29166": 0.22859740257263184, "29278": 0.04860413447022438, "29361": 0.004870930220931768, "29458": 0.7408206462860107} | 16760369 | CONTEXT Clinicians and trialists have difficulty with identifying which patients are highest risk for cardiovascular events. Prior ischemic events, polyvascular disease, and diabetes mellitus have all been identified as predictors of ischemic events, but their comparative contributions to future risk remain unclear. OBJECTIVE To categorize the risk of cardiovascular events in stable outpatients with various initial manifestations of atherothrombosis using simple clinical descriptors. DESIGN, SETTING, AND PATIENTS Outpatients with coronary artery disease, cerebrovascular disease, or peripheral arterial disease or with multiple risk factors for atherothrombosis were enrolled in the global Reduction of Atherothrombosis for Continued Health (REACH) Registry and were followed up for as long as 4 years. Patients from 3647 centers in 29 countries were enrolled between 2003 and 2004 and followed up until 2008. Final database lock was in April 2009. MAIN OUTCOME MEASURES Rates of cardiovascular death, myocardial infarction, and stroke. RESULTS A total of 45,227 patients with baseline data were included in this 4-year analysis. During the follow-up period, a total of 5481 patients experienced at least 1 event, including 2315 with cardiovascular death, 1228 with myocardial infarction, 1898 with stroke, and 40 with both a myocardial infarction and stroke on the same day. Among patients with atherothrombosis, those with a prior history of ischemic events at baseline (n = 21,890) had the highest rate of subsequent ischemic events (18.3%; 95% confidence interval [CI], 17.4%-19.1%); patients with stable coronary, cerebrovascular, or peripheral artery disease (n = 15,264) had a lower risk (12.2%; 95% CI, 11.4%-12.9%); and patients without established atherothrombosis but with risk factors only (n = 8073) had the lowest risk (9.1%; 95% CI, 8.3%-9.9%) (P < .001 for all comparisons). In addition, in multivariable modeling, the presence of diabetes (hazard ratio [HR], 1.44; 95% CI, 1.36-1.53; P < .001), an ischemic event in the previous year (HR, 1.71; 95% CI, 1.57-1.85; P < .001), and polyvascular disease (HR, 1.99; 95% CI, 1.78-2.24; P < .001) each were associated with a significantly higher risk of the primary end point. CONCLUSION Clinical descriptors can assist clinicians in identifying high-risk patients within the broad range of risk for outpatients with atherothrombosis. | Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. |
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0.4437839686870575} | 16787954 | Finding new treatment-shortening antibiotics to improve cure rates and curb the alarming emergence of drug resistance is the major objective of tuberculosis (TB) drug development. Using a matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging suite in a biosafety containment facility, we show that the key sterilizing drugs rifampicin and pyrazinamide efficiently penetrate the sites of TB infection in lung lesions. Rifampicin even accumulates in necrotic caseum, a critical lesion site where persisting tubercle bacilli reside. In contrast, moxifloxacin, which is active in vitro against a subpopulation of Mycobacterium tuberculosis that persists in specific niches under drug pressure and has achieved treatment shortening in mice, does not diffuse well in caseum, concordant with its failure to shorten therapy in recent clinical trials. We suggest that such differential spatial distribution and kinetics of accumulation in lesions may create temporal and spatial windows of monotherapy in specific niches, allowing the gradual development of multidrug-resistant TB. We propose an alternative working model to prioritize new antibiotic regimens based on quantitative and spatial distribution of TB drugs in the major lesion types found in human lungs. The finding that lesion penetration may contribute to treatment outcome has wide implications for TB. | The association between sterilizing activity and drug distribution into tuberculosis lesions |
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0.2622140049934387, "26773": 0.23864774405956268, "26986": 0.36358460783958435, "27099": 0.025073638185858727, "27169": 0.08244366943836212, "27325": 0.12728634476661682, "27333": 0.45994341373443604, "27381": 0.1229778528213501, "27424": 0.46117570996284485, "27854": 0.20102575421333313, "28086": 0.43938836455345154, "28228": 0.13414156436920166, "28642": 0.034552380442619324, "28938": 0.15526613593101501, "28997": 0.012615402229130268} | 16790253 | Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development. Signals exchanged between neighboring cells through the Notch receptor can amplify and consolidate molecular differences, which eventually dictate cell fates. Thus, Notch signals control how cells respond to intrinsic or extrinsic developmental cues that are necessary to unfold specific developmental programs. Notch activity affects the implementation of differentiation, proliferation, and apoptotic programs, providing a general developmental tool to influence organ formation and morphogenesis. | Notch signaling: cell fate control and signal integration in development. |
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0.018384648486971855, "28848": 0.7028654217720032, "28873": 0.2478361576795578, "29295": 0.1808556467294693, "29458": 0.9225212931632996, "29533": 0.17431432008743286} | 16806763 | Increasing evidence suggests long non-coding RNAs (lncRNAs) are frequently aberrantly expressed in cancers, however, few related lncRNA signatures have been established for prediction of cancer prognosis. We aimed to develop a lncRNA signature to improve prognosis prediction of colorectal cancer (CRC). Using a lncRNA-mining approach, we performed lncRNA expression profiling in large CRC cohorts from Gene Expression Ominus (GEO), including GSE39582 test series(N=436), internal validation series (N=117); and two independent validation series GSE14333 (N=197) and GSE17536(N=145). We established a set of six lncRNAs that were significantly correlated with the disease free survival (DFS) in the test series. Based on this six-lncRNA signature, the test series patients could be classified into high-risk and low-risk subgroups with significantly different DFS (HR=2.670; P<0.0001). The prognostic value of this six-lncRNA signature was confirmed in the internal validation series and another two independent CRC sets. Gene set enrichment analysis (GSEA) analysis suggested that risk score positively correlated with several cancer metastasis related pathways. Functional experiments demonstrated three dysregulated lncRNAs, AK123657, BX648207 and BX649059 were required for efficient invasion and proliferation suppression in CRC cell lines. Our results might provide an efficient classification tool for clinical prognosis evaluation of CRC. | A long non-coding RNA signature to improve prognosis prediction of colorectal cancer |
