Oncogenic Potential of Hepatitis C Virus Proteins

Chronic hepatitis C virus (HCV) infection is a major risk factor for liver disease progression, and may lead to cirrhosis and hepatocellular carcinoma (HCC). The HCV genome contains a single-stranded positive sense RNA with a cytoplasmic lifecycle. HCV proteins interact with many host-cell factors and are involved in a wide range of activities, including cell cycle regulation, transcriptional regulation, cell proliferation, apoptosis, lipid metabolism, and cell growth promotion. Increasing experimental evidences suggest that HCV contributes to HCC by modulating pathways that may promote malignant transformation of hepatocytes. At least four of the 10 HCV gene products, namely core, NS3, NS5A and NS5B play roles in several potentially oncogenic pathways. Induction of both endoplasmic reticulum (ER) stress and oxidative stress by HCV proteins may also contribute to hepatocyte growth promotion. The current review identifies important functions of the viral proteins connecting HCV infections and potential for development of HCC. However, most of the putative transforming potentials of the HCV proteins have been defined in artificial cellular systems, and need to be established relevant to infection and disease models. The new insight into the mechanisms for HCV mediated disease progression may offer novel therapeutic targets for one of the most devastating human malignancies in the world today

Hepatitis C virus infection

Hepatitis C virus (HCV) often causes persistent infection, and is an important factor in the etiology of fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are no preventive or therapeutic vaccines available against HCV. Treatment strategies of HCV infection are likely to improve with recently discovered direct antiviral agents (DAAs). However, a proportion of patients still progress to liver failure and/or HCC despite having been cured of the infection. Thus, there is a need for early diagnosis and therapeutic modalities for HCV relatedend stage liver disease prevention. HCV genome does not integrate into its host genome, and has a predominantly cytoplasmic life cycle. Therefore, HCV mediated liver disease progression appears to involve indirect mechanisms from persistent infection of hepatocytes. Studying the underlying mechanisms of HCV mediated evasion of immune responses and liver disease progression is challenging due to the lack of a naturally susceptible small animal model. We and other investigators have used a number of experimental systems to investigate the mechanisms for establishment of chronic HCV infection and liver disease progression. HCV infection modulates immune systems. Further, HCV infection of primary human hepatocytes promotes growth, induces phenotypic changes, modulates epithelial mesenchymal transition (EMT) related genes, and generates tumor initiating stem-like cells (TISCs). HCV infection also modulates microRNAs (miRNAs), and influences growth by overriding normal death progression of primary human hepatocytes for disease pathogenesis. Understanding these observations at the molecular level should aid in developing strategies for additional effective therapies against HCV mediated liver disease progression

MicroRNAs: Role in hepatitis C virus pathogenesis

AbstractHepatitis C virus (HCV) is a global health burden with an estimated 170–200 million peoples chronically infected worldwide. HCV infection remains as an independent risk factor for chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, and a major reason for liver transplantation. Discovery of direct acting antiviral (DAA) drugs have shown promising results with more than 90% success rate in clearing the HCV RNA in patients, although long-term consequences remain to be evaluated. microRNAs (miRNAs) are important players in establishment of HCV infection and target crucial host cellular factors needed for productive HCV replication and augmented cell growth. Altered expression of miRNAs is involved in the pathogenesis associated with HCV infection by controlling signaling pathways such as immune response, proliferation and apoptosis. miRNA is emerging as a means of communication between various cell types inside the liver. There is likely possibility of developing circulating miRNAs as biomarkers of disease progression and can also serve as diagnostic tool with potential of early therapeutic intervention in HCV associated end stage liver disease. This review focuses on recent studies highlighting the contribution of miRNAs in HCV life cycle and their coordinated regulation in HCV mediated liver disease progression

Variation of Gender Biases in Visual Recognition Models Before and After Finetuning

