Assessing the Effect of Cold Weather on Rural Cardiovascular Disease Deaths in Vermont

Objective: To study Vermont mortality and temperature data to determine if there is an increased incidence of cardiovascular disease related death on categorically cold streak days among rural residents. Methods: A retrospective study was conducted using a cohort of Vermont CVD deaths between 2009-2017 subset with corresponding daily temperature data. CVD deaths that occurred on a categorical cold streak day were then identified and analyzed using a Poisson Regression to assess the relationship between ambient temperature changes, CVD mortality, and rurality. Results: As compared to non-cold streak days, risk of CVD mortality was 4% higher on cold streak days (P (P\u3c0.001). However, when controlling for cold streak days, rurality, and tobacco use, the excess risk of CVD deaths was 4.5% lower for each successive year of age. Conclusion: Our findings highlight an increased risk of CVD death among rural residents on cold-streak days. However, further research is needed to understand why CVD death on cold-streak days was less likely with every year increase in age among our sample

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD

Mapping genetic variations to three- dimensional protein structures to enhance variant interpretation: a proposed framework

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods

The Ages of Passive Galaxies in a z = 1.62 Protocluster

We present a study of the relation between galaxy stellar age and mass for 14 members of the $z=1.62$ protocluster IRC 0218, using multiband imaging and HST G102 and G141 grism spectroscopy. Using $UVJ$ colors to separate galaxies into star forming and quiescent populations, we find that at stellar masses $M_* \geq 10^{10.85} M_{\odot}$, the quiescent fraction in the protocluster is $f_Q=1.0^{+0.00}_{-0.37}$, consistent with a $\sim 2\times$ enhancement relative to the field value, $f_Q=0.45^{+0.03}_{-0.03}$. At masses $10^{10.2} M_{\odot} \leq M_* \leq 10^{10.85} M_{\odot}$, $f_Q$ in the cluster is $f_Q=0.40^{+0.20}_{-0.18}$, consistent with the field value of $f_Q=0.28^{+0.02}_{-0.02}$. Using galaxy $D_{n}(4000)$ values derived from the G102 spectroscopy, we find no relation between galaxy stellar age and mass. These results may reflect the impact of merger-driven mass redistribution, which is plausible as this cluster is known to host many dry mergers. Alternately, they may imply that the trend in $f_Q$ in IRC 0218 was imprinted over a short timescale in the protocluster's assembly history. Comparing our results with those of other high-redshift studies and studies of clusters at $z\sim 1$, we determine that our observed relation between $f_Q$ and stellar mass only mildly evolves between $z\sim 1.6$ and $z \sim 1$, and only at stellar masses $M_* \leq 10^{10.85} M_{\odot}$. Both the $z\sim 1$ and $z\sim 1.6$ results are in agreement that the red sequence in dense environments was already populated at high redshift, $z \ge 3$, placing constraints on the mechanism(s) responsible for quenching in dense environments at $z\ge 1.5$Comment: 17 pages, 8 figures, 3 tables. Accepted for publication in Ap

The Intrinsic Characteristics of Galaxies on the SFR– M

We use the deep CANDELS observations in the GOODS North and South fields to revisit the correlations between stellar mass (M-*), star formation rate (SFR) and morphology, and to introduce a fourth dimension, the mass-weighted stellar age, in galaxies at 1.2 < z < 4. We do this by making new measures of M-*, SFR, and stellar age thanks to an improved SED fitting procedure that allows various star formation history for each galaxy. Like others, we find that the slope of the main sequence (MS) of star formation in the (M-*; SFR) plane bends at high mass. We observe clear morphological differences among galaxies across the MS, which also correlate with stellar age. At all redshifts, galaxies that are quenching or quenched, and thus old, have high Sigma(1) (the projected density within the central 1 kpc), while younger, star-forming galaxies span a much broader range of Sigma(1), which includes the high values observed for quenched galaxies, but also extends to much lower values. As galaxies age and quench, the stellar age and the dispersion of Sigma(1) for fixed values of M* shows two different regimes: one at the low-mass end, where quenching might be driven by causes external to the galaxies; the other at the high-mass end, where quenching is driven by internal causes, very likely the mass given the low scatter of Sigma(1) (mass quenching). We suggest that the monotonic increase of central density as galaxies grow is one manifestation of a more general phenomenon of structural transformation that galaxies undergo as they evolve.NASA [NAS5-26555]; NASA through Hubble Fellowship grant - Space Telescope Science Institute [HF2-51368]; Downsbrough familyThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, phase 3 trial

