Miracle-dz/UniFAR-FTUs huggingface dataset:
Response-guided telaprevir combination treatment for hepatitis C virus infection.

BACKGROUND Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. METHODS We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. RESULTS Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). CONCLUSIONS In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).
Estimation of variance components and prediction of breeding values for scrotal circumference and weaning weight in Limousin cattle.

Variance and covariance components were estimated for yearling scrotal circumference and weaning weight from Limousin field data. Records of 8.226 bulls were used to evaluate 584 sires and 653 maternal grandsires. Data included all herdbook records of bulls with a recorded scrotal circumference and their weaning contemporaries. Analyses were performed by restricted maximum likelihood techniques employing the expected maximization algorithm and fitting both single- and two-trait models. Scrotal circumference was first fitted in a single-trait, sire model to obtain starting values for variances for a later analysis. Likewise, weaning weight was fitted in a single-trait, sire-maternal grandsire model to obtain priors for (co)variances for a later analysis. Scrotal circumference and weaning weight were then fitted together in a two-trait model to estimate variance components. Estimates of variance components were calculated by equating (co)variances obtained from the models to their expectations. Estimates of heritability of scrotal circumference, direct weaning weight, and maternal weaning weight were . 46, . 25, and . 19, respectively. Estimates of genetic correlations between yearling scrotal circumference and direct weaning weight, scrotal circumference and maternal weaning weight, and direct weaning weight and maternal weaning weight were . 14, -. 22, and -. 44, respectively. The estimate of the environmental correlation between scrotal circumference and weaning weight was . 61. Genetic parameters obtained were then used in two-trait, reduced animal mixed-model equations for a maternally influenced trait to predict breeding values for animals.
The Junctional Adhesion Molecule-C Promotes Neutrophil Transendothelial Migration in Vitro and in Vivo*

The third member of the family of junctional adhesion molecules (JAMs), JAM-3, also called JAM-C, was recently shown to be a novel counter-receptor on platelets for the leukocyte β2-integrin Mac-1 (αMβ2, CD11b/CD18). Here, new functional aspects of the role of endothelial cell JAM-C were investigated. Endothelial cells express JAM-C, which is predominantly localized within junctions at interendothelial contacts, since it codistributes with a tight junction component, zonula occludens-1. Whereas JAM-C does not participate in neutrophil adhesion to endothelial cells, it mediates neutrophil transmigration in a Mac-1-dependent manner. In particular, inhibition of JAM-C significantly reduced neutrophil transendothelial migration, and the combination of JAM-C and platelet/endothelial cell adhesion molecule-1 blockade almost completely abolished neutrophil transendothelial migration in vitro. In vivo, inhibition of JAM-C with soluble mouse JAM-C resulted in a 50% reduction of neutrophil emigration in the mouse model of acute thioglycollate-induced peritonitis. Thus, JAM-C participates in neutrophil transmigration and thereby provides a novel molecular target for antagonizing interactions between vascular cells that promote inflammatory vascular pathologies.
Characterization of SLC26A9 in Patients with CF‐Like Lung Disease

Diffuse bronchiectasis is a common problem in respiratory clinics. We hypothesized that mutations in the solute carrier 26A9 (SLC26A9) gene, encoding for a chloride (Cl−) transporter mainly expressed in lungs, may lead to defects in mucociliary clearance. We describe two missense variants in the SLC26A9 gene in heterozygote patients presenting with diffuse idiopathic bronchiectasis : p.Arg575Trp, identified in a patient also heterozygote for p.Phe508del in the CFTR gene; and p.Val486Ile. Expression of both mutants in Xenopus laevis oocytes abolished SLC26A9‐mediated Cl− conductance without decreasing protein membrane expression. Coexpression of CFTR with SLC26A9–p.Val486Ile resulted in a significant increase in the Cl− current induced by PKA stimulation, similar to that obtained in oocytes expressing CFTR and SLC26A9–WT. In contrast, coexpression of CFTR with SLC26A9–p.Arg575Trp inhibited SLC26A9‐enhanced CFTR activation upon PKA. Further structure–function analyses led us to propose a site encompassing Arg575 in the SLC26A9–STAS domain for CFTR–SLC26A9 interaction. We hypothesize that SLC26A9–p.Arg575Trp prevented SLC26A9‐mediated functional activation of CFTR by altering SLC26A9–CFTR interaction. Although we cannot confirm that these mutations by themselves are deleterious, we propose that they trigger the pathogenic role of a single CFTR mutation and provide insight into a novel mechanism of Cl− transport alteration across the respiratory mucosa, based on functional inhibition of CFTR.
Different Rotavirus Strains Enter MA104 Cells through Different Endocytic Pathways: the Role of Clathrin-Mediated Endocytosis

