361 research outputs found
Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification
SummaryObjective/MethodAggrecanase activity, most notably ADAMTS-5, is implicated in pathogenic cartilage degradation. Selective monoclonal antibodies (mAbs) to both ADAMTS-5 and ADAMTS-4 were generated and in vitro, ex vivo and in vivo systems were utilized to assess target engagement, aggrecanase inhibition and modulation of disease-related endpoints with the intent of selecting a candidate for clinical development in osteoarthritis (OA).ResultsStructural mapping predicts the most potent mAbs employ a unique mode of inhibition by cross-linking the catalytic and disintegrin domains. In a surgical mouse model of OA, both ADAMTS-5 and ADAMTS-4-specific mAbs penetrate cartilage following systemic administration, demonstrating access to the anticipated site of action. Structural disease modification and associated alleviation of pain-related behavior were observed with ADAMTS-5 mAb treatment. Treatment of human OA cartilage demonstrated a preferential role for ADAMTS-5 inhibition over ADAMTS-4, as measured by ARGS neoepitope release in explant cultures. ADAMTS-5 mAb activity was most evident in a subset of patient-derived tissues and suppression of ARGS neoepitope release was sustained for weeks after a single treatment in human explants and in cynomolgus monkeys, consistent with high affinity target engagement and slow ADAMTS-5 turnover.ConclusionThis data supports a hypothesis set forth from knockout mouse studies that ADAMTS-5 is the major aggrecanase involved in cartilage degradation and provides a link between a biological pathway and pharmacology which translates to human tissues, non-human primate models and points to a target OA patient population. Therefore, a humanized ADAMTS-5-selective monoclonal antibody (GSK2394002) was progressed as a potential OA disease modifying therapeutic
Optical Sum Rule in Finite Bands
In a single finite electronic band the total optical spectral weight or
optical sum carries information on the interactions involved between the charge
carriers as well as on their band structure. It varies with temperature as well
as with impurity scattering. The single band optical sum also bears some
relationship to the charge carrier kinetic energy and, thus, can potentially
provide useful information, particularly on its change as the charge carriers
go from normal to superconducting state. Here we review the considerable
advances that have recently been made in the context of high oxides, both
theoretical and experimental.Comment: Review article accepted for publication in J. Low Temp. Phys. 29
pages, 33 figure
Nonperturbative renormalization group approach to frustrated magnets
This article is devoted to the study of the critical properties of classical
XY and Heisenberg frustrated magnets in three dimensions. We first analyze the
experimental and numerical situations. We show that the unusual behaviors
encountered in these systems, typically nonuniversal scaling, are hardly
compatible with the hypothesis of a second order phase transition. We then
review the various perturbative and early nonperturbative approaches used to
investigate these systems. We argue that none of them provides a completely
satisfactory description of the three-dimensional critical behavior. We then
recall the principles of the nonperturbative approach - the effective average
action method - that we have used to investigate the physics of frustrated
magnets. First, we recall the treatment of the unfrustrated - O(N) - case with
this method. This allows to introduce its technical aspects. Then, we show how
this method unables to clarify most of the problems encountered in the previous
theoretical descriptions of frustrated magnets. Firstly, we get an explanation
of the long-standing mismatch between different perturbative approaches which
consists in a nonperturbative mechanism of annihilation of fixed points between
two and three dimensions. Secondly, we get a coherent picture of the physics of
frustrated magnets in qualitative and (semi-) quantitative agreement with the
numerical and experimental results. The central feature that emerges from our
approach is the existence of scaling behaviors without fixed or pseudo-fixed
point and that relies on a slowing-down of the renormalization group flow in a
whole region in the coupling constants space. This phenomenon allows to explain
the occurence of generic weak first order behaviors and to understand the
absence of universality in the critical behavior of frustrated magnets.Comment: 58 pages, 15 PS figure
Low-Cycle Fatigue of Ultra-Fine-Grained Cryomilled 5083 Aluminum Alloy
The cyclic deformation behavior of cryomilled (CM) AA5083 alloys was compared to that of conventional AA5083-H131. The materials studied were a 100Â pct CM alloy with a Gaussian grain size average of 315Â nm and an alloy created by mixing 85Â pct CM powder with 15Â pct unmilled powder before consolidation to fabricate a plate with a bimodal grain size distribution with peak averages at 240Â nm and 1.8Â ÎŒm. Although the ultra-fine-grain (UFG) alloys exhibited considerably higher tensile strengths than those of the conventional material, the results from plastic-strain-controlled low-cycle fatigue tests demonstrate that all three materials exhibit identical fatigue lives across a range of plastic strain amplitudes. The CM materials exhibited softening during the first cycle, similar to other alloys produced by conventional powder metallurgy, followed by continual hardening to saturation before failure. The results reported in this study show that fatigue deformation in the CM material is accompanied by slight grain growth, pinning of dislocations at the grain boundaries, and grain rotation to produce macroscopic slip bands that localize strain, creating a single dominant fatigue crack. In contrast, the conventional alloy exhibits a cell structure and more diffuse fatigue damage accumulation
Scale-free static and dynamical correlations in melts of monodisperse and Flory-distributed homopolymers: A review of recent bond-fluctuation model studies
It has been assumed until very recently that all long-range correlations are
screened in three-dimensional melts of linear homopolymers on distances beyond
the correlation length characterizing the decay of the density
fluctuations. Summarizing simulation results obtained by means of a variant of
the bond-fluctuation model with finite monomer excluded volume interactions and
topology violating local and global Monte Carlo moves, we show that due to an
interplay of the chain connectivity and the incompressibility constraint, both
static and dynamical correlations arise on distances . These
correlations are scale-free and, surprisingly, do not depend explicitly on the
compressibility of the solution. Both monodisperse and (essentially)
Flory-distributed equilibrium polymers are considered.Comment: 60 pages, 49 figure
Heavy quarkonium: progress, puzzles, and opportunities
A golden age for heavy quarkonium physics dawned a decade ago, initiated by
the confluence of exciting advances in quantum chromodynamics (QCD) and an
explosion of related experimental activity. The early years of this period were
chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in
2004, which presented a comprehensive review of the status of the field at that
time and provided specific recommendations for further progress. However, the
broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles
could only be partially anticipated. Since the release of the YR, the BESII
program concluded only to give birth to BESIII; the -factories and CLEO-c
flourished; quarkonium production and polarization measurements at HERA and the
Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the
deconfinement regime. All these experiments leave legacies of quality,
precision, and unsolved mysteries for quarkonium physics, and therefore beg for
continuing investigations. The plethora of newly-found quarkonium-like states
unleashed a flood of theoretical investigations into new forms of matter such
as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the
spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b},
and b\bar{c} bound states have been shown to validate some theoretical
approaches to QCD and highlight lack of quantitative success for others. The
intriguing details of quarkonium suppression in heavy-ion collisions that have
emerged from RHIC have elevated the importance of separating hot- and
cold-nuclear-matter effects in quark-gluon plasma studies. This review
systematically addresses all these matters and concludes by prioritizing
directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K.
Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D.
Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A.
Petrov, P. Robbe, A. Vair
Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits
Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)
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