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0.25088030099868774, "26127": 0.18492233753204346, "26228": 0.07431721687316895, "26319": 0.00875066313892603, "26461": 0.17431432008743286, "26745": 0.6754127144813538, "26788": 0.13071982562541962, "26876": 1.1629066467285156, "27641": 0.05417001247406006, "28032": 0.9029204845428467, "28093": 0.04113444685935974, "28329": 0.2576959431171417, "28530": 0.176772341132164, "28929": 1.0855059623718262, "28993": 0.3170322775840759, "29392": 0.09228714555501938, "29458": 0.8517522215843201, "29477": 0.7951818704605103} | 16812091 | CONTEXT Osteoporosis causes substantial morbidity and costs $13.8 billion annually in the United States. Measurement of bone mass by densitometry is a primary part of diagnosing osteoporosis and deciding a preventive treatment course. Bone mineral densitometry has become more widely available and commonly used in practice. OBJECTIVE To review evidence about the value of various clinical applications of bone densitometry. DATA SOURCES A MEDLINE search was performed to update previous meta-analyses of the relationship between various measurements of bone density and risk of vertebral and hip fracture. We used data from the prospective Study of Osteoporotic Fractures to estimate risk of fracture from bone density and age in postmenopausal women. STUDY SELECTION AND DATA EXTRACTION When available, meta-analyses and systematic reviews are emphasized in the review. DATA SYNTHESIS Bone mineral density (BMD) predicts fracture and can be used in combination with age to estimate absolute risk of fractures in postmenopausal white women. Hip BMD predicts hip fracture more strongly than other measurements of BMD. There are insufficient data to translate BMD results into risk of fracture for men and nonwhite women. The benefits of treatments to prevent fractures depend on BMD: women with osteoporosis have a greater risk of fractures and greater benefit from treatments than women without osteoporosis. CONCLUSIONS Guidelines based on systematic reviews and a cost-effectiveness analysis have suggested that it is worthwhile to measure BMD in white women older than 65 years and perhaps to use risk factors to select younger postmenopausal women for densitometry. Other potential clinical applications of BMD that have not yet been adequately studied include screening men or nonwhite women, monitoring BMD in patients receiving treatment, and using BMD to identify patients who should be evaluated for secondary causes of osteoporosis. | Clinical use of bone densitometry: scientific review. |
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"29721": 0.5500838756561279} | 16826810 | Vascular calcification is an advanced feature of atherosclerosis for which no effective therapy is available. To investigate the modulation or reversal of calcification, we identified calcifying progenitor cells and investigated their calcifying/decalcifying potentials. Cells from the aortas of mice were sorted into four groups using Sca-1 and PDGFRα markers. Sca-1(+) (Sca-1(+)/PDGFRα(+) and Sca-1(+)/PDGFRα(-)) progenitor cells exhibited greater osteoblastic differentiation potentials than Sca-1(-) (Sca-1(-)/PDGFRα(+) and Sca-1(-)/PDGFRα(-)) progenitor cells. Among Sca-1(+) progenitor populations, Sca-1(+)/PDGFRα(-) cells possessed bidirectional differentiation potentials towards both osteoblastic and osteoclastic lineages, whereas Sca-1(+)/PDGFRα(+) cells differentiated into an osteoblastic lineage unidirectionally. When treated with a peroxisome proliferator activated receptor γ (PPARγ) agonist, Sca-1(+)/PDGFRα(-) cells preferentially differentiated into osteoclast-like cells. Sca-1(+) progenitor cells in the artery originated from the bone marrow (BM) and could be clonally expanded. Vessel-resident BM-derived Sca-1(+) calcifying progenitor cells displayed nonhematopoietic, mesenchymal characteristics. To evaluate the modulation of in vivo calcification, we established models of ectopic and atherosclerotic calcification. Computed tomography indicated that Sca-1(+) progenitor cells increased the volume and calcium scores of ectopic calcification. However, Sca-1(+)/PDGFRα(-) cells treated with a PPARγ agonist decreased bone formation 2-fold compared with untreated cells. Systemic infusion of Sca-1(+)/PDGFRα(-) cells into Apoe(-/-) mice increased the severity of calcified atherosclerotic plaques. However, Sca-1(+)/PDGFRα(-) cells in which PPARγ was activated displayed markedly decreased plaque severity. Immunofluorescent staining indicated that Sca-1(+)/PDGFRα(-) cells mainly expressed osteocalcin; however, activation of PPARγ triggered receptor activator for nuclear factor-κB (RANK) expression, indicating their bidirectional fate in vivo. These findings suggest that a subtype of BM-derived and vessel-resident progenitor cells offer a therapeutic target for the prevention of vascular calcification and that PPARγ activation may be an option to reverse calcification. | Vascular Calcifying Progenitor Cells Possess Bidirectional Differentiation Potentials |
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"24229": 0.08154398202896118, "24316": 0.1401015669107437, "24327": 0.053244512528181076, "24335": 0.5086748600006104, "24454": 0.469759464263916, "24710": 0.10203468054533005, "24848": 0.07250232994556427, "25456": 0.07884006202220917, "25476": 0.5651806592941284, "25502": 0.9317949414253235, "25644": 1.1369311809539795, "25662": 0.021256839856505394, "25778": 0.08064348995685577, "26512": 0.08244366943836212, "26520": 1.0073304176330566, "26524": 0.9409833550453186, "26629": 0.6921701431274414, "26773": 0.5968599319458008, "27287": 0.3526630103588104, "27854": 0.12814582884311676, "28696": 0.7445381283760071} | 16839245 | The basic biology of the cell division cycle and its control by protein kinases was originally studied through genetic and biochemical studies in yeast and other model organisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals. However, recent studies in different cell types or genetic models are now providing a new perspective on the function of these major cell cycle regulators in different tissues. Here, we review the physiological relevance of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-like kinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studied enzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue homeostasis, and human disease. Among these functions, the control of self-renewal or asymmetric cell division in stem/progenitor cells and the ability to regenerate injured tissues is a central issue in current research. In addition, many of these proteins play previously unexpected roles in metabolism, cardiovascular function, or neuron biology. The modulation of their enzymatic activity may therefore have multiple therapeutic benefits in human disease. | Physiological relevance of cell cycle kinases. |
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However, the precise mechanism of mobilization remains poorly defined. In this study, MSCs that expressed similar cell surface markers and exhibited multilineage differentiation potentials were isolated from various donors. Interestingly, different MSC isolates displayed differential migration ability toward human glioma cells. We hypothesized that distinct molecular signals may be involved in the varied tumor tropisms exhibited by different MSC isolates. To test this hypothesis, gene expression profiles of tumor-trophic MSCs were compared with those of non-tumor-trophic MSCs. Among the various differentially regulated genes, matrix metalloproteinase one (MMP1) gene expression and its protein activities were enhanced by 27-fold and 21-fold, respectively, in highly migrating MSCs compared with poorly migrating MSCs. By contrast, there was no change in the transcriptional levels of other MMPs. Functional inactivation of MMP1 abrogated the migratory potential of MSCs toward glioma-conditioned medium. Conversely, the nonmigratory phenotype of poorly migrating MSC could be rescued in the presence of either recombinant MMP1 or conditioned medium from the highly migrating MSCs. Ectopic expression of MMP1 in these poorly migrating cells also rendered the cells responsive to the signaling cues from the glioma cells in vivo. However, blocking the interaction of MMP1 and its cognate receptor PAR1 effectively diminished the migratory ability of MSCs. Taken together, this study provides, for the first time, supporting evidence that MMP1 is critically involved in the migration capacity of MSCs, acting through the MMP1/PAR1 axis. | Matrix Metalloproteinase 1 Is Necessary for the Migration of Human Bone Marrow-Derived Mesenchymal Stem Cells Toward Human Glioma |
