microRNA-27b regulates hepatic lipase enzyme LIPC and reduces triglyceride degradation during hepatitis C virus infection.

miRNAs are short, noncoding RNAs that negatively and specifically regulate protein expression, the cumulative effects of which can result in broad changes to cell systems and architecture. The miRNA miR-27b is known to regulate lipid regulatory pathways in the human liver and is also induced by the hepatitis C virus (HCV). However, the functional targets of miR-27b are not well established.

Profiling of MicroRNA Targets Using Activity-Based Protein Profiling: Linking Enzyme Activity to MicroRNA-185 Function.

MicroRNAs (miRNAs) act as cellular signal transducers through repression of protein translation. Elucidating targets using bioinformatics and traditional quantitation methods is often insufficient to uncover global miRNA function. Herein, alteration of protein function caused by miRNA-185 (miR-185), an immunometabolic miRNA, was determined using activity-based protein profiling, transcriptomics, and lipidomics.

A Bifunctional Nucleoside Probe for the Inhibition of the Human Immunodeficiency Virus-Type 1 Reverse Transcriptase.

Nucleoside analogs have proven effective for the inhibition of viral polymerases and are the foundation of many antiviral therapies. In this work, the antiretroviral potential of 6-azauracil analogs was assessed using activity-based protein profiling techniques and functional assays. Probes based on the 6-azauracil scaffold were examined and found to bind to HCV polymerase and HIV-1 reverse transcriptase through covalent modification of residues near the active site.

ABPP and Host-Virus Interactions.

Successful viral infection, as well as any resultant antiviral response, relies on numerous sequential interactions between host and viral factors. These interactions can take the form of affinity-based interactions between viral and host macromolecules or active, enzyme-based interactions, consisting both of direct enzyme activity performed by viral enzymes and indirect modulation of the activity of the host cell's enzymes via viral interference. This activity has the potential to transform the local microenvironment to the benefit or detriment of both the virus and the host, favouring either the continuation of the viral life cycle or the host's antiviral response.

Activity-Based Phosphatidylinositol Kinase Probes Detect Changes to Protein-Protein Interactions During Hepatitis C Virus Replication.

Protein-protein interactions are integral to host-virus interactions and can contribute significantly to enzyme regulation by changing the localization of both host and viral enzymes within the cell, inducing conformational change relevant to enzyme activity or recruiting other additional proteins to form functional complexes. Identifying the interactors of active enzymes using an activity-based protein profiling probe has allowed us to characterize both normal enzyme activation mechanisms and the manner by which these mechanisms are hijacked and altered by the hepatitis C virus (HCV). Here, we report use of a novel activity-based probe, PIKBPyne, which labels phosphatidylinositol kinases (PIKs) in an activity-based manner, to investigate HCV-dependent changes in protein-protein interactions for PI4KB.

Chemical Methods for Probing Virus-Host Proteomic Interactions.

Interactions between host and pathogen proteins constitute an important aspect of both infectivity and the host immune response. Different viruses have evolved complex mechanisms to hijack host-cell machinery and metabolic pathways to redirect resources and energy flow toward viral propagation. These interactions are often critical to the virus, and thus understanding these interactions at a molecular level gives rise to opportunities to develop novel antiviral strategies for therapeutic intervention.

Profiling Kinase Activity during Hepatitis C Virus Replication Using a Wortmannin Probe.

To complete its life cycle, the hepatitis C virus (HCV) induces changes to numerous aspects of its host cell. As kinases act as regulators of many pathways utilized by HCV, they are likely enzyme targets for virally induced inhibition or activation. Herein, we used activity-based protein profiling (ABPP), which allows for the identification of active enzymes in complex protein samples and the quantification of their activity, to identify kinases that displayed differential activity in HCV-expressing cells.

The role of microRNAs in metabolic interactions between viruses and their hosts.

