Waterdock 2.0: Water placement prediction for Holo-structures with a pymol plugin.

Water is often found to mediate interactions between a ligand and a protein. It can play a significant role in orientating the ligand within a binding pocket and contribute to the free energy of binding. It would thus be extremely useful to be able to accurately predict the position and orientation of water molecules within a binding pocket. Recently, we developed the WaterDock protocol that was able to predict 97% of the water molecules in a test set. However, this approach generated false positives at a rate of over 20% in most cases and whilst this might be acceptable for some applications, in high throughput scenarios this is not desirable. Here we tackle this problem via the inclusion of knowledge regarding the solvation structure of ligand functional groups. We call this new protocol WaterDock2 and demonstrate that this protocol maintains a similar true positive rate to the original implementation but is capable of reducing the false-positive rate by over 50%. To improve the usability of the method, we have also developed a plugin for the popular graphics program PyMOL. The plugin also contains an implementation of the original WaterDock.GAR is supported by the Memorial Sloan Kettering Cancer Center, NIH grant P30 CA008748

Waterdock 2.0: Water placement prediction for Holo-structures with a pymol plugin.

Water is often found to mediate interactions between a ligand and a protein. It can play a significant role in orientating the ligand within a binding pocket and contribute to the free energy of binding. It would thus be extremely useful to be able to accurately predict the position and orientation of water molecules within a binding pocket. Recently, we developed the WaterDock protocol that was able to predict 97% of the water molecules in a test set. However, this approach generated false positives at a rate of over 20% in most cases and whilst this might be acceptable for some applications, in high throughput scenarios this is not desirable. Here we tackle this problem via the inclusion of knowledge regarding the solvation structure of ligand functional groups. We call this new protocol WaterDock2 and demonstrate that this protocol maintains a similar true positive rate to the original implementation but is capable of reducing the false-positive rate by over 50%. To improve the usability of the method, we have also developed a plugin for the popular graphics program PyMOL. The plugin also contains an implementation of the original WaterDock.GAR is supported by the Memorial Sloan Kettering Cancer Center, NIH grant P30 CA008748

Spinal arthritis in invasive cane toads is linked to rate of dispersal as well as to latitude

Initial research on the spread of cane toads (Rhinella marina) through tropical Australia reported a high incidence of spinal arthritis (spondylosis) in toads at the invasion front (where toads disperse rapidly), but not in areas colonized earlier (where toads are more sedentary). The idea that spondylosis was a cost of rapid dispersal was challenged by wider spatial sampling which linked rates of spondylosis to hot (tropical) climates rather than to dispersal rates. Here, the authors of these competing interpretations collaborate to reinterpret the data. Our reanalysis supports both previous hypotheses; rates of spondylosis are higher in populations established by fast-dispersing toads, and are higher in tropical than in temperate environments; they are also higher in larger toads. The functional reason for climatic effects is unclear, but might involve effects on the soil-living bacteria involved in the induction of spondylosis; and/or may reflect higher movement (as opposed to dispersal) or more pronounced dry-season aggregation rates of toads in tropical conditions

An analysis of lecture video utilization in undergraduate medical education: associations with performance in the courses

<p>Abstract</p> <p>Background</p> <p>Increasing numbers of medical schools are providing videos of lectures to their students. This study sought to analyze utilization of lecture videos by medical students in their basic science courses and to determine if student utilization was associated with performance on exams.</p> <p>Methods</p> <p>Streaming videos of lectures (n = 149) to first year and second year medical students (n = 284) were made available through a password-protected server. Server logs were analyzed over a 10-week period for both classes. For each lecture, the logs recorded time and location from which students accessed the file. A survey was administered at the end of the courses to obtain additional information about student use of the videos.</p> <p>Results</p> <p>There was a wide disparity in the level of use of lecture videos by medical students with the majority of students accessing the lecture videos sparingly (60% of the students viewed less than 10% of the available videos. The anonymous student survey revealed that students tended to view the videos by themselves from home during weekends and prior to exams. Students who accessed lecture videos more frequently had significantly (p < 0.002) lower exam scores.</p> <p>Conclusion</p> <p>We conclude that videos of lectures are used by relatively few medical students and that individual use of videos is associated with the degree to which students are having difficulty with the subject matter.</p

