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However, no systematic study has previously tested this hypothesis in whole animals.
We report here the results of the first study to investigate in a natural mosquito host the functional significance of the opal stop codon in an alphavirus genome.
We used a full-length cDNA clone of ONNV to construct a series of mutants in which the arginine between nsP3 and nsP4 was replaced with an opal, ochre, or amber stop codon. | scifact_100 |
The presence of an opal stop codon upstream of nsP4 nearly doubled (75.5%) the infectivity of ONNV over that of virus possessing a codon for the amino acid arginine at the corresponding position (39.8%).
Although the frequency with which the opal virus disseminated from the mosquito midgut did not differ significantly from that of the arginine virus on days 8 and 10, dissemination did began earlier in mosquitoes infected with the opal virus. | scifact_101 |
Although a clear fitness advantage is provided to ONNV by the presence of an opal codon between nsP3 and nsP4 in Anopheles gambiae, sequence analysis of ONNV RNA extracted from mosquito bodies and heads indicated codon usage at this position corresponded with that of the virus administered in the blood meal.
These results suggest that while selection of ONNV variants is occurring, de novo mutation at the position between nsP3 and nsP4 does not readily occur in the mosquito. | scifact_102 |
Taken together, these results suggest that the primary fitness advantage provided to ONNV by the presence of an opal codon between nsP3 and nsP4 is related to mosquito infectivity. | scifact_103 |
T cells transformed by Herpesvirus saimiri express seven viral U-rich noncoding RNAs of unknown function called HSURs.
We noted that conserved sequences in HSURs 1 and 2 constitute potential binding sites for three host-cell microRNAs (miRNAs).
Coimmunoprecipitation experiments confirmed that HSURs 1 and 2 interact with the predicted miRNAs in virally transformed T cells. | scifact_104 |
The abundance of one of these miRNAs, miR-27, is dramatically lowered in transformed cells, with consequent effects on the expression of miR-27 target genes.
Transient knockdown and ectopic expression of HSUR 1 demonstrate that it directs degradation of mature miR-27 in a sequence-specific and binding-dependent manner.
This viral strategy illustrates use of a ncRNA to manipulate host-cell gene expression via the miRNA pathway. | scifact_105 |
HTRF (Homogeneous Time Resolved Fluorescence) is the most frequently used generic assay technology to measure analytes in a homogenous format, which is the ideal platform used for drug target studies in high-throughput screening (HTS).
This technology combines fluorescence resonance energy transfer technology (FRET) with time-resolved measurement (TR). | scifact_106 |
In TR-FRET assays, a signal is generated through fluorescent resonance energy transfer between a donor and an acceptor molecule when in close proximity to each other.
Buffer and media interference is dramatically reduced by dual-wavelength detection, and the final signal is proportional to the extent of product formation.
The HTRF assay is usually sensitive and robust that can be miniaturized into the 384 and 1536-well plate formats. | scifact_107 |
This assay technology has been applied to many antibody-based assays including GPCR signaling (cAMP and IP-One), kinases, cytokines and biomarkers, bioprocess (antibody and protein production), as well as the assays for protein-protein, proteinpeptide, and protein-DNA/RNA interactions.
Since its introduction to the drug-screening world over ten years ago, researchers have used HTRF to expedite the study of GPCRs, kinases, new biomarkers, protein-protein interactions, and other targets of interest. | scifact_108 |
HTRF has also been utilized as an alternative method for bioprocess monitoring.
The first-generation HTRF technology, which uses Europium cryptate as a fluorescence donor to monitor reactions between biomolecules, was extended in 2008 through the introduction of a second-generation donor, Terbium cryptate (Tb), enhancing screening performance.
Terbium cryptate possesses different photophysical properties compared to Europium, including increased quantum yield and a higher molar extinction coefficient. | scifact_109 |
In addition to being compatible with the same acceptor fluorophors used with Europium, it can serve as a donor fluorophore to green-emitting fluors because it has multiple emission peaks including one at 490 nm.
Moreover, all Terbium HTRF assays can be read on the same HTRF-compatible instruments as Europium HTRF assays. | scifact_110 |
Overall, HTRF is a highly sensitive, robust technology for the detection of molecular interactions in vitro and is widely used for primary and secondary screening phases of drug development.
