Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Molecular analysis of Mycobacterium isolates from extrapulmonary specimens obtained from patients in Mexico

<p>Abstract</p> <p>Background</p> <p>Little information is available on the molecular epidemiology in Mexico of <it>Mycobacterium </it>species infecting extrapulmonary sites in humans. This study used molecular methods to determine the <it>Mycobacterium </it>species present in tissues and body fluids in specimens obtained from patients in Mexico with extrapulmonary disease.</p> <p>Methods</p> <p>Bacterial or tissue specimens from patients with clinical or histological diagnosis of extrapulmonary tuberculosis were studied. DNA extracts from 30 bacterial cultures grown in Löwenstein Jensen medium and 42 paraffin-embedded tissues were prepared. Bacteria were cultured from urine, cerebrospinal fluid, pericardial fluid, gastric aspirate, or synovial fluid samples. Tissues samples were from lymph nodes, skin, brain, vagina, and peritoneum. The DNA extracts were analyzed by PCR and by line probe assay (INNO-LiPA MYCOBACTERIA v2. Innogenetics NV, Gent, Belgium) in order to identify the <it>Mycobacterium </it>species present. DNA samples positive for <it>M. tuberculosis </it>complex were further analyzed by PCR and line probe assay (INNO-LiPA Rif.TB, Innogenetics NV, Gent, Belgium) to detect mutations in the <it>rpo</it>B gene associated with rifampicin resistance.</p> <p>Results</p> <p>Of the 72 DNA extracts, 26 (36.1%) and 23 (31.9%) tested positive for <it>Mycobacterium species </it>by PCR or line probe assay, respectively. In tissues, <it>M. tuberculosis </it>complex and <it>M. genus </it>were found in lymph nodes, and <it>M. genus </it>was found in brain and vagina specimens. In body fluids, <it>M. tuberculosis </it>complex was found in synovial fluid. <it>M. gordonae</it>, <it>M. smegmatis</it>, <it>M. kansasii</it>, <it>M. genus</it>, <it>M. fortuitum/M. peregrinum </it>complex and <it>M. tuberculosis </it>complex were found in urine. <it>M. chelonae/M. abscessus </it>was found in pericardial fluid and <it>M. kansasii </it>was found in gastric aspirate. Two of <it>M. tuberculosis </it>complex isolates were also PCR and LiPA positive for the <it>rpo</it>B gene. These two isolates were from lymph nodes and were sensitive to rifampicin.</p> <p>Conclusion</p> <p>1) We describe the <it>Mycobacterium </it>species diversity in specimens derived from extrapulmonary sites in symptomatic patients in Mexico; 2) Nontuberculous mycobacteria were found in a considerable number of patients; 3) Genotypic rifampicin resistance in <it>M. tuberculosis </it>complex infections in lymph nodes was not found.</p

Characterizing associations and SNP-environment interactions for GWAS-identified prostate cancer risk markers--results from BPC3.

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, whether these associations can be consistently replicated, vary with disease aggressiveness (tumor stage and grade) and/or interact with non-genetic potential risk factors or other SNPs is unknown. We therefore genotyped 39 SNPs from regions identified by several prostate cancer GWAS in 10,501 prostate cancer cases and 10,831 controls from the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). We replicated 36 out of 39 SNPs (P-values ranging from 0.01 to 10-28). Two SNPs located near KLK3 associated with PSA levels showed differential association with Gleason grade (rs2735839, P = 0.0001 and rs266849, P = 0.0004; case-only test), where the alleles associated with decreasing PSA levels were inversely associated with low-grade (as defined by Gleason grade <8) tumors but positively associated with high-grade tumors. No other SNP showed differential associations according to disease stage or grade. We observed no effect modification by SNP for association with age at diagnosis, family history of prostate cancer, diabetes, BMI, height, smoking or alcohol intake. Moreover, we found no evidence of pair-wise SNP-SNP interactions. While these SNPs represent new independent risk factors for prostate cancer, we saw little evidence for effect modification by other SNPs or by the environmental factors examined

Valuing health states: is the MACBETH approach useful for valuing EQ-5D-3L health states?

