Miracle-dz/UniFAR-FTUs huggingface dataset:
Diabetes mellitus increases the in vivo activity of cytochrome P450 2E1 in humans.

AIMS Cytochrome P450 2E1 (CYP2E1) is thought to activate a number of protoxins, and has been implicated in the development of liver disease. Increased hepatic expression of CYP2E1 occurs in rat models of diabetes but it is unclear whether human diabetics display a similar up-regulation. This study was designed to test the hypothesis that human diabetics experience enhanced CYP2E1 expression. METHODS The pharmacokinetics of a single dose of chlorzoxazone (500 mg), used as an index of hepatic CYP2E1 activity, was determined in healthy subjects (n = 10), volunteers with Type I (n = 13), and Type II (n = 8) diabetes mellitus. Chlorzoxazone and 6-hydroxychlorzoxazone in serum and urine were analysed by high-performance liquid chromatography. The expression of CYP2E1 mRNA in peripheral blood mononuclear cells was quantified by reverse transcriptase-polymerase chain reaction. RESULTS The mean +/- s.d. (90% confidence interval of the difference) chlorzoxazone area under the plasma concentration-time curve was significantly (P </= 0.05) reduced in obese Type II diabetics (15.7 +/- 11.3 micro g h ml-1; 9, 22) compared with healthy subjects (43.5 +/- 16.9 micro g h ml-1; 16, 40) and Type I diabetics (32.8 +/- 9.2 micro g h ml-1; 9, 25). There was a significant two-fold increase in the oral clearance of chlorzoxazone in obese Type II diabetics compared with healthy volunteers and Type I diabetics. The protein binding of chlorzoxazone was not significantly different between the three groups. In contrast, Type 1 diabetics and healthy volunteers demonstrated no difference in the oral clearance of chlorzoxazone. The urinary recovery of 6-hydroxychlorzoxazone as a percentage of the administered dose was not different between healthy, Type I and obese Type II diabetics. The elimination half-life of chlorzoxazone did not differ between the three groups. CYP2E1 mRNA was significantly elevated in Type I and obese Type II diabetics compared with healthy volunteers. The oral clearance of chlorzoxazone, elimination half-life, Tmax, and Cmax were not significantly influenced by weight, body mass index, serum glucose, serum cholesterol, or glycosylated haemoglobin. CONCLUSIONS There was a marked increase in hepatic CYP2E1 activity in obese Type II diabetics as assessed by chlorzoxazone disposition. Increased expression of CYP2E1 mRNA in peripheral blood mononuclear cells was found in both types of diabetes mellitus. Adverse hepatic events associated with Type II diabetes may be in part a result of enhanced CYP2E1 expression and activity.
Hepatitis C Virus NS5A Disrupts STAT1 Phosphorylation and Suppresses Type I Interferon Signaling

ABSTRACT Responses to alpha interferon (IFN-α)-based treatment are dependent on both host and viral factors and vary markedly among patients infected with different hepatitis C virus (HCV) genotypes (GTs). Patients infected with GT3 viruses consistently respond better to IFN treatment than do patients infected with GT1 viruses. The mechanisms underlying this difference are not well understood. In this study, we sought to determine the effects of HCV NS5A proteins from different genotypes on IFN signaling. We found that the overexpression of either GT1 or GT3 NS5A proteins significantly inhibited IFN-induced IFN-stimulated response element (ISRE) signaling, phosphorylated STAT1 (P-STAT1) levels, and IFN-stimulated gene (ISG) expression compared to controls. GT1 NS5A protein expression exhibited stronger inhibitory effects on IFN signaling than did GT3 NS5A protein expression. Furthermore, GT1 NS5A bound to STAT1 with a higher affinity than did GT3 NS5A. Domain mapping revealed that the C-terminal region of NS5A conferred these inhibitory effects on IFN signaling. The overexpression of HCV NS5A increased HCV replication levels in JFH1-infected cells through the further reduction of levels of P-STAT1, ISRE signaling, and downstream ISG responses. We demonstrated that the overexpression of GT1 NS5A proteins resulted in less IFN responsiveness than did the expression of GT3 NS5A proteins through stronger binding to STAT1. We confirmed that GT1 NS5A proteins exerted stronger IFN signaling inhibition than did GT3 NS5A proteins in an infectious recombinant JFH1 virus. The potent antiviral NS5A inhibitor BMS-790052 did not block NS5A-mediated IFN signaling suppression in an overexpression model, suggesting that NS5A's contributions to replication are independent of its subversive action on IFN. We propose a model in which the binding of the C-terminal region of NS5A to STAT1 leads to decreased levels of P-STAT1, ISRE signaling, and ISG transcription and, ultimately, to preferential GT1 resistance to IFN treatment.
Does energy use cause economic growth in Latin America?

