Gender, marital and educational inequalities in mid- to late-life depressive symptoms: cross-cohort variation and moderation by urbanicity degree

Background: Although ageing populations are increasingly residing in cities, it is unknown whether depression inequalities are moderated by urbanicity degree. We estimated gender, marital and educational inequalities in depressive symptoms among older European and Canadian adults, and examined whether higher levels of urbanicity, captured by population density, heightened these inequalities. Methods: Harmonised cross-sectional data on 97 826 adults aged ≥50 years from eight cohorts were used. Prevalence ratios (PRs) were calculated for probable depression, depressed affect and depressive symptom severity by gender, marital status and education within each cohort, and combined using random-effects metaanalysis. Using a subsample of 73 123 adults from six cohorts with available data on population density, we tested moderating effects measured by the number of residents per square kilometre. Results: The pooled PRs for probable depression by female gender, unmarried or non-cohabitating status and low education were 1.48 (95% CI 1.28 to 1.72), 1.44 (95% CI 1.29 to 1.61) and 1.29 (95% CI 1.18 to 1.41), respectively. PRs for depressed affect and high symptom severity were broadly similar. Except for one Dutch cohort with findings in an unexpected direction, there was no evidence that population density modified depressive symptom inequalities. Conclusions: Despite cross-cohort variation in gender, marital status and educational inequalities in depressive symptoms, there was weak evidence that these inequalities differed by levels of population density

Subacute Sclerosing Panencephalitis: Results of the Canadian Paediatric Surveillance Program and review of the literature

BACKGROUND: Subacute Sclerosing Panencephalitis (SSPE) is so rare in developed countries with measles immunization programs that national active surveillance is now needed to capture sufficient number of cases for meaningful analysis of data. Through the Canadian Paediatric Surveillance Program (CPSP), the SSPE study was able to document a national incidence and determine the epidemiology of affected Canadian children. METHODS: Between 1997 and 2000, the CPSP surveyed monthly 1978 to 2294 Canadian pediatricians and sub-specialists for SSPE cases. The response rate varied from 82–86% over those years. RESULTS: Altogether, four SSPE cases were reported to the CPSP: one case before, two during and one after the study period. The incidence of SSPE in Canadian children was 0.06/million children/year. Of the four cases, diagnosed between ages four and 17 years, three children had measles infection in infancy. All children showed a progressive course of dementia, loss of motor skills and epilepsy. Two children were treated with isoprinosine and intraventricular interferon but died in less than three years from disease onset. One child did not have any treatment and died after seven years of illness. One child received intraventricular ribavirin and remains alive, but markedly impaired, nine years following diagnosis. CONCLUSION: The CPSP has demonstrated that Canadian paediatricians and paediatric neurologists may encounter cases of SSPE. This report highlights the clinical course of affected Canadian children and provides a review of the disease and its management

Clathrin Facilitates the Morphogenesis of Retrovirus Particles

The morphogenesis of retroviral particles is driven by Gag and GagPol proteins that provide the major structural component and enzymatic activities required for particle assembly and maturation. In addition, a number of cellular proteins are found in retrovirus particles; some of these are important for viral replication, but many lack a known functional role. One such protein is clathrin, which is assumed to be passively incorporated into virions due to its abundance at the plasma membrane. We found that clathrin is not only exceptionally abundant in highly purified HIV-1 particles but is recruited with high specificity. In particular, the HIV-1 Pol protein was absolutely required for clathrin incorporation and point mutations in reverse transcriptase or integrase domains of Pol could abolish incorporation. Clathrin was also specifically incorporated into other retrovirus particles, including members of the lentivirus (simian immunodeficiency virus, SIVmac), gammaretrovirus (murine leukemia virus, MLV) and betaretrovirus (Mason-Pfizer monkey virus, M-PMV) genera. However, unlike HIV-1, these other retroviruses recruited clathrin primarily using peptide motifs in their respective Gag proteins that mimicked motifs found in cellular clathrin adaptors. Perturbation of clathrin incorporation into these retroviruses, via mutagenesis of viral proteins, siRNA based clathrin depletion or adaptor protein (AP180) induced clathrin sequestration, had a range of effects on the accuracy of particle morphogenesis. These effects varied according to which retrovirus was examined, and included Gag and/or Pol protein destabilization, inhibition of particle assembly and reduction in virion infectivity. For each retrovirus examined, clathrin incorporation appeared to be important for optimal replication. These data indicate that a number of retroviruses employ clathrin to facilitate the accurate morphogenesis of infectious particles. We propose a model in which clathrin contributes to the spatial organization of Gag and Pol proteins, and thereby regulates proteolytic processing of virion components during particle assembly

The Gag Cleavage Product, p12, is a Functional Constituent of the Murine Leukemia Virus Pre-Integration Complex

