1,721,047 research outputs found
Recommended from our members
From Bedside to Bench-side: the Clinical, Epidemiological and Molecular Basis for Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma
Full text linkNon-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) affect 75-100 million U.S. citizens and carries an increased risk for liver, cardiovascular and cancer related morbidity and mortality. Similarly, chronic hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma (HCC) worldwide. Understanding the clinical, epidemiology and biological causes of NAFLD, with or without HCV, is of utmost importance given the lack of targeted therapies and the large economic burden it places on healthcare. Accordingly, we aimed to identify the clinical and epidemiological factors that affect HCV treatment in the setting of NAFLD and understand the risk of HCC in the NAFLD patients, compared to viral etiologies of HCC. To do so, we utilized the Electronic Medical Records of the Veterans Affairs Health Care System (VA HCS), the largest single-payer health system in the U.S., and UCLA Medical Center, one of the largest tertiary-care liver transplantation centers in the country. To further understand the molecular basis of NAFLD and NASH, we studied liver RNA-sequencing from a cohort of bariatric surgery patients with detailed liver histopathological data. We found that NAFLD does not affect HCV cure and that resolution of HCV leads to improvements in insulin resistance. We also observe that NAFLD HCC can occur in a non-cirrhosis background in 18% of cases and that older Hispanic patients with larger BMIs were more likely to have cirrhosis when diagnosed with NAFLD HCC. Through analysis of our transcriptomics human liver RNA-sequencing, we identify a lipid responsive non-coding gene, OLMALINC, as a novel enhancer RNA (eRNA) in the cis regulation of stearoyl Co-A desature, a key triglyceride gene that has been a therapeutic target in NASH human clinical trials. In this work, we present the clinical and epidemiological phenotypes of NAFLD and identify important associations between insulin resistance, dyslipidemia, and BMI in HCC. Our functional genomics data in statin-users help us identify the first eRNA in lipid metabolism described to date. Bridging the understanding of clinical phenotypes that translate to human-relevant molecular studies is key to elucidating the mechanisms of NAFLD, NASH and HCC
Recommended from our members
Contributors to Intestinal Fibrosis in the TNFSF15/TL1A Pathway
Full text linkTumor necrosis factor-like cytokine 1A (TL1A, TNFSF15) is implicated in inflammatory bowel disease (IBD), modulating the location and severity of intestinal inflammation and fibrosis. TL1A expression is increased in inflamed gut mucosa and associated with fibrostenosing Crohn’s disease. TL1A-overexpression in mice leads to spontaneous ileitis, and exacerbated induced proximal colitis and fibrosis. Studies of the role of TNFSF15/TL1A in fibrogenesis will help define pathogenesis and identify potential therapeutic targets for those most severely affected by IBD. The precise mechanisms and specific contributors to TL1A-driven fibrosis require further investigation. IBD is associated with shifts in the gut microbiome, but the effect of differing microbial populations and their interaction with TL1A on fibrosis has not been determined. Intestinal fibroblasts express the TL1A receptor, DR3, and stimulation with exogenous TL1A induces activation and collagen expression in vitro, but the contribution of direct TL1A-DR3 signaling on fibroblasts to the development of fibrosis in vivo is unknown. We show that the gut microbiome is required for TL1A-mediated intestinal fibrosis and optimal fibroblast activation into myofibroblasts. Moreover, we provide evidence that the TL1A-mediated intestinal fibrotic phenotype requires cues provided by unique bacterial populations, as opposed to any microbiome per se. Our analysis further identifies several candidate organisms that correlate with degree of fibrosis and directly impact fibroblast function. Thus, TL1A-mediated intestinal fibrosis and fibroblast phenotype are dependent on specific microbial populations.To evaluate for a selective role of direct TL1A-DR3 signaling on fibroblasts in fibrostenosing IBD, TL1A over-expressing na�ve T cells (Tl1a-Tg) were transferred into Rag-/- mice; Rag-/- mice lacking DR3 in all cell types (Rag-/-Dr3-/-); or Rag-/- mice lacking DR3 only on fibroblasts (Rag-/-Dr3delCol1a2). We show that Rag-/-Dr3-/- recipients demonstrate reduced disease