Multisecond ligand dissociation dynamics from atomistic simulations

Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal in order to allow the description of processes occurring on biologically relevant timescales. For example, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbinding is crucial for modern drug discovery. To achieve the enhanced sampling, we first perform dissipation-corrected targeted molecular dynamics simulations, which yield free energy and friction profiles of the molecular process under consideration. In a second step, we use these fields to perform temperature-boosted Langevin simulations which account for the desired molecular kinetics occurring on multisecond timescales and beyond. Adopting the dissociation of solvated sodium chloride as well as trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes as test problems, we are able to reproduce rates from molecular dynamics simulation and experiments within a factor of 2-20, and dissociation constants within a factor of 1-4. Analysis of the friction profiles reveals that binding and unbinding dynamics are mediated by changes of the surrounding hydration shells in all investigated systems.Comment: This unedited earlier version of the manuscript may be downloaded for personal use only. The final manuscript was published in Nature Communications 11, 2918 (2020) as open access publication and is available at https://www.nature.com/articles/s41467-020-16655-

Teaching Introductory Statistics with DataCamp

We designed a sequence of courses for the DataCamp online learning platform that approximates the content of a typical introductory statistics course. We discuss the design and implementation of these courses and illustrate how they can be successfully integrated into a brick-and-mortar class. We reflect on the process of creating content for online consumers, ruminate on the pedagogical considerations we faced, and describe an R package for statistical inference that became a by-product of this development process. We discuss the pros and cons of creating the course sequence and express our view that some aspects were particularly problematic. The issues raised should be relevant to nearly all statistics instructors. Supplementary materials for this article are available online

Fast and Accurate Coarsening Simulation with an Unconditionally Stable Time Step

We present Cahn-Hilliard and Allen-Cahn numerical integration algorithms that are unconditionally stable and so provide significantly faster accuracy-controlled simulation. Our stability analysis is based on Eyre's theorem and unconditional von Neumann stability analysis, both of which we present. Numerical tests confirm the accuracy of the von Neumann approach, which is straightforward and should be widely applicable in phase-field modeling. We show that accuracy can be controlled with an unbounded time step Delta-t that grows with time t as Delta-t ~ t^alpha. We develop a classification scheme for the step exponent alpha and demonstrate that a class of simple linear algorithms gives alpha=1/3. For this class the speed up relative to a fixed time step grows with the linear size of the system as N/log N, and we estimate conservatively that an 8192^2 lattice can be integrated 300 times faster than with the Euler method.Comment: 14 pages, 6 figure

Impact of dysphagia assessment and management on risk of stroke-associated pneumonia: A systematic review

Background Patients with dysphagia are at increased risk of stroke-associated pneumonia. There is wide variation in the way patients are screened and assessed during the acute phase. The aim of this review was to identify which methods of assessment and management in acute stroke influence the risk of stroke-associated pneumonia. Studies of stroke patients that reported dysphagia screening, assessment or management and occurrence of pneumonia during acute phase stroke were screened for inclusion after electronic searches of multiple databases from inception to November 2016. The primary outcome was association with stroke-associated pneumonia. Summary Twelve studies of 87824 patients were included. The type of dysphagia screening protocol varied widely across and within studies. There was limited information on what comprised a specialist swallow assessment and alternative feeding was the only management strategy, which was reported for association with stroke-associated pneumonia. Use of a formal screening protocol, early dysphagia screening and assessment by a speech and language pathologist (SLP) was associated with a reduced risk of stroke-associated pneumonia. There was marked heterogeneity between the included studies, which precluded meta-analysis. Key Messages There is variation in assessment and management of dysphagia in acute stroke. There is increasing evidence that early dysphagia screening and specialist swallow assessment by a SLP may reduce the odds of stroke-associated pneumonia. There is the potential for other factors to influence incidence of stroke-associated pneumonia during the acute phase

Asymptotics and Dimensional Dependence of the Number of Critical Points of Random Holomorphic Sections

We prove two conjectures from [M. R. Douglas, B. Shiffman and S. Zelditch, Critical points and supersymmetric vacua, II: Asymptotics and extremal metrics. J. Differential Geom. 72 (2006), no. 3, 381-427] concerning the expected number of critical points of random holomorphic sections of a positive line bundle. We show that, on average, the critical points of minimal Morse index are the most plentiful for holomorphic sections of {\mathcal O}(N) \to \CP^m and, in an asymptotic sense, for those of line bundles over general K\"ahler manifolds. We calculate the expected number of these critical points for the respective cases and use these to obtain growth rates and asymptotic bounds for the total expected number of critical points in these cases. This line of research was motivated by landscape problems in string theory and spin glasses.Comment: 14 pages, corrected typo

Dynamic Phase Transitions in Cell Spreading

We monitored isotropic spreading of mouse embryonic fibroblasts on fibronectin-coated substrates. Cell adhesion area versus time was measured via total internal reflection fluorescence microscopy. Spreading proceeds in well-defined phases. We found a power-law area growth with distinct exponents a_i in three sequential phases, which we denote basal (a_1=0.4+-0.2), continous (a_2=1.6+-0.9) and contractile (a_3=0.3+-0.2) spreading. High resolution differential interference contrast microscopy was used to characterize local membrane dynamics at the spreading front. Fourier power spectra of membrane velocity reveal the sudden development of periodic membrane retractions at the transition from continous to contractile spreading. We propose that the classification of cell spreading into phases with distinct functional characteristics and protein activity patterns serves as a paradigm for a general program of a phase classification of cellular phenotype. Biological variability is drastically reduced when only the corresponding phases are used for comparison across species/different cell lines.Comment: 4 pages, 5 figure

Monitoring Postoperative Opioid Use Following Simple Arthroscopic Meniscectomy: A Performance-Improvement Strategy for Prescribing Recommendations and Community Safety.

