Atomic-scale characterization of mature HIV-1 capsid stabilization by inositol hexakisphosphate (IP₆)

Inositol hexakisphosphates (IP6) are cellular cofactors that promote the assembly of mature capsids of HIV. These negatively charged molecules coordinate an electropositive ring of arginines at the center of pores distributed throughout the capsid surface. Kinetic studies indicate that the binding of IP6 increases the stable lifetimes of the capsid by several orders of magnitude from minutes to hours. Using all-atom molecular dynamics simulations, we uncover the mechanisms that underlie the unusually high stability of mature capsids in complex with IP6. We find that capsid hexamers and pentamers have differential binding modes for IP6. Ligand density calculations show three sites of interaction with IP6 including at a known capsid inhibitor binding pocket. Free energy calculations demonstrate that IP6 preferentially stabilizes pentamers over hexamers to enhance fullerene modes of assembly. These results elucidate the molecular role of IP6 in stabilizing and assembling the retroviral capsid

High abundance synovial fluid proteome: distinct profiles in health and osteoarthritis

The development of increasingly high-throughput and sensitive mass spectroscopy-based proteomic techniques provides new opportunities to examine the physiology and pathophysiology of many biologic fluids and tissues. The purpose of this study was to determine protein expression profiles of high-abundance synovial fluid (SF) proteins in health and in the prevalent joint disease osteoarthritis (OA). A cross-sectional study of 62 patients with early OA (n = 21), patients with late OA (n = 21), and control individuals (n = 20) was conducted. SF proteins were separated by using one-dimensional PAGE, and the in-gel digested proteins were analyzed by electrospray ionization tandem mass spectrometry. A total of 362 spots were examined and 135 high-abundance SF proteins were identified as being expressed across all three study cohorts. A total of 135 SF proteins were identified. Eighteen proteins were found to be significantly differentially expressed between control individuals and OA patients. Two subsets of OA that are not dependent on disease duration were identified using unsupervised analysis of the data. Several novel SF proteins were also identified. Our analyses demonstrate no disease duration-dependent differences in abundant protein composition of SF in OA, and we clearly identified two previously unappreciated yet distinct subsets of protein profiles in this disease cohort. Additionally, our findings reveal novel abundant protein species in healthy SF whose functional contribution to SF physiology was not previously recognized. Finally, our studies identify candidate biomarkers for OA with potential for use as highly sensitive and specific tests for diagnostic purposes or for evaluating therapeutic response

Defining Refractory Migraine: Results of the RHSIS Survey of American Headache Society Members

To gauge consensus regarding a proposed definition for refractory migraine proposed by Refractory Headache Special Interest Section, and where its use would be most appropriate. Background.— Headache experts have long recognized that a subgroup of headache sufferers remains refractory to treatment. Although different groups have proposed criteria to define refractory migraine, the definition remains controversial. The Refractory Headache Special Interest Section of the American Headache Society developed a definition through a consensus process, assisted by a literature review and initial membership survey. Design.— A 12-item questionnaire was distributed at the American Headache Society meeting in 2007 during a platform session and at the Refractory Headache Special Interest Section symposium. The same questionnaire was subsequently sent to all American Headache Society members via e-mail. A total of 151 responses from AHS members form the basis of this report. The survey instrument was designed using Survey Monkey. Frequencies and percentages of the survey were used to describe survey responses. Results.— American Headache Society members agreed that a definition for refractory migraine is needed (91%) that it should be added to the International Classification of Headache Disorders-2 (86%), and that refractory forms of non-migraine headache disorders should be defined (87%). Responders believed a refractory migraine definition would be of greatest value in selecting patients for clinical drug trials. The current refractory migraine definition requires a diagnosis of migraine, interference with function or quality of life despite modification of lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The proposed criteria for the refractory migraine definition require failing 2 preventive medications to meet the threshold for failure. Although 42% of respondents agreed with the working definition of refractory migraine, 43% favored increasing the number to 3 (50%) or 4 (26%) preventive treatment failures. When respondents were asked if they felt that the proposed definition was appropriate to select patients for invasive procedures (patent foramen ovale repair or stimulators) only 44% agreed. Conclusions.— There is a consensus for a need for a definition for refractory migraine and that it should be added to the International Classification of Headache Disorder-2. There was also general agreement by the responders that refractory forms of non-migraine headache disorders should be defined.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72860/1/j.1526-4610.2009.01370.x.pd

MicroRNA-146a regulates ICOS–ICOSL signalling to limit accumulation of T follicular helper cells and germinal centres

Tight control of T follicular helper (Tfh) cells is required for optimal maturation of the germinal centre (GC) response. The molecular mechanisms controlling Tfh-cell differentiation remain incompletely understood. Here we show that microRNA-146a (miR-146a) is highly expressed in Tfh cells and peak miR-146a expression marks the decline of the Tfh response after immunization. Loss of miR-146a causes cell-intrinsic accumulation of Tfh and GC B cells. MiR-146a represses several Tfh-cell-expressed messenger RNAs, and of these, ICOS is the most strongly cell autonomously upregulated target in miR-146a-deficient T cells. In addition, miR-146a deficiency leads to increased ICOSL expression on GC B cells and antigen-presenting cells. Partial blockade of ICOS signalling, either by injections of low dose of ICOSL blocking antibody or by halving the gene dose of Icos in miR-146a-deficient T cells, prevents the Tfh and GC B-cell accumulation. Collectively, miR-146a emerges as a post-transcriptional brake to limit Tfh cells and GC responses.This work was funded by the National Health and Medical Research Council (NHMRC) program and project grants and Elizabeth Blackburn Fellowship to C.G.V., International Postgraduate Research Scholarship to A.P., NHMRC/MSRA Betty Cuthbert Fellowship to M.A.J., National Research Service Award F30HL110691 and UCLA/Caltech Medical Scientist Training Program to J.L.Z

Proton strangeness form factors in (4,1) clustering configurations

We reexamine a recent result within a nonrelativistic constituent quark model (NRCQM) which maintains that the uuds\bar s component in the proton has its uuds subsystem in P state, with its \bar s in S state (configuration I). When the result are corrected, contrary to the previous result, we find that all the empirical signs of the form factors data can be described by the lowest-lying uuds\bar s configuration with \bar s in P state that has its uuds subsystem in $S$ state (configuration II). Further, it is also found that the removal of the center-of-mass (CM) motion of the clusters will enhance the contributions of the transition current considerably. We also show that a reasonable description of the existing form factors data can be obtained with a very small probability P_{s\bar s}=0.025% for the uuds\bar s component. We further see that the agreement of our prediction with the data for G_A^s at low-q^2 region can be markedly improved by a small admixture of configuration I. It is also found that by not removing CM motion, P_{s\bar s} would be overestimated by about a factor of four in the case when transition dominates over direct currents. Then, we also study the consequence of a recent estimate reached from analyzing the existing data on quark distributions that P_{s\bar s} lies between 2.4-2.9% which would lead to a large size for the five-quark (5q) system, as well as a small bump in both G^s_E+\eta G^s_M and G^s_E in the region of q^2 =< 0.1 GeV^2.Comment: Prepared for The Fifth Asia-Pacific Conference on Few-Body Problems in Physics 2011 in Seoul, South Korea, 22-26 August 201

Parents’ perceived neighborhood safety and children’s cognitive performance:Complexities by race, ethnicity, and cognitive domain

Background:Aim: To examine racial/ethnic variations in the effect of parents’ subjective neighborhood safety on children’s cognitive performance. Methods: This cross-sectional study included 10,027 children from the Adolescent Brain Cognitive Development (ABCD) study. The exposure variable was parents’ subjective neighborhood safety. The outcomes were three domains of children’s cognitive performance: general cognitive performance, executive functioning, and learning/memory. We used mixed-effects regression models for data analysis. Results: Overall, parents’ subjective neighborhood safety was positively associated with children’s executive functioning, but not general cognitive performance or learning/memory. Higher parents’ subjective neighborhood safety had a more positive influence on the executive functioning of non-Hispanic White than Asian American children. Higher parents’ subjective neighborhood safety was associated with higher general cognitive performance and learning/memory for non-White children relative to non-Hispanic White children. Conclusion: The race/ethnicity of children moderates the association between neighborhood safety and cognitive performance. This becomes more complicated, as the patterns seem to differ across ethnicity and cognitive domains. It is unknown whether the observed racial/ethnic variations in the effect of neighborhood safety on cognitive performance are neighborhood characteristics such as residential segregation. Addressing neighborhood inequalities is needed if we wish to reduce racial/ethnic inequities in the cognitive development of children

Clinical Validation of an Ultra High-Throughput Spiral Microfluidics for the Detection and Enrichment of Viable Circulating Tumor Cells

Background: Circulating tumor cells (CTCs) are cancer cells that can be isolated via liquid biopsy from blood and can be phenotypically and genetically characterized to provide critical information for guiding cancer treatment. Current analysis of CTCs is hindered by the throughput, selectivity and specificity of devices or assays used in CTC detection and isolation. Methodology/Principal Findings: Here, we enriched and characterized putative CTCs from blood samples of patients with both advanced stage metastatic breast and lung cancers using a novel multiplexed spiral microfluidic chip. This system detected putative CTCs under high sensitivity (100%, n = 56) (Breast cancer samples: 12–1275 CTCs/ml; Lung cancer samples: 10–1535 CTCs/ml) rapidly from clinically relevant blood volumes (7.5 ml under 5 min). Blood samples were completely separated into plasma, CTCs and PBMCs components and each fraction were characterized with immunophenotyping (Pan-cytokeratin/CD45, CD44/CD24, EpCAM), fluorescence in-situ hybridization (FISH) (EML4-ALK) or targeted somatic mutation analysis. We used an ultra-sensitive mass spectrometry based system to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples. Conclusions/Significance: We have clinically validated our multiplexed microfluidic chip for the ultra high-throughput, low-cost and label-free enrichment of CTCs. Retrieved cells were unlabeled and viable, enabling potential propagation and real-time downstream analysis using next generation sequencing (NGS) or proteomic analysis.Singapore-MIT Alliance for Research and Technolog

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

1968

Maintenance of Golf Carts by Thomas Pepe (page 1) Why a Golf Course Superintendent Should Play Golf by Stephen Skowronski (2) Tree Pruning by Martin Walsh (3) Golf Course Labor: A Dilemma by Robert Barber (5) Turf Problems by Alexander M. Radko (A-1) 1967 Turfgrass Problems by Lee Record (A-3) Southern Turfgrass Production and Problems by Ralph W. White Jr. (A-5) Canadian Turf Grass Production and Problems by David Moote (A-8) Turf Research Abroad by C.R. Skogley (A-13) Turf Research at Home by Victor B. Younger (A-14) Turfgrass Research - An Industrial Approach by J. A. Simmons (A-16) Cutting Labor Costs in Turfgrass Managemnt by Tom Mascaro (A-24) The Reluctant human by John W. Denison (A-28) The Problem Drinker - Management Responsibility by G.E. Osburn (A-31) Contemporary Design Standards by Geoffrey S. Cornish (A-34) Construction - Superintendents\u27 Viewpoint by Robert E. Grant (A-36) Construction b Contract and the Role of the Superintendent by David Canavan (A-39) Seed Production by Robert J. Peterson (A-41) Cemetery Turf Maintenance on a High and Low Budget by Stanley Sosenski (A-45) Ten Steps to a Good Lawn by John Zak (A-49) Review of Herbicides for Turf Weed Control by Alvin A. Baber (A-53