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 $T_c$ 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 100 pct CM alloy with a Gaussian grain size average of 315 nm and an alloy created by mixing 85 pct CM powder with 15 pct unmilled powder before consolidation to fabricate a plate with a bimodal grain size distribution with peak averages at 240 nm and 1.8 μm. 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 $\xi$ 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 $r \gg \xi$. 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 $B$-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)