ABSTRACT Rotaviruses, the single most important agents of acute severe gastroenteritis in children, are nonenveloped viruses formed by a three-layered capsid that encloses a genome formed by 11 segments of double-stranded RNA. The mechanism of entry of these viruses into the host cell is not well understood. The best-studied strain, RRV, which is sensitive to neuraminidase (NA) treatment of the cells, uses integrins α2β1 and αvβ3 and the heat shock protein hsc70 as receptors and enters MA104 cells through a non-clathrin-, non-caveolin-mediated pathway that depends on a functional dynamin and on the presence of cholesterol on the cell surface. In this work, using a combination of pharmacological, biochemical, and genetic approaches, we compared the entry characteristics of four rotavirus strains known to have different receptor requirements. We chose four rotavirus strains that represent all phenotypic combinations of NA resistance or sensitivity and integrin dependence or independence. We found that even though all the strains share their requirements for hsc70, dynamin, and cholesterol, three of them differ from the simian strain RRV in the endocytic pathway used. The human strain Wa, porcine strain TFR-41, and bovine strain UK seem to enter the cell through clathrin-mediated endocytosis, since treatments that inhibit this pathway block their infectivity; consistent with this entry route, these strains were sensitive to changes in the endosomal pH. The inhibition of other endocytic mechanisms, such as macropinocytosis or caveola-mediated uptake, had no effect on the internalization of the rotavirus strains tested here.
Influence of Phosphate on the Growth and Nodulation Characteristics of Rhizobium trifolii

The growth and nodulating characteristics of Rhizobium trifolii 6 and 36 differed under different external phosphate conditions. Under growth conditions designed to deplete the internal phosphate content of the rhizobia, strain 6 maintained a generation time of 5 h during the exponential phase over two cycles of growth in phosphate-depleted medium. In contrast, the generation time of strain 36 was extended from 3.5 to 9.8 h over two cycles of phosphate-depleted growth, although the organism eventually achieved the same cell density and cellular phosphate content as that of strain 6 at stationary phase. Phosphate-depleted strain 6 required 0.51 ± 0.08 μM phosphate to commence proliferation, whereas phosphate-depleted strain 36 required 0.89 ± 0.04 μM phosphate under the same conditions. Phosphate-depleted strain 6 maintained viability when exposed to external phosphate concentrations subcritical for growth to occur, whereas phosphate-depleted strain 36 lost viability within 48 h when exposed to medium containing phosphate at concentrations subcritical for growth. Phosphate-depleted strain 36 was inferior to phosphate-depleted strain 6 at nodulating subterranean clover (Trifolium subterraneum L. cv. Mt. Barker) by taking 2 to 4 days longer to develop nodules in phosphatedepleted plant grown medium at pH 5.5. Nodulation by phosphate-depleted strain 36 was accelerated either by including phosphate in the plant growth medium at pH 5.5 or by raising the solution pH of phosphate-depleted plant growth medium to pH 6.5. External phosphate and pH effects were not observed on the nodulating capabilities of phosphate-depleted strain 6 or on luxury phosphate-grown cells of either strain. Phosphatedepleted strains 6 and 36 proliferated to a similar extent on the rhizoplanes even under stringently low external Pi concentrations. The phosphatase activities of both phosphate-depleted strains were significantly (P = 0.05) higher at pH 6.5 than at pH 5.5, and the activity of strain 6 was significantly higher (P = 0.05) than that of strain 36 at pH 5.5 and 5.0.
Automated production of high density cosmid and YAC colony filters using a robotic workstation.

We report here on a system for automated preparation of high-density colony filters of arrayed libraries using the high density replicating system (HDR) for the Beckman Biomek 1000 robotic workstation. This system, consisting of a 96-pin tool, a sterilization station and controlling software, transfers samples from microplates onto target membranes in arrays up to 36 times the density of a 96-well microplate. The transfer operation can be completely automated with the addition of the Biomek Side Loader System, which consists of a robotic arm capable of transferring plates and filters between the Biomek working tablet and a storage area. Using the complete system, we are able to plate 32 replica filters (8 x 12 cm), each containing the clones from 16 different microplates (i.e., 1536 clones per filter), in a 16-h overnight run without any operator intervention. We describe conditions used for transfer of bacterial yeast colonies and fixation of DNA to the membranes, and we illustrate hybridization results obtained with cosmid and YAC filters.
Adjuvant steroid therapy in community-acquired pneumonia: a systematic review and meta-analysis.