This review addresses the general principles of HTRF and its current applications in drug discovery. | scifact_111 |
Replication origins are licensed by loading MCM2-7 hexamers before entry into S phase.
However, only ∼10% of licensed origins are normally used in S phase, with the others remaining dormant.
When fork progression is inhibited, dormant origins initiate nearby to ensure that all of the DNA is eventually replicated.
In apparent contrast, replicative stress activates ataxia telangiectasia and rad-3-related (ATR) and Chk1 checkpoint kinases that inhibit origin firing. | scifact_112 |
In this study, we show that at low levels of replication stress, ATR/Chk1 predominantly suppresses origin initiation by inhibiting the activation of new replication factories, thereby reducing the number of active factories.
At the same time, inhibition of replication fork progression allows dormant origins to initiate within existing replication factories. | scifact_113 |
The inhibition of new factory activation by ATR/Chk1 therefore redirects replication toward active factories where forks are inhibited and away from regions that have yet to start replication.
This minimizes the deleterious consequences of fork stalling and prevents similar problems from arising in unreplicated regions of the genome. | scifact_114 |
The tumor microenvironment (TME) plays a prominent role in the growth of tumor cells.
As the major inflammatory component of the TME, M2d macrophages are educated by the TME such that they adopt an immunosuppressive role that promotes tumor metastasis and progression.
Fra-1 forms activator protein-1 heterodimers with Jun partners and drives gene transcription.
Fra-1 is thought to drastically induce tumorigenesis and progression. | scifact_115 |
Fra-1 is thought to drastically induce tumorigenesis and progression.
However, the functional role of Fra-1 in the generation of M2d macrophages is poorly understood to date.
Here, we demonstrate that 4T1 mammary carcinoma cells, when co-cultured with RAW264.7 macrophage cells, skew the RAW264.7 macrophage cell differentiation into M2d macrophages. | scifact_116 |
The 4T1 cells stimulate de novo overexpression of Fra-1 in RAW264.7 cells, and then Fra-1 binds to the interleukin 6 (IL-6) promoter to increase the production of the cytokine IL-6 in RAW264.7 cells.
IL-6 acts in an autocrine fashion to skew RAW264.7 macrophage cell differentiation into M2d macrophages.
These findings open new insights into how to reverse M2d macrophage-induced immune tolerance to improve the efficacy of immunotherapeutic approaches. | scifact_117 |
A multitude of nanoparticles, such as titanium oxide (TiO2), zinc oxide, aluminum oxide, gold oxide, silver oxide, iron oxide, and silica oxide, are found in many chemical, cosmetic, pharmaceutical, and electronic products.
Recently, SiO2 nanoparticles were shown to have an inert toxicity profile and no association with an irreversible toxicological change in animal models.
Hence, exposure to SiO2 nanoparticles is on the increase. | scifact_118 |
Hence, exposure to SiO2 nanoparticles is on the increase.
SiO2 nanoparticles are routinely used in numerous materials, from strengthening filler for concrete and other construction composites, to nontoxic platforms for biomedical application, such as drug delivery and theragnostics.
On the other hand, recent in vitro experiments indicated that SiO2 nanoparticles were cytotoxic. | scifact_119 |
On the other hand, recent in vitro experiments indicated that SiO2 nanoparticles were cytotoxic.
Therefore, we investigated these nanoparticles to identify potentially toxic pathways by analyzing the adsorbed protein corona on the surface of SiO2 nanoparticles in the blood and brain of the rat.
Four types of SiO2 nanoparticles were chosen for investigation, and the protein corona of each type was analyzed using liquid chromatography-tandem mass spectrometry technology. | scifact_120 |
In total, 115 and 48 plasma proteins from the rat were identified as being bound to negatively charged 20 nm and 100 nm SiO2 nanoparticles, respectively, and 50 and 36 proteins were found for 20 nm and 100 nm arginine-coated SiO2 nanoparticles, respectively.
Higher numbers of proteins were adsorbed onto the 20 nm sized SiO2 nanoparticles than onto the 100 nm sized nanoparticles regardless of charge. | scifact_121 |
When proteins were compared between the two charges, higher numbers of proteins were found for arginine-coated positively charged SiO2 nanoparticles than for the negatively charged nanoparticles.
