Computer Aided Identification of Small Molecules Disrupting uPAR/α5β1- Integrin Interaction: A New Paradigm for Metastasis Prevention

Disseminated dormant cancer cells can resume growth and eventually form overt metastases, but the underlying molecular mechanism responsible for this change remains obscure. We previously established that cell surface interaction between urokinase receptor (uPAR) and alpha5beta1-integrin initiates a sequel of events, involving MAPK-ERK activation that culminates in progressive cancer growth. We also identified the site on uPAR that binds alpha5beta1-integrin. Disruption of uPAR/integrin interaction blocks ERK activation and forces cancer cells into dormancy.Using a target structure guided computation docking we identified 68 compounds from a diversity library of 13,000 small molecules that were predicted to interact with a previously identified integrin-binding site on uPAR. Of these 68 chemical hits, ten inhibited ERK activation in a cellular assay and of those, 2 compounds, 2-(Pyridin-2-ylamino)-quinolin-8-ol and, 2,2'-(methylimino)di (8-quinolinol) inhibited ERK activation by disrupting the uPAR/integrins interaction. These two compounds, when applied in vivo, inhibited ERK activity and tumor growth and blocked metastases of a model head and neck carcinoma.We showed that interaction between two large proteins (uPAR and alpha5beta1-integrin) can be disrupted by a small molecule leading to profound downstream effects. Because this interaction occurs in cells with high uPAR expression, a property almost exclusive to cancer cells, we expect a new therapy based on these lead compounds to be cancer cell specific and minimally toxic. This treatment, rather than killing disseminated metastatic cells, should induce a protracted state of dormancy and prevent overt metastases

Effects of caffeine on neuromuscular fatigue and performance during high-intensity cycling exercise in moderate hypoxia

Purpose: To investigate the effects of caffeine on performance, neuromuscular fatigue and perception of effort during high-intensity cycling exercise in moderate hypoxia. Methods: Seven adult male participants firstly underwent an incremental exercise test on a cycle ergometer in conditions of acute normobaric hypoxia (fraction inspired oxygen = 0.15) to establish peak power output (PPO). In the following two visits, they performed a time to exhaustion test (78 ± 3% PPO) in the same hypoxic conditions after caffeine ingestion (4 mg kg$^{−1}$) and one after placebo ingestion in a double-blind, randomized, counterbalanced cross-over design. Results: Caffeine significantly improved time to exhaustion by 12%. A significant decrease in subjective fatigue was found after caffeine consumption. Perception of effort and surface electromyographic signal amplitude of the vastus lateralis were lower and heart rate was higher in the caffeine condition when compared to placebo. However, caffeine did not reduce the peripheral and central fatigue induced by high-intensity cycling exercise in moderate hypoxia. Conclusion: The caffeine-induced improvement in time to exhaustion during high-intensity cycling exercise in moderate hypoxia seems to be mediated by a reduction in perception of effort, which occurs despite no reduction in neuromuscular fatigue

Discovery of the lensed quasar system DES J0408-5354

We report the discovery and spectroscopic confirmation of the quad-like lensed quasar system DES J0408-5354 found in the Dark Energy Survey (DES) Year 1 (Y1) data. This system was discovered during a search for DES Y1 strong lensing systems using a method that identified candidates as red galaxies with multiple blue neighbors. DES J0408-5354 consists of a central red galaxy surrounded by three bright (i<20) blue objects and a fourth red object. Subsequent spectroscopic observations using the Gemini South telescope confirmed that the three blue objects are indeed the lensed images of a quasar with redshift z = 2.375, and that the central red object is an early-type lensing galaxy with redshift z = 0.597. DES J0408-5354 is the first quad lensed quasar system to be found in DES and begins to demonstrate the potential of DES to discover and dramatically increase the sample size of these very rare objects

The STRong lensing Insights into the Dark Energy Survey (STRIDES) 2016 follow-up campaign - I. Overview and classification of candidates selected by two techniques

