Photocrosslinking Activity-Based Probes for Ubiquitin RING E3 Ligases

Summary: Activity-based protein profiling is an invaluable technique for studying enzyme biology and facilitating the development of therapeutics. Ubiquitin E3 ligases (E3s) are one of the largest enzyme families and regulate a host of (patho)physiological processes. The largest subtype are the RING E3s of which there are >600 members. RING E3s have adaptor-like activity that can be subject to diverse regulatory mechanisms and have become attractive drug targets. Activity-based probes (ABPs) for measuring RING E3 activity do not exist. Here we re-engineer ubiquitin-charged E2 conjugating enzymes to produce photocrosslinking ABPs. We demonstrate activity-dependent profiling of two divergent cancer-associated RING E3s, RNF4 and c-Cbl, in response to their native activation signals. We also demonstrate profiling of endogenous RING E3 ligase activation in response to epidermal growth factor (EGF) stimulation. These photocrosslinking ABPs should advance E3 ligase research and the development of selective modulators against this important class of enzymes

Locating Community among People with Schizophrenia living in a Diverse Urban Environment

Increasing the community participation of people with severe mental illness is a primary goal of recovery-oriented services. Despite this emphasis, the construct of community remains understudied and poorly articulated. This study provides an in-depth examination of the experiences, beliefs, behaviors, and spaces that constitute community participation for a highly diverse group of people with schizophrenia who are urban dwellers. An in-depth, longitudinal qualitative design was employed with 30 individuals with schizophrenia residing in inner-city neighborhoods in Canada’s largest city. For these individuals, community participation is a dynamic process, shaped by illness and non-illness-associated social relationships and spaces, self-concept, and the resources accessible to the person. The complexity of factors that are associated with “community” for people with schizophrenia, with overlays of culture, poverty, victimization, and discrimination, calls for a critical examination of the community rhetoric employed in practice and policy contexts

Commissioning of the CMS High Level Trigger

The CMS experiment will collect data from the proton-proton collisions delivered by the Large Hadron Collider (LHC) at a centre-of-mass energy up to 14 TeV. The CMS trigger system is designed to cope with unprecedented luminosities and LHC bunch-crossing rates up to 40 MHz. The unique CMS trigger architecture only employs two trigger levels. The Level-1 trigger is implemented using custom electronics, while the High Level Trigger (HLT) is based on software algorithms running on a large cluster of commercial processors, the Event Filter Farm. We present the major functionalities of the CMS High Level Trigger system as of the starting of LHC beams operations in September 2008. The validation of the HLT system in the online environment with Monte Carlo simulated data and its commissioning during cosmic rays data taking campaigns are discussed in detail. We conclude with the description of the HLT operations with the first circulating LHC beams before the incident occurred the 19th September 2008

Production of Scalar Higgs Bosons Associated with Z0Z^0 Boson at the CERN LHC in the MSSM

We investigate the associated production of a scalar Higgs boson ($h^0$ or $H^0$) with $Z^0$ boson in the minimal supersymmetric extension of the standard model (MSSM) at the CERN Large Hadron Collider (LHC), including the contributions from $b\bar{b}$ annihilation at the tree level and gluon fusion via quark and squark loops. We quantitatively analyze the total cross sections in the mSUGRA scenario. For the production of $h^0$ associated with $Z^0$, we find that in most of the parameter regions, the contributions from initial $b\bar{b}$ and $gg$ are at a level of one percent of the total cross section and therefore almost insignificant. For the production of $H^0$ associated with $Z^0$, the contributions from $b\bar{b}$ channel can be much larger than those from light quark initial states. Especially for large $\tan\beta$, the increment can reach about one order of magnitude. Thus, when considering the associated production of $H^0$ and $Z^0$ at the LHC, the contributions from $b\bar{b}$ annihilation should be taken into account seriously.Comment: 19 pages, 8 figures, RevTeX4; one reference added, minor changes, conclusion unchanged; Journal-ref adde

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Search for the standard model Higgs boson in the H to ZZ to 2l 2nu channel in pp collisions at sqrt(s) = 7 TeV

A search for the standard model Higgs boson in the H to ZZ to 2l 2nu decay channel, where l = e or mu, in pp collisions at a center-of-mass energy of 7 TeV is presented. The data were collected at the LHC, with the CMS detector, and correspond to an integrated luminosity of 4.6 inverse femtobarns. No significant excess is observed above the background expectation, and upper limits are set on the Higgs boson production cross section. The presence of the standard model Higgs boson with a mass in the 270-440 GeV range is excluded at 95% confidence level.Comment: Submitted to JHE