Johannesenbennetsen8067

The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these "variants of concern" has increased immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (kappa and delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.About 4% of the population in Taiwan are seropositive for anti-HCV Ab and 70% with HCV RNA. To address this high chronic hepatitis C disease load, Taiwan National Health Insurance started reimbursing genotype-specific DAAs in 2017 and pangenotype DAAs in mid-2018. With a 97% SVR12 rate, there were still 2-3% of patients that failed to clear HCV. To understand the causes of DAA failure in Taiwan, we conducted a multi-center, clinical, and virologic study. A total of 147 DAA-failure patients were recruited, and we searched HCV NS3/4A, NS5A and NS5B for known resistance-associated substitutions (RASs) by population sequencing, and conducted whole genome sequencing (WGS) for those without known RASs. A total of 107 patients received genotype-specific DAAs while 40 had pangenotype DAAs. Clinically, the important cause of failure is poor adherence. Virologically, common RASs in genotype-specific DAAs were NS5A-L31, NS5A-Y93, and NS5B-C316, while common RASs in pangenotype DAAs were NS5A-L31, NS5A-A/Q/R30, and NS5A-Y93. Additionally, new amino acid changes were found by WGS. Finally, we identified 12 cases with inconsistent baseline and post-treatment HCV genotypes, which is suggestive of re-infection rather than treatment failure. read more Our study described the drug resistance profile for DAA failure in Taiwan, showing differences from other countries.Rocio virus (ROCV) is a mosquito-borne flavivirus and human pathogen. The virus is indigenous to Brazil and was first detected in 1975 in the Sao Paulo State, and over a period of two years was responsible for several epidemics of meningoencephalitis in coastal communities leading to over 100 deaths. The vast majority of ROCV infections are believed to be subclinical and clinical manifestations can range from uncomplicated fever to fatal meningoencephalitis. Birds are the natural reservoir and amplification hosts and ROCV is maintained in nature in a mosquito-bird-mosquito transmission cycle, primarily involving Psorophora ferox mosquitoes. While ROCV has remained mostly undetected since 1976, in 2011 it re-emerged in Goiás State causing a limited outbreak. Control of ROCV outbreaks depends on sustainable vector control measures and public education. To date there is no specific treatment or licensed vaccine available. Here we provide an overview of the ecology, transmission cycles, epidemiology, pathogenesis, and treatment options, aiming to improve our ability to understand, predict, and ideally avert further ROCV emergence.Cytomegalovirus (CMV) causes significant morbidity and mortality in recipients of allogeneic hematopoietic cell transplantation (HCT). Whereas insights gained from mathematical modeling of other chronic viral infections such as HIV, hepatitis C, and herpes simplex virus-2 have aided in optimizing therapy, previous CMV modeling has been hindered by a lack of comprehensive quantitative PCR viral load data from untreated episodes of viremia in HCT recipients. We performed quantitative CMV DNA PCR on stored, frozen serum samples from the placebo group of participants in a historic randomized controlled trial of ganciclovir for the early treatment of CMV infection in bone marrow transplant recipients. We developed four main ordinary differential Equation mathematical models and used model selection theory to choose between 38 competing versions of these models. Models were fit using a population, nonlinear, mixed-effects approach. We found that CMV kinetics from untreated HCT recipients are highly variable. The models that recapitulated the observed patterns most parsimoniously included explicit, dynamic immune cell compartments and did not include dynamic target cell compartments, consistent with the large number of tissue and cell types that CMV infects. In addition, in our best-fitting models, viral clearance was extremely slow, suggesting severe impairment of the immune response after HCT. Parameters from our best model correlated well with participants' clinical risk factors and outcomes from the trial, further validating our model. Our models suggest that CMV dynamics in HCT recipients are determined by host immune response rather than target cell limitation in the absence of antiviral treatment.

Dengue virus and Japanese encephalitis virus are two common flaviviruses that are spread widely by

and

mosquitoes. Livestock keeping is vital for cities; however, it can pose the risk of increasing the mosquito population. Our study explored how livestock keeping in and around a large city is associated with the presence of mosquitoes and the risk of them spreading flaviviruses.

An entomological study was conducted in 6 districts with 233 households with livestock, and 280 households without livestock, in Hanoi city. BG-Sentinel traps and CDC light traps were used to collect mosquitoes close to animal farms and human habitats. Adult mosquitoes were counted, identified to species level, and grouped into 385 pools, which were screened for flaviviruses using a pan-flavivirus qPCR protocol and sequencing.

