Late-Stage Molecular Editing Enabled by Ketone Chain-Walking Isomerization

Herein, a method for the isomerization of ketones in a manner akin to the chain-walking reaction of alkenes is described. Widely available and inexpensive pyrrolidine and elemental sulfur are deployed as catalysts to achieve this reversible transformation. Key to the utility of this approach was the elucidation of a stereochemical model to determine the thermodynamically favored product of the reaction and the kinetic selectivity observed. With the distinct selectivity profile of our ketone chain-walking process, the isomerization of various steroids was demonstrated to rapidly access novel steroids with "unnatural" oxidation patterns.ISSN:0002-7863ISSN:1520-512

SPIRITS 15c and SPIRITS 14buu: Two Obscured Supernovae in the Nearby Star-Forming Galaxy IC 2163

SPIRITS---SPitzer InfraRed Intensive Transients Survey---is an ongoing survey of nearby galaxies searching for infrared (IR) transients with Spitzer/IRAC. We present the discovery and follow-up observations of one of our most luminous ($M_{[4.5]} = -17.1\pm0.4$ mag, Vega) and red ($[3.6] - [4.5] = 3.0 \pm 0.2$ mag) transients, SPIRITS 15c. The transient was detected in a dusty spiral arm of IC 2163 ($D\approx35.5$ Mpc). Pre-discovery ground-based imaging revealed an associated, shorter-duration transient in the optical and near-IR (NIR). NIR spectroscopy showed a broad ($\approx 8400$ km s$^{-1}$), double-peaked emission line of He I at $1.083 \mu$m, indicating an explosive origin. The NIR spectrum of SPIRITS 15c is similar to that of the Type IIb SN 2011dh at a phase of $\approx 200$ days. Assuming $A_V = 2.2$ mag of extinction in SPIRITS 15c provides a good match between their optical light curves. The IR light curves and the extreme $[3.6]-[4.5]$ color cannot be explained using only a standard extinction law. Another luminous ($M_{4.5} = -16.1\pm0.4$ mag) event, SPIRITS 14buu, was serendipitously discovered in the same galaxy. The source displays an optical plateau lasting $\gtrsim 80$ days, and we suggest a scenario similar to the low-luminosity Type IIP SN 2005cs obscured by $A_V \approx 1.5$ mag. Other classes of IR-luminous transients can likely be ruled out in both cases. If both events are indeed SNe, this may suggest $\gtrsim 18\%$ of nearby core-collapse SNe are missed by currently operating optical surveys.Comment: 19 pages, 7 Figures, 4 Table

Static Charges in the Low-Energy Theory of the S-Duality Twist

We continue the study of the low-energy limit of N=4 super Yang-Mills theory compactified on a circle with S-duality and R-symmetry twists that preserve N=6 supersymmetry in 2+1D. We introduce external static supersymmetric quark and anti-quark sources into the theory and calculate the Witten Index of the resulting Hilbert space of ground states on a torus. Using these results we compute the action of simple Wilson loops on the Hilbert space of ground states without sources. In some cases we find disagreement between our results for the Wilson loop eigenvalues and previous conjectures about a connection with Chern-Simons theory.Comment: 73 pages, two paragraphs added, one to the introduction and one to the discussio

Self-Similarity in General Relativity \endtitle

The different kinds of self-similarity in general relativity are discussed, with special emphasis on similarity of the ``first'' kind, corresponding to spacetimes admitting a homothetic vector. We then survey the various classes of self-similar solutions to Einstein's field equations and the different mathematical approaches used in studying them. We focus mainly on spatially homogenous and spherically symmetric self-similar solutions, emphasizing their possible roles as asymptotic states for more general models. Perfect fluid spherically symmetric similarity solutions have recently been completely classified, and we discuss various astrophysical and cosmological applications of such solutions. Finally we consider more general types of self-similar models.Comment: TeX document, 53 page

Improving Genetic Prediction by Leveraging Genetic Correlations Among Human Diseases and Traits

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7 for height to 47 for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait. © 2018 The Author(s)

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

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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