Background Quality Adjusted Life Years (QALYs) are a key outcome measure widely used within health technology assessment and health service research studies. QALYs combine quantity and quality of life, with quality of life calculations relying on the value of distinct health states. Such health states’ values capture the preferences of a population and have been typically built through numerical elicitation methods. Evidence points to these value scores being influenced by methods in use and individuals reporting cognitive difficulties in eliciting their preferences. Evidence from other areas has further suggested that individuals may prefer using distinct elicitation techniques and that this preference can be influenced by their numeracy. In this study we explore the use of the MACBETH (Measuring Attractiveness by a Categorical Based Evaluation Technique) non-numerical preference elicitation approach for health states’ evaluation. Methods A new protocol for preference elicitation based on MACBETH (only requiring qualitative judgments) was developed and tested within a web survey format. A sample of the Portuguese general population (n=243) valued 25 EQ-5D-3L health states with the MACBETH protocol and with a variant of the time trade-off (TTO) protocol, for comparison purposes and for understanding respondents’ preference for distinct protocols and differences in inconsistent evaluations. Respondents answered to a short numeracy test, and basic socio-economic information collected. Results Results show that the mean values derived from MACBETH and the TTO variant are strongly correlated; however, there are substantial differences for several health states’ values. Large and similar numbers of logical inconsistencies were found in respondents’ answers with both methods. Participants with higher levels of numeracy according to the test preferred expressing value judgments with MACBETH, while participants with lower levels were mostly indifferent to both methods. Higher correlations between MACBETH and TTO variant evaluations were observed for individuals with higher numeracy. Conclusion Results suggest that it is worth researching the use of non-numerical preference elicitation methods. Numeracy tests more appropriate for preference elicitation when no explicit considerations of uncertainty are made need to be explored and used. Further behavioural research is needed to fully understand the potential for using these methods in distinct settings (e.g. in different evaluation contexts and in face-to-face and non-face-to-face environments), as well as to explore the effect of literacy on assessments and on respondents’ preferences.UID/MULTI/4066/2016info:eu-repo/semantics/publishedVersio

Control of Bone Mass and Remodeling by PTH Receptor Signaling in Osteocytes

Osteocytes, former osteoblasts buried within bone, are thought to orchestrate skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control skeletal homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and -independent mechanisms, respectively

Combined Analysis of Murine and Human Microarrays and ChIP Analysis Reveals Genes Associated with the Ability of MYC To Maintain Tumorigenesis

The MYC oncogene has been implicated in the regulation of up to thousands of genes involved in many cellular programs including proliferation, growth, differentiation, self-renewal, and apoptosis. MYC is thought to induce cancer through an exaggerated effect on these physiologic programs. Which of these genes are responsible for the ability of MYC to initiate and/or maintain tumorigenesis is not clear. Previously, we have shown that upon brief MYC inactivation, some tumors undergo sustained regression. Here we demonstrate that upon MYC inactivation there are global permanent changes in gene expression detected by microarray analysis. By applying StepMiner analysis, we identified genes whose expression most strongly correlated with the ability of MYC to induce a neoplastic state. Notably, genes were identified that exhibited permanent changes in mRNA expression upon MYC inactivation. Importantly, permanent changes in gene expression could be shown by chromatin immunoprecipitation (ChIP) to be associated with permanent changes in the ability of MYC to bind to the promoter regions. Our list of candidate genes associated with tumor maintenance was further refined by comparing our analysis with other published results to generate a gene signature associated with MYC-induced tumorigenesis in mice. To validate the role of gene signatures associated with MYC in human tumorigenesis, we examined the expression of human homologs in 273 published human lymphoma microarray datasets in Affymetrix U133A format. One large functional group of these genes included the ribosomal structural proteins. In addition, we identified a group of genes involved in a diverse array of cellular functions including: BZW2, H2AFY, SFRS3, NAP1L1, NOLA2, UBE2D2, CCNG1, LIFR, FABP3, and EDG1. Hence, through our analysis of gene expression in murine tumor models and human lymphomas, we have identified a novel gene signature correlated with the ability of MYC to maintain tumorigenesis

Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations

Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type) and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition and the enhanced stabilization of the active kinase form. The results of this study reconcile current experimental data with insights from theoretical approaches, pointing to general mechanistic aspects of activating transitions in protein kinases