A total of 12,861 adult mosquitoes were collected at the 513 households, with 5 different genera collected, of which the

genus was the most abundant. Our study found that there was a positive association between livestock keeping and the size of the mosquito population-most predominantly between pig rearing and

species (

< 0.001). One pool of

, collected in a peri-urban district, was found to be positive for Japanese encephalitis virus.

The risk of flavivirus transmission in urban areas of Hanoi city due to the spread of

and

mosquitoes could be facilitated by livestock keeping.

The risk of flavivirus transmission in urban areas of Hanoi city due to the spread of Culex and Aedes mosquitoes could be facilitated by livestock keeping.With the exception of inactivated vaccines, all SARS-CoV-2 vaccines currently used for clinical application focus on the spike envelope glycoprotein as a virus-specific antigen. Compared to other SARS-CoV-2 genes, mutations in the spike protein gene are more rapidly selected and spread within the population, which carries the risk of impairing the efficacy of spike-based vaccines. It is unclear to what extent the loss of neutralizing antibody epitopes can be compensated by cellular immune responses, and whether the use of other SARS-CoV-2 antigens might cause a more diverse immune response and better long-term protection, particularly in light of the continued evolution towards new SARS-CoV-2 variants. To address this question, we explored immunogenicity and protective effects of adenoviral vectors encoding either the full-length spike protein (S), the nucleocapsid protein (N), the receptor binding domain (RBD) or a hybrid construct of RBD and the membrane protein (M) in a highly susceptible COVID-19 hamster model. All adenoviral vaccines provided life-saving protection against SARS-CoV-2-infection. The most efficient protection was achieved after exposure to full-length spike. However, the nucleocapsid protein, which triggered a robust T-cell response but did not facilitate the formation of neutralizing antibodies, controlled early virus replication efficiently and prevented severe pneumonia. Although the full-length spike protein is an excellent target for vaccines, it does not appear to be the only option for future vaccine design.Primary varicella-zoster virus (VZV) infection leads to varicella and the establishment of lifelong latency in sensory ganglion neurons. Reactivation of latent VZV causes herpes zoster, which is frequently associated with chronic pain. Latent viral gene expression is restricted to the VZV latency-associated transcript (VLT) and VLT-ORF63 (VLT63) fusion transcripts. Since VLT and VLT63 encode proteins that are expressed during lytic infection, we investigated whether pVLT and pVLT-ORF63 are essential for VZV replication by performing VZV genome mutagenesis using CRISPR/Cas9 and BAC technologies. We first established that CRISPR/Cas9 can efficiently mutate VZV genomes in lytically VZV-infected cells through targeting non-essential genes ORF8 and ORF11 and subsequently show recovery of viable mutant viruses. By contrast, the VLT region was markedly resistant to CRISPR/Cas9 editing. Whereas most mutants expressed wild-type or N-terminally altered versions of pVLT and pVLT-ORF63, only a minority of the resulting mutant viruses lacked pVLT and pVLT-ORF63 coding potential. Growth curve analysis showed that pVLT/pVLT-ORF63 negative viruses were viable, but impaired in growth in epithelial cells. We confirmed this phenotype independently using BAC-derived pVLT/pVLT-ORF63 negative and repaired viruses. Collectively, these data demonstrate that pVLT and/or pVLT-ORF63 are dispensable for lytic VZV replication but promote efficient VZV infection in epithelial cells.Prion diseases, or transmissible spongiform encephalopathies (TSEs), are a class of fatal neurodegenerative diseases caused by the entry and spread of infectious prion proteins (PrPSc) in the central nervous system (CNS). These diseases are endemic to certain mammalian animal species that use their sense of smell for a variety of purposes and therefore expose their nasal cavity (NC) to PrPSc in the environment. Prion diseases that affect humans are either inherited due to a mutation of the gene that encodes the prion protein, acquired by exposure to contaminated tissues or medical devices, or develop without a known cause (referred to as sporadic). The purpose of this review is to identify components of the NC that are involved in prion transport and to summarize the evidence that the NC serves as a route of entry (centripetal spread) and/or a source of shedding (centrifugal spread) of PrPSc, and thus plays a role in the pathogenesis of the TSEs.