The proteins identified as bound in the corona from SiO2 nanoparticles were further analyzed with ClueGO, a Cytoscape plugin used in protein ontology and for identifying biological interaction pathways. | scifact_122 |
Proteins bound on the surface of nanoparticles may affect functional and conformational properties and distributions in complicated biological processes. | scifact_123 |
MOTIVATION The nucleosome is the basic repeating unit of chromatin.
It contains two copies each of the four core histones H2A, H2B, H3 and H4 and about 147 bp of DNA.
The residues of the histone proteins are subject to numerous post-translational modifications, such as methylation or acetylation.
Chromatin immunoprecipitiation followed by sequencing (ChIP-seq) is a technique that provides genome-wide occupancy data of these modified histone proteins, and it requires appropriate computational methods. | scifact_124 |
RESULTS We present NucHunter, an algorithm that uses the data from ChIP-seq experiments directed against many histone modifications to infer positioned nucleosomes.
NucHunter annotates each of these nucleosomes with the intensities of the histone modifications. | scifact_125 |
NucHunter annotates each of these nucleosomes with the intensities of the histone modifications.
We demonstrate that these annotations can be used to infer nucleosomal states with distinct correlations to underlying genomic features and chromatin-related processes, such as transcriptional start sites, enhancers, elongation by RNA polymerase II and chromatin-mediated repression. | scifact_126 |
Thus, NucHunter is a versatile tool that can be used to predict positioned nucleosomes from a panel of histone modification ChIP-seq experiments and infer distinct histone modification patterns associated to different chromatin states.
AVAILABILITY The software is available at http://epigen.molgen.mpg.de/nuchunter/. | scifact_127 |
Antigen-presenting, major histocompatibility complex (MHC) class II-rich dendritic cells are known to arise from bone marrow.
However, marrow lacks mature dendritic cells, and substantial numbers of proliferating less-mature cells have yet to be identified.
The methodology for inducing dendritic cell growth that was recently described for mouse blood now has been modified to MHC class II-negative precursors in marrow. | scifact_128 |
A key step is to remove the majority of nonadherent, newly formed granulocytes by gentle washes during the first 2-4 d of culture.
This leaves behind proliferating clusters that are loosely attached to a more firmly adherent "stroma.
"
At days 4-6 the clusters can be dislodged, isolated by 1-g sedimentation, and upon reculture, large numbers of dendritic cells are released. | scifact_129 |
The latter are readily identified on the basis of their distinct cell shape, ultrastructure, and repertoire of antigens, as detected with a panel of monoclonal antibodies.
The dendritic cells express high levels of MHC class II products and act as powerful accessory cells for initiating the mixed leukocyte reaction.
Neither the clusters nor mature dendritic cells are generated if macrophage colony-stimulating factor rather than granulocyte/macrophage colony-stimulating factor (GM-CSF) is applied. | scifact_130 |
Therefore, GM-CSF generates all three lineages of myeloid cells (granulocytes, macrophages, and dendritic cells).
Since > 5 x 10(6) dendritic cells develop in 1 wk from precursors within the large hind limb bones of a single animal, marrow progenitors can act as a major source of dendritic cells.
This feature should prove useful for future molecular and clinical studies of this otherwise trace cell type. | scifact_131 |
Nutritional excess is a major forerunner of type 2 diabetes.
It enhances the secretion of insulin, but attenuates insulin's metabolic actions in the liver, skeletal muscle and adipose tissue.
However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes, pointing to a key gap in our understanding of metabolic disease. | scifact_132 |
This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance.
Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity seems to be largely elicited downstream of these steps.
New findings also connect insulin resistance to extensive metabolic cross-talk between the liver, adipose tissue, pancreas and skeletal muscle. | scifact_133 |
These and other advances over the past 5 years offer exciting opportunities and daunting challenges for the development of new therapeutic strategies for the treatment of type 2 diabetes. | scifact_134 |
BACKGROUND Patients undergoing dialysis have a substantially increased risk of cardiovascular mortality and morbidity.