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"25775": 0.058784693479537964, "25883": 0.0029254043474793434, "25947": 0.8433839678764343, "25953": 0.0038986403960734606, "26262": 0.22937409579753876, "26264": 0.38905516266822815, "26319": 0.010684899985790253, "26453": 0.0058422754518687725, "27084": 0.3423145115375519, "27204": 0.05786345899105072, "27247": 0.010684899985790253, "27322": 0.06154331564903259, "27378": 0.011650617234408855, "27466": 0.009718249551951885, "27550": 0.21687394380569458, "27559": 0.23864774405956268, "27675": 0.3269403576850891, "27794": 0.06429435312747955, "27836": 0.14264501631259918, "27886": 1.2123361825942993, "28297": 0.36900100111961365, "28498": 0.24325250089168549, "28973": 0.03266380727291107, "29101": 0.6492279767990112, "29172": 0.18492233753204346, "29486": 0.503966212272644} | 16855829 | Bullying is still prevalent in schools and is clearly stressful for victims. 1 2 It may also have undesirable consequences for bullies, with antisocial behaviour persisting into adulthood. Victims are generally reported to be weaker than the bullies. 2 3 This would suggest that very short pupils are more likely to be victims and less likely to be the aggressors. The Wessex growth study allowed us to examine the prevalence of bullying, as experienced or perpetrated by pupils of different heights. Ninety two short normal adolescents who had been below the third centile for height at school entry4 and 117 controls matched for age and sex completed a bullying questionnaire, derived from work by Whitney and Smith.5 There were no refusals or any significant differences in sex or social class between the groups. Mean age (range) was 14.7 (13.4-15.7) years. Mean height SD scores were: short pupils −1.90 (−3.53 to −0.01), controls 0.31 (−1.41 … | Bullying in school: are short pupils at risk? Questionnaire study in a cohort. |
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Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophages and dendritic cells, much less is known about microglia, resident tissue macrophages of the brain that originate from a distinct progenitor. To directly compare inflammasome-mediated activation in different types of macrophages, we isolated primary microglia and hematopoietic macrophages from adult, healthy rhesus macaques. We analyzed the expression profile of NOD (nucleotide-binding oligomerization domain)-like receptors, adaptor proteins, and caspases and characterized inflammasome activation and regulation in detail. We here demonstrate that primary microglia can respond to the same innate stimuli as hematopoietic macrophages. However, microglial responses are more persistent due to lack of negative regulation on pro-IL-1β expression. In addition, we show that while caspase 1, 4, and 5 activation is pivotal for inflammasome-induced IL-1β secretion by hematopoietic macrophages, microglial secretion of IL-1β is only partially dependent on these inflammatory caspases. These results identify key cell type-specific differences that may aid the development of strategies to modulate innate immune responses in the brain. | Inflammasome-induced IL-1β secretion in microglia is characterized by delayed kinetics and is only partially dependent on inflammatory caspases. |
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0.056018441915512085, "29490": 0.436867892742157} | 16882895 | In the present study, we constructed a lentivirus vector encoding the miR-29a precursor and established two stably infected cell lines, PLC-29a and 97L-29a. The overexpression of miR-29a was confirmed by TaqMan RT-PCR and significantly suppressed the growth of the hepatocellular carcinoma cell lines MHCC-97L and PLC. Dual-luciferase reporter assays indicated that the SPARC mRNA 3'UTR was directly targeted by miR-29a since the mutated 3'UTR was not affected. Silencing SPARC expression by RNAi knockdown resulted in a similar effect as miR-29a overexpression on hepatocellular carcinoma (HCC) cell growth regulation. Anti-miR-29a oligonucleotides (AMOs) upregulated the levels of SPARC in the HCC cells. The phosphorylation of AKT/mTOR downstream of SPARC was inhibited in miR-29a-overexpressing HCC cells. We further examined and compared the expression levels of miR-29a in HCC tissues and the corresponding nearby non-cancerous liver tissues of 110 patients with HCC by qRT-PCR, and significantly lower expression of miR-29a was observed in the tissues affected by HCC. Our findings demonstrate that the expression of miR-29a is important in the regulation of the SPARC-AKT pathway and HCC growth. | microRNA-29a suppresses cell proliferation by targeting SPARC in hepatocellular carcinoma. |
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"28711": 0.06612417846918106, "28788": 0.14939609169960022, "29129": 0.7239188551902771, "29290": 0.6244332790374756, "29543": 0.4041621685028076} | 16905344 | Injured axons of the adult CNS undergo lengthy retraction from the initial site of axotomy after spinal cord injury. Macrophage infiltration correlates spatiotemporally with this deleterious phenomenon, but the direct involvement of these inflammatory cells has not been demonstrated. In the present study, we examined the role of macrophages in axonal retraction within the dorsal columns after spinal cord injury in vivo and found that retraction occurred between days 2 and 28 after lesion and that the ends of injured axons were associated with ED-1+ cells. Clodronate liposome-mediated depletion of infiltrating macrophages resulted in a significant reduction in axonal retraction; however, we saw no evidence of regeneration. We used time-lapse imaging of adult dorsal root ganglion neurons in an in vitro model of the glial scar to examine macrophage-axon interactions and observed that adhesive contacts and considerable physical interplay between macrophages and dystrophic axons led to extensive axonal retraction. The induction of retraction was dependent on both the growth state of the axon and the activation state of the macrophage. Only dystrophic adult axons were susceptible to macrophage "attack. " Unlike intrinsically active cell line macrophages, both primary macrophages and microglia required activation to induce axonal retraction. Contact with astrocytes had no deleterious effect on adult dystrophic axons, suggesting that the induction of extensive retraction was specific to phagocytic cells. Our data are the first to indicate a direct role of activated macrophages in axonal retraction by physical cell-cell interactions with injured axons. | Another Barrier to Regeneration in the CNS: Activated Macrophages Induce Extensive Retraction of Dystrophic Axons through Direct Physical Interactions |
