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Objective Molecular markers in DNA methylation at a subset of CpG sites are affected by the environment and contribute to biological (epigenetic) age. We hypothesized that shorter sleep duration and possibly irregular sleep would be associated with accelerated epigenetic aging. We examined epigenetic vs. chronological age in 12 young women selected as shorter or longer sleepers studied prospectively across the first 9 weeks of college using a daily online sleep log. Genomic DNA was isolated from two blood samples spanning the interval, and DNA methylation levels were determined and used to measure epigenetic age. Results Epigenetic vs. chronological age differences averaged 2.07 at Time 1 and 1.21 at Time 2. Sleep duration was computed as average daily total sleep time and sleep regularity was indexed using the Sleep Regularity Index. Participants with longer and more regular sleep showed reduced age difference: mean = − 2.48 [95% CI − 6.11; 1.15]; those with shorter and more irregular sleep showed an increased age difference: 3.03 [0.02; 6.03]; and those with either shorter or more irregular sleep averaged no significant change: − 0.49 [− 3.55; 2.56]. These pilot data suggest that short and irregular sleep, even in a young healthy sample, may be associated with accelerated epigenetic aging.

Introduction DNA methylation is affected by the environment and provides an index of biological (epigenetic) age. Factors associated with poor health (e.g., smoking, inactivity) accelerate epigenetic aging. We hypothesize that shorter and irregular sleep impact epigenetic age. Methods Twelve women (chronological ages 18.2 to 19.8 y) were selected as shorter or longer sleepers (extreme quintiles) from 503 first-semester college students with daily sleep diary across 9. Sleep Regularity Index (SRI) was computed from diary data. Participants gave blood samples at study start and end. DNA methylation ages were determined at each time from Infinium HumanMethylation450 (Illumina, San Diego) arrays corrected for cell type; epigenetic ages were computed using Horvath’s method. Chronological ages were subtracted from epigenetic ages at each time to compute age-difference. Results Epigenetic ages at Time1 ranged from 15.8 to 26.3 y (mean=20.8[SD=3.3]); epigenetic ages computed from Time2 ranged from 16 to 25.9 y (20.1 [3.2]). Mean age-difference at Time1 was 2.1[3.3] y and 1.2[3.4] at Time2. Participants were grouped using median splits for TST (median=7.19) and SRI (median=76.44), resulting in three groups: Good Sleep (TST and SRI above median; TST=8.0[0.1]; SRI=80.6 [3.1]), Mixed Sleep (either TST or SRI above median; TST=6.9[1.6]; SRI=74.8[9.6]), and Poor Sleep (both TST and SRI below median; TST=6.1[0.4]; SRI=65.8[9.9]).Epigenetic aging patterns were consistent with hypotheses: Good Sleep group decreased age-difference across time; Mixed Sleep group showed inconsistent patterns; Poor Sleep group increased age-difference. One-way ANOVA showed statistically significant differences in group patterns (F(2,9)=5.58, p=.03); Group Marginal Mean Estimate[95%CI]: Good Sleep=-4.06[-7.24;-0.88]; Mixed Sleep=-1.10[-4.28;2.08]; Poor Sleep=2.57[-0.61;5.75]). Conclusion Poorer sleep was associated with epigenetic aging acceleration in all Poor Sleep participants; better sleep, was associated with decelerated epigenetic aging in three of four Good Sleep participants. More work is needed to confirm findings in a larger sample, determine mechanism, and assess epigenetic aging in clinical sleep patients. Support (If Any) MH079179 (MAC); NS055813 (ACH); shared equipment grants from the U.S. Department of Veteran Affairs shared equipment program (JEM). Contents do not represent the views of the U.S. Department of Veterans Affairs or the US Government.

Among hospitalized patients with Covid-19, treatment with dexamethasone resulted in lower 28-day mortality than usual care, according to the level of respiratory support the patients were receiving, indicating a possible correlation between efficacy and the stage of infection.

Among 4716 hospitalized adult patients with Covid-19 in the United Kingdom, those who were treated with hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care.

Lopinavir–ritonavir has been proposed as a treatment for COVID-19 on the basis of in vitro activity, preclinical studies, and observational studies. Here, we report the results of a randomised trial to assess whether lopinavir–ritonavir improves outcomes in patients admitted to hospital with COVID-19. In this randomised, controlled, open-label, platform trial, a range of possible treatments was compared with usual care in patients admitted to hospital with COVID-19. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus lopinavir–ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge (or one of the other RECOVERY treatment groups: hydroxychloroquine, dexamethasone, or azithromycin) using web-based simple (unstratified) randomisation with allocation concealment. Randomisation to usual care was twice that of any of the active treatment groups (eg, 2:1 in favour of usual care if the patient was eligible for only one active group, 2:1:1 if the patient was eligible for two active groups). The primary outcome was 28-day all-cause mortality. Analyses were done on an intention-to-treat basis in all randomly assigned participants. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Between March 19, 2020, and June 29, 2020, 1616 patients were randomly allocated to receive lopinavir–ritonavir and 3424 patients to receive usual care. Overall, 374 (23%) patients allocated to lopinavir–ritonavir and 767 (22%) patients allocated to usual care died within 28 days (rate ratio 1·03, 95% CI 0·91–1·17; p=0·60). Results were consistent across all prespecified subgroups of patients. We observed no significant difference in time until discharge alive from hospital (median 11 days [IQR 5 to >28] in both groups) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 0·98, 95% CI 0·91–1·05; p=0·53). Among patients not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion who met the composite endpoint of invasive mechanical ventilation or death (risk ratio 1·09, 95% CI 0·99–1·20; p=0·092). In patients admitted to hospital with COVID-19, lopinavir–ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir–ritonavir for treatment of patients admitted to hospital with COVID-19. Medical Research Council and National Institute for Health Research.