BACKGROUND Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality among adults. Although steroids appear to be beneficial in animal models of CAP, clinical trial data in humans are either equivocal or conflicting. PURPOSE Our purpose was to perform a systematic review and meta-analysis of studies examining the impact of steroid therapy on clinical outcomes among adults admitted with CAP. DATA SOURCES AND STUDY SELECTION We identified randomized controlled trials (RCTs) through a systematic search of published literature up to July 2011. DATA EXTRACTION We estimated relative risks (RR) and weighted mean differences, pooled from each study using a random effects model. DATA SYNTHESIS Eight RCTs, comprising 1119 patients, met our selection criteria. Overall quality of the studies was moderate. Adjunctive steroid therapy had no effect on hospital mortality or length of stay in the intensive care unit, but reduced the overall length of hospital stay (RR: -1.21 days [95% confidence interval (CI): -2.12 to -0.29]). Less robust data also demonstrated reduced incidence of delayed shock (RR: 0.12 [95% CI: 0.03 to 0.41]) and reduced persistence of chest x-ray abnormalities (RR: 0.13 [95% CI: 0.06 to 0.27]). A priori subgroup and sensitivity analyses did not alter these findings. CONCLUSIONS Moderate-quality evidence suggests that adjunctive steroid therapy for adults hospitalized with CAP reduced the length of hospital stay but did not alter mortality.
Semantic Based Image Retrieval Using Relevance Feedback

In this paper, we propose a method for image categorization and retrieval, by integrating knowledge from low-level and semantic features extracted from images. The low -level descriptors, like color, position, dimension and texture are extracted from each image region. These mathematical descriptors are automatically associated with intermediate semantic descriptors. The intermediate descriptors are used also for image categorization and for qualitative definition of semantic keywords in the user queries. For improving the initial query results, we apply a relevance feedback mechanism that uses the low -level descriptors of the images selected as relevant by user for producing the final query results. A support vector machine classifier can be learned from training data of relevance images and irrelevance images marked by users. Using the classifier and the semantic indexing, we implement a software system that can retrieve more images relevant to the query in the database efficiently.
Socioeconomic aspects of fractures within universal public healthcare: A nationwide case-control study from Denmark

Aims: To investigate the effects of income and other socioeconomic variables on fracture risk adjusted for disease-related confounders as fractures are a major public health problem. Methods: Case-control study where all subjects in Denmark with a fracture during the year 2000 (n=124,655) served as cases. From the general population three age- and gender-matched subjects were selected as controls (n=373,962). Adjustment were made for income, living with someone vs. living alone, having a job vs. being out of work, education, comorbidity (Charlson index), number of bed days in hospital, number of contacts with general practitioner, use of corticosteroids, prior fracture, and alcoholism. Results: Income was not associated with fracture risk on adjustment for the other covariates. Living with someone was associated with a decreased risk of any fracture in all ages. A higher level of education was associated with a decreased fracture risk in the age groups<60 years, but an increased fracture risk among subjects≥60 years. Being at work was associated with a decreased hip fracture risk among subjects≥40 years. Alcoholism and a prior fracture were significant predictors of fracture in all age groups. Conclusions: Income does not predict fracture risk in Denmark after adjustment for other social and comorbidity variables. This may signal neutralization of the effect by socioeconomic compensation or that income was the product of underlying socioeconomic variables.
An 8-bit 800-$muhboxW$1.23-MS/s Successive Approximation ADC in SOI CMOS

We report on an 8-bit successive approximation analog-to-digital converter (SA-ADC) that was designed and fabricated in 0.5-mum silicon on sapphire CMOS technology. The SA-ADC is capable of 32-MHz operation, providing 1.23-MS/s conversion rates, and consumes 800 muW at 3.3-V supply. The lack of substrate parasitic capacitances enables the use of small-area capacitors and reduces the noise coupling to the analog nodes. The circuits employ MOS transistors of different thresholds to optimize the performance and power dissipation of the system
Ventral striatopallidal parts of the basal ganglia in the rat: I. Neurochemical compartmentation as reflected by the distributions of neurotensin and substance P immunoreactivity

The distribution of neurotensin immunoreactivity in the basal ganglia of the adult rat was evaluated by studying alternate serial vibratome sections that were exposed to antiserum against neurotensin, substance P, or cholecystokinin. It was observed that a heterogeneous distribution of neurotensin‐immunoreactive fibers and terminals contributes to the neurochemical compartmentation of the ventral pallidum and ventral striatum, and that significant numbers of neurotensin‐immunoreactive neurons occupy striatal districts of the olfactory tubercle, nucleus accumbens, and ventromedial caudate‐putamen. An intense band of pallidal neurotensin immunoreactivity characterizes the medial part of the ventral pallidum adjacent to the nucleus accumbens, whose medial boundary is conveniently defined in sections incubated with cholecystokinin antiserum. Electron microscopic studies showed that the pallidal plexus of neurotensin‐immunoreactive elements consists primarily of boutons, which contact large dendrites in arrangements that in all respects appear to be of the classical striatopallidal variety. A gradual decrese in immunolabel was observed approaching the lateral parts of the ventral pallidum, which display sparse neurotensin immunoreactivity. The results thus indicate the existence of a significant neurotensinergic striatopallidal pathway confined primarily, if not exclusively, to the medial part of the ventral striatopallidal system. The contribution of neurotensin‐immunoreactive fibers and terminals to the compartmentation of ventral striatum is expressed most vividly in their exclusion from clusters of tightly packed medium‐sized neurons, many of which are intensely substance P immunoreactive. Such clusters appear identical with those previously described as rich in opiate receptors and poor in acetylcholinesterase activity. In the ventral striatal region where the nucleus accumbens and ventromedial caudate‐putamen merge, neurotensin‐immunoreactive neurons are organized in clusters. Further rostral in the nucleus accumbens, they are more evenly distributed. Few were found in the dorsolateral quadrant of the neostriatum.
Functionally Distinct Groups of Interneurons Identified During Rhythmic Carbachol Oscillations in Hippocampus In Vitro

During distinct behavioral states, the hippocampus exhibits characteristic rhythmic electrical activity. Evidence in vivo suggests that both principal pyramidal cells and GABAergic interneurons participate in generating oscillations. We found that during rhythmic oscillations in area CA3, functionally distinct classes of interneurons could be identified, although all recorded interneurons had similar dendritic and axonal arbors. One group of interneurons was powerfully excited by CA3 pyramidal cells, whereas two other interneuron groups were relatively unaffected by pyramidal cell firing. One of these groups of interneurons was potently inhibited by other local interneurons during the pyramidal cell bursts. Our findings emphasize that morphologically similar cells are wired together very differently within the local circuit. The classes of hippocampal interneurons we have tentatively defined may be used during distinct behavioral states to switch the local network from one oscillatory state to another.
Glucose and Insulin Chronically Regulate Insulin Action via Different Mechanisms in BC3H1 Myocytes: Effects on Glucose Transporter Gene Expression

We previously reported that, in primary cultured adipocytes, chronic exposure to glucose plus insulin impairs the insulin-responsive glucose transport system. In this study, we examined regulation of glucose transport in BC3H1 myocytes as a model for muscle and found important differences between BC3HI cells and adipocytes. In myocytes, chronic glucose exposure per se (25 mM) decreased basal glucose transport activity by 78% and insulin's acute ability to maximally stimulate transport by 68% (ED50 ∼2.5 mM; T½ ∼4 h). D-Mannose and 3-O-methylglucose diminished transport rates with ∼100 and 50% of the potency of D-glucose, respectively, wherea L-glucose, D-fructose, and D-galactose were inactive. Chronic glucose exposure also reduced cell surface insulin binding by 30% via an apparent decrease in receptor affinity, and this effect was associated with a comparable rightward shift in the insulin-glucose transport dose-response curve. In other studies, persistent stimulation with 15 nM insulin also decreased maximally stimulated glucose transport activity, which was independent and additive to the regulatory effect of glucose. Moreover, glucose and insulin-induced insulin resistance via different mechanisms. Glucose (25 mM) reduced the number of cellular glucose transporter proteins by 84% and levels of GLUT1 transporter mRNA by 50% (whether normalized to total RNA or CHO-B mRNA). In contrast, chronic insulin exposure led to a 2.1-fold increase in GLUT1 mRNA but did not alter cellular levels of transporter protein. Cotreatment with glucose prevented the insulin-induced rise in GLUT1 mRNA. BC3HI cells did not express GLUT4 mRNA thatencodes the major transporter isoform in skeletal muscle. In conclusion, in BC3H1 myocytes 1) glucose diminished insulin sensitivity by decreasing insulin receptor binding affinity and decreased basal and maximally insulin-stimulated glucose transport rates via cellular depletion of glucose transporters and suppression of GLUT1 mRNA; 2) chronic insulin exposure exerted an independent and additive effect to reduce maximal transport activity; however, insulin increased levels of GLUT1 mRNA and did not alter the cellular content of glucose transporters; and 3) although BC3H1 cells are commonly used as a model for skeletal muscle, studies examining glucose transport should be interpreted cautiously due to the absence of GLUT4 expression. Nevertheless, the data generally support the idea that, in non-insulindependent diabetes mellitus, hyperglycemia and hyperinsulinemia can induce or exacerbate insulin resistance in target tissues.