Update on hepatitis C virus resistance to direct-acting antiviral agents

Review[Abstract] Resistance to direct-acting antiviral (DAA) agents against hepatitis C virus (HCV) infection is driven by the selection of mutations at different positions in the NS3 protease, NS5B polymerase and NS5A proteins. With the exception of NS5B nucleos(t)ide inhibitors, most DAAs possess a low genetic barrier to resistance, with significant cross-resistance between compounds belonging to the same family. However, a specific mutation profile is associated with each agent or drug class and varies depending on the genotype/subtype (e.g., genotype 1b showed higher rates of sustained virological response (SVR) and a higher genetic barrier for resistance than genotype 1a). Moreover, some resistance mutations exist as natural polymorphisms in certain genotypes/subtypes at frequencies that require baseline drug resistance testing before recommending certain antivirals. For example, the polymorphism Q80K is frequently found among genotype 1a (19–48%) and is associated with resistance to simeprevir. Similarly, L31M and Y93H, key resistance mutations to NS5A inhibitors, are frequently found (6–12%) among NS5A genotype 1 sequences. In particular, the presence of these polymorphisms may be of relevance in poorly interferon-responsive patients (i.e., null responders and non-CC IL28B) under DAA-based therapies in combination with pegylated interferon-α plus ribavirin. The relevance of pre-existing resistance mutations for responses to interferon-free DAA therapies is unclear for most regimens and requires further study.Instituto de Salud Carlos III; CP08/00214Instituto de Salud Carlos III; PI10/0216

Aphanomyces-Resistant Alfalfa: A Solution to a Common Problem in Spring Seedings

For several decades, farmers have experienced a common stand-establishment disease syndrome when spring-seeded alfalfa was followed by extended periods of wet weather. Seedlings affected by this syndrome exhibit severe stunting as well as yellowing and reddening of seed leaves (cotyledons), but they do not wilt or collapse, as they might from a damping-off disease. Commonly, the problem affects most or all of the field. Based on research that began in the 1980\u27s, we suspected that a fungus called Aphanomyces euteiches (hereafter simply called Aphanomyces) was responsible. This root-rot fungus can be found in the majority of alfalfa fields we have sampled in central and western Kentucky. However, for many years we lacked conclusive proof that Aphanomyces was, in fact, the cause of this common problem in spring-seeded alfalfa. We also did not have rigorous proof that the syndrome could be avoided by sowing Aphanomyces-resistant alfalfa varieties, which started becoming commercially available in the early 1990\u27s. In this report, we provide a brief summary of research to support our new recommendation: that spring-seeded alfalfa should be sown only with varieties having an R or HR rating to Aphanomyces root rot (ARR)

Oxysterol Binding Protein-dependent Activation of Sphingomyelin Synthesis in the Golgi Apparatus Requires Phosphatidylinositol 4-Kinase IIα

The study identifies a sterol- and oxysterol binding protein (OSBP)-regulated phosphatidylinositol 4-kinase that regulates ceramide transport protein (CERT) activity and sphingomyelin (SM) synthesis. RNA interference silencing experiments identify PI4KIIα; as the mediator of Golgi recruitment of CERT, providing a potential mechanism for coordinating assembly of SM and cholesterol in the Golgi or more distal compartments

Smart Moves: Effects of Relative Brain Size on Establishment Success of Invasive Amphibians and Reptiles

Brain size relative to body size varies considerably among animals, but the ecological consequences of that variation remain poorly understood. Plausibly, larger brains confer increased behavioural flexibility, and an ability to respond to novel challenges. In keeping with that hypothesis, successful invasive species of birds and mammals that flourish after translocation to a new area tend to have larger brains than do unsuccessful invaders. We found the same pattern in ectothermic terrestrial vertebrates. Brain size relative to body size was larger in species of amphibians and reptiles reported to be successful invaders, compared to species that failed to thrive after translocation to new sites. This pattern was found in six of seven global biogeographic realms; the exception (where relatively larger brains did not facilitate invasion success) was Australasia. Establishment success was also higher in amphibian and reptile families with larger relative brain sizes. Future work could usefully explore whether invasion success is differentially associated with enlargement of specific parts of the brain (as predicted by the functional role of the forebrain in promoting behavioural flexibility), or with a general size increase (suggesting that invasion success is facilitated by enhanced perceptual and motor skills, as well as cognitive ability)

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity

IMPORTANCE: Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients

Environmental volunteer well-being: managers’ perception and actual well-being of volunteers

