Citalopram was found to be more efficacious than placebo in the short-term hospital treatment of psychotic symptoms and behavioral disturbances in nondepressed, demented patients.
BackgroundUncoating of the HIV-1 core plays a critical role during early post-fusion stages of infection but is poorly understood. Microscopy-based assays are unable to easily distinguish between intact and partially uncoated viral cores.ResultsIn this study, we used 5-ethynyl uridine (EU) to label viral-associated RNA during HIV production. At early time points after infection with EU-labeled virions, the viral-associated RNA was stained with an EU-specific dye and was detected by confocal microscopy together with viral proteins. We observed that detection of the viral-associated RNA was specific for EU-labeled virions, was detected only after viral fusion with target cells, and occurred after an initial opening of the core. In vitro staining of cores showed that the opening of the core allowed the small molecule dye, but not RNase A or antibodies, inside. Also, staining of the viral-associated RNA, which is co-localized with nucleocapsid, decays over time after viral infection. The decay rate of RNA staining is dependent on capsid (CA) stability, which was altered by CA mutations or a small molecule inducer of HIV-1 uncoating. While the staining of EU-labeled RNA was not affected by inhibition of reverse transcription, the kinetics of core opening of different CA mutants correlated with initiation of reverse transcription. Analysis of the E45A CA mutant suggests that initial core opening is independent of complete capsid disassembly.ConclusionsTaken together, our results establish a novel RNA accessibility-based assay that detects an early event in HIV-1 uncoating and can be used to further define this process.
Background Emerging cross-sectional reports find that the COVID-19 pandemic and related social restrictions negatively affect lifestyle behaviours and mental health in general populations. Aims To study the longitudinal impact of COVID-19 on work practices, lifestyle and well-being among desk workers during shelter-at-home restrictions. Methods We added follow-up after completion of a clinical trial among desk workers to longitudinally measure sedentary behaviour, physical activity, sleep, diet, mood, quality of life and work-related health using validated questionnaires and surveys. We compared outcomes assessed before and during COVID-19 shelter-at-home restrictions. We assessed whether changes in outcomes differed by remote working status (always, changed to or never remote) using analysis of covariance (ANCOVA). Results Participants (N = 112; 69% female; mean (SD) age = 45.4 (12.3) years; follow-up = 13.5 (6.8) months) had substantial changes to work practices, including 72% changing to remote work. Deleterious changes from before to during shelter-at-home included: 1.3 (3.5)-h increase in non-workday sedentary behaviour; 0.7 (2.8)-point worsening of sleep quality; 8.5 (21.2)-point increase in mood disturbance; reductions in five of eight quality of life subscales; 0.5 (1.1)-point decrease in work-related health (P < 0.05). Other outcomes, including diet, physical activity and workday sedentary behaviour, remained stable (P ≥ 0.05). Workers who were remote before and during the pandemic had greater increases in non-workday sedentary behaviour and stress, with greater declines in physical functioning. Wake time was delayed overall by 41 (61) min, and more so in workers who changed to remote. Conclusions Employers should consider supporting healthy lifestyle and well-being among desk workers during pandemic-related social restrictions, regardless of remote working status.
Deacetylation of histone proteins at the HIV type 1 (HIV-1) long terminal repeat (LTR) by histone deactylases (HDACs) can promote transcriptional repression and virus latency. As such, HDAC inhibitors (HDACI) could be used to deplete reservoirs of persistent, quiescent HIV-1 proviral infection. However, the development of HDACI to purge latent HIV-1 requires knowledge of the HDAC isoforms contributing to viral latency and the development of inhibitors specific to these isoforms. In this study, we identify the HDACs responsible for HIV-1 latency in Jurkat J89GFP cells using a chemical approach that correlates HDACI isoform specificity with their ability to reactivate latent HIV-1 expression. We demonstrate that potent inhibition or knockdown of HDAC1, an HDAC isoform reported to drive HIV-1 into latency, was not sufficient to de-repress the viral LTR. Instead, we found that inhibition of HDAC3 was necessary to activate latent HIV-1. Consistent with this finding, we identified HDAC3 at the HIV-1 LTR by chromatin immunoprecipitation. Interestingly, we show that valproic acid is a weak inhibitor of HDAC3 (IC 50 ؍ 5.5 mM) relative to HDAC1 (IC 50 ؍ 170 M). Because the total therapeutic concentration of valproic acid ranges from 275 to 700 M in adults, these data may explain why this inhibitor has no effect on the decay of latent HIV reservoirs in patients. Taken together, our study suggests an important role for HDAC3 in HIV-1 latency and, importantly, describes a chemical approach that can readily be used to identify the HDAC isoforms that contribute to HIV-1 latency in other cell types.
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