Predicting extreme p K a shifts in staphylococcal nuclease mutants with constant pH molecular dynamics

Accurate computational methods of determining protein and nucleic acid p K a values are vital to understanding pH‐dependent processes in biological systems. In this article, we use the recently developed method constant pH molecular dynamics (CPHMD) to explore the calculation of highly perturbed p K a values in variants of staphylococcal nuclease (SNase). Simulations were performed using the replica exchange (REX) protocol for improved conformational sampling with eight temperature windows, and yielded converged proton populations in a total sampling time of 4 ns. Our REX‐CPHMD simulations resulted in calculated p K a values with an average unsigned error (AUE) of 0.75 pK units for the acidic residues in Δ + PHS, a hyperstable variant of SNase. For highly p K a ‐perturbed SNase mutants with known crystal structures, our calculations yielded an AUE of 1.5 pK units and for those mutants based on modeled structures an AUE of 1.4 pK units was found. Although a systematic underestimate of pK shifts was observed in most of the cases for the highly perturbed pK mutants, correlations between conformational rearrangement and plasticity associated with the mutation and error in p K a prediction was not evident in the data. This study further extends the scope of electrostatic environments explored using the REX‐CPHMD methodology and suggests that it is a reliable tool for rapidly characterizing ionizable amino acids within proteins even when modeled structures are employed. Proteins 2011; © 2011 Wiley‐Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/88038/1/23195_ftp.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/88038/2/PROT_23195_sm_SuppInfo.pd

Eartharxiv: Today and Tomorrow

EarthArXiv is a preprint service for the Earth sciences — a web-based system that enables open access publishing of non peer-reviewed scholarly manuscripts before publication in a peer-reviewed journal. In this presentation, we provide analytics on the usage of EarthArXiv across a number of sub-disciplines of Earth science. Data indicate that the service in general is growing, but with submission rates varying amongst discipline. The trend of the preprint-to-postprint ratio for each discipline also provides insight into how the various Earth science communities are using the service. We investigate were preprints are published after submission to EarthArXiv and examine how many of these publication venues are listed in the Directory of Open Access Journals. Finally, we will discuss future opportunities we are exploring to make preprints more accepted and easier to use

Survey of endoscopic skull base surgery practice patterns among otolaryngologists

Background Endoscopic skull base surgery (ESBS) is a rapidly expanding field. Despite divergent reported preferences for reconstructive techniques and perioperative management, limited data exist regarding contemporary practice patterns among otolaryngologists performing ESBS. This study aims to elucidate current practice patterns, primarily the volumes of cases performed and secondarily a variety of other perioperative preferences. Methods An anonymous 32-item electronic survey examining perioperative ESBS preferences was distributed to the American Rhinologic Society membership. Statistical significance between variables was determined utilizing Student t, chi-square, and Fisher exact tests. Results Seventy otolaryngologists completed the survey. The effective response rate was approximately 22.5%. Sixty percent of respondents were in full-time academic practice and 70% had completed rhinology/skull base fellowships. Annually, 43.3 mean ESBS cases were performed (29.1 private practice vs. 52.9 academic practice, P = .009). Academic practice averaged 24.1 expanded cases versus only 11 in private practice (P = .01). Of respondents, 55.7% stood on the same side as the neurosurgeon and 72.9% remained present for the entire case. Current procedural terminology coding and antibiotic regimens were widely divergent; 31.4% never placed lumbar drains preoperatively, while 41.4% did so for anticipated high-flow cerebrospinal fluid leaks. While considerable variation in reconstructive techniques were noted, intradural defect repairs utilized vascularized flaps 86.3% of the time versus only 51.3% for extradural repairs (P < 0.001). Major complications were rare. Postoperative restrictions varied considerably, with most activity limitations between 2–8 weeks and positive airway pressure use for 2–6 weeks. Most respondents started saline irrigations 0–2 weeks postoperatively. Conclusions Based on responses from fellowship- and non-fellowship-trained otolaryngologists in various practice settings, there remains considerable variation in the perioperative management of patients undergoing ESBS. Level of Evidence

Sexual and drug use risk behaviour trajectories among people treated for recent HCV infection: the REACT study.

INTRODUCTION Exploration of sexual and drug use behaviours following treatment for recent hepatitis C virus (HCV) is limited. This analysis modelled behavioural trajectories following treatment for recent HCV and assessed reinfection. METHODS Participants treated for recent HCV in an international trial (enrolled 2017-2019) were followed at 3-monthly intervals for up to 2 years to assess longitudinal behaviours. Population-averaged changes were assessed using generalized estimating equations. Distinct behavioural trajectories were identified using group-based trajectory modelling. HCV reinfection incidence was calculated using person-years (PY) of observation. RESULTS During the follow-up of 212 participants (84% gay and bisexual men [GBM]; 69% HIV; 26% current injecting drug use [IDU]), behavioural trajectories for IDU and stimulant use (past month) did not change. However, population-averaged decreases in the likelihood of daily IDU (adjusted odds ratio [AOR] 0.83; 95% CI 0.72, 0.95) and opioid use (AOR 0.84; 95% CI 0.75, 0.93) were observed. Among GBM, behavioural trajectories for chemsex did not change. Population-averaged decreases in condomless anal intercourse with casual male partners (CAI-CMP) (AOR 0.95; 95% CI 0.90, 0.99) and group-sex (AOR 0.86; 95% CI 0.80, 0.93) were observed, but masked distinct trajectories. While a proportion had a decreased probability of CAI-CMP (23%) and group-sex (59%) post-treatment, a substantial proportion retained a high probability of these behaviours. High HCV reinfection incidence was observed for the sustained high probability IDU (33.0/100 PY; 95% CI 17.7, 61.3) and chemsex (23.3/100 PY; 95% CI 14.5, 37.5) trajectories. CONCLUSIONS Limited sexual and drug use behavioural change was observed following treatment for recent HCV, supporting access to surveillance and (re)treatment

UV-driven Chemistry as a Signpost for Late-stage Planet Formation

The chemical reservoir within protoplanetary disks has a direct impact on planetary compositions and the potential for life. A long-lived carbon-and nitrogen-rich chemistry at cold temperatures (<=50K) is observed within cold and evolved planet-forming disks. This is evidenced by bright emission from small organic radicals in 1-10 Myr aged systems that would otherwise have frozen out onto grains within 1 Myr. We explain how the chemistry of a planet-forming disk evolves from a cosmic-ray/X-ray-dominated regime to an ultraviolet-dominated chemical equilibrium. This, in turn, will bring about a temporal transition in the chemical reservoir from which planets will accrete. This photochemical dominated gas phase chemistry develops as dust evolves via growth, settling and drift, and the small grain population is depleted from the disk atmosphere. A higher gas-to-dust mass ratio allows for deeper penetration of ultraviolet photons is coupled with a carbon-rich gas (C/O > 1) to form carbon-bearing radicals and ions. This further results in gas phase formation of organic molecules, which then would be accreted by any actively forming planets present in the evolved disk.Comment: Accepted to Nature Astronomy, Published Dec 8th 202