The Middle East respiratory syndrome is caused by a coronavirus that was first identified in Saudi Arabia in 2012. Periodic outbreaks continue to occur in the Middle East and elsewhere. This report provides the latest information on MERS.

A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity 1 . This principle has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation. Here we show that mRNA-1273 induces potent neutralizing antibody responses to both wild-type (D614) and D614G mutant 2 SARS-CoV-2 as well as CD8 + T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a phase III trial to evaluate its efficacy. mRNA-1273, an mRNA vaccine that encodes a stabilized prefusion-state severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, elicits robust immune responses and protects mice against replication of SARS-CoV-2 in the upper and lower airways.

The COVID-19 pandemic response has shown how vaccine platform technologies can be used to rapidly and effectively counteract a novel emerging infectious disease. The speed of development for mRNA and vector-based vaccines outpaced those of subunit vaccines, however, subunit vaccines can offer advantages in terms of safety and stability. Here we describe a subunit vaccine platform technology, the molecular clamp, in application to four viruses from divergent taxonomic families: Middle Eastern respiratory syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), Lassa virus (LASV) and Nipah virus (NiV). The clamp streamlines subunit antigen production by both stabilising the immunologically important prefusion epitopes of trimeric viral fusion proteins while enabling purification without target-specific reagents by acting as an affinity tag. Conformations for each viral antigen were confirmed by monoclonal antibody binding, size exclusion chromatography and electron microscopy. Notably, all four antigens tested remained stable over four weeks of incubation at 40°C. Of the four vaccines tested, a neutralising immune response was stimulated by clamp stabilised MERS-CoV spike, EBOV glycoprotein and NiV fusion protein. Only the clamp stabilised LASV glycoprotein precursor failed to elicit virus neutralising antibodies. MERS-CoV and EBOV vaccine candidates were both tested in animal models and found to provide protection against viral challenge.

The discovery of the endosymbiotic bacteria Wolbachia as an obligate symbiont of. filarial nematodes has led to antibiotic-based treatments for filarial diseases. While lab. and clinical studies have yielded promising results, recent animal studies revealed that Wolbachia levels rebound following treatment with the antibiotic rifampicin. Previous work revealed that a potential source of the bacterial rebound in female worms were dense clusters of Wolbachia in ovarian tissue. The number, size, and density of these Wolbachia clusters were not diminished despite antibiotic treatment. Here we define the cellular characteristics of the Wolbachia clusters in Brugia pahangi (wBp) and identify drugs that target them. We show that the Wolbachia clusters originate from newly formed sheath cells adjacent to the distal tip cell. The dramatically enlarged volume of a Wolbachia -infected sheath cell is strikingly similar to endosymbiont-induced bacteriocytes found in many insect species. Ultrastructural analysis reveals that the clustered Wolbachia present within the sheath cells have a distinct morphology from those present within the oocytes, and that the sheath cell membrane appears to have interdigitations with the adjacent oocyte membrane. This includes membrane-based channels that provide a connection between Wolbachia -infected sheath cells and oocytes. We determined that the Wolbachia within the sheath cells are either quiescent or replicating at a very low rate. Screens of 11 known antibiotics and other drugs revealed that Fexinidazole, Corallopyronin A and Rapamycin reduced the number of Wolbachia clusters infecting sheath cells but only Fexinidazole and Corallopyronin A showed a highly significant difference (p < 0.0001) compared to the control group.

The discovery of the endosymbiotic bacteria as an obligate symbiont of filarial nematodes has led to antibiotic-based treatments for filarial diseases. While lab and clinical studies have yielded promising results, recent animal studies reveal that levels may rebound following treatment with suboptimal doses of the antibiotic rifampicin. Previous work showed that a likely source of the bacterial rebound in females were dense clusters of in ovarian tissue. The number, size, and density of these clusters were not diminished despite antibiotic treatment. Here we define the cellular characteristics of the clusters in (wBp) and identify drugs that also target them. We have evidence that the clusters originate from newly formed sheath cells adjacent to the ovarian Distal Tip Cells. The dramatically enlarged volume of an infected sheath cell is strikingly similar to endosymbiont-induced bacteriocytes found in many insect species. Ultrastructural analysis reveals that the clustered present within the sheath cells exhibit a distinct morphology and form direct connections with the oocyte membrane and possibly the cytoplasm. This includes membrane-based channels providing a connection between -infected sheath cells and oocytes. We also determined that the within the sheath cells are either quiescent or replicating at a very low rate. Screens of known antibiotics and other drugs revealed that two drugs, Fexinidazole and Corallopyronin A, significantly reduced the number of clustered located within the sheath cells.