The Role of the Phosphatidylinositol 4-Kinase PI4KA in Hepatitis C Virus-Induced Host Membrane Rearrangement

Background: Hepatitis C virus (HCV), like other positive-sense RNA viruses, replicates on an altered host membrane compartment that has been called the ‘‘membranous web.’ ’ The mechanisms by which the membranous web are formed from cellular membranes are poorly understood. Several recent RNA interference screens have demonstrated a critical role for the host phosphatidylinositol 4-kinase PI4KA in HCV replication. We have sought to define the function of PI4KA in viral replication. Methodology/Principal Findings: Using a nonreplicative model of membranous web formation, we show that PI4KA silencing leads to aberrant web morphology. Furthermore, we find that PI4KA and its product, phosphatidylinositol 4-phosphate, are enriched on membranous webs and that PI4KA is found in association with NS5A in HCV-infected cells. While the related lipid kinase PI4KB also appears to support HCV replication, it does not interact with NS5A. Silencing of PI4KB does not overtly impair membranous web morphology or phosphatidylinositol 4-phosphate enrichment at webs, suggesting that it acts at a different point in viral replication. Finally, we demonstrate that the aberrant webs induced by PI4KA silencing require the activity of the viral NS3-4A serine protease but not integrity of the host secretory pathway. Conclusions/Significance: PI4KA is necessary for the local enrichment of PI 4-phosphate at the HCV membranous web and for the generation of morphologically normal webs. We also show that nonreplicative systems of web formation can b

Effect of water temperature and induced acoustic pressure on cavitation erosion behaviour of aluminium alloys

Data availability: The raw/processed data required to reproduce these findings are available from the corresponding author on request.Copyright © 2023 The Author(s). Cavitation erosion is a major challenge for marine and fluid machinery systems. This study investigated the erosion performance of two as-cast aluminium alloys exposed to acoustic cavitation in water at temperatures of 10–50 °C and those were then compared with an extruded wrought alloy tested specifically at the temperature of maximum erosion. The results showed that the as-cast A380 alloy displayed exceptional resistance to cavitation erosion, with the lowest mass loss and surface roughness. This finding suggests that the as-cast A380 alloy is a suitable choice for lightweight, high-performance components in applications where cavitation resistance is critical.This work was financially sponsored by the PAAM (grants EP/W006774/1, EP/W00593X/1 and EP/W006154/1), UltraMelt2 (grants EP/R011001/1, EP/R011095/1 and EP/R011044/1) and EcoUltra2D (grants EP/R031401/1, EP/R031665/1, EP/R031819/1, EP/R031975/1) projects funded by the UK Engineering and Physical Sciences Research Council (EPSRC)

Increase of weight-bearing capacity of patients with lesions of the TFCC using a wrist brace

Study design: Retrospective cross-sectional case series. Background: Lesions of the triangular fibrocartilage complex (TFCC) can result in pain during axial load and unstable distal radioulnar joint (DRUJ). Conventional wrist orthoses decrease initial pain sufficiently but also prevent any movement during recovery and do not contribute to the stabilization of the DRUJ. Purpose: In this retrospective analysis, we tested if the weight-bearing capacity of patients with lesions of the triangular fibrocartilage complex was increased by wearing a brace that stabilizes the distal radioulnar joint. Methods: Twenty-three patients had an arthroscopically confirmed TFCC lesion. We compared preoperative dynamic weight-bearing capacity of both hands with and without a commercially available wrist brace (WristWidget). Subgroup analysis was performed for stability of the distal radioulnar joint and etiology of the TFCC lesion. The dynamic ulnar variance was measured in a modified weight bearing test. We used parametric tests for normally distributed values. Results: The weight-bearing capacity of the hand with TFCC lesion was significantly lower than of the control hand (16 verus 36 kg; p <0.001). The relative load of the affected hand compared to the unaffected hand increased from 48 % (CI 37-60, SD 27) to 59 % (CI 47-72, SD 29 with a brace. The device had no effect on the control hand. Twelve patients with unstable DRUJ had a lower weight-bearing capacity compared to the eleven with stable joint. The percentage improvement with bracing was higher for those with unstable joints (versus stable) and traumatic lesions (versus degenrative). Conclusion: The use of a wrist brace significantly increases the weight-bearing capacity and therefore the maximum tolerated axial load of patients with a lesion of the TFCC. Patients with traumatic lesion or unstable DRUJ tend to show lower values than with degenerative lesions or stable joints