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0.20501139760017395, "26591": 0.4487839937210083, "26601": 0.21765978634357452, "26616": 0.9021284580230713, "26835": 0.06429435312747955, "26874": 0.2689530849456787, "27000": 0.21293537318706512, "27034": 0.0354953333735466, "27099": 0.11168810725212097, "27169": 0.040196798741817474, "27405": 0.684319257736206, "27606": 0.021256839856505394, "27642": 0.791648268699646, "27777": 0.6016870141029358, "27790": 0.0354953333735466, "27854": 0.03831886500120163, "28775": 0.030771657824516296, "28848": 1.035461664199829, "28959": 0.15359249711036682, "29050": 1.1965231895446777, "29105": 0.7665573358535767, "29129": 0.5180262327194214, "29290": 0.2918238639831543} | 16927286 | In bacterial translational initiation, three initiation factors (IFs 1-3) enable the selection of initiator tRNA and the start codon in the P site of the 30S ribosomal subunit. Here, we report 11 single-particle cryo-electron microscopy (cryoEM) reconstructions of the complex of bacterial 30S subunit with initiator tRNA, mRNA, and IFs 1-3, representing different steps along the initiation pathway. IF1 provides key anchoring points for IF2 and IF3, thereby enhancing their activities. IF2 positions a domain in an extended conformation appropriate for capturing the formylmethionyl moiety charged on tRNA. IF3 and tRNA undergo large conformational changes to facilitate the accommodation of the formylmethionyl-tRNA (fMet-tRNA(fMet)) into the P site for start codon recognition. | Large-Scale Movements of IF3 and tRNA during Bacterial Translation Initiation |
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By comparing the differences between spliceosomal proteins from many basal eukaryotic lineages, it is possible to infer properties of the splicing system in the last common ancestor of extant eukaryotes, the eukaryotic ancestor. We begin with the hypothesis that, similar to intron length (that appears to have increased in multicellular eukaryotes), the spliceosome has increased in complexity throughout eukaryotic evolution. However, examination of the distribution of spliceosomal components indicates that not only was a spliceosome present in the eukaryotic ancestor but it also contained most of the key components found in today's eukaryotes. All the small nuclear ribonucleoproteins (snRNPs) protein components are likely to have been present, as well as many splicing-related proteins. Both major and trans-splicing are likely to have been present, and the spliceosome had already formed links with other cellular processes such as transcription and capping. However, there is no evidence as yet to suggest that minor (U12-dependent) splicing was present in the eukaryotic ancestor. Although the last common ancestor of extant eukaryotes appears to show much of the molecular complexity seen today, we do not, from this work, infer anything of the properties of the earlier "first eukaryote. " | Corresponding Author: |
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Here we compare cortical progenitor cell output in humans and three nonhuman primates using directed differentiation of pluripotent stem cells (PSCs) in adherent two-dimensional (2D) and organoid three-dimensional (3D) culture systems. Clonal lineage analysis showed that primate cortical progenitors proliferate for a protracted period of time, during which they generate early-born neurons, in contrast to rodents, where this expansion phase largely ceases before neurogenesis begins. The extent of this additional cortical progenitor expansion differs among primates, leading to differences in the number of neurons generated by each progenitor cell. We found that this mechanism for controlling cortical size is regulated cell autonomously in culture, suggesting that primate cerebral cortex size is regulated at least in part at the level of individual cortical progenitor cell clonal output. | 2D and 3D Stem Cell Models of Primate Cortical Development Identify Species-Specific Differences in Progenitor Behavior Contributing to Brain Size. |
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0.8161250352859497, "28433": 0.129004567861557, "28637": 0.03831886500120163, "28757": 0.20421554148197174, "28788": 0.022212404757738113, "28815": 0.5871354341506958, "28847": 1.3989098072052002, "29000": 0.13157635927200317, "29035": 0.10379679501056671, "29105": 0.24401791393756866, "29129": 0.1734936386346817, "29167": 0.08154398202896118, "29494": 0.01934296265244484, "29577": 0.02887592278420925} | 16962732 | We describe a technique for rapid labeling of a large number of cells in the nervous system with many different colors. By delivering lipophilic dye-coated particles to neuronal preparations with a "gene gun," individual neurons and glia whose membranes are contacted by the particles are quickly labeled. Using particles that are each coated with different combinations of various lipophilic dyes, many cells within a complex neuronal network can be simultaneously labeled with a wide variety of colors. This approach is most effective in living material but also labels previously fixed material. In living material, labeled neurons continue to show normal synaptic responses and undergo dendritic remodeling. This technique is thus useful for studying structural plasticity of neuronal circuits in living preparations. In addition, the Golgi-like labeling of neurons with many different colors provides a novel way to study neuronal connectivity. | Multicolor “DiOlistic” Labeling of the Nervous System Using Lipophilic Dye Combinations |
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"28290": 0.2990913391113281, "28764": 0.13157635927200317, "28911": 0.2652147710323334, "29010": 0.30989447236061096, "29260": 0.1602703034877777} | 16963081 | Birds are difficult to sex. Nestlings rarely show sex-linked morphology and we estimate that adult females appear identical to males in over 50% of the world's bird species. This problem can hinder both evolutionary studies and human-assisted breeding of birds. DNA-based sex identification provides a solution. We describe a test based on two conserved CHD (chromo-helicase-DNA-binding) genes that are located on the avian sex chromosomes of all birds, with the possible exception of the ratites (ostriches, etc.; Struthioniformes). The CHD-W gene is located on the W chromosome; therefore it is unique to females. The other gene, CHD-Z, is found on the Z chromosome and therefore occurs in both sexes (female, ZW; male, ZZ). The test employs PCR with a single set of primers. It amplifies homologous sections of both genes and incorporates introns whose lengths usually differ. When examined on a gel there is a single CHD-Z band in males but females have a second, distinctive CHD-W band. | A DNA test to sex most birds. |