Identification of Small Molecule Inhibitors of the Mitotic Kinase Haspin by High-Throughput Screening Using a Homogeneous Time-Resolved Fluorescence Resonance Energy Transfer Assay

Haspin/Gsg2 is a kinase that phosphorylates histone H3 at Thr-3 (H3T3ph) during mitosis. Its depletion by RNA interference results in failure of chromosome alignment and a block in mitosis. Haspin, therefore, is a novel target for development of antimitotic agents. We report the development of a high-throughput time-resolved fluorescence resonance energy transfer (TR-FRET) kinase assay for haspin. Histone H3 peptide was used as a substrate, and a europium-labeled H3T3ph phosphospecific monoclonal antibody was used to detect phosphorylation. A library of 137632 small molecules was screened at Km concentrations of ATP and peptide to allow identification of diverse inhibitor types. Reconfirmation of hits and IC 50 determinations were carried out with the TR-FRET assay and by a radiometric assay using recombinant histone H3 as the substrate. A preliminary assessment of specificity was made by testing inhibition of 2 unrelated kinases. EC 50 values in cells were determined using a cell-based ELISA of H3T3ph. Five compounds were selected as leads based on potency and chemical structure considerations. These leads form the basis for the development of specific inhibitors of haspin that will have clear utility in basic research and possible use as starting points for development of antimitotic anticancer therapeutic

The implementation research institute: Training mental health implementation researchers in the United States

Abstract Background The Implementation Research Institute (IRI) provides two years of training in mental health implementation science for 10 new fellows each year. The IRI is supported by a National Institute of Mental Health (NIMH) R25 grant and the Department of Veterans Affairs (VA). Fellows attend two annual week-long trainings at Washington University in St. Louis. Training is provided through a rigorous curriculum, local and national mentoring, a ‘learning site visit’ to a federally funded implementation research project, pilot research, and grant writing. Methods This paper describes the rationale, components, outcomes to date, and participant experiences with IRI. Results IRI outcomes include 31 newly trained implementation researchers, their new grant proposals, contributions to other national dissemination and implementation research training, and publications in implementation science authored by the Core Faculty and fellows. Former fellows have obtained independent research funding in implementation science and are beginning to serve as mentors for more junior investigators. Conclusions Based on the number of implementation research grant proposals and papers produced by fellows to date, the IRI is proving successful in preparing new researchers who can inform the process of making evidence-based mental healthcare more available through real-world settings of care and who are advancing the field of implementation science

Stability of the non-extremal enhancon solution I: perturbation equations

We consider the stability of the two branches of non-extremal enhancon solutions. We argue that one would expect a transition between the two branches at some value of the non-extremality, which should manifest itself in some instability. We study small perturbations of these solutions, constructing a sufficiently general ansatz for linearised perturbations of the non-extremal solutions, and show that the linearised equations are consistent. We show that the simplest kind of perturbation does not lead to any instability. We reduce the problem of studying the more general spherically symmetric perturbation to solving a set of three coupled second-order differential equations.Comment: 20 pages, 1 figure, references added, typos fixed, version to appear in PR

A new spin-anisotropic harmonic honeycomb iridate

The physics of Mott insulators underlies diverse phenomena ranging from high temperature superconductivity to exotic magnetism. Although both the electron spin and the structure of the local orbitals play a key role in this physics, in most systems these are connected only indirectly --- via the Pauli exclusion principle and the Coulomb interaction. Iridium-based oxides (iridates) open a further dimension to this problem by introducing strong spin-orbit interactions, such that the Mott physics has a strong orbital character. In the layered honeycomb iridates this is thought to generate highly spin-anisotropic interactions, coupling the spin orientation to a given spatial direction of exchange and leading to strongly frustrated magnetism. The potential for new physics emerging from such interactions has driven much scientific excitement, most recently in the search for a new quantum spin liquid, first discussed by Kitaev \cite{kitaev_anyons_2006}. Here we report a new iridate structure that has the same local connectivity as the layered honeycomb, but in a three-dimensional framework. The temperature dependence of the magnetic susceptibility exhibits a striking reordering of the magnetic anisotropy, giving evidence for highly spin-anisotropic exchange interactions. Furthermore, the basic structural units of this material suggest the possibility of a new family of structures, the `harmonic honeycomb' iridates. This compound thus provides a unique and exciting glimpse into the physics of a new class of strongly spin-orbit coupled Mott insulators.Comment: 12 pages including bibliography, 5 figure