A mouse model of heart failure with preserved ejection fraction due to chronic infusion of a low subpressor dose of angiotensin II

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of HF symptoms associated with impaired diastolic function. Although it represents ∼50% of patients with HF, the mechanisms of disease are poorly understood, and therapies are generally ineffective in reducing HF progression. Animal models of HFpEF not due to pressure or volume overload are lacking, therefore limiting in-depth understanding of the pathophysiological mechanisms and the development of novel therapies. We hypothesize that a continuous infusion of low-dose angiotensin II (AT(II)) is sufficient to induce left ventricular (LV) diastolic dysfunction and HFpEF, without increasing blood pressure or inducing LV hypertrophy or dilatation. Osmotic pumps were implanted subcutaneously in 8-wk-old male mice assigned to the AT(II) (0.2 mg·kg(−1)·day(−1)) or volume-matched vehicle (N = 8/group) for 4 wk. We measured systolic and diastolic arterial blood pressures through a tail-cuff transducer, LV dimensions and ejection fraction through echocardiography, and LV relaxation through pulsed-wave Doppler and LV catheterization. Myocardial fibrosis and cardiomyocyte cross-sectional area were measured. AT(II) infusion had no effects on systemic arterial blood pressure. AT(II) induced significant impairment in LV diastolic function, as measured by an increase (worsening) in LV isovolumetric relaxation time, myocardial performance index, isovolumetric relaxation time constant, and LV end-diastolic pressure without altering LV dimensions, mass, or ejection fraction. Chronic infusion of low-dose AT(II) recapitulates the HFpEF phenotype in the mouse, without increasing systemic arterial blood pressure. This mouse model may provide insight into the mechanisms of HFpEF

Individual-level determinants of waterpipe smoking demand in four Eastern-Mediterranean countries

© 2018 The Author(s) 2018. Published by Oxford University Press. All rights reserved. The prevalence of waterpipe tobacco smoking in the Eastern Mediterranean Region is at alarmingly high levels, especially among young people. The objective of this research was to evaluate the preferences of young adult waterpipe smokers with respect to potential individual-level determinants of waterpipe smoking using discrete choice experiment methodology. Participants were young adult university students (18-29 years) who were ever waterpipe smokers, recruited from universities across four Eastern Mediterranean countries: Jordan, Oman, Palestine and the United Arab Emirates. The Internet-based discrete choice experiment, with 6 × 3 × 2 block design, evaluated preferences for choices of waterpipe smoking sessions, presented on hypothetical waterpipe café menus. Participants evaluated nine choice sets, each with five fruit-flavored options, a tobacco flavored option (non-flavored), and an opt-out option. Choices also varied based on nicotine content (0.0% vs. 0.05% vs. 0.5%) and price (low vs. high). Participants were randomized to receive menus with either a pictorial + text health-warning message or no message (between-subjects attribute). Multinomial logit regression models evaluated the influence of these attributes on waterpipe smoking choices. Across all four samples (n = 1859), participants preferred fruit-flavored varieties to tobacco flavor, lower nicotine content and lower prices. Exposure to the health warning did not significantly predict likelihood to opt-out. Flavor accounted for 81.4% of waterpipe smoking decisions. Limiting the use of fruit flavors in waterpipe tobacco, in addition to accurate nicotine content labeling and higher pricing may be effective at curbing the demand for waterpipe smoking among young adults

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

Bridging the gap between atomistic phenomena and continuum behavior in electrochemical energy storage processes.