The primary goals of the STRong lensing Insights into the Dark Energy Survey (STRIDES) collaboration are to measure the dark energy equation of state parameter and the free streaming length of dark matter. To this aim, STRIDES is discovering strongly lensed quasars in the imaging data of the Dark Energy Survey and following them up to measure time delays, high resolution imaging, and spectroscopy sufficient to construct accurate lens models. In this paper, we first present forecasts for STRIDES. Then, we describe the STRIDES classification scheme, and give an overview of the Fall 2016 follow-up campaign. We continue by detailing the results of two selection methods, the Outlier Selection Technique and a morphological algorithm, and presenting lens models of a system, which could possibly be a lensed quasar in an unusual configuration. We conclude with the summary statistics of the Fall 2016 campaign. Including searches presented in companion papers (Anguita et al.; Ostrovski et al.), STRIDES followed up 117 targets identifying 7 new strongly lensed systems, and 7 nearly identical quasars (NIQs), which could be confirmed as lenses by the detection of the lens galaxy. 76 candidates were rejected and 27 remain otherwise inconclusive, for a success rate in the range 6-35\%. This rate is comparable to that of previous searches like SQLS even though the parent dataset of STRIDES is purely photometric and our selection of candidates cannot rely on spectroscopic information

A DESGW Search for the Electromagnetic Counterpart to the LIGO/Virgo Gravitational-wave Binary Neutron Star Merger Candidate S190510g

We present the results from a search for the electromagnetic counterpart of the LIGO/Virgo event S190510g using the Dark Energy Camera (DECam). S190510g is a binary neutron star (BNS) merger candidate of moderate significance detected at a distance of 227 ± 92 Mpc and localized within an area of 31 (1166) square degrees at 50% (90%) confidence. While this event was later classified as likely nonastrophysical in nature within 30 hours of the event, our short latency search and discovery pipeline identified 11 counterpart candidates, all of which appear consistent with supernovae following offline analysis and spectroscopy by other instruments. Later reprocessing of the images enabled the recovery of six more candidates. Additionally, we implement our candidate selection procedure on simulated kilonovae and supernovae under DECam observing conditions (e.g., seeing and exposure time) with the intent of quantifying our search efficiency and making informed decisions on observing strategy for future similar events. This is the first BNS counterpart search to employ a comprehensive simulation-based efficiency study. We find that using the current follow-up strategy, there would need to be 19 events similar to S190510g for us to have a 99% chance of detecting an optical counterpart, assuming a GW170817-like kilonova. We further conclude that optimization of observing plans, which should include preference for deeper images over multiple color information, could result in up to a factor of 1.5 reduction in the total number of follow-ups needed for discovery

Evaluating the Psychometric Quality of Social Skills Measures: A Systematic Review

Introduction - Impairments in social functioning are associated with an array of adverse outcomes. Social skills measures are commonly used by health professionals to assess and plan the treatment of social skills difficulties. There is a need to comprehensively evaluate the quality of psychometric properties reported across these measures to guide assessment and treatment planning. Objective - To conduct a systematic review of the literature on the psychometric properties of social skills and behaviours measures for both children and adults. Methods - A systematic search was performed using four electronic databases: CINAHL, PsycINFO, Embase and Pubmed; the Health and Psychosocial Instruments database; and grey literature using PsycExtra and Google Scholar. The psychometric properties of the social skills measures were evaluated against the COSMIN taxonomy of measurement properties using pre-set psychometric criteria. Results - Thirty-Six studies and nine manuals were included to assess the psychometric properties of thirteen social skills measures that met the inclusion criteria. Most measures obtained excellent overall methodological quality scores for internal consistency and reliability. However, eight measures did not report measurement error, nine measures did not report cross-cultural validity and eleven measures did not report criterion validity. Conclusions - The overall quality of the psychometric properties of most measures was satisfactory. The SSBS-2, HCSBS and PKBS-2 were the three measures with the most robust evidence of sound psychometric quality in at least seven of the eight psychometric properties that were appraised. A universal working definition of social functioning as an overarching construct is recommended. There is a need for ongoing research in the area of the psychometric properties of social skills and behaviours instruments