activity, inflammation, and an accompanying reduction in fibrosis and fibroblast activation compared with DR3-sufficient Rag-/- recipients. In contrast to pan-DR3-deficient recipients, Rag-/-Dr3delCol1a2 recipients exhibit a similar degree of severe inflammatory disease as Rag-/- recipients. Despite the presence of abundant inflammation, however, fibroblast-selective DR3-deficiency significantly reduces intestinal fibrosis and decreases activation of fibroblasts. Ex vivo, DR3-deficient fibroblasts isolated from these colitic mice exhibit a significant reduction in gap-closure compared to those from DR3-intact Rag-/- mice. These data demonstrate that direct TL1A-DR3 signaling on fibroblasts in vivo significantly contributes to TL1A-mediated intestinal fibrosis, independent of inflammation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Recommended from our members
Vasoactive Intestinal Polypeptide (VIP) Regulates Metabolic Processes in Human and Murine Adipocytes by Modulating PPARγ Expression
Full text linkVasoactive intestinal peptide (VIP) is a neuropeptide expressed centrally in the hypothalamus and peripherally in the GI tract and adipose tissue. VIP and its VPAC receptors regulate body composition, as implicated by pathway-based, genome-wide association studies. We have previously shown that VIP-/- mice have lower fat mass and higher lean mass than their wild-type littermates. To elucidate the role of VIP in fat mass accumulation, VIP-/- mice were fed a 45% high-fat diet for 12 weeks. We determined that VIP-/- mice were resistant to weight gain and fat mass accumulation and had altered feeding behaviors and metabolic hormone levels. VIP antagonism of differentiating pre-adipocytes inhibited induction of adipocyte-related genes, such as PPARγ and C/EBP. Genetic association analyses using data from the METAbolic Syndrome in Men (METSIM) study showed a positive correlation between VIP, VPAC1R and key genetic drivers of adipogenesis. These results implicate VIP’s role in modulating fat accumulation
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Recommended from our members
The Intestinal Gut Microbiome as a Biomarker and Driver of Obesity and Non-Alcoholic Fatty Liver Disease
Full text linkNonalcoholic fatty liver disease (NAFLD) affects almost 1 out of every 5 Americans. The development of NAFLD increases an individual’s risk for cardiovascular disease, cirrhosis, and cancer. Given that there are few treatments available for NALFD, it is imperative to understand the features that can prognosticate and alter the progression of NAFLD. One area of research that has gained significant traction is the role of the gut microbiome in the development and progression of NAFLD. By utilizing a multi’omics approach, we discovered that the gut microbiome can affect obesity through alterations of the brain-gut axis. In a study of over 100 patients, we saw that the gut microbiome was highly associated to food addiction. Patients with food addiction had significantly lower abundances of Bacteroides, Akkermansia, and Eubacterium, and a higher abundance of Megamonas. This was associated with a reduction in a neuroprotective tryptophan-related metabolite, indolepropionate, and altered connectivity in the brain’s reward regions. This data suggests that the gut microbiome plays a role in eating behavior and is likely a modifiable risk factor for obesity. Furthermore, research has shown that the microbiome and metabolite profile of patients with NAFLD differs at each stage of the disease. Using a machine learning algorithm, we created and validated a classifier based on the gut microbiome that highly predicts advanced fibrosis in patients with NAFLD. To explore the causal effects of the gut microbiome on the development of NAFLD, we utilized the microbiome of bariatric surgery patients and transplanted them into antibiotic treated mice. Through this model, we see that an obese phenotype microbiome is able to induce significant weight gain and hepatic steatosis. Associated with these changes we see a significant alteration of the expression levels of natural killer T-cells, cytotoxic T-cells, Kupffer cells, and monocyte-derived macrophages. The data shows that not only can the gut microbiome prognosticate NAFLD, it can also alter the progression of NAFLD through changes of the innate immune system of the liver. This work shows the feasibility of the gut microbiome both as a biomarker but also as a source for potential novel therapeutics against obesity and NAFLD
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
- …