Background: Orthopaedic surgeons are confronted with a difficult dilemma: managing acute pain postoperatively and balancing the risk of prescription opioid use. To our knowledge, a prospective performance-improvement project providing opioid-prescription recommendations based on the actual amounts of usual and customary medication consumed following simple knee meniscectomy has not been described. Methods: One hundred and two patients undergoing arthroscopic knee meniscectomy prospectively recorded postoperative pain medications in a pain journal. Arthroscopic procedures were performed at 2 centers by 9 fellowship-trained senior surgeons. Various usual and customary prescribing protocols were observed, and the amount of medication consumed was recorded. Prescription and over-the-counter pain medication, quantity, frequency, and visual analog scale (VAS) pain scores were collected. Results: One hundred and two patients filled a prescription opioid medication and were included in the study. A total of 3,765 pills were prescribed, and a total of 573.5 were consumed. For the 102 patients who filled a prescription, the average time consuming opioid medication was 2 ± 2 days (range, 0 to 13 days) postoperatively. No cases of persistent use were recorded. Of the 102 patients who filled a prescription, 29.4% did not take any prescription opioids postoperatively. A total of 3,191.5 pills (or 22,183.75 morphine milligram equivalents [MME]) were unused and were potentially available to the community. Conclusions: Following simple knee arthroscopy, the amount of prescribed opioid medication exceeds the need for postoperative pain management. In general, 68% of patients require a maximum of 13 pills postoperatively for 6 days. Surgeons should adjust prescribing standards accordingly to limit the amount of prescription opioids available to the community. Furthermore, a comprehensive response to include increased patient screening and monitoring as well as opioid use and disposal education is recommended

Self-directed self-management interventions to prevent or address distress in young people with long-term physical conditions: a rapid review.

Background: Comorbid distress in adolescents and young adults with physical long‐ term conditions (LTCs) is common but can be difficult to identify and manage. Self‐ directed self‐management interventions to reduce distress and improve wellbeing may be beneficial. It is unknown, however, which intervention characteristics are successful in supporting young people. This rapid review aimed to identify characteristics of self‐directed self‐management interventions that aimed, in whole or part, to address distress, wellbeing or self‐efficacy in this population. Methods: A systematic search was conducted for relevant controlled studies in six databases. Data on study settings, population, intervention characteristics, outcome measures, process measures and summary effects were extracted. The risk of bias was assessed using the Cochrane Risk of Bias tool v1, and the strength of evidence was rated (informed by Grading of Recommendations, Assessment, Development and Evaluations). Patient and public involvement members supported the review process, including interpretation of results. The rapid review was registered with PROSPERO (ID: CRD42021285867). Results: Fourteen studies were included, all of which were randomised trials. Heterogeneity was identified in the health conditions targeted; type of intervention; outcome measures; duration of intervention and follow‐up. Three had distress, wellbeing or self‐efficacy as their primary outcome. Four modes of delivery were identified across interventions—websites, smartphone applications, text messages and workbooks; and within these, 38 individual components. Six interventions had a significant benefit in mental health, wellbeing or self‐efficacy; however, intervention characteristics were similar for beneficial and non‐beneficial interventions. Conclusions: There is a paucity of interventions directly targeting distress and wellbeing in young people with physical LTCs. In those identified, the heterogeneity of interventions and study design makes it difficult to identify which characteristics result in positive outcomes. We propose the need for high‐quality, evidence‐based self‐management interventions for this population; including (1) more detailed reporting of intervention design, content and delivery; (2) robust process evaluation; (3) a core outcome set for measuring mental health and wellbeing for self‐ management interventions and (4) consistency in follow up periods. Public Contribution: Seven young people with an LTC were involved throughout the rapid review, from the development of the review protocol where they informed the focus and aims, with a central role in the interpretation of findings.peer-reviewe

Treatment of Marburg and Ebola hemorrhagic fevers: A strategy for testing new drugs and vaccines under outbreak conditions.

The filoviruses, Marburg and Ebola, have the dubious distinction of being associated with some of the highest case-fatality rates of any known infectious disease-approaching 90% in many outbreaks. In recent years, laboratory research on the filoviruses has produced treatments and vaccines that are effective in laboratory animals and that could potentially drastically reduce case-fatality rates and curtail outbreaks in humans. However, there are significant challenges in clinical testing of these products and eventual delivery to populations in need. Most cases of filovirus infection are recognized only in the setting of large outbreaks, often in the most remote and resource-poor areas of sub-Saharan Africa, with little infrastructure and few personnel experienced in clinical research. Significant political, legal, and socio-cultural barriers also exist. Here, we review the present research priorities and environment for field study of the filovirus hemorrhagic fevers and outline a strategy for future prospective clinical research on treatment and vaccine prevention