Environmental volunteering is known to be able to increase well-being but environmental volunteer well-being has rarely been compared to participant well-being associated with other types of volunteering or nature-based activities. This paper aims to use a multidimensional approach to well-being to explore the immediately experienced and later remembered well-being of environmental volunteers and to compare this to the increased well-being of participants in other types of nature-based activities and volunteering. Furthermore, it aims to compare volunteer managers’ perception of their volunteers’ well-being with the self-reported well-being of the volunteers. Onsite surveys were conducted of practical conservation and biodiversity monitoring volunteers as well as their control groups, walkers and fieldwork students, respectively, to measure general well-being before their nature-based activity and activity-related well-being immediately after their activity. Online surveys of current, former and potential volunteers and volunteer managers in environmental volunteering and other types of volunteering measured remembered volunteering-related well-being and volunteer managers’ perceptions of their volunteers’ well-being. Data were analysed based on Seligman’s multidimensional PERMA (‘Positive emotion’, ‘Engagement’, ‘positive Relationship’, ‘Meaning’, ‘Achievement’) model of well-being. Factor analysis recovered three of the five PERMA elements, ‘engagement’, ‘relationship’ and ‘meaning’, as well as ‘negative emotion’ and ‘health’ as factors. Environmental volunteering significantly improved positive elements and significantly decreased negative elements of participants’ immediate well-being and it did so more than walking or student fieldwork did. Even remembering their volunteering up to six months later, volunteers rated their volunteering-related well-being higher than volunteers rated their well-being generally in life. However, volunteering was not found to have an effect on overall mean well-being generally in life. Volunteer managers did not perceive the significant increase in well-being that volunteers reported during volunteering. Multidimensional well-being assessments offer the potential for volunteer organisations and managers to more systematically understand, support and enhance volunteer well-being

Multiple effects of toxins isolated from Crotalus durissus terrificus on the hepatitis C virus life cycle

Hepatitis C virus (HCV) is one of the main causes of liver disease and transplantation worldwide. Current therapy is expensive, presents additional side effects and viral resistance has been described. Therefore, studies for developing more efficient antivirals against HCV are needed. Compounds isolated from animal venoms have shown antiviral activity against some viruses such as Dengue virus, Yellow fever virus and Measles virus. In this study, we evaluated the effect of the complex crotoxin (CX) and its subunits crotapotin (CP) and phospholipase A2 (PLA2-CB) isolated from the venom of Crotalus durissus terrificus on HCV life cycle. Huh 7.5 cells were infected with HCVcc JFH-1 strain in the presence or absence of these toxins and virus was titrated by focus formation units assay or by qPCR. Toxins were added to the cells at different time points depending on the stage of virus life cycle to be evaluated. The results showed that treatment with PLA2-CB inhibited HCV entry and replication but no effect on HCV release was observed. CX reduced virus entry and release but not replication. By treating cells with CP, an antiviral effect was observed on HCV release, the only stage inhibited by this compound. Our data demonstrated the multiple antiviral effects of toxins from animal venoms on HCV life cycle

Circulating sCD14 Is Associated with Virological Response to Pegylated-Interferon-Alpha/Ribavirin Treatment in HIV/HCV Co-Infected Patients

Microbial translocation (MT) through the gut accounts for immune activation and CD4+ loss in HIV and may influence HCV disease progression in HIV/HCV co-infection. We asked whether increased MT and immune activation may hamper anti-HCV response in HIV/HCV patients.98 HIV/HCV patients who received pegylated-alpha-interferon (peg-INF-alpha)/ribavirin were retrospectively analyzed. Baseline MT (lipopolysaccharide, LPS), host response to MT (sCD14), CD38+HLA-DR+CD4+/CD8+, HCV genotype, severity of liver disease were assessed according to Early Virological Response (EVR: HCV-RNA <50 IU/mL at week 12 of therapy or ≥2 log(10) reduction from baseline after 12 weeks of therapy) and Sustained Virological Response (SVR: HCV-RNA <50 IU/mL 24 weeks after end of therapy). Mann-Whitney/Chi-square test and Pearson's correlation were used. Multivariable regression was performed to determine factors associated with EVR/SVR.71 patients displayed EVR; 41 SVR. Patients with HCV genotypes 1-4 and cirrhosis presented a trend to higher sCD14, compared to patients with genotypes 2-3 (p = 0.053) and no cirrhosis (p = 0.052). EVR and SVR patients showed lower levels of circulating sCD14 (p = 0.0001, p = 0.026, respectively), but similar T-cell activation compared to Non-EVR (Null Responders, NR) and Non-SVR (N-SVR) subjects. sCD14 resulted the main predictive factor of EVR (0.145 for each sCD14 unit more, 95%CI 0.031-0.688, p = 0.015). SVR was associated only with HCV genotypes 2-3 (AOR 0.022 for genotypes 1-4 vs 2-3, 95%CI 0.001-0.469, p = 0.014).In HIV/HCV patients sCD14 correlates with the severity of liver disease and predicts early response to peg-INF-alpha/ribavirin, suggesting MT-driven immune activation as pathway of HIV/HCV co-infection and response to therapy