HIV Gag mimics the Tsg101-recruiting activity of the human Hrs protein

The HIV-1 Gag protein recruits the cellular factor Tsg101 to facilitate the final stages of virus budding. A conserved P(S/T)AP tetrapeptide motif within Gag (the “late domain”) binds directly to the NH2-terminal ubiquitin E2 variant (UEV) domain of Tsg101. In the cell, Tsg101 is required for biogenesis of vesicles that bud into the lumen of late endosomal compartments called multivesicular bodies (MVBs). However, the mechanism by which Tsg101 is recruited from the cytoplasm onto the endosomal membrane has not been known. Now, we report that Tsg101 binds the COOH-terminal region of the endosomal protein hepatocyte growth factor–regulated tyrosine kinase substrate (Hrs; residues 222–777). This interaction is mediated, in part, by binding of the Tsg101 UEV domain to the Hrs 348PSAP351 motif. Importantly, Hrs222–777 can recruit Tsg101 and rescue the budding of virus-like Gag particles that are missing native late domains. These observations indicate that Hrs normally functions to recruit Tsg101 to the endosomal membrane. HIV-1 Gag apparently mimics this Hrs activity, and thereby usurps Tsg101 and other components of the MVB vesicle fission machinery to facilitate viral budding

Slow development of woodland vegetation and bird communities during 33 years of passive rewilding in open farmland

Passive rewilding is a potential tool for expanding woodland cover and restoring biodiversity by abandoning land management and allowing natural vegetation succession to occur. Land can be abandoned to passive rewilding deliberately or due to socio-economic change. Despite abandonment being a major driver of land use change, few have studied the long-term outcomes for vegetation and biodiversity in Western Europe. Studies are also biased towards sites that are close to seed sources and favourable to woodland colonisation. In this case-study, we reconstruct a time series of passive rewilding over 33 years on 25 ha of former farmland that had been subject to soil tipping, far from woodland seed sources. Natural colonisation by shrubs and trees was surveyed at three points during the time series, using field mapping and lidar. Breeding birds were surveyed at three time points, and compared with surveys from nearby farmland. Results showed that natural colonisation of woody vegetation was slow, with open grassland dominating the old fields for two decades, and small wetlands developing spontaneously. After 33 years, thorny shrub thickets covered 53% of the site and former hedgerows became subsumed or degraded, but trees remained scarce. However, the resulting habitat mosaic of shrubland, grassland and wetland supported a locally distinctive bird community. Farmland bird species declined as passive rewilding progressed, but this was countered by relatively more wetland birds and an increase in woodland birds, particularly songbirds, compared to nearby farmland. Alongside biodiversity benefits, shrubland establishment by passive rewilding could potentially provide ecosystem services via abundant blossom resources for pollinators, and recreation and berry-gathering opportunities for people. Although closed-canopy woodland remained a distant prospect even after 33 years, the habitat mosaic arising from passive rewilding could be considered a valuable outcome, which could contribute to nature recovery and provision of ecosystem services

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Interprofessional Extracorporeal Membrane Oxygenation Cardiopulmonary Resuscitation Simulations Aimed at Decreasing Actual Cannulation Times: A Longitudinal Study

BACKGROUND: Since 2013, the cardiac intensive care unit (CICU) at Children\u27s National has conducted annual extracorporeal membrane oxygenation cardiopulmonary resuscitation (ECPR) simulations that focus on team dynamics, room setup, and high-quality CPR. In 2019 and 2020, the simulations were expanded to include the surgical and extracorporeal membrane oxygenation (ECMO) teams in an effort to better understand and improve this process. METHODS: During a 4-week period in 2019, 7 peripheral ECPR simulations were conducted, and through a 3-week period in 2020, 7 central ECPR simulations were conducted. Participants in each session included: 8 to 10 CICU nurses, 1 CICU attending, 1 to 2 ICU or cardiology fellows, 1 cardiovascular surgery fellow or attending, and 1 ECMO specialist. For each session, the scenario continued until the simulated patient was on full cardiopulmonary bypass. An ECMO trainer was used for peripheral simulations and a 3-dimensionally-printed heart was used for central cannulations. An ECMO checklist was used to objectively determine when the patient and room were fully prepared for surgical intervention, and simulated cannulation times were recorded for both groups. A retrospective chart review was conducted to compare actual cannulation times before and after the intervention period, and video was used to review the events and assist in dividing them into medical versus surgical phases. Control charts were used to trend the total ECPR times before and after the intervention period, and mean and P values were calculated for both ECPR times and for all other categorical data. RESULTS: Mean peripheral ECPR times decreased significantly from 71.7 to 45.1 minutes ( P = 0.036) after the intervention period, and this was reflected by a centerline shift. Although we could not describe a similar decrease in central ECPR times because there were only 6 postintervention events, the times for each of these events were shorter than the historical mean of 37.8 minutes. There was a trend in improved survival, which did not meet significance both among patients undergoing peripheral ECPR (15.4% ± 10% to 43.8% ± 12.4%, P = 0.10) and central ECPR (36.4% ± 8.4% to 50% ± 25%, P = 0.60). The percentage of time dedicated to the medical phases of the actual versus simulated procedures was very consistent among both peripheral (33.0% vs. 31.9%) and central (39.6% vs. 39.8%) cannulations. CONCLUSIONS: We observed a significant decrease in peripheral cannulation times at our institution after conducting interprofessional ECPR simulations taken to the establishment of full cardiopulmonary bypass. The use of an ECMO trainer and a 3-dimensionally-printed heart allowed for both the medical and surgical phases of the procedure to be studied in detail, providing opportunities to streamline and improve this complex process. Larger multisite studies will be needed in the future to assess the effect of efforts like these on patient survival

A dwarf planet class object in the 21:5 resonance with Neptune

We report the discovery of an Hr = 3.4 ± 0.1 dwarf planet candidate by the Pan-STARRS Outer Solar System Survey. 2010 JO179 is red with (g − r) = 0.88 ± 0.21, roughly round, and slowly rotating, with a period of 30.6 hr. Estimates of its albedo imply a diameter of 600–900 km. Observations sampling the span between 2005 and 2016 provide an exceptionally well determined orbit for 2010 JO179, with a semimajor axis of 78.307 ± 0.009 au; distant orbits known to this precision are rare. We find that 2010 JO179 librates securely within the 21:5 mean-motion resonance with Neptune on 100 Myr timescales, joining the small but growing set of known distant dwarf planets on metastable resonant orbits. These imply a substantial trans-Neptunian population that shifts between stability in high-order resonances, the detached population, and the eroding population of the scattering disk