Few treatments with a distinct mechanism of action are available for patients with platinum-refractory advanced or metastatic urothelial carcinoma. We assessed the efficacy and safety of treatment with docetaxel plus either ramucirumab-a human IgG1 VEGFR-2 antagonist-or placebo in this patient population

Tumor-associated mutations in a conserved structural motif alter physical and biochemical properties of human RAD51 recombinase.

Human RAD51 protein catalyzes DNA pairing and strand exchange reactions that are central to homologous recombination and homology-directed DNA repair. Successful recombination/repair requires the formation of a presynaptic filament of RAD51 on ssDNA. Mutations in BRCA2 and other proteins that control RAD51 activity are associated with human cancer. Here we describe a set of mutations associated with human breast tumors that occur in a common structural motif of RAD51. Tumor-associated D149N, R150Q and G151D mutations map to a Schellman loop motif located on the surface of the RecA homology domain of RAD51. All three variants are proficient in DNA strand exchange, but G151D is slightly more sensitive to salt than wild-type (WT). Both G151D and R150Q exhibit markedly lower catalytic efficiency for adenosine triphosphate hydrolysis compared to WT. All three mutations alter the physical properties of RAD51 nucleoprotein filaments, with G151D showing the most dramatic changes. G151D forms mixed nucleoprotein filaments with WT RAD51 that have intermediate properties compared to unmixed filaments. These findings raise the possibility that mutations in RAD51 itself may contribute to genome instability in tumor cells, either directly through changes in recombinase properties, or indirectly through changes in interactions with regulatory proteins

Galaxy Merger Fractions in Two Clusters at z similar to 2 Using the Hubble Space Telescope

We measure the fraction of galaxy-galaxy mergers in two clusters at z similar to 2 using imaging and grism observations from the Hubble Space Telescope. The two galaxy cluster candidates were originally identified as overdensities of objects using deep mid-infrared imaging and observations from the Spitzer Space Telescope, and were subsequently followed up with HST/WFC3 imaging and grism observations. We identify galaxy-galaxy merger candidates using high-resolution imaging with the WFC3 in the F105W, F125W, and F160W bands. Coarse redshifts for the same objects are obtained with grism observations in G102 for the z similar to 1.6 cluster (IRC0222A) and G141 for the z similar to 2 cluster (IRC0222B). Using visual classifications as well as a variety of selection techniques, we measure merger fractions of 11(-3.2)(+8.2) in IRC0222A and 18(-4.5)(+7.8) in IRC0222B. In comparison, we measure a merger fraction of 5.0(-0.8)(+1.1)% for field galaxies at z similar to 2. Our study indicates that the galaxy-galaxy merger fraction in clusters at z similar to 2 is enhanced compared to the field population, but note that more cluster measurements at this epoch are needed to confirm our findings.National Science FoundationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Latent TGF-β–binding protein 4 modifies muscular dystrophy in mice

Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-β–binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-β–binding protein that sequesters TGF-β and regulates its availability for binding to the TGF-β receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-β signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-β signaling and modify outcomes in muscular dystrophy

Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma.

PURPOSE: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown. EXPERIMENTAL DESIGN: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products. RESULTS: Whole exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR were enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy. CONCLUSIONS: Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection