Reovirus non-structural protein σ1s is required for the establishment of viremia and hematogenous viral dissemination. However, the function of the σ1s protein during the reovirus replication cycle is not known. In this study, we found that σ1s was required for efficient reovirus replication in SV40-immortalized endothelial cells (SVECs), mouse embryonic fibroblasts, human umbilical vein endothelial cells (HUVECs), and T84 human colonic epithelial cells. In each of these cell lines, wild type reovirus produced substantially higher viral titers than a σ1s-deficient mutant. The σ1s protein was not required for early events in the reovirus infection, as no difference in infectivity between the wild type and σ1s-null viruses was observed. However, wild type virus produced markedly higher viral protein levels than the σ1s-deficient strain. The disparity in viral replication did not result from differences in viral transcription or protein stability. We further found that the σ1s protein was dispensable for cell killing and induction of type-1 interferon responses. In the absence of σ1s, viral factory (VF) maturation was impaired, but sufficient to support low levels of reovirus replication. Together, our results indicate that σ1s is not absolutely essential for viral protein production, but rather potentiates reovirus protein expression to facilitate reovirus replication. Our findings suggest that σ1s enables hematogenous reovirus dissemination by promoting efficient viral protein synthesis, and thereby reovirus replication, in cells that are required for reovirus spread to the blood.Hematogenous dissemination is critical a step in the pathogenesis of many viruses. For reovirus, nonstructural protein σ1s is required for viral spread via the blood. However, the mechanism by σ1s promotes reovirus dissemination is unknown. Here, we identified σ1s as a viral mediator of reovirus protein expression. We found several cultured cell lines in which σ1s is required for efficient reovirus replication. In these cells, wild type virus produced substantially higher levels of viral protein than a σ1s-deficient mutant. The σ1s protein was not required for viral mRNA transcription or viral protein stability. Owing to reduced levels of viral protein synthesized in the absence of σ1s, maturation of viral factories was impaired and significantly fewer viral progeny were produced. Taken together, our findings indicate that σ1s is required for optimal reovirus protein production, and thereby viral replication, in cells required hematogenous reovirus dissemination.
The surface glycoprotein (GP) of Ebola virus causes many of the virus's pathogenic effects, including a dramatic loss of endothelial cell adhesion associated with widespread hemorrhaging during infection. Although the GP-mediated deadhesion depends on its extracellular mucin-like domain, it is unknown whether any, or all, of this domain's densely clustered O-glycosylation sites are required. It is also unknown whether any of the 20 distinct polypeptide GalNAc-transferases (ppGalNAc-Ts) that initiate mucin-type O-glycosylation in human cells are functionally required. Here, using HEK293 cell lines lacking specific glycosylation enzymes, we demonstrate that GP requires extended O-glycans to exert its deadhesion effect. We also identified ppGalNAc-T1 as largely required for the GP-mediated adhesion defects. Despite its profound effect on GP function, the absence of ppGalNAc-T1 only modestly reduced the O-glycan mass of GP, indicating that even small changes in the bulky glycodomain can cause loss of GP function. Indeed, protein-mapping studies identified a small segment of the mucinlike domain critical for function and revealed that mutation of five glycan acceptor sites within this segment are sufficient to abrogate GP function. Together, these results argue against a mechanism of Ebola GP-induced cell detachment that depends solely on ectodomain bulkiness and identify a single host-derived glycosylation enzyme, ppGalNAc-T1, as a potential target for therapeutic intervention against Ebola virus disease.
Reovirus is under development as a therapeutic for numerous types of cancer. In contrast to other oncolytic viruses, the safety and efficacy of reovirus have not been improved through genetic manipulation. Here, we tested the oncolytic capacity of recombinant strains (rs) of prototype reovirus laboratory strains T1L and T3D (rsT1L and rsT3D, respectively) in a panel of non-small cell lung cancer (NSCLC) cell lines. We found that rsT1L was markedly more cytolytic than rsT3D in the large cell carcinoma cell lines tested, whereas killing of adenocarcinoma cell lines was comparable between rsT1L and rsT3D. Importantly, non-recombinant T1L and T3D phenocopied the kinetics and magnitude of cell death induced by recombinant strains. We identified gene segments L2, L3, and M1 as viral determinants of strain-specific differences cell killing of the large cell carcinoma cell lines. Together, these results indicate that recombinant reoviruses recapitulate the cell killing properties of non-recombinant, tissue culture-passaged strains. These studies provide a baseline for the use of reverse genetics with the specific objective of engineering more effective reovirus oncolytics. This work raises the possibility that type 1 reoviruses may have the capacity to serve as more effective oncolytics than type 3 reoviruses in some tumor types.