Tuberculosis care designed with barramarrany (family): Participatory action research that prioritised partnership, healthy housing and nutrition

Issue addressed Ongoing tuberculosis (TB) transmission in Aboriginal communities in Australia is unfair and unacceptable. Redressing the inequity in TB affecting Aboriginal peoples is a priority in Australia’s Strategic Plan for Tuberculosis Control. Improving TB care needs not to just identify barriers but do something about them. Privileging the voices of Aboriginal people affected by TB is essential to identify effective and enabling strategies. Methods A barramarrany (Aboriginal family) affected by recurring TB partnered with TB and Environmental Health teams using a participatory action research (PAR) methodology to improve housing health hardware and nutrition alongside biomedical TB prevention and care. A combination of the Ottawa Charter for Health Promotion; the International ‘End TB’ Strategy; and Aboriginal barramarrany leadership, worldviews and traditional values guided actions to reduce TB transmission. Results Together the partners improved housing hardware and access to nutritious food, so the barramarrany could create a setting for good health and wellbeing. These actions supported the barramarrany to regain the physical, social and emotional wellbeing to deal with day-to-day challenges and stresses. The barramarrany were able to better sustain supportive relationships; grow, prepare and eat healthy food; and participate in healthcare activities. The barramarrany could better engage with medical approaches for TB and four barramarrany members completed TB treatment. The PAR action-project enabled and supported early TB diagnosis, treatment and prevention. Conclusion Amplifying the voices of Aboriginal people and shared ownership of TB diagnosis, treatment and prevention by the barramarrany, was underpinned with principles of self-determination, capacity building and social justice. This PAR action-project provides further evidence that improving housing and nutrition can assist in Ending TB while improving wellbeing. So what? Our action-research project undertaken within a PAR framework demonstrates the implementation of End TB Strategies by utilising the Ottawa Charter’s five actions to promote health, by understanding and centralising the social determinants of health

Characterization of an Oct1 orthologue in the channel catfish, Ictalurus punctatus: A negative regulator of immunoglobulin gene transcription?

BACKGROUND: The enhancer (Eμ3') of the immunoglobulin heavy chain locus (IGH) of the channel catfish (Ictalurus punctatus) has been well characterized. The functional core region consists of two variant Oct transcription factor binding octamer motifs and one E-protein binding μE5 site. An orthologue to the Oct2 transcription factor has previously been cloned in catfish and is a functionally active transcription factor. This study was undertaken to clone and characterize the Oct1 transcription factor, which has also been shown to be important in driving immunoglobulin gene transcription in mammals. RESULTS: An orthologue of Oct1, a POU family transcription factor, was cloned from a catfish macrophage cDNA library. The inferred amino acid sequence of the catfish Oct1, when aligned with other vertebrate Oct1 sequences, revealed clear conservation of structure, with the POU specific subdomain of catfish Oct1 showing 96% identity to that of mouse Oct1. Expression of Oct1 was observed in clonal T and B cell lines and in all tissues examined. Catfish Oct1, when transfected into both mammalian (mouse) and catfish B cell lines, unexpectedly failed to drive transcription from three different octamer-containing reporter constructs. These contained a trimer of octamer motifs, a fish V(H )promoter, and the core region of the catfish Eμ3' IGH enhancer, respectively. This failure of catfish Oct1 to drive transcription was not rescued by human BOB.1, a co-activator of Oct transcription factors that stimulates transcription driven by catfish Oct2. When co-transfected with catfish Oct2, Oct1 reduced Oct2 driven transcriptional activation. Electrophoretic mobility shift assays showed that catfish Oct1 (native or expressed in vitro) bound both consensus and variant octamer motifs. Putative N- and C-terminal activation domains of Oct1, when fused to a Gal4 DNA binding domain and co-transfected with Gal4-dependent reporter constructs were transcriptionally inactive, which may be due in part to a lack of residues associated with activation domain function. CONCLUSION: An orthologue to mammalian Oct1 has been found in the catfish. It is similar to mammalian Oct1 in structure and expression. However, these results indicate that the physiological functions of catfish Oct1 differ from those of mammalian Oct1 and include negative regulation of transcription