This study analyses the relationship between energy consumption and economic growth, using annual panel data from 16 Latin American countries over the period 1971–2001. We use a random coefficient (RC) method to control for both finite sample and sample-heterogeneity biases. Our results show (1) a long-run relationship between real GDP, energy consumption, labour force and real capital stock and (2) a long-run unidirectional causality running from energy to economic growth. These results support the energy-driven growth hypothesis.
Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological process

Diabetic macular oedema (DMO) is an important cause of vision loss in patients with diabetes mellitus. The underlying mechanisms of DMO, on both macrocellular and microcellular levels, are discussed in this review. The pathophysiology of DMO can be described as a process whereby hyperglycaemia leads to overlapping and inter‐related pathways that play a role not only in the initial vascular events, but also in the continued tissue insult that leads to chronic DMO. On a macrocellular level, DMO is believed to be in part caused by alterations in hydrostatic pressure, oxygen tension, oncotic pressure and shear stress. Three key components of the microvascular pathways include angiogenic factor expression, inflammation and oxidative stress. These molecular mediators, acting in conjunction with macrocellular factors, which are all stimulated in part by the hyperglycaemia and hypoxia, can have a direct endothelial effect leading to hyperpermeability, disruption of vascular endothelial cell junctions, and leukostasis. The interactions, signalling events and feedback loops between the various molecules are complicated and are not completely understood. However, by attempting to understand the pathways involved in DMO, we can help guide new treatment options targeted towards specific factors or mediators.
Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study.

BACKGROUND There are concerns about highly active antiretroviral therapy (HAART) causing a progressive increase in the risk of ischemic heart disease. We examined this issue in a nationwide cohort study of patients with human immunodeficiency virus (HIV) infection and a population-based control group. METHODS We determined the rate of first hospitalization for ischemic heart disease in all Danish patients with HIV infection (3953 patients) from 1 January 1995 through 31 December 2004 and compared this rate with that for 373,856 subjects in a population-based control group. Data on first hospitalization for ischemic heart disease and comorbidity were obtained from the Danish National Hospital Registry for all study participants. We used Cox's regression to compute the hospitalization rate ratio as an estimate of relative risk, adjusting for comorbidity. RESULTS Although the difference was not statistically significant, patients with HIV infection who had not initiated HAART were slightly more likely to be hospitalized for the first time with ischemic heart disease than were control subjects (adjusted relative risk, 1.39; 95% confidence interval, 0.81-2.33). After HAART initiation, the risk increase became substantially higher (adjusted relative risk, 2.12; 95% confidence interval, 1.62-2.76), but the relative risk did not further increase in the initial 8 years of HAART. CONCLUSIONS Compared with the general population, HIV-infected patients receiving HAART have an increased risk of ischemic heart disease, but the relative risk is stable up to 8 years after treatment initiation.
Canstatin, a Novel Matrix-derived Inhibitor of Angiogenesis and Tumor Growth*

