Engineering the Redox Potential over a Wide Range within a New Class of FeS Proteins

Abstract: MitoNEET is a newly discovered mitochondrial protein and a target of the TZD class of antidiabetes drugs. MitoNEET is homodimeric with each protomer binding a [2Fe-2S] center through a rare 3-Cys and 1-His coordination geometry. Both the fold and the coordination of the [2Fe-2S] centers suggest that it could have novel properties compared to other known [2Fe-2S] proteins. We tested the robustness of mitoNEET to mutation and the range over which the redox potential (EM) could be tuned. We found that the protein could tolerate an array of mutations that modified the EM of the [2Fe-2S] center over a range of ∼700 mV, which is the largest EM range engineered in an FeS protein and, importantly, spans the cellular redox range (+200 to-300 mV). These properties make mitoNEET potentially useful for both physiological studies and industrial applications as a stable, water-soluble, redox agent

Equidistribution for higher-rank Abelian actions on Heisenberg nilmanifolds

2010 Mathematics Subject Classification: Primary: 37C85, 37A17, 37A45; Secondary: 11K36, 11L07.We prove quantitative equidistribution results for actions of Abelian subgroups of the (2g + 1)-dimensional Heisenberg group acting on compact (2g + 1)-dimensional homogeneous nilmanifolds. The results are based on the study of the C∞-cohomology of the action of such groups, on tame estimates of the associated cohomological equations and on a renormalization method initially applied by Forni to surface flows and by Forni and the second author to other parabolic flows. As an application we obtain bounds for finite Theta sums defined by real quadratic forms in g variables, generalizing the classical results of Hardy and Littlewood [25, 26] and the optimal result of Fiedler, Jurkat, and Körner [17] to higher dimension.This work was partially done while L. Flaminio visited the Isaac Newton Institute in Cambridge, UK. He wishes to thank the Institute and the organizers of the program Interactions between Dynamics of Group Actions and Number Theory for their hospitality. L. Flaminio was supported in part by the Labex CEMPI (ANR-11-LABX-07). S. Cosentino was partially supported by CMAT - Centro de Matematica da Universidade do Minho, financed by the Strategic Project PEst-OE/MAT/UI0013/2014

Exposure-in-vivo containing interventions to improve work functioning of workers with anxiety disorder: a systematic review

<p>Abstract</p> <p>Background</p> <p>Anxiety disorders are associated with functional disability, sickness absence, and decreased productivity. Effective treatments of anxiety disorders can result in remission of symptoms. However the effects on work related outcomes are largely unknown. Exposure in vivo is potentially well fit to improve work-related outcomes. This study systematically reviews the effectiveness of exposure-in-vivo containing interventions in reducing work-related adverse outcomes in workers with anxiety disorders.</p> <p>Methods</p> <p>A systematic study search was conducted in Medline, Cinahl, Embase and Psycinfo. Two reviewers independently extracted data and from each study assessed the quality of evidence by using the GRADE approach. We performed a meta-analysis if data showed sufficient clinical homogeneity.</p> <p>Results</p> <p>Seven studies containing 11 exposure-in-vivo interventions were included. Four studies were focused on Obsessive Compulsive Disorder (OCD), two on Post Traumatic Stress Disorder (PTSD), and one on a mixed group of OCD and severe phobias. The studies were grouped according to type of anxiety disorder and subsequently according to type of comparisons. For OCD, exposure-in-vivo containing interventions can yield better work-related outcomes compared to medication (SSRIs) and relaxation but not better compared to response prevention. The results on anxiety outcomes were similar. The net contribution of exposure in vivo in two OCD intervention programs is also presented as a meta-analysis and shows significant positive results on work role limitations. The calculated pooled effect size with 95% confidence interval was 0.72 (0.28, 1.15). For PTSD, exposure-in-vivo containing interventions can yield better work-related and anxiety-related outcomes compared to a waiting-list but not better compared to imaginal exposure.</p> <p>Conclusions</p> <p>Exposure in vivo as part of an anxiety treatment can reduce work-related adverse outcomes in workers with OCD and PTSD better than various other anxiety treatments or a waiting-list. We recommend that it should be studied how the results of these studies can be transferred to the practice of occupational health professionals and how clinicians can make better use of them to improve work-related outcomes. In future research, priority should be given to high-quality randomised controlled trials (RCTs) in which exposure-in-vivo containing interventions are applied to a variety of anxiety disorders and compared with other clinical anxiety treatments such as SSRIs. Work-related outcomes, in particular work functioning and sickness absence, need to be assessed with reliable and valid measures.</p

Catalytic Cycle of Multicopper Oxidases Studied by Combined Quantum- and Molecular-Mechanical Free-Energy Perturbation Methods

We have used combined quantum mechanical and molecular mechanical free-energy perturbation methods in combination with explicit solvent simulations to study the reaction mechanism of the multicopper oxidases, in particular the regeneration of the reduced state from the native intermediate. For 52 putative states of the trinuclear copper cluster, differing in the oxidation states of the copper ions and the protonation states of water- and O2-derived ligands, we have studied redox potentials, acidity constants, isomerisation reactions, as well as water- and O2 binding reactions. Thereby, we can propose a full reaction mechanism of the multicopper oxidases with atomic detail. We also show that the two copper sites in the protein communicate so that redox potentials and acidity constants of one site are affected by up to 0.2 V or 3 pKa units by a change in the oxidation state of the other site

Central limit theorem for Artin L-functions

We show that the sum of the traces of Frobenius elements of Artin (Formula presented.)-functions in a family of (Formula presented.)-fields satisfies the Gaussian distribution under certain counting conjectures. We prove the counting conjectures for (Formula presented.) and (Formula presented.)-fields. We also prove a central limit theorem for the (Formula presented.)-functions of modular forms on congruence subgroups (Formula presented.) as (Formula presented.).ope