Fast Methods for Simulation of Biomolecule of Electrostatics

Biomolecular structure and interactions in aqueous environment are determined by a complicated interplay between physical and chemical forces including solvation, electrostatics, van der Waals forces, the hydrophobic effect and covalent bonding. Among them, electrostatics has been of particular interest due to its long-range nature and the tradeoff between desolvation and interaction effects [1]. In addition, electrostatic interactions play a significant role within a biomolecule as well as between biomolecules, making the balance between the two vital to the understanding of macromolecular systems. As a result, much effort has been devoted to accurate modeling and simulation of biomolecule electrostatics. One important application of this work is to compute the structure of electrostatic interactions for a biomolecule in an electrolyte solution, as well as the potential that the molecule generates in space. There are two valuable uses for these simulations. First, it provides a full picture of the electrostatic energetics of a biomolecular system, improving our understanding of how electrostatics contributes to stability, specificity, function, and molecular interaction [2]. Second, these simulations serve as a tool for molecular design, since electrostatic complementarity is an important feature of interacting molecules. Through examination of the electrostatics and potential field generated by a protein molecule, for example, it may be possible to suggest improvements to other proteins or drug molecules that interact with it, or perhaps even design new interacting molecules de novo [3]. There are two approaches in simulating a protein macromolecule in an aqueous solution with nonzero ionic strength. Discrete/atomistic approaches based on Monte-Carlo or molecular dynamics simulations treat the macromolecule and solvent explicitly at the atomic level. Therefore, an enormous number of solvent molecules are required to provide reasonable accuracy, especially when electric fields far away from macroscopic surface are of interest, leading to computational infeasibility. In this work, we adopt instead an approach based on a continuum description of the macromolecule and solvent. Although the continuum model of biomolecule electrostatics is widely used, the numerical techniques used to evaluate the model do not exploit fast solver approaches developed for analyzing integrated circuit interconnect. I will describe the formulation used for analyzing biomolecule electrostatics, and then derive an integral formulation of the problem that can be rapidly solved with precorrected-FFT method [4].Singapore-MIT Alliance (SMA

Testing the Substrate-Envelope Hypothesis with Designed Pairs of Compounds

Acquired resistance to therapeutic agents is a significant barrier to the development of clinically effective treatments for diseases in which evolution occurs on clinical time scales, frequently arising from target mutations. We previously reported a general strategy to design effective inhibitors for rapidly mutating enzyme targets, which we demonstrated for HIV-1 protease inhibition [Altman et al. J. Am. Chem. Soc. 2008, 130, 6099–6113]. Specifically, we developed a computational inverse design procedure with the added constraint that designed inhibitors bind entirely inside the substrate envelope, a consensus volume occupied by natural substrates. The rationale for the substrate-envelope constraint is that it prevents designed inhibitors from making interactions beyond those required by substrates and thus limits the availability of mutations tolerated by substrates but not by designed inhibitors. The strategy resulted in subnanomolar inhibitors that bind robustly across a clinically derived panel of drug-resistant variants. To further test the substrate-envelope hypothesis, here we have designed, synthesized, and assayed derivatives of our original compounds that are larger and extend outside the substrate envelope. Our designs resulted in pairs of compounds that are very similar to one another, but one respects and one violates the substrate envelope. The envelope-respecting inhibitor demonstrates robust binding across a panel of drug-resistant protease variants, whereas the envelope-violating one binds tightly to wild type but loses affinity to at least one variant. This study provides strong support for the substrate-envelope hypothesis as a design strategy for inhibitors that reduce susceptibility to resistance mutations.National Science Foundation (U.S.) (NSF grant 0821391)National Institute of General Medical Sciences (U.S.) (NIH (GM066524))National Institute of General Medical Sciences (U.S.) (GM065418)National Institute of General Medical Sciences (U.S.) (the NIH (GM082209)National Institute of General Medical Sciences (U.S.) (AI41404)National Institute of General Medical Sciences (U.S.) (AI43198

Disguise and Deception of Action Outcomes Through Sports Garment Design Impair Anticipation Judgments.

The ability to disguise and deceive action outcomes was examined by manipulating sports garments. In Experiment 1, those with higher and lower skill levels in anticipation predicted the throw direction of an opponent who wore a garment designed to disguise kinetic-chain information. Higher skill anticipators were more adversely affected by the disguise garment than the lower skill anticipators, demonstrating that disguise removed the anticipation advantage. In Experiment 2, using the same occlusion methodology, the effect of deception was examined using 2 garments designed to create visual illusions of motion across the proximal-to-distal sequence of the thrower's action and compared with a white-garment control. Performances for the deceptive garments were reduced relative to the control garment at the earliest occlusion points for the rightmost targets, but this effect was reversed for the leftmost targets at the earliest occlusion point, suggesting that the visual illusion garments were deceiving participants about motion information from the proximal-to-distal sequence of the action