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sequentially generate neurons and then glial cells, but the mechanisms regulating this neurogenic-to-gliogenic transition are unclear. Using cortical precursor cultures, which temporally mimic this in vivo differentiation pattern, we demonstrate that cortical neurons synthesize and secrete the neurotrophic cytokine cardiotrophin-1, which activates the gp130-JAK-STAT pathway and is essential for the timed genesis of astrocytes in vitro. Our data indicate that a similar phenomenon also occurs in vivo. In utero electroporation of neurotrophic cytokines in the environment of embryonic cortical precursors causes premature gliogenesis, while acute perturbation of gp130 in cortical precursors delays the normal timed appearance of astrocytes. Moreover, the neonatal cardiotrophin-1-/- cortex contains fewer astrocytes. Together, these results describe a neural feedback mechanism; newly born neurons produce cardiotrophin-1, which instructs multipotent cortical precursors to generate astrocytes, thereby ensuring that gliogenesis does not occur until neurogenesis is largely complete. | Evidence that Embryonic Neurons Regulate the Onset of Cortical Gliogenesis via Cardiotrophin-1 |
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TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration. | The Inhibition of TDP-43 Mitochondrial Localization Blocks Its Neuronal Toxicity |
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accountability, and poor quality of peer review has led to questions about the imbalance in anonymity between reviewers and authors. OBJECTIVE To evaluate the effect on the quality of peer review of blinding reviewers to the authors' identities and requiring reviewers to sign their reports. DESIGN Randomized controlled trial. SETTING A general medical journal. PARTICIPANTS A total of 420 reviewers from the journal's database. INTERVENTION We modified a paper accepted for publication introducing 8 areas of weakness. Reviewers were randomly allocated to 5 groups. Groups 1 and 2 received manuscripts from which the authors' names and affiliations had been removed, while groups 3 and 4 were aware of the authors' identities. Groups 1 and 3 were asked to sign their reports, while groups 2 and 4 were asked to return their reports unsigned. The fifth group was sent the paper in the usual manner of the journal, with authors' identities revealed and a request to comment anonymously. Group 5 differed from group 4 only in that its members were unaware that they were taking part in a study. MAIN OUTCOME MEASURE The number of weaknesses in the paper that were commented on by the reviewers. RESULTS Reports were received from 221 reviewers (53%). The mean number of weaknesses commented on was 2 (1.7, 2.1, 1.8, and 1.9 for groups 1, 2, 3, and 4 and 5 combined, respectively). There were no statistically significant differences between groups in their performance. Reviewers who were blinded to authors' dentities were less likely to recommend rejection than those who were aware of the authors' identities (odds ratio, 0.5; 95% confidence interval, 0.3-1.0). CONCLUSIONS Neither blinding reviewers to the authors and origin of the paper nor requiring them to sign their reports had any effect on rate of detection of errors. Such measures are unlikely to improve the quality of peer review reports. | Effect on the quality of peer review of blinding reviewers and asking them to sign their reports: a randomized controlled trial. |
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0.0354953333735466, "29490": 0.07884006202220917} | 16980892 | BACKGROUND More than 2 million U.S. women receive an equivocal cervical cytologic diagnosis (atypical squamous cells of undetermined significance [ASCUS]) each year. Effective colposcopy triage strategies are needed to identify the minority of women who have clinically significant disease while avoiding excessive follow-up evaluation for others. METHODS The ASCUS/LSIL (i.e., low-grade squamous intraepithelial lesion) Triage Study (ALTS) is a multicenter, randomized trial comparing the sensitivity and specificity of the following three management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3): 1) immediate colposcopy (considered to be the reference standard), 2) triage to colposcopy based on human papillomavirus (HPV) results from Hybrid Capture 2(TM) (HC 2) and thin-layer cytology results, or 3) triage based on cytology results alone. This article summarizes the cross-sectional enrollment results for 3488 women with a referral diagnosis of ASCUS. All statistical tests are two-sided. RESULTS Among participants with ASCUS, the underlying prevalence of histologically confirmed CIN3 was 5.1%. Sensitivity to detect CIN3 or above by testing for cancer-associated HPV DNA was 96.3% (95% confidence interval [CI] = 91.6% to 98.8%), with 56.1% of women referred to colposcopy. Sensitivity of a single repeat cytology specimen with a triage threshold of HSIL or above was 44.1% (95% CI = 35.6% to 52.9%), with 6.9% referred. Sensitivity of a lower cytology triage threshold of ASCUS or above was 85.3% (95% CI = 78.2% to 90.8%), with 58.6% referred. CONCLUSIONS HC 2 testing for cancer-associated HPV DNA is a viable option in the management of women with ASCUS. It has greater sensitivity to detect CIN3 or above and specificity comparable to a single additional cytologic test indicating ASCUS or above. | 2001. Comparison of three management strategies for patients with atypical squamous cells of undetermined significance. Baseline results from a randomized trial |
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"26013": 0.8281423449516296, "26261": 0.3443928062915802, "26838": 0.17759032547473907, "27116": 0.37371641397476196, "27287": 0.8957691192626953, "27321": 0.732405424118042, "27462": 0.06429435312747955, "28086": 0.3141832649707794, "28156": 0.40285754203796387, "28177": 0.04113444685935974, "28625": 0.6950984001159668, "28691": 0.04860413447022438, "28788": 0.2763880789279938, "28873": 0.01934296265244484, "29206": 0.07884006202220917} | 16999023 | To characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate-tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as at a single-cell level. A subpopulation of Sox2+ cells gives rise to cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response to mitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs as well as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role in maintaining the constant size of the NSC pool and producing newly born neurons during adult neurogenesis. | Cell Stem Cell Article In Vivo Fate Analysis Reveals the Multipotent and Self-Renewal Capacities of Sox2 + Neural Stem Cells in the Adult Hippocampus |
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exposure is associated with a reduced risk of multiple sclerosis. DESIGN Population based case-control study. SETTING Tasmania, latitudes 41-3 degrees S. PARTICIPANTS 136 cases with multiple sclerosis and 272 controls randomly drawn from the community and matched on sex and year of birth. MAIN OUTCOME MEASURE Multiple sclerosis defined by both clinical and magnetic resonance imaging criteria. RESULTS Higher sun exposure when aged 6-15 years (average 2-3 hours or more a day in summer during weekends and holidays) was associated with a decreased risk of multiple sclerosis (adjusted odds ratio 0.31, 95% confidence interval 0.16 to 0.59). Higher exposure in winter seemed more important than higher exposure in summer. Greater actinic damage was also independently associated with a decreased risk of multiple sclerosis (0.32, 0.11 to 0.88 for grades 4-6 disease). A dose-response relation was observed between multiple sclerosis and decreasing sun exposure when aged 6-15 years and with actinic damage. CONCLUSION Higher sun exposure during childhood and early adolescence is associated with a reduced risk of multiple sclerosis. Insufficient ultraviolet radiation may therefore influence the development of multiple sclerosis. | Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case-control study. |
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"27512": 1.2192846536636353, "27570": 0.052318159490823746, "27642": 0.46608972549438477, "27777": 0.022212404757738113, "27854": 0.41389304399490356, "27989": 0.0797421783208847, "28086": 0.27786844968795776, "28242": 0.22001366317272186, "28636": 0.3923587501049042, "28667": 0.09317722171545029, "28696": 0.03266380727291107, "29145": 1.2522047758102417, "29290": 0.37102460861206055, "29304": 0.06703783571720123, "29431": 0.12986256182193756, "29461": 0.02887592278420925, "29516": 0.11778303235769272} | 17017465 | The small GTPases, Rab5 and Rac, are essential for endocytosis and actin remodeling, respectively. Coordination of these processes is critical to achieve spatial restriction of intracellular signaling, which is essential for a variety of polarized functions. Here, we show that clathrin- and Rab5-mediated endocytosis are required for the activation of Rac induced by motogenic stimuli. Rac activation occurs on early endosomes, where the RacGEF Tiam1 is also recruited. Subsequent recycling of Rac to the plasma membrane ensures localized signaling, leading to the formation of actin-based migratory protrusions. Thus, membrane trafficking of Rac is required for the spatial resolution of Rac-dependent motogenic signals. We further demonstrate that a Rab5-to-Rac circuitry controls the morphology of motile mammalian tumor cells and primordial germinal cells during zebrafish development, suggesting that this circuitry is relevant for the regulation of migratory programs in various cells, in both in vitro settings and whole organisms. | Endocytic Trafficking of Rac Is Required for the Spatial Restriction of Signaling in Cell Migration |
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0.021256839856505394, "26305": 0.12556517124176025, "26520": 0.31560876965522766, "26601": 0.0606246218085289, "26605": 0.052318159490823746, "26745": 0.822151780128479, "26986": 0.11865071207284927, "27144": 0.043007105588912964, "27528": 0.04487626627087593, "27711": 0.7827593088150024, "27781": 0.11430477350950241, "27793": 0.1477125883102417, "27881": 0.2667117714881897, "28086": 0.10555581003427505, "28207": 0.20580662786960602, "28293": 0.12986256182193756, "28378": 0.75193190574646, "28637": 0.0913962796330452, "28873": 0.3127557039260864, "28991": 1.5841201543807983, "29191": 0.06520967930555344, "29295": 0.32270604372024536, "29490": 0.15860503911972046} | 17021845 | The aim of the present study was to analyze the stem cell marker, Nanog gene, for the diagnosis and prognosis of lung cancer cases, and to study its application in the diagnosis of lung cancer. In total, 100 patients diagnosed with lung cancer between April, 2013 and May, 2015 were included in the present study. The patients were randomly divided into group A (lung cancer) and group B (squamous cell lung carcinoma). RT-PCR was used to detect the cancer and adjacent tissues, and Nanog gene expression was detected in groups A and B in cells. The results showed that, analysis of Nanog gene expression in the two groups of patients varied to different degrees. There was no significant difference between the two groups with regard to age, gender, disease stage and lymph node metastasis. Nanog gene expression in patients with carcinoma were significantly higher than that in the adjacent tissues (p<0.05). By contrast, differentiated and well-differentiated carcinoma tissue showed a significantly higher Nanog gene expression than poorly differentiated and undifferentiated carcinoma (p<0.05). The expression of Nanog in normal cells was significantly higher than that in normal lung tissues and benign lesions in lung cancer stem cells. Nanog was highly expressed in CD44+ cells, and Nanog expression in lung cancer stem cells was significantly higher (p<0.05). In conclusion, for groups A (lung cancer) and B (squamous cell lung carcinoma) the Nanog gene expression was significantly higher. The data of the present study show that the patients with stage III and IV lung cancer had a higher Nanog gene expression. In addition, there was a higher expression of Nanog in lung cancer patients. By contrast, a lower degree of cell differentiation was associated with strong Nanog gene expression in lung cancer. | Significance of stem cell marker Nanog gene in the diagnosis and prognosis of lung cancer |
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of dying from the condition. Sepsis care costs billions annually in the United States. Death from sepsis is understood to be a complex process, driven by a lack of normal immune homeostatic functions and excessive production of proinflammatory cytokines, which leads to multi-organ failure. The Toll-like receptor (TLR) family, one of whose members was initially discovered in Drosophila, performs an important role in the recognition of microbial pathogens. These pattern recognition receptors (PRRs), upon sensing invading microorganisms, activate intracellular signal transduction pathways. NOD signaling is also involved in the recognition of bacteria and acts synergistically with the TLR family in initiating an efficient immune response for the eradication of invading microbial pathogens. TLRs and NOD1/NOD2 respond to different pathogen-associated molecular patterns (PAMPs). Modulation of both TLR and NOD signaling is an area of research that has prompted much excitement and debate as a therapeutic strategy in the management of sepsis. Molecules targeting TLR and NOD signaling pathways exist but regrettably thus far none have proven efficacy from clinical trials. | Current knowledge and future directions of TLR and NOD signaling in sepsis |
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neuroepithelium, the nucleus in neural progenitor cells (NPCs) moves from the apex toward the base and returns to the apex (called interkinetic nuclear migration) at which point the cell divides. The fate of the resulting daughter cells is thought to depend on the sampling by the moving nucleus of a spatial concentration profile of the cytoplasmic Notch intracellular domain (NICD). However, the nucleus executes complex stochastic motions including random waiting and back and forth motions, which can expose the nucleus to randomly varying levels of cytoplasmic NICD. How nuclear position can determine daughter cell fate despite the stochastic nature of nuclear migration is not clear. Here we derived a mathematical model for reaction, diffusion, and nuclear accumulation of NICD in NPCs during interkinetic nuclear migration (INM). Using experimentally measured trajectory-dependent probabilities of nuclear turning, nuclear waiting times and average nuclear speeds in NPCs in the developing zebrafish retina, we performed stochastic simulations to compute the nuclear trajectory-dependent probabilities of NPC differentiation. Comparison with experimentally measured nuclear NICD concentrations and trajectory-dependent probabilities of differentiation allowed estimation of the NICD cytoplasmic gradient. Spatially polarized production of NICD, rapid NICD cytoplasmic consumption and the time-averaging effect of nuclear import/export kinetics are sufficient to explain the experimentally observed differentiation probabilities. Our computational studies lend quantitative support to the feasibility of the nuclear concentration-sensing mechanism for NPC fate determination in zebrafish retina. | Concentration Sensing by the Moving Nucleus in Cell Fate Determination: A Computational Analysis |
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"23691": 0.3499138653278351, "23758": 0.3560888469219208, "23892": 0.5381823778152466, "23958": 0.41840189695358276, "24411": 0.004870930220931768, "24836": 0.007782140281051397, "25185": 0.15023678541183472, "25206": 0.18492233753204346, "25357": 0.9045027494430542, "25476": 0.08782484382390976, "25604": 0.0770333781838417, "25605": 0.3141832649707794, "25700": 0.014542185701429844, "26014": 0.11865071207284927, "26083": 0.4196864068508148, "26305": 0.0606246218085289, "26524": 0.1401015669107437, "26534": 0.13414156436920166, "26651": 0.512191891670227, "26741": 0.06246116757392883, "26797": 0.6202403903007507, "27136": 0.5540198087692261, "27178": 0.045809537172317505, "27325": 0.2018241584300995, "27574": 0.013579257763922215, "28163": 0.2822965085506439, "28696": 0.2478361576795578} | 17050065 | Following prolonged exposure to an odorant, C. elegans exhibits a diminished response to the odorant for several hours. This olfactory adaptation is odorant selective; animals can adapt independently to different odorants sensed by a single pair of olfactory neurons, the AWC neurons. The mechanism of olfactory adaptation is genetically complex, with different genes required for adaptation to different odorants. Animals mutant for the gene adp-1 fail to adapt to a subset of AWC-sensed odorants; adp-1 affects a calcium-dependent process required for adaptation. Mutations in another gene, osm-9, affect adaptation to a different but overlapping subset of AWC-sensed odorants. Mutations in adp-1 and osm-9 do not diminish the ability of unadapted animals to respond to odorants, indicating that odorant sensation and odorant adaptation are distinct processes. | Odorant-specific adaptation pathways generate olfactory plasticity in C. elegans |
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"25032": 0.8349450826644897, "25194": 0.20102575421333313, "25202": 0.574020504951477, "25456": 0.5330380201339722, "25524": 0.6389714479446411, "25644": 0.7500885725021362, "25761": 0.1212492436170578, "26083": 1.138809084892273, "26208": 0.13243216276168823, "26288": 0.22548456490039825, "26305": 0.09495500475168228, "26402": 1.024303913116455, "26462": 0.7258110046386719, "26512": 0.7881022095680237, "26534": 0.4556184411048889, "26585": 0.3743882179260254, "26773": 0.3409265875816345, "26775": 0.42990362644195557, "26906": 0.3615458607673645, "26944": 0.4374985992908478, "27226": 0.3982778787612915, "27295": 0.014542185701429844, "27330": 0.03831886500120163, "27749": 0.1946154683828354, "28144": 0.9084475636482239} | 17055665 | FoxO transcription factors, inhibited by insulin/insulin-like growth factor signalling (IIS), are crucial players in numerous organismal processes including lifespan. Using genomic tools, we uncover over 700 direct dFOXO targets in adult female Drosophila. dFOXO is directly required for transcription of several IIS components and interacting pathways, such as TOR, in the wild-type fly. The genomic locations occupied by dFOXO in adults are different from those observed in larvae or cultured cells. These locations remain unchanged upon activation by stresses or reduced IIS, but the binding is increased and additional targets activated upon genetic reduction in IIS. We identify the part of the IIS transcriptional response directly controlled by dFOXO and the indirect effects and show that parts of the transcriptional response to IIS reduction do not require dfoxo. Promoter analyses revealed GATA and other forkhead factors as candidate mediators of the indirect and dfoxo-independent effects. We demonstrate genome-wide evolutionary conservation of dFOXO targets between the fly and the worm Caenorhabditis elegans, enriched for a second tier of regulators including the dHR96/daf-12 nuclear hormone receptor. | Genome-wide dFOXO targets and topology of the transcriptomic response to stress and insulin signalling |
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17077004 | OBJECTIVES To explore the association between a stable partnership and clinical outcome in HIV infected patients receiving highly active antiretroviral therapy (HAART). DESIGN Prospective cohort study of adults with HIV (Swiss HIV cohort study). SETTING Seven outpatient clinics throughout Switzerland. PARTICIPANTS The 3736 patients in the cohort who started HAART before 2002 (median age 36 years, 29% female, median follow up 3.6 years). MAIN OUTCOME MEASURES Time to AIDS or death (primary endpoint), death alone, increases in CD4 cell count of at least 50 and 100 above baseline, optimal viral suppression (a viral load below 400 copies/ml), and viral rebound. RESULTS During follow up 2985 (80%) participants reported a stable partnership on at least one occasion. When starting HAART, 52% (545/1042) of participants reported a stable partnership; after five years of follow up 46% (190/412) of participants reported a stable partnership. In an analysis stratified by previous antiretroviral therapy and clinical stage when starting HAART (US Centers for Disease Control and Prevention group A, B, or C), the adjusted hazard ratio for progression to AIDS or death was 0.79 (95% confidence interval 0.63 to 0.98) for participants with a stable partnership compared with those without. Adjusted hazards ratios for other endpoints were 0.59 (0.44 to 0.79) for progression to death, 1.15 (1.06 to 1.24) for an increase in CD4 cells of 100 counts/microl or more, and 1.06 (0.98 to 1.14) for optimal viral suppression. CONCLUSIONS A stable partnership is associated with a slower rate of progression to AIDS or death in HIV infected patients receiving HAART. | Stable partnership and progression to AIDS or death in HIV infected patients receiving highly active antiretroviral therapy: Swiss HIV cohort study. |
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retinal ON bipolar cells, we generated knockout mice lacking mGluR6 expression. The homozygous mutant mice showed a loss of ON responses but unchanged OFF responses to light. The mutant mice displayed no obvious changes in retinal cell organization nor in the projection of optic fibers to the brain. Furthermore, the mGluR6-deficient mice showed visual behavioral responses to light stimulation as examined by shuttle box avoidance behavior experiments using light exposure as a conditioned stimulus. The results demonstrate that mGluR6 is essential in synaptic transmission to the ON bipolar cell and that the OFF response provides an important means for transmitting visual information. | Specific deficit of the ON response in visual transmission by targeted disruption of the mGIuR6 gene |
