Effect of scavenger receptor BI antagonist ITX5061 in patients with hepatitis C virus infection undergoing liver transplantation

Hepatitis C virus (HCV) entry inhibitors have been hypothesized to prevent infection of the liver after transplantation. ITX5061 is a Scavenger Receptor B-I (SR-BI) antagonist that blocks HCV entry and infection in vitro. We assessed the safety and efficacy of ITX5061 to limit HCV infection of the graft. The study included 23 HCV infected patients undergoing liver transplantation. The first 13 "control" patients did not receive drug. The subsequent 10 patients received ITX5061 150 mg immediately pre- and post-transplant, and daily for 1 week thereafter. ITX5061 pharmacokinetics and plasma HCV RNA were quantified. Viral genetic diversity was measured by ultradeep pyrosequencing. ITX5061 was well tolerated with measurable plasma concentrations during therapy. Whilst the median HCV RNA reduction was greater in ITX treated patients at all time points in the first week after transplantation there was no difference in the overall change in the area over the HCV RNA curve in the 7-day treatment period. However, in genotype 1 infected patients treatment was associated with a sustained reduction in HCV RNA levels compared to the control group (area over the HCV RNA curve analysis, p=0.004). Ultradeep pyrosequencing revealed a complex and evolving pattern of HCV variants infecting the graft during the first week. ITX5061 significantly limited viral evolution where the median divergence between day 0 and day 7 was 3.5% in the control group compared to 0.1% in the treated group.CONCLUSIONS: ITX5061 reduces plasma HCV RNA post transplant notably in genotype 1 infected patients and slows viral evolution. Following liver transplantation the likely contribution of extrahepatic reservoirs of HCV necessitates combining entry inhibitors such as ITX5061 with inhibitors of replication in future studies. Clinicaltrials.gov NCT01292824. This article is protected by copyright. All rights reserved.</p

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome

Purpose: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). Methods: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. Results: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. Conclusion: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.16-17/10/Newlife - The Charity for Disabled Children FS/13/32/30069/BHF_/British Heart Foundation/United Kingdom 72160007/Chile's National Commission for Scientific and Technological Research MR/K011154/1/MRC_/Medical Research Council/United Kingdom WT_/Wellcome Trust/United Kingdompre-prin

Fused 3-Hydroxy-3-trifluoromethylpyrazoles Inhibit Mutant Huntingtin Toxicity

[Image: see text] Here, we describe the selection and optimization of a chemical series active in both a full-length and a fragment-based Huntington’s disease (HD) assay. Twenty-four thousand small molecules were screened in a phenotypic HD assay, identifying a series of compounds bearing a 3-hydroxy-3-trifluoromethylpyrazole moiety as able to revert the toxicity induced by full-length mutant Htt by up to 50%. A chemical exploration around the series led to the identification of compound 4f, which demonstrated to be active in a Htt171–82Q rat primary striatal neuron assay and a PC12-Exon-1 based assay. This compound was selected for testing in R6/2 mice, in which it was well-tolerated and showed a positive effect on body weight and a positive trend in preventing ventricular volume enlargment. These studies provide strong rationale for further testing the potential benefits of 3-hydroxy-3-trifluoromethylpyrazoles in treating HD

ALICE: Physics Performance Report, Volume I

ALICE is a general-purpose heavy-ion experiment designed to study the physics of strongly interacting matter and the quark-gluon plasma in nucleus-nucleus collisions at the LHC. It currently includes more than 900 physicists and senior engineers, from both nuclear and high-energy physics, from about 80 institutions in 28 countries. The experiment was approved in February 1997. The detailed design of the different detector systems has been laid down in a number of Technical Design Reports issued between mid-1998 and the end of 2001 and construction has started for most detectors. Since the last comprehensive information on detector and physics performance was published in the ALICE Technical Proposal in 1996, the detector as well as simulation, reconstruction and analysis software have undergone significant development. The Physics Performance Report (PPR) will give an updated and comprehensive summary of the current status and performance of the various ALICE subsystems, including updates to the Technical Design Reports, where appropriate, as well as a description of systems which have not been published in a Technical Design Report. The PPR will be published in two volumes. The current Volume I contains: 1. a short theoretical overview and an extensive reference list concerning the physics topics of interest to ALICE, 2. relevant experimental conditions at the LHC, 3. a short summary and update of the subsystem designs, and 4. a description of the offline framework and Monte Carlo generators. Volume II, which will be published separately, will contain detailed simulations of combined detector performance, event reconstruction, and analysis of a representative sample of relevant physics observables from global event characteristics to hard processes

The Truth Machine of Involuntary Movement: FPGA Based Cortico-muscular Analysis for Fall Prevention

Voluntary movements are managed by movement related potentials (MRPs) which are brain activity patterns detectable even 500ms before the movement itself. The cortico-muscular matching between brain (EEG) and muscles (EMG) activity allows the assessment of the intentionality of the performed movement. Basing on this knowledge, a real-time algorithm for falling risk prediction based on EMG/EEG coupled analysis is presented. The system architecture involves 8 EMG (limbs) and 8 EEG (motor-cortex) channels wirelessly collected by a FPGA (gateway) that contextually performs the real-time processing based on an event triggered time-frequency approach. The digital architecture is validated on the FPGA to determine resources utilization, related timing constraints and performance figures of a dedicated real-time ASIC implementation for wearable applications. The system resource utilization is 85.95% ALMs, 43283 ALUTs, 73.0% registers, 9.9% block memory of an Altera Cyclone V FPGA. The processing latency is lower than 1ms and the output are available in 56ms, respecting the time limit of 300ms. Outputs enables decision-taking for feedback delivering

Electrodynamic tethers for deorbiting applications

In this paper the de-orbiting performance of various tether configurations have been studied and compared with each other. Three different configurations have been analyzed. An insulated conducting tether terminated with a balloon at the upper end (ITB), a bare tether only (BTO) and a bare tether terminated with a balloon (BTB). The drag forces obtained with the various systems have been computed taking into account the tether equivalent electric circuit which includes, besides the ohmic resistance of the wire, the effects of the plasma sheaths resulting from the interaction with the ionospheric plasma. The orbit decay times for a spacecraft of 500 kg mass equipped with a 5 km long tether, in the three different configurations, have been computed by using a simple model of the average ionospheric density profile. The BTB configuration turns out to be the one which exhibits the best de-orbiting performance. The total de-orbiting time from an altitude of 1300 km down to 200 km is 23 days for a system BTB, 32 days for ITB and 66 days for BTO

Cortical reactive balance responses to unexpected slippages while walking: A pilot study

Understanding how the human brain cortex behaves when the dynamical balance is unexpectedly challenged can be useful to enable fall prevention strategies during daily activities. In this respect, we designed and tested a novel methodological approach to early detect modifications of the scalp-level signals when steady walking is perturbed.Four young adults were asked to manage unexpected bilateral slippages while steadily walking at their self-selected speed. Lower limb kinematics, electromyographic (EMG) and electroencephalographic (EEG; 13 channels from motor and sensory-motor cortex areas) signals were synchronously recorded.EMG signals from Vastus Medialis (both sides) were used to trigger the analysis of the EEG before and after the perturbation onset. Cortical activity was then assessed and compared pre vs. post perturbation. Specifically, for each gait cycle, the rate of variation of the EEG power spectrum density, named m, was used to describe the cortical responsiveness in five bands of interests: (4-7 Hz), α (8-12 Hz), β I, β II, β III rhythms (13-15, 15-20, 18-28 Hz).Results revealed a sharp increment of m early after the onset of the perturbation (perturbed step) compared to steady locomotion, for all rhythms. This cortical behavior disappeared during the recovery step.This study promisingly supports the evidence that the proposed approach can distinguish between steady walking and early reactive balance recovery, paving the way for the EEG-based monitoring of the fall risk during daily activities