The expanded public works programme : perspectives of direct beneficiaries

Abstract: Scholarship on the Expanded Public Works Programme (EPWP) in South Africa tends to focus on quantitative evaluation to measure the progress made in the implementation of EPWP projects. The number of employment opportunities created by EPWP, demographic profiling, skills acquired by beneficiaries and training opportunities related to the Programme form the basis of typical statistical evaluations of it, but exclude comment by the workers who participate in its projects. Based on primary sources, including in-depth interviews, newspaper reports and internet sources, this article seeks to provide a qualitative review of the EPWP from the perspective of the beneficiaries of municipal EPWP projects. Various South African government sectors hire EPWP workers to provide local services such as cleaning and maintaining infrastructure, but the employment of these workers can still be regarded as precarious, in the sense that they have no job security, earn low wages and have no benefits such as medical aid or pension fund. The interviewees indicated that, although they appreciate the temporary employment opportunities provided by the EPWP, they also experience health and safety risks and lack the advantages of organised labour groupings. Their main disadvantage, however, is that they cannot access permanent employment, which offers better wages and concomitant benefits

Reliability and Initial Validation of the Ulcerative Colitis Endoscopic Index of Severity

Background & AimsWe studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators.MethodsWe created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors (“vascular pattern”, “bleeding”, and “erosions and ulcers”) comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores.ResultsThere was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details.ConclusionsThe UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details

Pevonedistat (MLN4924), a First‐in‐Class NEDD8‐activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111220/1/bjh13323.pd

Gender, age and the MBA: An analysis of extrinsic and intrinsic career benefits

Against the background of an earlier UK study, this paper presents the findings of a Canadian based survey of career benefits from the MBA. Results indicate firstly that gender and age interact to influence perceptions of career outcomes (young men gain most in terms of extrinsic benefits of career change and pay), and secondly that both men and women gain intrinsic benefits from the MBA. However, intrinsic benefits vary by gender: men in the study were more likely to say they gained confidence from having a fuller skill set while women were more likely to say they gained confidence from feelings of self worth; men emphasised how they had learned to give up control while women argued that they had gained a ‘voice’ in the organization. The role of the MBA in career self- management and the acquisition of key skills are examined as well as the implications for the design of programmes in meeting the varied need of men and women in different age groups

Protocol for the saMS trial (supportive adjustment for multiple sclerosis): a randomized controlled trial comparing cognitive behavioral therapy to supportive listening for adjustment to multiple sclerosis

BackgroundMultiple Sclerosis (MS) is an incurable, chronic, potentially progressive and unpredictable disease of the central nervous system. The disease produces a range of unpleasant and debilitating symptoms, which can have a profound impact including disrupting activities of daily living, employment, income, relationships, social and leisure activities, and life goals. Adjusting to the illness is therefore particularly challenging. This trial tests the effectiveness of a cognitive behavioural intervention compared to supportive listening to assist adjustment in the early stages of MS.MethodsThis is a two arm randomized multi-centre parallel group controlled trial. 122 consenting participants who meet eligibility criteria will be randomly allocated to receive either Cognitive Behavioral Therapy or Supportive Listening. Eight one hour sessions of therapy (delivered over a period of 10 weeks) will be delivered by general nurses trained in both treatments. Self-report questionnaire data will be collected at baseline (0 weeks), mid-therapy (week 5 of therapy), post-therapy (15 weeks) and at six months (26 weeks) and twelve months (52 weeks) follow-up. Primary outcomes are distress and MS-related social and role impairment at twelve month follow-up. Analysis will also consider predictors and mechanisms of change during therapy. In-depth interviews to examine participants’ experiences of the interventions will be conducted with a purposively sampled sub-set of the trial participants. An economic analysis will also take place. DiscussionThis trial is distinctive in its aims in that it aids adjustment to MS in a broad sense. It is not a treatment specifically for depression. Use of nurses as therapists makes the interventions potentially viable in terms of being rolled out in the NHS. The trial benefits from incorporating patient input in the development and evaluation stages. The trial will provide important information about the efficacy, cost-effectiveness and acceptability of the interventions as well as mechanisms of psychosocial adjustment.Trial registrationCurrent Controlled Trials ISRCTN91377356<br/

Is there a relationship between pain intensity and postural sway in patients with non-specific low back pain?

Background Increased center of pressure excursions are well documented in patients suffering from non-specific low back pain, whereby the altered postural sway includes both higher mean sway velocities and larger sway area. No investigation has been conducted to evaluate a relationship between pain intensity and postural sway in adults (aged 50 or less) with non-specific low back pain. Methods Seventy-seven patients with non-specific low back pain and a matching number of healthy controls were enrolled. Center of pressure parameters were measured by three static bipedal standing tasks of 90sec duration with eyes closed in narrow stance on a firm surface. The perceived pain intensity was assessed by a numeric rating scale (NRS-11), an equal number of patients (n=11) was enrolled per pain score. Results Generally, our results confirmed increased postural instability in pain sufferers compared to healthy controls. In addition, regression analysis revealed a significant and linear increase in postural sway with higher pain ratings for all included COP parameters. Statistically significant changes in mean sway velocity in antero-posterior and medio lateral direction and sway area were reached with an incremental change in NRS scores of two to three points. Conclusions COP mean velocity and sway area are closely related to self-reported pain scores. This relationship may be of clinical use as an objective monitoring tool for patients under treatment or rehabilitation