We isolated and identified an endogenous 24-kDa human basement membrane-derived inhibitor of angiogenesis and tumor growth, termed canstatin. Canstatin, a fragment of the α2 chain of type IV collagen, was produced as a recombinant molecule inEscherichia coli and 293 embryonic kidneys cells. Canstatin significantly inhibited human endothelial cell migration and murine endothelial cell tube formation. Additionally, canstatin potently inhibited 10% fetal bovine serum-stimulated endothelial cell proliferation and induced apoptosis, with no inhibition of proliferation or apoptosis observed on non-endothelial cells. Inhibition of endothelial proliferation was not concomitant with a change in extracellular signal-regulated kinase activation. We demonstrate that apoptosis induced by canstatin was associated with a down-regulation of the anti-apoptotic protein, FLIP. Canstatin also suppressed in vivo growth of large and small size tumors in two human xenograft mouse models with histology revealing decreased CD31-positive vasculature. Collectively, these results suggest that canstatin is a powerful therapeutic molecule for suppressing angiogenesis.
Two gene members of the murine HOX‐5 complex show regional and cell‐type specific expression in developing limbs and gonads.

This study reports the expression domains of two murine HOX gene members of the HOX‐5 complex (Hox‐5.2, Hox‐5.3). These two genes have very similar homeodomain sequences, as well as temporal and spatial specificities of expression. They are both expressed at very posterior levels in the central nervous system, in sclerotome derivatives and in a few internal organs. In addition to these expression domains which are shared with other HOX genes, transcripts from both Hox‐5.2 and Hox‐5.3 are present at high levels in developing limbs. After an early homogeneous expression in mesodermal limb bud cells, transcription becomes restricted to cartilage‐differentiating cells. In addition, Hox‐5.2 is a marker for gonadal development. The possible involvement of such genes during inductive processes or organogenesis is discussed.
Creepage discharge of oil-pressboard Insulation in AC-DC composite field: phenomenon and characteristics

Converter transformers use oil-pressboard as its main dielectric medium and are operated mainly in AC-DC composite electric field. Creepage discharge is one of the common defects for oil-pressboard insulation, especially in converter transformers. Oil-pressboard insulation shows distinctive flashover behaviors and surface electric strengths in AC-DC composite electric field from that in pure AC or DC electric field. Compared to conventional power transformers, there remain bigger challenges to realize insulation assessment and fault diagnosis for the converter transformers. Adequate knowledge of the phenomenon and characteristics of oil-pressboard insulation creepage discharge is critical for fault diagnosis of converter transformers. This paper attempts to fill the existing research gap by studying the dynamic process and phenomenon of creepage discharge in the composite field so as to provide criteria for insulation diagnosis and assessment. With the established experimental platform, the present paper observed the phenomenon of oil-pressboard insulation creepage discharge from its initiation till final flashover under composite AC-DC voltages, identified the trends of partial discharge and dissolved gas throughout the entire process, and summarized accordingly the criteria for insulation diagnosis and assessment. Results indicate that 1) for creepage discharge of oil-pressboard insulation under AC-DC superimposed voltages, abrupt changes were observed in terms of discharge repetition rate and magnitude. Discharge phases kept enlarging during the whole discharge evolution process; 2) based on the observed discharge characteristics, the evolution process of creepage discharge could be classified into three stages which imply three severity levels of the discharge; 3) compared to that in AC electric field, the creepage discharge in AC-DC composite field witnessed much less amount of and different composition of dissolved gas in oil. More C2H6 and C2H2 were observed in the AC-DC composite electric field whereas CH4 and C2H2 dominated the AC electric field. The research results indicate that as much as both PD-identification and DGA methods are recognized as effective means of fault diagnosis for converter transformers, the referential assessment criteria should be enriched and adjusted for diagnosis of creep discharge under AC-DC composite voltages, taking into full consideration of the distinctive characteristics of both discharge and gases dissolved in oil.
Occurrence of a Sequence in Marine Cyanophages Similar to That of T4 g20 and Its Application to PCR-Based Detection and Quantification Techniques

ABSTRACT Viruses are ubiquitous components of marine ecosystems and are known to infect unicellular phycoerythrin-containing cyanobacteria belonging to the genus Synechococcus. A conserved region from the cyanophage genome was identified in three genetically distinct cyanomyoviruses, and a sequence analysis revealed that this region exhibited significant similarity to a gene encoding a capsid assembly protein (gp20) from the enteric coliphage T4. The results of a comparison of gene 20 sequences from three cyanomyoviruses and T4 allowed us to design two degenerate PCR primers, CPS1 and CPS2, which specifically amplified a 165-bp region from the majority of cyanomyoviruses tested. A competitive PCR (cPCR) analysis revealed that cyanomyovirus strains could be accurately enumerated, and it was demonstrated that quantification was log-linear over ca. 3 orders of magnitude. Different calibration curves were obtained for each of the three cyanomyovirus strains tested; consequently, cPCR performed with primers CPS1 and CPS2 could lead to substantial inaccuracies in estimates of phage abundance in natural assemblages. Further sequence analysis of cyanomyovirus gene 20 homologs would be necessary in order to design primers which do not exhibit phage-to-phage variability in priming efficiency. It was demonstrated that PCR products of the correct size could be amplified from seawater samples following 100× concentration and even directly without any prior concentration. Hence, the use of degenerate primers in PCR analyses of cyanophage populations should provide valuable data on the diversity of cyanophages in natural assemblages. Further optimization of procedures may ultimately lead to a sensitive assay which can be used to analyze natural cyanophage populations both quantitatively (by cPCR) and qualitatively following phylogenetic analysis of amplified products.
Evaluating Social and Environmental Issues by Integrating the Legitimacy Gap With Expectational Gaps

This article adopts an issues management approach to corporate social responsibility (CSR) implementation. Issues evaluation, which is an integral component of issues management, can be conducted by using the concept of three expectational gaps (factual, conformance, and ideal gaps). However, the concept of expectational gaps suffers from an ambiguity that limits its application to issues evaluation. The legitimacy gap concept is used in this article to clarify the ambiguity surrounding expectational gaps. The study thus develops a four-gap framework for conducting a quantitative issues evaluation. This framework is applied to six social and six environmental issues in the context of the forest products industry in the Northwest United States by means of a survey of 278 society and 94 industry respondents. Results empirically demonstrate the existence of expectational gaps and also provide insights into the nature of misalignment between societal and business perceptions along these social and environmental issues. Appropriate managerial responses are suggested to narrow or bridge different types of gaps.
Genetic Algorithm Based Parallel Matrix Factorization for Recommender Systems

Matrix Factorization is one of the popular approaches for learning the latent characteristics from the sparse utility matrix of recommendation systems. In recent times, Coordinate Descent based matrix factorization approach (CCD) have outperformed the other existing approaches such as Alternating Least Squares (ALS) and Stochastic Gradient Descent (SGD). While ALS is not scalable due to its cubic time complexity, SGD suffers from slow convergence. An improved version of CCD, CCD++ was recently proposed to overcome the shortcomings of CCD. The difference in these two approaches lies in their update rules and the update sequences. CCD++ was shown to converge faster than CCD. In this paper, we hypothesize that use of Genetic Algorithm (GA) for initializing matrices may significantly speed up the convergence of CCD++. Also, parallelism could be exploited more efficiently at update stage. We update the rating matrix at regular intervals with GA, so that the convergence of CCD++ is relatively fast. Our experimental results show that optimum update of matrices enhances the convergence of CCD++ appreciably.
Signal Transduction—Receptors, Mediators, and Genes

Cell signaling researchers gathered in Weimar, Germany, for the annual meeting of the Signal Transduction Society. The 2008 annual meeting of the Signal Transduction Society covered a broad spectrum of topics, with signaling in immune cells as the special focus of the meeting. Many of the immune signaling talks concerned B and T lymphocytes in particular; the role of inflammatory cytokines in cancer progression was also addressed. Neoplastic development was also discussed with regard to aspects of cell cycle control, aging, and transformation. Topics extended to signaling pathways induced by bacteria, viruses, and environmental toxins, as well as those involved in differentiation, morphogenesis, and cell death. This international and interdisciplinary scientific gathering induced lively discussions and close interactions between participants.
The hidden risks of energy innovation

This article discusses climate change and warns against efforts involving technological innovations, which could run the risk of dangerously overreaching both in the U.S. and abroad, in favor of a more modest program, which could produce better results. The author states that in the face of a depressed economy, it may be difficult to justify expenditures on energy-saving technology; older strategies, such as cap-and-trade, and a focus on research, instead of subsidizing deployment of new technologies, are still advisable. There is an emphasis on the need for regulatory policy as a route to economic growth, with a view to supporting clean energy with government funds over less expensive "dirty" alternatives.
Screen Space Particle Selection

Analyses of large 3D particle datasets typically involve many different exploration and visualization steps. Interactive exploration techniques are essential to reveal and select interesting subsets like clusters or other sophisticated structures. State-of-the-art techniques allow for context-aware selections that can be reﬁned dynamically. However, these techniques require large amounts of memory and have high computational complexity which heavily limits their applicability to large datasets. We propose a novel, massively parallel particle selection method that is easy to implement and has a processing complexity of O ( n ∗ k ) (where n is the number of particles and k the maximum number of neighbors per particle) and requires only O ( n ) memory. Furthermore, our algorithm is designed for GPUs and performs a selection step in several milliseconds while still being able to achieve high-quality results.
Choosing Topics for Technology Assessment

An agenda for technology assessment in the field of materials was developed through a process of dialogue among experts by use of a procedure known as a "science forum. " Materials scientists and technologists formed one group of experts, and social scientists formed another group. A scenario of a "constrained economy" provided a background for the forecast of science and technology for the remainder of this century. From this forecast, "candidates for technology assessment" were proposed and were rated as to urgency by both groups of experts. Two statistical procedures were used to estimate the degree of urgency for technology assessment (TA), as seen by each group of experts. An impressive degree of correlation was found between the ratings of the two groups and between the ranks as measured by the two statistical procedures. Five of the 21 candidates for technology assessment were judged to be "prime," and four more were judged to be "secondary. " While the study was done for materials technologies it should be applicable also to other fields of technology.
The safety of vedolizumab for the treatment of ulcerative colitis

ABSTRACT Introduction: Vedolizumab is a humanized monoclonal antibody to the α4β7-integrin that blocks lymphocyte trafficking to the gut and is approved for treatment of patients with moderate-to-severe ulcerative colitis (UC). The gut-selective mechanism of action has the potential to improve vedolizumab’s safety profile compared to other approved biologic drugs. Areas covered: We review the mechanism of action, efficacy and safety of vedolizumab treatment for UC. The positioning of vedolizumab in management algorithms is also discussed. Expert opinion: The highly selective mechanism of action of vedolizumab restricts immunosuppressive effects to the gut. Vedolizumab is efficacious as induction and maintenance therapy in UC patients who are naïve or refractory to tumor necrosis factor antagonists. No clinically important safety signals have been identified. Infusion reactions are reported in <5% of cases. The rates of adverse events (AE), serious AEs, and serious infections were not different between patients treated with placebo and those who received vedolizumab in a pooled analysis of six randomized controlled trials. Rates of malignancy and mortality in vedolizumab-exposed patients are similar to those of the general UC patient population. Progressive multifocal leukoencephalopathy has not been observed. Vedolizumab is a safe and effective therapy for UC with a unique mechanism of action.
Bacterial endophytes and their interactions with hosts.

Recent molecular studies on endophytic bacterial diversity have revealed a large richness of species. Endophytes promote plant growth and yield, suppress pathogens, may help to remove contaminants, solubilize phosphate, or contribute assimilable nitrogen to plants. Some endophytes are seedborne, but others have mechanisms to colonize the plants that are being studied. Bacterial mutants unable to produce secreted proteins are impaired in the colonization process. Plant genes expressed in the presence of endophytes provide clues as to the effects of endophytes in plants. Molecular analysis showed that plant defense responses limit bacterial populations inside plants. Some human pathogens, such as Salmonella spp. , have been found as endophytes, and these bacteria are not removed by disinfection procedures that eliminate superficially occurring bacteria. Delivery of endophytes to the environment or agricultural fields should be carefully evaluated to avoid introducing pathogens.