Differences in somatic TP53 mutation type in breast tumors by race and receptor status

Purpose: Somatic driver mutations in TP53 are associated with triple-negative breast cancer (TNBC) and poorer outcomes. Breast cancers in women of African ancestry (AA) are more likely to be TNBC and have somatic TP53 mutations than cancers in non-Hispanic White (NHW) women. Missense driver mutations in TP53 have varied functional impact including loss-of-function (LOF) or gain-of-function (GOF) activity, and dominant negative (DNE) effects. We aimed to determine if there were differences in somatic TP53 mutation types by patient ancestry or TNBC status. Methods: We identified breast cancer datasets with somatic TP53 mutation data, ancestry, age, and hormone receptor status. Mutations were classified for functional impact using published data and type of mutation. We assessed differences using Fisher’s exact test. Results: From 96 breast cancer studies, we identified 2964 women with somatic TP53 mutations: 715 (24.1%) Asian, 258 (8.7%) AA, 1931 (65.2%) NHW, and 60 (2%) Latina. The distribution of TP53 mutation type was similar by ancestry. However, 35.8% of tumors from NHW individuals had GOF mutations compared to 29% from AA individuals (p = 0.04). Mutations with DNE activity were positively associated with TNBC (OR 1.37, p = 0.03) and estrogen receptor (ER) negative status (OR 1.38; p = 0.005). Conclusions: Somatic TP53 mutation types did not differ by ancestry overall, but GOF mutations were more common in NHW women than AA women. ER-negative and TNBC tumors are less likely to have DNE+ TP53 mutations which could reflect biological processes. Larger cohorts and functional studies are needed to further elucidate these findings

Grain Surface Models and Data for Astrochemistry

AbstractThe cross-disciplinary field of astrochemistry exists to understand the formation, destruction, and survival of molecules in astrophysical environments. Molecules in space are synthesized via a large variety of gas-phase reactions, and reactions on dust-grain surfaces, where the surface acts as a catalyst. A broad consensus has been reached in the astrochemistry community on how to suitably treat gas-phase processes in models, and also on how to present the necessary reaction data in databases; however, no such consensus has yet been reached for grain-surface processes. A team of ∼25 experts covering observational, laboratory and theoretical (astro)chemistry met in summer of 2014 at the Lorentz Center in Leiden with the aim to provide solutions for this problem and to review the current state-of-the-art of grain surface models, both in terms of technical implementation into models as well as the most up-to-date information available from experiments and chemical computations. This review builds on the results of this workshop and gives an outlook for future directions

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar disorder working group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and to the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. The views expressed are those of the authors and not necessarily those of any funding or regulatory body. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org ) hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu).Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P<1x10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (GWS, p < 5x10-8) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene-sets including regulation of insulin secretion and endocannabinoid signaling. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr. Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs. Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M O'Neil and Betty C Lynch

Spatial patterns in markers of contaminant exposure, glucose and glycogen metabolism, and immunological response in juvenile winter flounder (Pseudopleuronectes americanus)

Inshore winter flounder (Pseudopleuronectes americanus) populations in NY, USA have reached record low numbers in recent years, and recruitment into the fishery appears to be limited by survival of post-settlement juvenile fish. In order to identify cellular pathways associated with site-specific variation in condition and mortality, we examined differential mRNA expression in juvenile winter flounder collected from six different bays across a gradient in human population density and sewage inputs. Illumina sequencing of pooled samples of flounder from contrasting degraded sites and less impacted sites was used to guide our choice of targets for qPCR analysis. 253 transcripts of > 100 bp were differentially expressed, with 60% showing strong homology to mostly teleost sequences within the NCBI database. Based on these data, transcripts representing nine genes of interest associated with contaminant exposure, immune response and glucose and glycogen metabolism were examined by qPCR in individual flounder from each site. Statistically significant site-specific differences were observed in expression of all but one gene, although patterns in expression were complex with only one, (vitellogenin) demonstrating a west to east gradient consistent with known loadings of municipal sewage effluent. Principal components analysis (PCA) identified relationships among the genes evaluated. Our data indicate that juvenile winter flounder are responding to estrogenic chemicals in more urbanized coastal bays, and suggests potential mechanistic links between immune response, contaminant exposure and energy metabolism

Tuataras and salamanders show that walking and running mechanics are ancient features of tetrapod locomotion

The lumbering locomotor behaviours of tuataras and salamanders are the best examples of quadrupedal locomotion of early terrestrial vertebrates. We show they use the same walking (out-of-phase) and running (in-phase) patterns of external mechanical energy fluctuations of the centre-of-mass known in fast moving (cursorial) animals. Thus, walking and running centre-of-mass mechanics have been a feature of tetrapods since quadrupedal locomotion emerged over 400 million years ago. When walking, these sprawling animals save external mechanical energy with the same pendular effectiveness observed in cursorial animals. However, unlike cursorial animals (that change footfall patterns and mechanics with speed), tuataras and salamanders use only diagonal couplet gaits and indifferently change from walking to running mechanics with no significant change in total mechanical energy. Thus, the change from walking to running is not related to speed and the advantage of walking versus running is unclear. Furthermore, lumbering mechanics in primitive tetrapods is reflected in having total mechanical energy driven by potential energy (rather than kinetic energy as in cursorial animals) and relative centre-of-mass displacements an order of magnitude greater than cursorial animals. Thus, large vertical displacements associated with lumbering locomotion in primitive tetrapods may preclude their ability to increase speed

Validation of ACE-FTS version 3.5 NO<i>y</i> species profiles using correlative satellite measurements

The ACE-FTS (Atmospheric Chemistry Experiment-Fourier Transform Spectrometer) instrument on the Canadian SCISAT satellite, which has been in operation for over 12 years, has the capability of deriving stratospheric profiles of many of the NO (N+NO+NO+NO+2×NO+HNO+HNO+ClONO+BrONO) species. Version 2.2 of ACE-FTS NO, NO, HNO, NO, and ClONO has previously been validated, and this study compares the most recent version (v3.5) of these five ACE-FTS products to spatially and temporally coincident measurements from other satellite instruments-GOMOS, HALOE, MAESTRO, MIPAS, MLS, OSIRIS, POAM III, SAGE III, SCIAMACHY, SMILES, and SMR. For each ACE-FTS measurement, a photochemical box model was used to simulate the diurnal variations of the NOy species and the ACE-FTS measurements were scaled to the local times of the coincident measurements. The comparisons for all five species show good agreement with correlative satellite measurements. For NO in the altitude range of 25-50 km, ACE-FTS typically agrees with correlative data to within .10 %. Instrumentaveraged mean relative differences are approximately.10% at 30-40 km for NO, within-7% at 8-30 km for HNO, better than.7% at 21-34 km for local morning NO, and better than.8% at 21-34 km for ClONO. Where possible, the variations in the mean differences due to changes in the comparison local time and latitude are also discussed.©2016 Author(s).The Atmospheric Chemistry Experiment is a Canadian-led mission mainly supported by the CSA. Odin is a Swedish-led satellite project funded jointly by Sweden (Swedish National Space Board), Canada (CSA), France (Centre National d'Etudes Spatiales), and Finland (Tekes), with support by the third-party mission programme of the European Space Agency (ESA). Coauthor CER was funded by NASA grant NNX14AH54G. The University of Bremen team was funded in parts by the DLR Space Agency (Germany) and by the University and State of Bremen.Peer Reviewe