Adaptive Accelerated Molecular Dynamics (Ad-AMD) Revealing the Molecular Plasticity of P450cam

An extended accelerated molecular dynamics (AMD) methodology called adaptive AMD is presented. Adaptive AMD (Ad-AMD) is an efficient and robust conformational space sampling algorithm that is particularly-well suited to proteins with highly structured potential energy surfaces exhibiting complex, large-scale collective conformational transitions. Ad-AMD simulations of substrate-free P450cam reveal that this system exists in equilibrium between a fully and partially open conformational state. The mechanism for substrate binding depends on the size of the ligand. Larger ligands enter the P450cam binding pocket, and the resulting substrate-bound system is trapped in an open conformation via a population shift mechanism. Small ligands, which fully enter the binding pocket, cause an induced-fit mechanism, resulting in the formation of an energetically stable closed conformational state. These results are corroborated by recent experimental studies and potentially provide detailed insight into the functional dynamics and conformational behavior of the entire cytochrome-P450 superfamily

Analysis of clinical outcomes according to original treatment groups 16 years after the pivotal IFNB-1b trial

BACKGROUND: Evidence for efficacy of disease-modifying drugs in multiple sclerosis (MS) comes from trials of short duration. We report results from a 16 y, retrospective follow-up of the pivotal interferon beta-1b (IFNB-1b) study. METHODS: The 372 trial patients were randomly assigned to placebo (n=123), IFNB-1b 50 microg (n=125) or IFNB-1b 250 microg (n=124) subcutaneously every other day for at least 2 y. Some remained randomised for up to 5 y but, subsequently, patients received treatment according to physicians' discretion. Patients were re-contacted and asked to participate. Efficacy related measures included MRI parameters, relapse rate, the Expanded Disability Status Scale, the Multiple Sclerosis Functional Composite Measure and conversion to secondary progressive MS. RESULTS: Of the 88.2% (328/372) of patients who were identified, 69.9% (260/372) had available case report forms. No differences in outcome between original randomisation groups could be discerned using standard disability and MRI measures. However, mortality rates among patients originally treated with IFNB-1b were lower than in the original placebo group (18.3% (20/109) for placebo versus 8.3% (9/108) for IFNB-1b 50 microg and 5.4% (6/111) for IFNB-1b 250 microg). CONCLUSIONS: The original treatment assignment could not be shown to influence standard assessments of long-term efficacy. On-study behaviour of patients was influenced by factors that could not be controlled with the sacrifice of randomisation and blinding. Mortality was higher in patients originally assigned to placebo than those who had received IFNB-1b 50 microg or 250 microg. The dataset provides important resources to explore early predictors of long-term outcome

Evidence of Hantavirus Infection among Bats in Brazil

Citation: Sabino-Santos, G., Maia, F. G. M., Vieira, T. M., Muylaert, R. D., Lima, S. M., Goncalves, C. B., . . . Figueiredo, L. T. M. (2015). Evidence of Hantavirus Infection among Bats in Brazil. American Journal of Tropical Medicine and Hygiene, 93(2), 404-406. doi:10.4269/ajtmh.15-0032Hantaviruses are zoonotic viruses harbored by rodents, bats, and shrews. At present, only rodent-borne hantaviruses are associated with severe illness in humans. New species of hantaviruses have been recently identified in bats and shrews greatly expanding the potential reservoirs and ranges of these viruses. Brazil has one of the highest incidences of hantavirus cardiopulmonary syndrome in South America, hence it is critical to know what is the prevalence of hantaviruses in Brazil. Although much is known about rodent reservoirs, little is known regarding bats. We captured 270 bats from February 2012 to April 2014. Serum was screened for the presence of antibodies against a recombinant nucleoprotein (rN) of Araraquara virus (ARAQV). The prevalence of antibody to hantavirus was 9/53 with an overall seroprevalence of 17%. Previous studies have shown only insectivorous bats to harbor hantavirus; however, in our study, of the nine seropositive bats, five were frugivorous, one was carnivorous, and three were sanguivorous phyllostomid bats

Problematizing Choice: Responsible consumers and sceptical citizens

About the book: Governance, Consumers and Citizens is the first book to bring together a study of governance with consumption, examining the changing place of the consumer as citizen in recent trends in governance, the tensions between competing ideas and practices of consumerism and the active role consumers play in the construction and practice of governance. Radically pushing forward the debate on consumers and governance, this collection outlines new conceptions and posits new policy agendas. Bringing together international experts from political science, history, geography, social policy and media studies, this study shows how governance and consumption are intertwined in crucial aspects of public policy and contemporary politics

"Actual" does not imply "feasible"

The familiar complaint that some ambitious proposal is infeasible naturally invites the following response: Once upon a time, the abolition of slavery and the enfranchisement of women seemed infeasible, yet these things were actually achieved. Presumably, then, many of those things that seem infeasible in our own time may well be achieved too and, thus, turn out to have been perfectly feasible after all. The Appeal to History, as we call it, is a bad argument. It is not true that if some desirable state of affairs was actually achieved, then it was feasible that it was achieved. “Actual” does not imply “feasible,” as we put it. Here is our objection. “Feasible” implies “not counterfactually fluky.” But “actual” does not imply “not counterfactually fluky.” So, “actual” does not imply “feasible.” While something like the Flukiness Objection is sometimes hinted at in the context of the related literature on abilities, it has not been developed in any detail, and both premises are inadequately motivated. We offer a novel articulation of the Flukiness Objection that is both more precise and better motivated. Our conclusions have important implications, not only for the admissible use of history in normative argument, but also by potentially circumscribing the normative claims that are applicable to us

State of the field: What can political ethnography tell us about anti-politics and democratic disaffection?

This article adopts and reinvents the ethnographic approach to uncover what governing elites do, and how they respond to public disaffection. Although there is significant work on the citizens’ attitudes to the governing elite (the demand side) there is little work on how elites interpret and respond to public disaffection (the supply side). We argue that ethnography is the best available research method for collecting data on the supply side. In doing so, we tackle long-standing stereotypes in political science about the ethnographic method and what it is good for. We highlight how the innovative and varied practices of contemporary ethnography are ideally suited to shedding light into the ‘black box’ of elite politics. We demonstrate the potential pay-off with reference to important examples of elite ethnography from the margins of political science scholarship. The implications from these rich studies, we argue, suggest a reorientation of how we understand the drivers of public disaffection and the role that political elites play in exacerbating cynicism and disappointment. We conclude by pointing to the benefits to the discipline in embracing elite ethnography both to diversify the methodological toolkit in explaining the complex dynamics of disaffection,and to better enable engagement in renewed public debate about the political establishment

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNB-1b trial

OBJECTIVE: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. METHODS: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. RESULTS: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. CONCLUSIONS: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis