418 research outputs found
Conformational exchange in the potassium channel blocker ShK
ShK is a 35-residue disulfide-linked polypeptide produced by the sea anemone Stichodactyla helianthus, which blocks the potassium channels Kv1.1 and Kv1.3 with pM affinity. An analogue of ShK has been developed that blocks Kv1.3â>â100 times more potently than Kv1.1, and has completed Phase 1b clinical trials for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. Previous studies have indicated that ShK undergoes a conformational exchange that is critical to its function, but this has proved difficult to characterise. Here, we have used high hydrostatic pressure as a tool to increase the population of the alternative state, which is likely to resemble the active form that binds to the Kv1.3 channel. By following changes in chemical shift with pressure, we have derived the chemical shift values of the low- and high-pressure states, and thus characterised the locations of structural changes. The main difference is in the conformation of the Cys17-Cys32 disulfide, which is likely to affect the positions of the critical Lys22-Tyr23 pair by twisting the 21â24 helix and increasing the solvent exposure of the Lys22 sidechain, as indicated by molecular dynamics simulations
Novel gonadal characteristics in an aged bovine freemartin
The gonads from a five year old freemartin Holstein animal were subjected to morphological analysis and to immunohistochemistry using antibodies against developmental and functional markers. We demonstrate, for the first time, the retention of anti-mullerian hormone (AMH) producing intratubular cells (Sertoli cells) in the context of abundant steroidogenic interstitial cells, and structures consistent with clusters of luteal cells. This novel report describes the clinical, gross and histological findings accompanying this newly described gonadal immunophenotype, and its implication in the understanding of freemartin development
Kosterlitz Thouless Universality in Dimer Models
Using the monomer-dimer representation of strongly coupled U(N) lattice gauge
theories with staggered fermions, we study finite temperature chiral phase
transitions in (2+1) dimensions. A new cluster algorithm allows us to compute
monomer-monomer and dimer-dimer correlations at zero monomer density (chiral
limit) accurately on large lattices. This makes it possible to show
convincingly, for the first time, that these models undergo a finite
temperature phase transition which belongs to the Kosterlitz-Thouless
universality class. We find that this universality class is unaffected even in
the large N limit. This shows that the mean field analysis often used in this
limit breaks down in the critical region.Comment: 4 pages, 4 figure
Attentive Learning of Sequential Handwriting Movements: A Neural Network Model
Defense Advanced research Projects Agency and the Office of Naval Research (N00014-95-1-0409, N00014-92-J-1309); National Science Foundation (IRI-97-20333); National Institutes of Health (I-R29-DC02952-01)
A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study.
A phase 2, randomized, placebo-controlled trial was conducted in women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a chemotherapeutic that induces immunogenic cell death.
Women with ovarian, fallopian tube, or primary peritoneal carcinoma were randomized 1 : 1 to receive PLD in combination with blinded motolimod or placebo. Randomization was stratified by platinum-free interval (â€6 versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 versus 1). Treatment cycles were repeated every 28 days until disease progression.
The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was well tolerated, with no synergistic or unexpected serious toxicity. Most patients experienced adverse events of fatigue, anemia, nausea, decreased white blood cells, and constipation. In pre-specified subgroup analyses, motolimod-treated patients who experienced injection site reactions (ISR) had a lower risk of death compared with those who did not experience ISR. Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 stimulation predicted OS outcomes in patients receiving motolimod on study. Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide polymorphisms, mutational status in BRCA and other DNA repair genes, and autoantibody biomarkers did not correlate with OS or PFS.
The addition of motolimod to PLD did not improve clinical outcomes compared with placebo. However, subset analyses identified statistically significant differences in the OS of motolimod-treated patients on the basis of ISR and in vitro immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.
Clinicaltrials.gov, NCT 01666444
Formation of dense partonic matter in relativistic nucleus-nucleus collisions at RHIC: Experimental evaluation by the PHENIX collaboration
Extensive experimental data from high-energy nucleus-nucleus collisions were
recorded using the PHENIX detector at the Relativistic Heavy Ion Collider
(RHIC). The comprehensive set of measurements from the first three years of
RHIC operation includes charged particle multiplicities, transverse energy,
yield ratios and spectra of identified hadrons in a wide range of transverse
momenta (p_T), elliptic flow, two-particle correlations, non-statistical
fluctuations, and suppression of particle production at high p_T. The results
are examined with an emphasis on implications for the formation of a new state
of dense matter. We find that the state of matter created at RHIC cannot be
described in terms of ordinary color neutral hadrons.Comment: 510 authors, 127 pages text, 56 figures, 1 tables, LaTeX. Submitted
to Nuclear Physics A as a regular article; v3 has minor changes in response
to referee comments. Plain text data tables for the points plotted in figures
for this and previous PHENIX publications are (or will be) publicly available
at http://www.phenix.bnl.gov/papers.htm
Does It Really Work? Re-Assessing the Impact of Pre-Departure Cross-Cultural Training on Expatriate Adjustment
Cultural adjustment is considered to be a prerequisite for expatriate success abroad. One way to enhance adjustment is to provide employees with knowledge and awareness of appropriate norms and behaviors of the host country through cross-cultural training (CCT). This article analyzes the impact of pre-departure CCT on expatriate adjustment and focuses on variations in participation, length and the comprehensiveness of training. Unlike previous research, the study focuses on the effectiveness of pre-departure CCT for non-US employees expatriated to a broad range of host country settings. Employing data from 339 expatriates from 20 German Multinational Corporations (MNCs) the study finds CCT has little if any effect on general, interactional or work setting expatriate adjustment. However, a significant impact of foreign language competence was found for all three dimensions of expatriate adjustment. We used interviews with 20 expatriates to supplement our discussion and provide further implications for practice
Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS
We present the results of a search for new, heavy particles that decay at a
significant distance from their production point into a final state containing
charged hadrons in association with a high-momentum muon. The search is
conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV
and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS
detector operating at the Large Hadron Collider. Production of such particles
is expected in various scenarios of physics beyond the standard model. We
observe no signal and place limits on the production cross-section of
supersymmetric particles in an R-parity-violating scenario as a function of the
neutralino lifetime. Limits are presented for different squark and neutralino
masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final
version to appear in Physics Letters
Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment
This paper describes an analysis of the angular distribution of W->enu and
W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with
the ATLAS detector at the LHC in 2010, corresponding to an integrated
luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and
the missing transverse energy, the W decay angular distribution projected onto
the transverse plane is obtained and analysed in terms of helicity fractions
f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV
and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw
> 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour,
are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017
+/- 0.030, where the first uncertainties are statistical, and the second
include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables,
revised author list, matches European Journal of Physics C versio
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