Abstract Not Provide

Narrative Exposure Therapy as a treatment for child war survivors with posttraumatic stress disorder: Two case reports and a pilot study in an African refugee settlement

BACKGROUND: Little data exists on the effectiveness of psychological interventions for children with posttraumatic stress disorder (PTSD) that has resulted from exposure to war or conflict-related violence, especially in non-industrialized countries. We created and evaluated the efficacy of KIDNET, a child-friendly version of Narrative Exposure Therapy (NET), as a short-term treatment for children. METHODS: Six Somali children suffering from PTSD aged 12–17 years resident in a refugee settlement in Uganda were treated with four to six individual sessions of KIDNET by expert clinicians. Symptoms of PTSD and depression were assessed pre-treatment, post-treatment and at nine months follow-up using the CIDI Sections K and E. RESULTS: Important symptom reduction was evident immediately after treatment and treatment outcomes were sustained at the 9-month follow-up. All patients completed therapy, reported functioning gains and could be helped to reconstruct their traumatic experiences into a narrative with the use of illustrative material. CONCLUSIONS: NET may be safe and effective to treat children with war related PTSD in the setting of refugee settlements in developing countries

Alterations in the Interleukin-1/Interleukin-1 Receptor Antagonist Balance Modulate Cardiac Remodeling following Myocardial Infarction in the Mouse

Background Healing after acute myocardial infarction (AMI) is characterized by an intense inflammatory response and increased Interleukin-1 (IL-1) tissue activity. Genetically engineered mice lacking the IL-1 receptor (IL-1R1-/-, not responsive to IL-1) or the IL-1 receptor antagonist (IL-1Ra, enhanced response to IL-1) have an altered IL-1/IL-1Ra balance that we hypothesize modulates infarct healing and cardiac remodeling after AMI. Methods IL-1R1-/- and IL-1Ra-/- male mice and their correspondent wild-types (WT) were subjected to permanent coronary artery ligation or sham surgery. Infarct size (trichrome scar size), apoptotic cell death (TUNEL) and left ventricular (LV) dimensions and function (echocardiography) were measured prior to and 7 days after surgery. Results When compared with the corresponding WT, IL-1R1-/- mice had significantly smaller infarcts (−25%), less cardiomyocyte apoptosis (−50%), and reduced LV enlargement (LV end-diastolic diameter increase [LVEDD], −20%) and dysfunction (LV ejection fraction [LVEF] decrease, −50%), whereas IL-1Ra-/- mice had significantly larger infarcts (+75%), more apoptosis (5-fold increase), and more severe LV enlargement (LVEDD increase,+30%) and dysfunction (LVEF decrease, +70%)(all P values \u3c0.05). Conclusions An imbalance in IL-1/IL-1Ra signaling at the IL-1R1 level modulates the severity of cardiac remodeling after AMI in the mouse, with reduced IL-1R1 signaling providing protection and unopposed IL-1R1 signaling providing harm

A role for domain I of the hepatitis C virus NS5A protein in virus assembly

The NS5A protein of hepatitis C virus (HCV) plays roles in both virus genome replication and assembly. NS5A comprises three domains, of these domain I is believed to be involved exclusively in genome replication. In contrast, domains II and III are required for the production of infectious virus particles and are largely dispensable for genome replication. Domain I is highly conserved between HCV and related hepaciviruses, and is highly structured, exhibiting different dimeric conformations. To investigate the functions of domain I in more detail, we conducted a mutagenic study of 12 absolutely conserved and surface-exposed residues within the context of a JFH-1-derived sub-genomic replicon and infectious virus. Whilst most of these abrogated genome replication, three mutants (P35A, V67A and P145A) retained the ability to replicate but showed defects in virus assembly. P35A exhibited a modest reduction in infectivity, however V67A and P145A produced no infectious virus. Using a combination of density gradient fractionation, biochemical analysis and high resolution confocal microscopy we demonstrate that V67A and P145A disrupted the localisation of NS5A to lipid droplets. In addition, the localisation and size of lipid droplets in cells infected with these two mutants were perturbed compared to wildtype HCV. Biophysical analysis revealed that V67A and P145A abrogated the ability of purified domain I to dimerize and resulted in an increased affinity of binding to HCV 3’UTR RNA. Taken together, we propose that domain I of NS5A plays multiple roles in assembly, binding nascent genomic RNA and transporting it to lipid droplets where it is transferred to Core. Domain I also contributes to a change in lipid droplet morphology, increasing their size. This study reveals novel functions of NS5A domain I in assembly of infectious HCV and provides new perspectives on the virus lifecycle