Production of HIV Particles Is Regulated by Altering Sub-Cellular Localization and Dynamics of Rev Induced by Double-Strand RNA Binding Protein

Human immunodeficiency virus (HIV)-1 encoded Rev is essential for export from the nucleus to the cytoplasm, of unspliced and singly spliced transcripts coding for structural and nonstructural viral proteins. This process is spatially and temporally coordinated resulting from the interactions between cellular and viral proteins. Here we examined the effects of the sub-cellular localization and dynamics of Rev on the efficiency of nucleocytoplasmic transport of HIV-1 Gag transcripts and virus particle production. Using confocal microscopy and fluorescence recovery after bleaching (FRAP), we report that NF90ctv, a cellular protein involved in Rev function, alters both the sub-cellular localization and dynamics of Rev in vivo, which drastically affects the accumulation of the viral protein p24. The CRM1–dependent nuclear export of Gag mRNA linked to the Rev Response Element (RRE) is dependent on specific domains of the NF90ctv protein. Taken together, our results demonstrate that the appropriate intracellular localization and dynamics of Rev could regulate Gag assembly and HIV-1 replication

The pch2Δ Mutation in Baker's Yeast Alters Meiotic Crossover Levels and Confers a Defect in Crossover Interference

Pch2 is a widely conserved protein that is required in baker's yeast for the organization of meiotic chromosome axes into specific domains. We provide four lines of evidence suggesting that it regulates the formation and distribution of crossover events required to promote chromosome segregation at Meiosis I. First, pch2Δ mutants display wild-type crossover levels on a small (III) chromosome, but increased levels on larger (VII, VIII, XV) chromosomes. Second, pch2Δ mutants show defects in crossover interference. Third, crossovers observed in pch2Δ require both Msh4-Msh5 and Mms4-Mus81 functions. Lastly, the pch2Δ mutation decreases spore viability and disrupts crossover interference in spo11 hypomorph strains that have reduced levels of meiosis-induced double-strand breaks. Based on these and previous observations, we propose a model in which Pch2 functions at an early step in crossover control to ensure that every homolog pair receives an obligate crossover

The benefit of directly comparing autism and schizophrenia for revealing mechanisms of social cognitive impairment

Autism and schizophrenia share a history of diagnostic conflation that was not definitively resolved until the publication of the DSM-III in 1980. Though now recognized as heterogeneous disorders with distinct developmental trajectories and dissociative features, much of the early nosological confusion stemmed from apparent overlap in certain areas of social dysfunction. In more recent years, separate but substantial literatures have accumulated for autism and schizophrenia demonstrating that abnormalities in social cognition directly contribute to the characteristic social deficits of both disorders. The current paper argues that direct comparison of social cognitive impairment can highlight shared and divergent mechanisms underlying pathways to social dysfunction, a process that can provide significant clinical benefit by informing the development of tailored treatment efforts. Thus, while the history of diagnostic conflation between autism and schizophrenia may have originated in similarities in social dysfunction, the goal of direct comparisons is not to conflate them once again but rather to reveal distinctions that illuminate disorder-specific mechanisms and pathways that contribute to social cognitive impairment

Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study

Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing. Findings 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. Funding UK Research and Innovation and National Institute for Health Research

Development and clinical application of an innovative fluorescence in situ hybridization technique which detects submicroscopic rearrangements involving telomeres.

We report an innovative fluorescence in situ hybridization technique which exploits a unique resource of 41 telomere-specific probes and allows the simultaneous analysis of the subtelomeric region of every chromosome for deletion, triplication and balanced translocation events. This technique requires only a single microscope slide per patient and is expected to be a useful diagnostic tool with applications in the fields of idiopathic mental retardation, the detection of congenital abnormalities and in some forms of cancer. This will lead to more accurate genetic counselling of patients and their families and will provide the basis for future diagnostic, therapeutic and preventative measures

Demonstration during life of rabies antigen in humans.

In three cases of human rabies, in which the diagnosis was proved postmortem, rabies antigen was detected by direct immunofluorescence of frozen sections of facial skin. The antigen was thought to be in nerve fibers in association with hair follicles. Development of this technique might enable the establishment of a method for the diagnosis of human rabies during life

Deconstructing depression and negative symptoms of schizophrenia; differential and longitudinal immune correlates, and response to minocycline treatment

BACKGROUND: Immune dysfunction has been implicated in negative symptoms of schizophrenia and also in depression. These disorders are frequently co-morbid, with some symptoms such as anhedonia and apathy common to both. The anti-inflammatory agent minocycline may be ineffective in schizophrenia, but more positive effects have been seen in depression. Our aim was to investigate the role of immune dysfunction in depression and sub-domains of negative symptoms in schizophrenia by investigating their intercorrelation and the influence of treatment with minocycline. METHODS: We analysed longitudinal data from 207 patients within 5 years of onset of schizophrenia, from the randomised double-blind, placebo-controlled trial of minocycline (BeneMin). Symptom ratings and circulating IL-6, C-reactive protein (CRP) and TNF-α concentrations were collected at baseline and repeated over twelve months. The sample was not stratified by CRP prior to randomisation. Positive and Negative Syndrome Scale composite ratings of avolition-apathy and diminished expression, Calgary Depression Scale total scores, and immune markers were examined cross-sectionally using Spearman's rank, and longitudinally by linear mixed effect models that included body mass index and minocycline. Additionally, post hoc analysis of the sample stratified by elevated CRP (>1 mg/l and <10 mg/l at baseline) was carried out to assess whether minocycline had any effect on specific symptoms in an immune active sub-group of patients. RESULTS: Depression and avolition-apathy were significantly positively related, and depression correlated weakly with IL-6 at baseline. Diminished expression was associated with increased TNF-α both cross-sectionally and longitudinally. CRP was unrelated to any symptom domain. Minocycline did not affect any individual symptom or sub-domain in the full sample or in the immune active sub-group. DISCUSSION: IL-6 may have some specificity to depression in early schizophrenia. TNF-α may be an indicator of immune dysfunction relevant to negative symptoms, and our longitudinal findings add to this evidence. However, minocycline continues to show very little promise as a treatment for any symptom dimension of early schizophrenia