Although several trials have shown the cardiovascular benefits of lowering blood pressure in the general population, there is uncertainty about the efficacy and tolerability of reducing blood pressure in patients on dialysis.
We did a systematic review and meta-analysis to assess the effect of blood pressure lowering in patients on dialysis. | scifact_135 |
METHODS We systematically searched Medline, Embase, and the Cochrane Library database for trials reported between 1950 and November, 2008, without language restriction.
We extracted a standardised dataset from randomised controlled trials of blood pressure lowering in patients on dialysis that reported cardiovascular outcomes.
Meta-analysis was done with a random effects model. | scifact_136 |
FINDINGS We identified eight relevant trials, which provided data for 1679 patients and 495 cardiovascular events.
Weighted mean systolic blood pressure was 4.5 mm Hg lower and diastolic blood pressure 2.3 mm Hg lower in actively treated patients than in controls. | scifact_137 |
Blood pressure lowering treatment was associated with lower risks of cardiovascular events (RR 0.71, 95% CI 0.55-0.92; p=0.009), all-cause mortality (RR 0.80, 0.66-0.96; p=0.014), and cardiovascular mortality (RR 0.71, 0.50-0.99; p=0.044) than control regimens.
The effects seem to be consistent across a range of patient groups included in the studies. | scifact_138 |
INTERPRETATION Treatment with agents that lower blood pressure should routinely be considered for individuals undergoing dialysis to reduce the very high cardiovascular morbidity and mortality rate in this population. | scifact_139 |
Early region 3 (E3) of group C human adenoviruses (Ad) encodes several inhibitors of tumor necrosis factor alpha (TNF-alpha) cytolysis, including an E3 14.7-kDa protein (E3-14.7K) and a heterodimer containing two polypeptides of 10.4 and 14.5 kDa.
To understand the mechanism by which the viral proteins inhibit TNF-alpha functions, the E3-14.7K protein was used to screen a HeLa cell cDNA library to search for interacting proteins in the yeast two-hybrid system. | scifact_140 |
A novel protein containing multiple leucine zipper domains without any significant homology with any known protein was identified and has been named FIP-2 (for 14.7K-interacting protein).
FIP-2 interacted with E3-14.7K both in vitro and in vivo.
It colocalized with Ad E3-14.7K in the cytoplasm, especially near the nuclear membrane, and caused redistribution of the viral protein. | scifact_141 |
FIP-2 by itself does not cause cell death; however, it can reverse the protective effect of E3-14.7K on cell killing induced by overexpression of the intracellular domain of the 55-kDa TNF receptor or by RIP, a death protein involved in the TNF-alpha and Fas apoptosis pathways.
Deletion analysis indicates that the reversal effect of FIP-2 depends on its interaction with E3-14.7K. | scifact_142 |
Three major mRNA forms of FIP-2 have been detected in multiple human tissues, and expression of the transcripts was induced by TNF-alpha treatment in a time-dependent manner in two different cell lines.
FIP-2 has consensus sequences for several potential posttranslational modifications.
These data suggest that FIP-2 is one of the cellular targets for Ad E3-14.7K and that its mechanism of affecting cell death involves the TNF receptor, RIP, or a downstream molecule affected by either of these two molecules. | scifact_143 |
The alternative lengthening of telomeres (ALT) mechanism allows cancer cells to escape senescence and apoptosis in the absence of active telomerase.
A characteristic feature of this pathway is the assembly of ALT-associated promyelocytic leukemia (PML) nuclear bodies (APBs) at telomeres.
Here, we dissected the role of APBs in a human ALT cell line by performing an RNA interference screen using an automated 3D fluorescence microscopy platform and advanced 3D image analysis. | scifact_144 |
We identified 29 proteins that affected APB formation, which included proteins involved in telomere and chromatin organization, protein sumoylation and DNA repair.
By integrating and extending these findings, we found that APB formation induced clustering of telomere repeats, telomere compaction and concomitant depletion of the shelterin protein TRF2 (also known as TERF2). | scifact_145 |
These APB-dependent changes correlated with the induction of a DNA damage response at telomeres in APBs as evident by a strong enrichment of the phosphorylated form of the ataxia telangiectasia mutated (ATM) kinase.
