Defining the Defect in F508 del CFTR: A Soluble Problem?

Previously reported crystal structures of CFTR F508 del-NBD1 were determined in the presence of solubilizing mutations. In this issue of Chemistry & Biology, Pissarra et al. (2008) show that partial rescue of the trafficking and gating defects of full-length CFTR occurs in vivo upon recapitulation of the solubilizing F494N/Q637R or F428S/F494N/Q637R substitutions in cis with F508 del

PKS 1510-089: A Head-On View of a Relativistic Jet

The gamma-ray blazar PKS 1510-089 has a highly superluminal milli-arcsecond jet at a position angle (PA) of -28 degrees and an arcsecond jet with an initial PA of 155 degrees. With a PA difference of 177 degrees between the arcsecond and milli-arcsecond jets, PKS 1510-089 is perhaps the most highly misaligned radio jet ever observed and serves as a graphic example of projection effects in a highly beamed relativistic jet. Here we present the results of observations designed to bridge the gap between the milli-arcsecond and arcsecond scales. We find that a previously detected ``counter-feature'' to the arcsecond jet is directly fed by the milli-arcsecond jet. This feature is located 0.3" from the core, corresponding to a de-projected distance of 30 kiloparsecs. The feature appears to be dominated by shocked emission and has an almost perfectly ordered magnetic field along its outside edge. We conclude that it is most likely a shocked bend, viewed end-on, where the jet crosses our line of sight to form the southern arcsecond jet. While the bend appears to be nearly 180 degrees when viewed in projection, we estimate the intrinsic bending angle to be between 12 and 24 degrees. The cause of the bend is uncertain; however, we favor a scenario where the jet is bent after it departs the galaxy, either by ram pressure due to winds in the intracluster medium or simply by the density gradient in the transition to the intergalactic medium.Comment: 8 pages, 4 figures, Accepted for publication in Ap

Top-Charm Associated Production in High Energy e+e−e^+e^- Collisions

The possibility of exploring the flavor changing neutral current $tcZ/tc\gamma$ couplings in the production vertex for the reaction \epem\to t\bar c + \bar tc is examined. Using a model independent parameterization for the effective Lagrangian to describe the most general three-point interactions, production cross sections are found to be relatively small at LEP II, but potentially sizeable at higher energy \epem colliders. The kinematic characteristics of the signal are studied and a set of cuts are devised for clean separation of the signal from background. The resulting sensitivity to anomalous flavor changing couplings at LEP II with an integrated luminosity of $4\times 500$ pb$^{-1}$ is found to be comparable to their present indirect constraints from loop processes, while at higher energy colliders with $0.5-1$ TeV center-of-mass energy and 50-200 fb$^{-1}$ luminosity, one expects to reach a sensitivity at or below the percentage level.Comment: Latex, 22 page

Supersymmetric Extra Dimensions: Gravitino Effects in Selectron Pair Production

We examine the phenomenological consequences of a supersymmetric bulk in the scenario of large extra dimensions. We assume supersymmetry is realized in the bulk and study the interactions of the resulting bulk gravitino Kaluza-Klein (KK) tower of states, with supersymmetry breaking on the brane inducing a light mass for the zero-mode gravitino. We derive the 4-d effective theory, including the couplings of the bulk gravitino KK states to fermions and their scalar superpartners. The virtual exchange of the gravitino KK states in selectron pair production in polarized \epem collisions is then examined. We find that the leading order operator for this exchange is dimension six, in contrast to that of bulk graviton KK exchange which induces a dimension eight operator at lowest order. The resulting kinematic distributions for selectron production are dramatically altered from those in D=4 supersymmetric scenarios, and can lead to a enormous sensitivity to the fundamental higher dimensional Planck scale, of order $20-25\times \sqrt s$.Comment: 48 pg

Experimental validation of computerised models of clustering of platelet glycoprotein receptors that signal via tandem SH2 domain proteins

The clustering of platelet glycoprotein receptors with cytosolic YxxL and YxxM motifs, including GPVI, CLEC-2 and PEAR1, triggers activation via phosphorylation of the conserved tyrosine residues and recruitment of the tandem SH2 (Src homology 2) domain effector proteins, Syk and PI 3-kinase. We have modelled the clustering of these receptors with monovalent, divalent and tetravalent soluble ligands and with transmembrane ligands based on the law of mass action using ordinary differential equations and agent-based modelling. The models were experimentally evaluated in platelets and transfected cell lines using monovalent and multivalent ligands, including novel nanobody-based divalent and tetravalent ligands, by fluorescence correlation spectroscopy. Ligand valency, receptor number, receptor dimerisation, receptor phosphorylation and a cytosolic tandem SH2 domain protein act in synergy to drive receptor clustering. Threshold concentrations of a CLEC-2-blocking antibody and Syk inhibitor act in synergy to block platelet aggregation. This offers a strategy for countering the effect of avidity of multivalent ligands and in limiting off-target effects

Simplified Models for LHC New Physics Searches

This document proposes a collection of simplified models relevant to the design of new-physics searches at the LHC and the characterization of their results. Both ATLAS and CMS have already presented some results in terms of simplified models, and we encourage them to continue and expand this effort, which supplements both signature-based results and benchmark model interpretations. A simplified model is defined by an effective Lagrangian describing the interactions of a small number of new particles. Simplified models can equally well be described by a small number of masses and cross-sections. These parameters are directly related to collider physics observables, making simplified models a particularly effective framework for evaluating searches and a useful starting point for characterizing positive signals of new physics. This document serves as an official summary of the results from the "Topologies for Early LHC Searches" workshop, held at SLAC in September of 2010, the purpose of which was to develop a set of representative models that can be used to cover all relevant phase space in experimental searches. Particular emphasis is placed on searches relevant for the first ~50-500 pb-1 of data and those motivated by supersymmetric models. This note largely summarizes material posted at http://lhcnewphysics.org/, which includes simplified model definitions, Monte Carlo material, and supporting contacts within the theory community. We also comment on future developments that may be useful as more data is gathered and analyzed by the experiments.Comment: 40 pages, 2 figures. This document is the official summary of results from "Topologies for Early LHC Searches" workshop (SLAC, September 2010). Supplementary material can be found at http://lhcnewphysics.or

Establishing a core outcome set for peritoneal dialysis : report of the SONG-PD (standardized outcomes in nephrology-peritoneal dialysis) consensus workshop

Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD

Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities

Background and Aims Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). Approach and Results We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such asTP53(35.5%),KRAS(28.0%),CDKN2A(14.5%), andSMAD4(11.3%), as well as potentially druggable mutations (e.g.,HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). Conclusions Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.Peer reviewe