We introduce a framework to measure how biases change before and after fine-tuning a large scale visual recognition model for a downstream task. Deep learning models trained on increasing amounts of data are known to encode societal biases. Many computer vision systems today rely on models typically pretrained on large scale datasets. While bias mitigation techniques have been developed for tuning models for downstream tasks, it is currently unclear what are the effects of biases already encoded in a pretrained model. Our framework incorporates sets of canonical images representing individual and pairs of concepts to highlight changes in biases for an array of off-the-shelf pretrained models across model sizes, dataset sizes, and training objectives. Through our analyses, we find that (1) supervised models trained on datasets such as ImageNet-21k are more likely to retain their pretraining biases regardless of the target dataset compared to self-supervised models. We also find that (2) models finetuned on larger scale datasets are more likely to introduce new biased associations. Our results also suggest that (3) biases can transfer to finetuned models and the finetuning objective and dataset can impact the extent of transferred biases.Comment: 10 pages, 3 Figure

Accessibility and partner number of protein residues, their relationship and a webserver, ContPlot for their display

<p>Abstract</p> <p>Background</p> <p>Depending on chemical features residues have preferred locations – interior or exterior – in protein structures, which also determine how many other residues are found around them. The close packing of residues is the hallmark of protein interior and protein-protein interaction sites.</p> <p>Results</p> <p>The average values of accessible surface area (ASA) and partner number (PN, the number of other residues within a distance of 4.5 Å from any atom of a given residue) of different residues have been determined and a webserver, ContPlot has been designed to display these values (relative to the average values) along the protein sequence. This would be useful to visually identify residues that are densely packed, or those involved in protein-protein interactions. The skewness observed in the distribution of PNs is indicative of the hydrophobic or hydrophilic nature of the residue. The variation of ASA with PN can be analytically expressed in terms of a cubic equation. These equations (one for each residue) can be used to estimate the ASA of a polypeptide chain using the PNs of the individual residues in the structure.</p> <p>Conclusion</p> <p>The atom-based PNs (obtained by counting surrounding atoms) are highly correlated to the residue-based PN, indicating that the latter can adequately capture the atomic details of packing. The average values of ASA and PN associated with each residue should be useful in protein structure prediction or fold-recognition algorithm. ContPlot would provide a handy tool to assess the importance of a residue in the protein structure or interaction site.</p

A randomised trial of early palliative care for maternal stress in infants prenatally diagnosed with single-ventricle heart disease

AbstractChildren with single-ventricle disease experience high mortality and complex care. In other life-limiting childhood illnesses, paediatric palliative care may mitigate maternal stress. We hypothesised that early palliative care in the single-ventricle population may have the same benefit for mothers. In this pilot randomised trial of early palliative care, mothers of infants with prenatal single-ventricle diagnoses completed surveys measuring depression, anxiety, coping, and quality of life at a prenatal visit and neonatal discharge. Infants were randomised to receive early palliative care – structured evaluation, psychosocial/spiritual, and communication support before surgery – or standard care. Among 56 eligible mothers, 40 enrolled and completed baseline surveys; 38 neonates were randomised, 18 early palliative care and 20 standard care; and 34 postnatal surveys were completed. Baseline Beck Depression Inventory-II and State-Trait Anxiety Index scores exceeded normal pregnant sample scores (mean 13.76±8.46 versus 7.0±5.0 and 46.34±12.59 versus 29.8±6.35, respectively; p=0.0001); there were no significant differences between study groups. The early palliative care group had a decrease in prenatal to postnatal State-Trait Anxiety Index scores (−7.6 versus 0.3 in standard care, p=0.02), higher postnatal Brief Cope Inventory positive reframing scores (p=0.03), and a positive change in PedsQL Family Impact Module communication and family relationships scores (effect size 0.46 and 0.41, respectively). In conclusion, these data show that mothers of infants with single-ventricle disease experience significant depression and anxiety prenatally. Early palliative care resulted in decreased maternal anxiety, improved maternal positive reframing, and improved communication and family relationships.</jats:p