The p12 protein is a cleavage product of the Gag precursor of the murine leukemia virus (MLV). Specific mutations in p12 have been described that affect early stages of infection, rendering the virus replication-defective. Such mutants showed normal generation of genomic DNA but no formation of circular forms, which are markers of nuclear entry by the viral DNA. This suggested that p12 may function in early stages of infection but the precise mechanism of p12 action is not known. To address the function and follow the intracellular localization of the wt p12 protein, we generated tagged p12 proteins in the context of a replication-competent virus, which allowed for the detection of p12 at early stages of infection by immunofluorescence. p12 was found to be distributed to discrete puncta, indicative of macromolecular complexes. These complexes were localized to the cytoplasm early after infection, and thereafter accumulated adjacent to mitotic chromosomes. This chromosomal accumulation was impaired for p12 proteins with a mutation that rendered the virus integration-defective. Immunofluorescence demonstrated that intracellular p12 complexes co-localized with capsid, a known constituent of the MLV pre-integration complex (PIC), and immunofluorescence combined with fluorescent in situ hybridization (FISH) revealed co-localization of the p12 proteins with the incoming reverse transcribed viral DNA. Interactions of p12 with the capsid and with the viral DNA were also demonstrated by co-immunoprecipitation. These results imply that p12 proteins are components of the MLV PIC. Furthermore, a large excess of wt PICs did not rescue the defect in integration of PICs derived from mutant p12 particles, demonstrating that p12 exerts its function as part of this complex. Altogether, these results imply that p12 proteins are constituent of the MLV PIC and function in directing the PIC from the cytoplasm towards integration

SUMO-Interacting Motifs of Human TRIM5α are Important for Antiviral Activity

Human TRIM5α potently restricts particular strains of murine leukemia viruses (the so-called N-tropic strains) but not others (the B- or NB-tropic strains) during early stages of infection. We show that overexpression of SUMO-1 in human 293T cells, but not in mouse MDTF cells, profoundly blocks N-MLV infection. This block is dependent on the tropism of the incoming virus, as neither B-, NB-, nor the mutant R110E of N-MLV CA (a B-tropic switch) are affected by SUMO-1 overexpression. The block occurred prior to reverse transcription and could be abrogated by large amounts of restricted virus. Knockdown of TRIM5α in 293T SUMO-1-overexpressing cells resulted in ablation of the SUMO-1 antiviral effects, and this loss of restriction could be restored by expression of a human TRIM5α shRNA-resistant plasmid. Amino acid sequence analysis of human TRIM5α revealed a consensus SUMO conjugation site at the N-terminus and three putative SUMO interacting motifs (SIMs) in the B30.2 domain. Mutations of the TRIM5α consensus SUMO conjugation site did not affect the antiviral activity of TRIM5α in any of the cell types tested. Mutation of the SIM consensus sequences, however, abolished TRIM5α antiviral activity against N-MLV. Mutation of lysines at a potential site of SUMOylation in the CA region of the Gag gene reduced the SUMO-1 block and the TRIM5α restriction of N-MLV. Our data suggest a novel aspect of TRIM5α-mediated restriction, in which the presence of intact SIMs in TRIM5α, and also the SUMO conjugation of CA, are required for restriction. We propose that at least a portion of the antiviral activity of TRIM5α is mediated through the binding of its SIMs to SUMO-conjugated CA

Gender, marital and educational inequalities in mid-to late-life depressive symptoms: Cross-cohort variation and moderation by urbanicity degree

Background: Although ageing populations are increasingly residing in cities, it is unknown whether depression inequalities are moderated by urbanicity de

Cellular Proteins in Influenza Virus Particles

Virions are thought to contain all the essential proteins that govern virus egress from the host cell and initiation of replication in the target cell. It has been known for some time that influenza virions contain nine viral proteins; however, analyses of other enveloped viruses have revealed that proteins from the host cell can also be detected in virions. To address whether the same is true for influenza virus, we used two complementary mass spectrometry approaches to perform a comprehensive proteomic analysis of purified influenza virus particles. In addition to the aforementioned nine virus-encoded proteins, we detected the presence of 36 host-encoded proteins. These include both cytoplasmic and membrane-bound proteins that can be grouped into several functional categories, such as cytoskeletal proteins, annexins, glycolytic enzymes, and tetraspanins. Interestingly, a significant number of these have also been reported to be present in virions of other virus families. Protease treatment of virions combined with immunoblot analysis was used to verify the presence of the cellular protein and also to determine whether it is located in the core of the influenza virus particle. Immunogold labeling confirmed the presence of membrane-bound host proteins on the influenza virus envelope. The identification of cellular constituents of influenza virions has important implications for understanding the interactions of influenza virus with its host and brings us a step closer to defining the cellular requirements for influenza virus replication. While not all of the host proteins are necessarily incorporated specifically, those that are and are found to have an essential role represent novel targets for antiviral drugs and for attenuation of viruses for vaccine purposes

Proteomic Modeling for HIV-1 Infected Microglia-Astrocyte Crosstalk

Background: HIV-1-infected and immune competent brain mononuclear phagocytes (MP; macrophages and microglia) secrete cellular and viral toxins that affect neuronal damage during advanced disease. In contrast, astrocytes can affect disease by modulating the nervous system’s microenvironment. Interestingly, little is known how astrocytes communicate with MP to influence disease. Methods and Findings: MP-astrocyte crosstalk was investigated by a proteomic platform analysis using vesicular stomatitis virus pseudotyped HIV infected murine microglia. The microglial-astrocyte dialogue was significant and affected microglial cytoskeleton by modulation of cell death and migratory pathways. These were mediated, in part, through F-actin polymerization and filament formation. Astrocyte secretions attenuated HIV-1 infected microglia neurotoxicity and viral growth linked to the regulation of reactive oxygen species. Conclusions: These observations provide unique insights into glial crosstalk during disease by supporting astrocytemediated regulation of microglial function and its influence on the onset and progression of neuroAIDS. The results open new insights into previously undisclosed pathogenic mechanisms and open the potential for biomarker discovery an