553,219 research outputs found
Predicted Structures and Dynamics for Agonists and Antagonists Bound to Serotonin 5-HT2B and 5-HT2C Receptors
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...
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
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Substrate-Specific Inhibition Constants for Phospholipase A2 Acting on Unique Phospholipid Substrates in Mixed Micelles and Membranes Using Lipidomics.
Assaying lipolytic enzymes is extremely challenging because they act on water-insoluble lipid substrates, which are normally components of micelles, vesicles, and cellular membranes. We extended a new lipidomics-based liquid chromatographic-mass spectrometric assay for phospholipases A2 to perform inhibition analysis using a variety of commercially available synthetic and natural phospholipids as substrates. Potent and selective inhibitors of three recombinant human enzymes, including cytosolic, calcium-independent, and secreted phospholipases A2 were used to establish and validate this assay. This is a novel use of dose-response curves with a mixture of phospholipid substrates, not previously feasible using traditional radioactive assays. The new application of lipidomics to developing assays for lipolytic enzymes revolutionizes in vitro testing for the discovery of potent and selective inhibitors using mixtures of membranelike substrates
The developmental dynamics of terrorist organizations
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
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
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
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
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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