Productive viral infection requires changes to the cellular metabolic landscape in order to obtain the building blocks and create the microenvironments necessary for the viral life cycle. In mammals, these alterations of metabolic pathways have been shown to be mediated in part by host and virus-encoded microRNAs. To counteract virally-induced changes in the cellular metabolic profile, the interferon-regulated antiviral response restricts viral access to key metabolites by altering cellular metabolism, mediated through induction of specific microRNAs regulating key lipid biosynthetic processes.

Soraphen A: A Probe for Investigating the Role of de Novo Lipogenesis during Viral Infection.

Many viruses including the hepatitis C virus (HCV) induce changes to the infected host cell metabolism that include the up-regulation of lipogenesis to create a favorable environment for the virus to propagate. The enzyme acetyl-CoA carboxylase (ACC) polymerizes to form a supramolecular complex that catalyzes the rate-limiting step of de novo lipogenesis. The small molecule natural product Soraphen A (SorA) acts as a nanomolar inhibitor of acetyl-CoA carboxylase activity through disruption of the formation of long highly active ACC polymers from less active ACC dimers.

Attributions about pain as predictors of psychological symptomatology, sexual function, and dyadic adjustment in women with vestibulodynia.

The present study examined whether attributions for vulvo-vaginal pain predicted pain intensity, sexual function, as well as psychological and dyadic adjustment in women with vestibulodynia. Women with vestibulodynia (N = 77) completed measures of attributions, pain, psychological distress, sexual functioning, and dyadic adjustment. They also took part in a structured interview and a gynaecological examination for diagnostic purposes.

Provoked vestibulodynia: psychological predictors of topical and cognitive-behavioral treatment outcome.

Psychological factors have been found to impact the pain experience and associated sexual impairment of women suffering from provoked vestibulodynia (PV). Despite a lack of randomized treatment outcome studies, particularly concerning psychological predictors of outcome, recent studies have shown that topical applications and cognitive-behavioral therapy (CBT) are among the most popular first-line interventions for PV. The present study aimed to determine the extent to which baseline fear-avoidance variables and pain self-efficacy were differentially associated with topical application and CBT outcomes at six-month follow-up.

Fear avoidance and self-efficacy in relation to pain and sexual impairment in women with provoked vestibulodynia.

Background: Provoked vestibulodynia is believed to be the most frequent cause of vulvodynia in women of childbearing age, with prevalence rates of up to 12% in the general population. Despite this high prevalence and the fact that vestibulodynia impacts negatively on quality of life, in particular sexual functioning, there has been a paucity of sound research to elucidate the condition's etiology. More specifically, few studies have focused on the role of psychologic factors in the experience of vulvo-vaginal pain and associated sexual impairment.

Male partners of women with provoked vestibulodynia: attributions for pain and their implications for dyadic adjustment, sexual satisfaction, and psychological distress.

Introduction: Provoked vestibulodynia is a female genital pain condition that results in sexual dysfunction and impacts negatively on the couple. Although patients' causal attributions have been linked to worse psychosexual outcomes, no study has documented the male partners' perspective of this distressing problem and its potential influence on their psychosexual adaptation.

Aim: To identify whether male partners' attributions for vestibulodynia are possible predictors of their dyadic adjustment, sexual functioning, sexual satisfaction, and psychological distress, as well as of women's pain and sexual functioning.

Do psychosexual factors play a role in the etiology of provoked vestibulodynia? A critical review.

The aim of this review was to critically examine published studies concerning the psychosexual aspects of provoked vestibulodynia. Despite the presence of several methodological limitations, some findings were consistently replicated. Overall, women with vestibulodynia demonstrate impaired sexual functioning, namely, lower levels of sexual desire, arousal, and frequency of intercourse.

The treatment of provoked vestibulodynia: a critical review.

Objective: To carry out a critical review of published studies concerning the treatment of provoked vestibulodynia.

Methods: MEDLINE, PsycINFO, and Cochrane were used to identify treatment studies published between January 1996 and December 2006. All studies published in English that dealt specifically with the treatment of provoked vestibulodynia were included in the review regardless of their methodological quality.