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"27881": 0.05046287178993225, "28207": 0.19782574474811554, "28290": 0.52266925573349, "28436": 0.10555581003427505, "28873": 0.1510767638683319, "29060": 0.1358480453491211, "29206": 0.14518201351165771} | 17088791 | Most multiple case families of young onset breast cancer and ovarian cancer are thought to be due to highly penetrant mutations in the predisposing genes BRCA1 and BRCA2. However, these mutations are uncommon in the population and they probably account for only a few percent of all breast cancer incidence. A much larger fraction of breast cancer might, in principle, be due to common variants which confer more modest individual risks. There are several common polymorphisms in the BRCA1 gene which generate amino acid substitutions. We have examined the frequency of four of these polymorphisms: Gln356Arg, Pro871Leu, Glu1038Gly and Ser1613Gly in large series of breast and ovarian cancer cases and matched controls. Due to strong linkage disequilibrium, these four sites generate only three haplotypes with a frequency > 1.3%. The most common haplotypes, defined by the alleles Gln356Pro871Glu1038Ser1613 and Gln356Leu871Gly1038Gly1613, have frequencies of 0.57 and 0.32 respectively, and these frequencies do not differ significantly between patient and control groups. Thus the most common polymorphisms of the BRCA1 gene do not make a significant contribution to breast or ovarian cancer risk. However, our data suggest that the Arg356 allele may have a different genotype distribution in breast cancer patients from that in controls (Arg356 homozygotes are more frequent in the control groups, P = 0.01), indicating that it may be protective against breast cancer. If this finding can be confirmed, it may provide an insight into the structural features of the BRCA1 protein that are important for its function. | Common BRCA1 variants and susceptibility to breast and ovarian cancer in the general population. |
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(NO) is produced in the vascular endothelium and is a potent vasodilator substance that participates in the regulation of local vascular tone. Exercise causes peculiar changes in systemic and regional blood flow, i.e., an increase of systemic blood flow and a redistribution of local tissue blood flow, by which the blood flow is greatly increased in the working muscles, whereas it is decreased in some organs such as the kidney and intestine. Thus we hypothesized that exercise causes a tissue-specific change of NO production in some internal organs. We studied whether exercise affects expression of NO synthase (NOS) mRNA and protein, NOS activity, and tissue level of nitrite/nitrate (stable end products of NO) in the kidneys (in which blood flow during exercise is decreased) and lungs (in which blood flow during exercise is increased with the increase of cardiac output) of rat. Rats ran on a treadmill for 45 min at a speed of 25 m/min. Immediately after this exercise, kidneys and lungs were quickly removed. Control rats remained at rest during this 45-min period. Expression of endothelial NOS (eNOS) mRNA in the kidneys was markedly lower in exercise rats than in control rats, whereas that in the lungs was significantly higher in exercise rats than in control rats. Western blot analysis confirmed down- and upregulation of eNOS protein in the kidney and lung, respectively, after exercise. On the other hand, neither expression of neuronal NOS (nNOS) mRNA and nNOS protein nor inducible NOS (iNOS) mRNA and iNOS protein in the kidneys and lungs differed between exercise and control rats. NOS activity in the kidney was significantly lower in exercise rats than in control rats, whereas that in the lung was significantly higher in exercise rats than in control rats. On the other hand, the iNOS activity in the kidneys and lungs did not differ between exercise rats and control rats. Tissue nitrite/nitrate level in the kidneys was markedly lower in exercise rats, whereas that in the lungs was significantly higher in exercise rats. The present results show that production of NO is markedly and tissue-specifically changed in the kidney and lung by exercise. | Exercise causes a tissue-specific change of NO production in the kidney and lung. |
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0.17759032547473907, "28788": 0.5324648022651672, "28815": 0.1946154683828354, "28847": 0.9546096324920654, "29060": 0.48430517315864563, "29076": 0.06154331564903259, "29105": 0.06246116757392883, "29107": 0.15526613593101501, "29129": 0.0797421783208847, "29215": 1.2041680812835693, "29304": 0.6862877607345581} | 17101262 | Protoplasmic astrocytes in mammalian CNS tissues in vivo have a highly complex 3D morphology, but in dissociated cell cultures they often assume a flattened, fibroblast-like morphology bearing only a few, simple processes. By fluorescent labeling and confocal reconstruction we show that many astrocytes in organotypic hippocampal slice cultures exhibit a more native complex cytoarchitecture. Although astrocytes at the surface of slice cultures show a reactive form with several thick glial fibrillary acidic protein (GFAP)-positive processes, astrocytes situated in deeper portions of tissue slices retain a highly complex 3D morphology with many fine spine- or veil-like protrusions. Dozens of astrocytes can be labeled in single slice cultures by gene gun-mediated ballistic delivery of gold or tungsten particles carrying cDNAs (Biolistics), lipophilic dyes (DiOlistics), or fluorescent intracellular calcium indicators (Calistics). Expression of a membrane-targeted form of eGFP (Lck-GFP) is superior to soluble eGFP for resolving fine astrocytic processes. Time-lapse confocal imaging of Lck-GFP transfected astrocytes or "calistically" labeled astrocytes show structural remodeling and calcium transients, respectively. This approach provides an in vitro system for investigating the functional architecture, development and dynamic remodeling of astrocytes and their relationships to neurons and glia in live mammalian brain tissues. | Ballistic labeling and dynamic imaging of astrocytes in organotypic hippocampal slice cultures |
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"26340": 0.0009760859538801014, "26402": 0.3923587501049042, "26417": 0.24018502235412598, "26475": 0.8057082891464233, "26616": 0.41195443272590637, "26802": 1.0285027027130127, "27000": 0.15860503911972046, "27118": 0.7124901413917542, "27345": 0.7647408246994019, "27381": 1.2358801364898682, "27454": 0.10731173306703568, "27920": 0.6823468804359436, "28086": 1.3128622770309448, "28156": 0.3601844012737274, "28214": 0.21372433006763458, "28667": 0.6719275116920471, "29290": 0.37707099318504333} | 17119869 | The pancreas emerges independently from dorsal and ventral domains of embryonic gut endoderm. Gene inactivation experiments in mice have identified factors required for dorsal pancreas development, but factors that initiate the ventral pancreas have remained elusive. In this study, we investigated the hypothesis that the emergence of the ventral pancreas is related to the emergence of the liver. We find that the liver and ventral pancreas are specified at the same time and in the same general domain of cells. Using embryo tissue explantation experiments, we find that the default fate of the ventral foregut endoderm is to activate the pancreas gene program. FGF signalling from the cardiac mesoderm diverts this endoderm to express genes for liver instead of those for pancreas. No evidence was found to indicate that the cell type choice for pancreas or liver involves a selection for growth or viability. Cardiac mesoderm or FGF induces the local expression of sonic hedgehog, which in turn is inhibitory to pancreas but not to liver. The bipotential precursor cell population for pancreas and liver in embryonic development and its fate selection by FGF has features that appear to be recapitulated in the adult pancreas and are reflected in the evolution of these organs. | A bipotential precursor population for pancreas and liver within the embryonic endoderm. |
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