Ten years after completion of the first national oral health survey, the second such survey was carried out in 1995. Application of a multi-stage sampling procedure resulted in 3,709 persons being examined according to the WHO oral health assessment form and criteria. The background variables studied were age, gender, type of location, socio-economic status. Comparison with results from major studies in other African nations are presented. It was concluded that the prevalence of dental caries in all age groups was high but that the severity was low. The prevalence of unmet treatment needs was very high with extraction as the predominant mode of treatment. The survey has shown that the vast majority of Zimbabweans are not receiving and/or are not seeking oral care.
Ten years after completion of the first national oral health survey, a second national oral health survey was carried out in 1995. Application of a multi-stage sampling procedure resulted in 3,709 persons being examined. WHO's oral health assessment form and CPITN index was used. The background variables studied were age (15-19, and 35-44-year olds), gender, type of location, socio-economic status and level of education. Results suggest that the periodontal health of adolescents was better in 1985 than in 1995. Overall, the prevalence of periodontal conditions in both age groups was high but its severity was low. The need for complex periodontal treatment was only 4 per cent for adults. The survey has shown that the vast majority of Zimbabweans are not receiving and/or are not seeking periodontal care.
Background: The burden of chronic psychotic disorders (CPDs) in sub-Saharan Africa (SSA) is significant. Poorly medically adherent patients are more likely to have worse outcomes and require more resources. However, factors impacting effective treatment of CPD in this population are unclear.Aim: Examine the relationship between alcohol use and disease management and compare alcohol risk stratification between the Alcohol Use Disorders Identification Test (AUDIT) and Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) in poorly medication adherent Tanzanians with CPD.Setting: Muhimbili National Hospital and ambulatory clinics in Dar es Salaam, Tanzania.Methods: 100 Tanzanians with CPDs and suboptimal medication adherence were dichotomized into low and moderate-to-high risk alcohol use based on AUDIT scores and compared regarding medication attitudes, adherence and psychiatric symptoms. Patients completed the ASSIST for comparison to AUDIT risk stratification.Results: Moderate-to-high risk alcohol users had worse medication attitudes (p 0.01), medication adherence (previous week, p = 0.01; previous month, p 0.001), and psychiatric symptoms (p = 0.03). They were younger, predominately male and more likely to have a family history of alcohol abuse. A logistic regression analysis found age, gender and family history of abuse as significant predictors of hazardous alcohol use (p = 0.02, 0.02, 0.01, respectively). Risk stratification between AUDIT and ASSIST aligned in 85% of participants.Conclusion: Alcohol use is an important consideration in treating poorly adherent Tanzanians with CPD. The ASSIST was comparable to the AUDIT in stratifying risky alcohol use with the additional benefit of screening for other substances.
Purpose Repetition priming has been suggested as a method for targeting implicit processes in anomia treatment. Prior studies have used masked priming for this purpose. This study extends that work with visible primes, a more clinically feasible approach. Method This study used a single-subject design across three participants with aphasia. Treatment involved repeated exposure to identity primes (trained condition) or sham primes (untrained condition) paired with pictures. Analyses assessed acquisition effects for trained items and untrained items that were seen during the training period, generalization to untrained items that had not been seen, and generalization to broader language skills, immediately and 3 months post-treatment. Results All participants improved in naming trained items immediately after treatment, with greater improvements for trained than for untrained items. All participants maintained some degree of improvement on trained items 3 months post-treatment, although the degree differed across participants. Inconsistent generalization occurred to unexposed items. Improvements were noted in some areas of broader language ability, although these varied. Conclusions These data suggest a repetition priming treatment paradigm may increase naming accuracy for individuals with anomia and may benefit other aspects of language. Participant factors may have influenced response to treatment. Directions for future investigation are discussed.
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