Accordingly, we propose that APBs promote telomere maintenance by inducing a DNA damage response in ALT-positive tumor cells through changing the telomeric chromatin state to trigger ATM phosphorylation. | scifact_146 |
The mechanisms by which a primary tumor affects a selected distant organ before tumor cell arrival remain to be elucidated.
This report shows that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival.
In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production and increase proinflammatory cytokines. | scifact_147 |
In addition, they produce large quantities of matrix metalloproteinase 9 (MMP9) and promote vascular remodeling.
Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung and diminishes lung metastasis.
The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. | scifact_148 |
Our work reveals a novel protumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection, and promotes metastasis through aberrant vasculature formation.
Thus, inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis. | scifact_149 |
Activin/Nodal growth factors control a broad range of biological processes, including early cell fate decisions, organogenesis and adult tissue homeostasis.
Here, we provide an overview of the mechanisms by which the Activin/Nodal signalling pathway governs stem cell function in these different stages of development.
We describe recent findings that associate Activin/Nodal signalling to pathological conditions, focusing on cancer stem cells in tumorigenesis and its potential as a target for therapies. | scifact_150 |
Moreover, we will discuss future directions and questions that currently remain unanswered on the role of Activin/Nodal signalling in stem cell self-renewal, differentiation and proliferation. | scifact_151 |
In many eukaryotes, RNA-dependent RNA polymerases (RdRPs) play key roles in the RNAi pathway.
They have been implicated in the recognition and processing of aberrant transcripts triggering the process, and in amplification of the silencing response.
We have tested the functions of RdRP genes from the ciliate Paramecium tetraurelia in experimentally induced and endogenous mechanisms of gene silencing. | scifact_152 |
In this organism, RNAi can be triggered either by high-copy, truncated transgenes or by directly feeding cells with double-stranded RNA (dsRNA).
Surprisingly, dsRNA-induced silencing depends on the putatively functional RDR1 and RDR2 genes, which are required for the accumulation of both primary siRNAs and a distinct class of small RNAs suggestive of secondary siRNAs. | scifact_153 |
In contrast, a third gene with a highly divergent catalytic domain, RDR3, is required for siRNA accumulation when RNAi is triggered by truncated transgenes.
Our data further implicate RDR3 in the accumulation of previously described endogenous siRNAs and in the regulation of the surface antigen gene family.
While only one of these genes is normally expressed in any clonal cell line, the knockdown of RDR3 leads to co-expression of multiple antigens. | scifact_154 |
These results provide evidence for a functional specialization of Paramecium RdRP genes in distinct RNAi pathways operating during vegetative growth. | scifact_155 |
Background:Chronic cyclosporine A (CsA) nephrotoxicity (CCN) is a major cause of chronic renal dysfunction and has no effective clinical interventions yet.
Objective: To reveal the mechanisms of renal cell apoptosis in CCN, we analyzed all in vitro studies of such mechanisms. | scifact_156 |
Methods: We collected all in vitro studies about the mechanisms of renal cell apoptosis induced by CsA in Medline (1966 to July 2010), Embase (1980 to July 2010) and ISI (1986 to July 2010), evaluated their quality according to in vitro standards and extracted data following the PICOS principles and synthesized the data. | scifact_157 |
Results: First,CsA could upregulate Fas and Fas-L expression, increase FADD and apoptosis enzymes (caspase-2, -3, -4, -7, -8, -9 and -10) and downregulate the Bcl-2 and Bcl-xL. Second, CsA could induce oxidative stress and damage the antioxidant defense system.
Third, CsA could increase the expression of HERP, GRP78 and CHOP.
Fourth, CsA could induce renal cell apoptosis and increase their iNOS and p53 expression in cultured cells. | scifact_158 |
Conclusions: At least four pathways are involved in renal cell apoptosis induced by CsA in different cell species.
Caspases might be their final common pathway in vitro.
They might all provide potential points for interventions, but these need to be confirmed in vivo. | scifact_159 |
The ontogeny of haematopoietic stem cells (HSCs) during embryonic development is still highly debated, especially their possible lineage relationship to vascular endothelial cells.
