553,219 research outputs found

    Predicted Structures and Dynamics for Agonists and Antagonists Bound to Serotonin 5-HT2B and 5-HT2C Receptors

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    Subtype 2 serotonin (5-hydroxytryptamine, 5-HT) receptors are major drug targets for schizophrenia, feeding disorders, perception, depression, migraines, hypertension, anxiety, hallucinogens, and gastrointestinal dysfunctions.' We report here the predicted structure of 5-HT2B and 5-HT2C receptors bound to highly potent and selective 5-HT2B antagonist PRX-08066 3, (pKi: 30 nM), including the key binding residues [V103 (2.53), L132 (3.29), V190 (4.60), and L347 (6.58)] determining the selectivity of binding to 5-HT2B over 5-HT2A. We also report structures of the endogenous agonist (5 HT) and a HT2B selective antagonist 2 (1-methyl-1-1,6,7,8-tetrahydro-pyrrolo [2,3-g]quinoline-5-carboxylic acid pyridine-3-ylamide). We examine the dynamics for the agonist-and antagonist-bound HT2B receptors in explicit membrane and water finding dramatically different patterns of water migration into the NPxxY motif and the binding site that correlates with the stability of ionic locks in the D(E)RY region

    Toward a Better Future for this Generation and the Next...

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    The Oak Foundation commissioned Promundo-US to review and assess Oak's overall strategy in relation to its goal of engaging men and boys in the elimination of sexual abuse of children and comment more specifically on possible priorities and directions for work with respect to its objective that: Men and boys will have greater opportunities to engage positively in children's lives and to protect them from sexual abuse This report is the result of this assessment. The report is based on an extensive desk review of published research and program and policy evaluations, as well as the 'grey' literature on work with men and boys on child sexual abuse and other forms of intimate violence in the lives of children. Out of this review, a total of 35 key informants across a range of targeted sectors both internationally and within Oak's priority regions were identified and interviewed in person or over the phone, using a semi-structured interview tool. These key informant phone interviews gathered detailed information on both experiences and lessons from current thinking, policy and practice as well as on opportunities and priorities for future grant-making

    The developmental dynamics of terrorist organizations

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    We identify robust statistical patterns in the frequency and severity of violent attacks by terrorist organizations as they grow and age. Using group-level static and dynamic analyses of terrorist events worldwide from 1968-2008 and a simulation model of organizational dynamics, we show that the production of violent events tends to accelerate with increasing size and experience. This coupling of frequency, experience and size arises from a fundamental positive feedback loop in which attacks lead to growth which leads to increased production of new attacks. In contrast, event severity is independent of both size and experience. Thus larger, more experienced organizations are more deadly because they attack more frequently, not because their attacks are more deadly, and large events are equally likely to come from large and small organizations. These results hold across political ideologies and time, suggesting that the frequency and severity of terrorism may be constrained by fundamental processes.Comment: 28 pages, 8 figures, 4 tables, supplementary materia

    Simulating Dye-Sensitized TiO2 Heterointerfaces in Explicit Solvent: Absorption Spectra, Energy Levels, and Dye Desorption

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    Dye-sensitized solar cells (DSCs) represent a valuable, efficient, and low-cost alternative to conventional semiconductor photovoltaic devices. A deeper understanding of the dye/semiconductor heterointerface and of the dye-sensitized semiconductor/ electrolyte interactions are fundamental for further progress in DSC technology. Here we report an ab initio molecular dynamics simulation of a dye-sensitized TiO2 heterointerface “immersed” in an explicit water environment for an efficient organic dye, followed by TDDFT excited state calculations of the coupled dye/semiconductor/ solvent system. This new computational protocol and the extended model system allows us to gain unprecedented insight into the excited state changes occurring for the solvated dye-sensitized heterointerface at room temperature, and to provide an atomistic picture of water-mediated dye desorption

    Truth, Beauty, Freedom, and Money: Technology-Based Art and the Dynamics of Sustainability

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    Proposes innovative new approaches and models for art and technology institutions, and provides details for an "Arts Lab," a unique hybrid art center and research lab

    Underlying socio-political processes behind the 2016 US election

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    Recently we have witnessed a number of rapid shifts toward populism in the rhetoric and policies of major political parties, as exemplified in the 2016 Brexit Referendum, 2016 US Election, and 2017 UK General Election. Our perspective here is to focus on understanding the underlying societal processes behind these recent political shifts. We use novel methods to study social dynamics behind the 2016 Presidential election. This is done by using network science methods to identify key groups associated with the US right-wing during the election. We investigate how the groups grew on Twitter, and how their associated accounts changed their following behaviour over time. We find a new external faction of Trump supporters took a strong influence over the traditional Republican Party (GOP) base during the election campaign. The new group dominated the GOP group in terms of new members and endorsement via Twitter follows. Growth of new accounts for the GOP party all but collapsed during the campaign. While the Alt-right group was growing exponentially, it has remained relatively isolated. Counter to the mainstream view, we detected an unexpectedly low number of automated ‘bot’ accounts and accounts associated with foreign intervention in the Trump-supporting group. Our work demonstrates a powerful method for tracking the evolution of societal groups and reveals complex social processes behind political changes

    Predicting the effects of basepair mutations in DNA-protein complexes by thermodynamic integration

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    AbstractThermodynamically rigorous free energy methods in principle allow the exact computation of binding free energies in biological systems. Here, we use thermodynamic integration together with molecular dynamics simulations of a DNA-protein complex to compute relative binding free energies of a series of mutants of a protein-binding DNA operator sequence. A guanine-cytosine basepair that interacts strongly with the DNA-binding protein is mutated into adenine-thymine, cytosine-guanine, and thymine-adenine. It is shown that basepair mutations can be performed using a conservative protocol that gives error estimates of ∼10% of the change in free energy of binding. Despite the high CPU-time requirements, this work opens the exciting opportunity of being able to perform basepair scans to investigate protein-DNA binding specificity in great detail computationally
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