text
stringlengths
174
850
embeddings_A
sequence
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
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0.008429958, 0.0022314594, -0.0018595495 ]
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
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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
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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
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-0.009019133, 0.0014440838 ]
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
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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 Circ
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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,
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Sex differences in longevity and aging are seen throughout the animal kingdom. 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
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H2-M3 is a class Ib MHC molecule of the mouse with a 10(4)-fold preference for binding N-formylated peptides. 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
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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
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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 astrogl
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Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. 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
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Endocytic mechanisms control the lipid and protein composition of the plasma membrane, thereby regulating how cells interact with their environments. 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,
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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
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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 PT
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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 integr
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Notch receptors expressed on hematopoietic stem cells interact with their ligands on bone marrow stromal cells 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
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-0.014272432, 0.000619785, -0.009770922 ]
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
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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
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Dysfunction of the pancreatic beta cell is an important defect in the pathogenesis of type 2 diabetes, although its exact relationship to the insulin resistance is unclear. 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
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OBJECTIVES To determine the extent to which type of hospital 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
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Genomes are arranged 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
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Afferent activity can induce fast, feed-forward changes in synaptic efficacy that are synapse specific. 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
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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
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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,
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Macromolecular X-ray crystallography is routinely applied to understand biological processes at a molecular level. 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
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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
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G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. 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
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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
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Receptor tyrosine kinases are involved in regulation of key processes in endothelial biology, including proliferation, migration, and angiogenesis. 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-
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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 (
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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.
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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
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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
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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 SW
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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 imprint
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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
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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-
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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
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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
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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 is
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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 (
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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
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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
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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
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Stem cells persist throughout life in diverse tissues by undergoing self-renewing divisions. 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
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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
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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 RRM
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Telomeres protect chromosome ends from being detected as lesions and from triggering DNA damage checkpoints. 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)
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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 qu
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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
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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
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The estrogen receptor is the master transcriptional regulator of breast cancer phenotype and the archetype of a molecular therapeutic target. 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.
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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
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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
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Chemical-protein interaction (CPI) is the central topic of target identification and drug discovery. 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
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Healthy cells utilize intricate systems to monitor their environment and mount robust responses in the event of cellular stress. 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
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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
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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)
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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 OR
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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
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Kinetochores couple chromosomes to the assembling and disassembling tips of microtubules, a dynamic behavior that is fundamental to mitosis in all eukaryotes but poorly understood. 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 N
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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
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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
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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.
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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 A
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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
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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.
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0.0091758715, 0.0063793208, -0.0032593254, -0.031209907 ]
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
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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 Fr
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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(-)/
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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
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Human mesenchymal stem cells (MSCs) have increasingly been used as cellular vectors for the delivery of therapeutic genes to tumors. 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
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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
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Inflammasomes are multiprotein complexes that link pathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1β (IL-1β). 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
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-0.002973127, -0.017381864 ]
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
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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
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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
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In higher eukaryotes, introns are spliced out of protein-coding mRNAs by the spliceosome, a massive complex comprising five non-coding RNAs (ncRNAs) and about 200 proteins. 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
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Variation in cerebral cortex size and complexity is thought to contribute to differences in cognitive ability between humans and other animals. 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
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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
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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;
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Precursor cells of the embryonic cortex 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
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Genetic mutations in 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
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CONTEXT Anxiety about bias, lack of 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
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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
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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
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OBJECTIVE To examine whether past high sun 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
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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.
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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
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The incidence of sepsis is increasing over time, along with an increased risk 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
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During development of the vertebrate 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
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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
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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
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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
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Taking advantage of the restricted expression of metabotropic glutamate receptor subtype 6 (mGluR6) in 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
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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, Glu103
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Nitric oxide (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
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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
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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 pancre
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