The first anatomical site from which cells with long-term HSC potential have been isolated is the aorta-gonad-mesonephros (AGM), more specifically the vicinity of the dorsal aortic floor. | scifact_160 |
But although some authors have presented evidence that HSCs may arise directly from the aortic floor into the dorsal aortic lumen, others support the notion that HSCs first emerge within the underlying mesenchyme. | scifact_161 |
Here we show by non-invasive, high-resolution imaging of live zebrafish embryos, that HSCs emerge directly from the aortic floor, through a stereotyped process that does not involve cell division but a strong bending then egress of single endothelial cells from the aortic ventral wall into the sub-aortic space, and their concomitant transformation into haematopoietic cells. | scifact_162 |
The process is polarized not only in the dorso-ventral but also in the rostro-caudal versus medio-lateral direction, and depends on Runx1 expression: in Runx1-deficient embryos, the exit events are initially similar, but much rarer, and abort into violent death of the exiting cell. | scifact_163 |
These results demonstrate that the aortic floor is haemogenic and that HSCs emerge from it into the sub-aortic space, not by asymmetric cell division but through a new type of cell behaviour, which we call an endothelial haematopoietic transition. | scifact_164 |
OBJECTIVE To determine whether the novel avian influenza H7N9 virus can transmit from person to person and its efficiency.
DESIGN Epidemiological investigations conducted after a family cluster of two patients with avian H7N9 in March 2013.
SETTING Wuxi, Eastern China. | scifact_165 |
SETTING Wuxi, Eastern China.
PARTICIPANTS Two patients, their close contacts, and relevant environments.
Samples from the patients and environments were collected and tested by real time reverse transcriptase-polymerase chain reaction (rRT-PCR), viral culture, and haemagglutination inhibition assay.
Any contacts who became ill had samples tested for avian H7N9 by rRT-PCR.
Paired serum samples were obtained from contacts for serological testing by haemagglutination inhibition assays. | scifact_166 |
MAIN OUTCOMES MEASURES Clinical data, history of exposure before the onset of illnesses, and results of laboratory testing of pathogens and further analysis of sequences and phylogenetic tree to isolated strains. | scifact_167 |
RESULTS The index patient became ill five to six days after his last exposure to poultry.
The second patient, his daughter aged 32, who provided unprotected bedside care in the hospital, had no known exposure to poultry.
She developed symptoms six days after her last contact with her father.
Two strains were isolated successfully from the two patients.
Genome sequence and analyses of phylogenetic trees showed that both viruses were almost genetically identical. | scifact_168 |
Forty three close contacts of both patients were identified.
One had mild illness but had negative results for avian H7N9 by rRT-PCR.
All 43 close contacts tested negative for haemagglutination inhibition antibodies specific for avian H7N9. | scifact_169 |
CONCLUSIONS The infection of the daughter probably resulted from contact with her father (the index patient) during unprotected exposure, suggesting that in this cluster the virus was able to transmit from person to person.
The transmissibility was limited and non-sustainable. | scifact_170 |
BACKGROUND Genetic variation in the IL28B gene has been strongly associated with treatment outcomes, spontaneous clearance and progression of the hepatitis C virus infection (HCV).
The aim of the present study was to investigate the role of polymorphisms at this locus with progression and outcome of HCV infection in a Moroccan population. | scifact_171 |
METHODS We analyzed a cohort of 438 individuals among them 232 patients with persistent HCV infection, of whom 115 patients had mild chronic hepatitis and 117 had advanced liver disease (cirrhosis and hepatocellular carcinoma), 68 individuals who had naturally cleared HCV and 138 healthy subjects.
The IL28B SNPs rs12979860 and rs8099917 were genotyped using a TaqMan 5' allelic discrimination assay. | scifact_172 |
RESULTS The protective rs12979860-C and rs8099917-T alleles were more common in subjects with spontaneous clearance (77.9% vs 55.2%; p = 0.00001 and 95.6% vs 83.2%; p = 0.0025, respectively).
Individuals with clearance were 4.69 (95% CI, 1.99-11.07) times more likely to have the C/C genotype for rs12979860 polymorphism (p = 0.0017) and 3.55 (95% CI, 0.19-66.89) times more likely to have the T/T genotype at rs8099917. | scifact_173 |
Patients with advanced liver disease carried the rs12979860-T/T genotype more frequently than patients with mild chronic hepatitis C (OR = 1.89; 95% CI, 0.99-3.61; p = 0.0532) and this risk was even more pronounced when we compared them with healthy controls (OR = 4.27; 95% CI, 2.08-8.76; p = 0.0005).
The rs8099917-G allele was also associated with advanced liver disease (OR = 2.34; 95% CI, 1.40-3.93; p = 0.0100). | scifact_174 |
CONCLUSIONS In the Moroccan population, polymorphisms near the IL28B gene play a role both in spontaneous clearance and progression of HCV infection. | scifact_175 |
Regulatory T (T reg) cells are critical regulators of immune tolerance.
Most T reg cells are defined based on expression of CD4, CD25, and the transcription factor, FoxP3.
However, these markers have proven problematic for uniquely defining this specialized T cell subset in humans.
We found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4+ T cells in peripheral blood.
We demonstrate that the majority of these cells are FoxP3+, including those that express low levels or no CD25. | scifact_176 |
A combination of CD4, CD25, and CD127 resulted in a highly purified population of T reg cells accounting for significantly more cells that previously identified based on other cell surface markers.
These cells were highly suppressive in functional suppressor assays. | scifact_177 |
These cells were highly suppressive in functional suppressor assays.
In fact, cells separated based solely on CD4 and CD127 expression were anergic and, although representing at least three times the number of cells (including both CD25+CD4+ and CD25−CD4+ T cell subsets), were as suppressive as the “classic” CD4+CD25hi T reg cell subset. | scifact_178 |
Finally, we show that CD127 can be used to quantitate T reg cell subsets in individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells. | scifact_179 |
All vertebrates, including humans, obtain most of their daily vitamin D requirement from casual exposure to sunlight.
During exposure to sunlight, the solar ultraviolet B photons (290-315 nm) penetrate into the skin where they cause the photolysis of 7-dehydrocholesterol to precholecalciferol.
Once formed, precholecalciferol undergoes a thermally induced rearrangement of its double bonds to form cholecalciferol. | scifact_180 |
An increase in skin pigmentation, aging, and the topical application of a sunscreen diminishes the cutaneous production of cholecalciferol.
Latitude, season, and time of day as well as ozone pollution in the atmosphere influence the number of solar ultraviolet B photons that reach the earth's surface, and thereby, alter the cutaneous production of cholecalciferol. | scifact_181 |
In Boston, exposure to sunlight during the months of November through February will not produce any significant amounts of cholecalciferol in the skin.
Because windowpane glass absorbs ultraviolet B radiation, exposure of sunlight through glass windows will not result in any production of cholecalciferol. | scifact_182 |
It is now recognized that vitamin D insufficiency and vitamin D deficiency are common in elderly people, especially in those who are infirm and not exposed to sunlight or who live at latitudes that do not provide them with sunlight-mediated cholecalciferol during the winter months.
Vitamin D insufficiency and deficiency exacerbate osteoporosis, cause osteomalacia, and increase the risk of skeletal fractures. | scifact_183 |
Vitamin D insufficiency and deficiency can be prevented by encouraging responsible exposure to sunlight and/or consumption of a multivitamin tablet that contains 10 micrograms (400 IU) vitamin D. | scifact_184 |
Genes that are subject to genomic imprinting in mammals are preferentially expressed from a single parental allele.
This imprinted expression of a small number of genes is crucial for normal development, as these genes often directly regulate fetal growth.
Recent work has also demonstrated intricate roles for imprinted genes in the brain, with important consequences on behavior and neuronal function. | scifact_185 |
Finally, new studies have revealed the importance of proper expression of specific imprinted genes in induced pluripotent stem cells and in adult stem cells.
As we review here, these findings highlight the complex nature and developmental importance of imprinted genes. | scifact_186 |
The new Light Cycler technology was adapted to the detection of hepatitis C virus (HCV) RNA in clinical samples.
Sera from 81 patients were tested by Light Cycler PCR, AMPLICOR HCV Monitor assay, and in-house PCR.
Our data demonstrate that Light Cycler is a fast and reliable method for the detection and quantitation of HCV RNA. | scifact_187 |
The significant disparities in metabolism between tumor and normal cells have inspired the development of metabolism-based anti-tumor therapeutics.
Arginine is a semi-essential amino acid because normal cells can not only synthesize arginine de novo but also take up extracellular arginine.
Several types of tumors have abnormalities in arginine metabolism enzymes and completely rely on extracellular arginine to support necessary biological processes.
This property is referred to as arginine auxotrophy. | scifact_188 |
This property is referred to as arginine auxotrophy.
Taking advantage of characteristic arginine auxotrophy in tumors, arginine deprivation, which is generally induced by the use of arginine deiminase (ADI) and arginase I, has been investigated as a novel strategy for cancer therapy.
Arginine deprivation demonstrated promising efficacy against arginine-auxotrophic tumors. | scifact_189 |
Arginine deprivation demonstrated promising efficacy against arginine-auxotrophic tumors.
By integrating perspectives from both clinical oncologists and laboratory scientists, this article reviews the important aspects of arginine deprivation as a promising anticancer therapy. | scifact_190 |
The thymic medulla provides a specialized microenvironment for the negative selection of T cells, with the presence of autoimmune regulator (Aire)-expressing medullary thymic epithelial cells (mTECs) during the embryonic-neonatal period being both necessary and sufficient to establish long-lasting tolerance. | scifact_191 |
Here we showed that emergence of the first cohorts of Aire(+) mTECs at this key developmental stage, prior to αβ T cell repertoire selection, was jointly directed by Rankl(+) lymphoid tissue inducer cells and invariant Vγ5(+) dendritic epidermal T cell (DETC) progenitors that are the first thymocytes to express the products of gene rearrangement. | scifact_192 |
In turn, generation of Aire(+) mTECs then fostered Skint-1-dependent, but Aire-independent, DETC progenitor maturation and the emergence of an invariant DETC repertoire.
Hence, our data attributed a functional importance to the temporal development of Vγ5(+) γδ T cells during thymus medulla formation for αβ T cell tolerance induction and demonstrated a Rank-mediated reciprocal link between DETC and Aire(+) mTEC maturation. | scifact_193 |
Immune reconstitution was analyzed in 140 consecutive patients who were 2-year disease-free and who underwent myeloablative allogeneic transplantation.
A CD4 and CD8 defect was observed involving naive, terminally differentiated, memory and competent cells and above limits values for activated subsets.
Natural killer cells normalize at six months while we observed expansion of CD19(+)/CD5(+) B cells after three months and a persisting defect of memory B cells. | scifact_194 |
Chronic graft-versus-host disease did not influence significantly those parameters for CD8 subsets while the naïve and competent CD4 subsets were strongly affected.
But the most profound impact of chronic graft-versus-host disease was on B-cell subsets, especially on the memory B population.
The cumulative incidence of late severe infections was low (14% at four years). | scifact_195 |
The cumulative incidence of late severe infections was low (14% at four years).
Using Cox's models, only low B-cell counts at 12 (P=0.02) and 24 (P=0.001) months were associated with the hazard of developing late infection, in particular if patients did not develop chronic graft-versus-host disease. | scifact_196 |
T cell activation is predicated on the interaction between the T cell receptor and peptide-major histocompatibility (pMHC) ligands.
The factors that determine the stimulatory potency of a pMHC molecule remain unclear.
We describe results showing that a peptide exhibiting many hallmarks of a weak agonist stimulates T cells to proliferate more than the wild-type agonist ligand. | scifact_197 |
An in silico approach suggested that the inability to form the central supramolecular activation cluster (cSMAC) could underlie the increased proliferation.
This conclusion was supported by experiments that showed that enhancing cSMAC formation reduced stimulatory capacity of the weak peptide.
Our studies highlight the fact that a complex interplay of factors determines the quality of a T cell antigen. | scifact_198 |
Analysis of excitatory synaptic transmission in the rat hypothalamic supraoptic nucleus revealed that glutamate clearance and, as a consequence, glutamate concentration and diffusion in the extracellular space, is associated with the degree of astrocytic coverage of its neurons. | scifact_199 |
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