Extensions to the Proximal Distance of Method of Constrained Optimization

The current paper studies the problem of minimizing a loss $f(\boldsymbol{x})$ subject to constraints of the form $\boldsymbol{D}\boldsymbol{x} \in S$, where $S$ is a closed set, convex or not, and $\boldsymbol{D}$ is a fusion matrix. Fusion constraints can capture smoothness, sparsity, or more general constraint patterns. To tackle this generic class of problems, we combine the Beltrami-Courant penalty method of optimization with the proximal distance principle. The latter is driven by minimization of penalized objectives $f(\boldsymbol{x})+\frac{\rho}{2}\text{dist}(\boldsymbol{D}\boldsymbol{x},S)^2$ involving large tuning constants $\rho$ and the squared Euclidean distance of $\boldsymbol{D}\boldsymbol{x}$ from $S$. The next iterate $\boldsymbol{x}_{n+1}$ of the corresponding proximal distance algorithm is constructed from the current iterate $\boldsymbol{x}_n$ by minimizing the majorizing surrogate function $f(\boldsymbol{x})+\frac{\rho}{2}\|\boldsymbol{D}\boldsymbol{x}-\mathcal{P}_S(\boldsymbol{D}\boldsymbol{x}_n)\|^2$. For fixed $\rho$ and convex $f(\boldsymbol{x})$ and $S$, we prove convergence, provide convergence rates, and demonstrate linear convergence under stronger assumptions. We also construct a steepest descent (SD) variant to avoid costly linear system solves. To benchmark our algorithms, we adapt the alternating direction method of multipliers (ADMM) and compare on extensive numerical tests including problems in metric projection, convex regression, convex clustering, total variation image denoising, and projection of a matrix to one that has a good condition number. Our experiments demonstrate the superior speed and acceptable accuracy of the steepest variant on high-dimensional problems. Julia code to replicate all of our experiments can be found at https://github.com/alanderos91/ProximalDistanceAlgorithms.jl.Comment: 35 pages (22 main text, 10 appendices, 3 references), 9 tables, 1 figur

chroGPS, a global chromatin positioning system for the functional analysis and visualization of the epigenome

Development of tools to jointly visualize the genome and the epigenome remains a challenge. chroGPS is a computational approach that addresses this question. chroGPS uses multidimensional scaling techniques to represent similarity between epigenetic factors, or between genetic elements on the basis of their epigenetic state, in 2D/3D reference maps. We emphasize biological interpretability, statistical robustness, integration of genetic and epigenetic data from heterogeneous sources, and computational feasibility. Although chroGPS is a general methodology to create reference maps and study the epigenetic state of any class of genetic element or genomic region, we focus on two specific kinds of maps: chroGPSfactors, which visualizes functional similarities between epigenetic factors, and chroGPSgenes, which describes the epigenetic state of genes and integrates gene expression and other functional data. We use data from the modENCODE project on the genomic distribution of a large collection of epigenetic factors in Drosophila, a model system extensively used to study genome organization and function. Our results show that the maps allow straightforward visualization of relationships between factors and elements, capturing relevant information about their functional properties that helps to interpret epigenetic information in a functional context and derive testable hypotheses

The Phenomenon of Darboux Displacements

For a class of Schrodinger Hamiltonians the supersymmetry transformations can degenerate to simple coordinate displacements. We examine this phenomenon and show that it distinguishes the Weierstrass potentials including the one-soliton wells and periodic Lame functions. A supersymmetric sense of the addition formula for the Weierstrass functions is elucidated.Comment: 11 pages, latex, 2 eps figure

ATR is required to complete meiotic recombination in mice

Precise execution of recombination during meiosis is essential for forming chromosomally-balanced gametes. Meiotic recombination initiates with the formation and resection of DNA double-strand breaks (DSBs). Cellular responses to meiotic DSBs are critical for efficient repair and quality control, but molecular features of these remain poorly understood, particularly in mammals. Here we report that the DNA damage response protein kinase ATR is crucial for meiotic recombination and completion of meiotic prophase in mice. Using a hypomorphic Atr mutation and pharmacological inhibition of ATR in vivo and in cultured spermatocytes, we show that ATR, through its effector kinase CHK1, promotes efficient RAD51 and DMC1 assembly at RPA-coated resected DSB sites and establishment of interhomolog connections during meiosis. Furthermore, our findings suggest that ATR promotes local accumulation of recombination markers on unsynapsed axes during meiotic prophase to favor homologous chromosome synapsis. These data reveal that ATR plays multiple roles in mammalian meiotic recombination.We thank M. A. Handel (The Jackson Laboratory, Bar Harbor, USA) for the anti-H1T antibody; E. Marcon for the anti-RPA antibody (University of Toronto, Canada); A. Toth for the anti-pHORMAD2 antibody (U. Dresden, Germany) and N. Hunter for the anti- RNF212 antibody (UC Davis, USA); J. Turner (National Institute for Medical Research,London, UK) for assistance in the RNA-FISH experiments, for the X chromosome probe,for providing AtrFL/−testis samples and for sharing unpublished data; L. Kauppi(University of Helsinki, Finland) for providing us with protocols for the testis cultures;and members of the Roig lab and the Spanish Ministerio de Ciencia e Innovación-funded Network of Spanish groups working on Meiosis (MeioNet, BFU201‐71786‐REDT) and Enrique Martínez Pérez (Imperial College, London, UK) for helpful discussions. M.M.O. was supported by a FPI fellowship from the Ministerio de Ciencia e Innovación (BES-2011-045381). J.L. was supported in part by American Cancer Society post-doctoral fellowship (PF-12-157-01-DMC). S.K. is an Investigator of the Howard Hughes Medical Institute. This work was supported by the Ministerio de Ciencia e Innovación (BFU2010-18965, BFU2013-43965-P and BFU2016-80370-P, I.R.), by the UAB-Aposta award to young investigators (APOSTA2011-03, I.R.) and by the NIH (R35 GM118175, to M.J.and R35 GM118092 to S.K.).S

Identificación del Virus Epstein-Barr por Hibridación in situ en pacientes con Cáncer Gástrico que asisten al Instituto de Cancerología (Incan) de Guatemala

El Virus Epstein Barr (EBV) está relacionado como agente oncogénico en el desarrollo del cáncer gástrico, atribuyéndosele el 10 % de los casos de esta neoplasia a nivel mundial. No existen estudios previos que identifiquen la presencia EBV en los pacientes con cáncer gástrico en Guatemala, por lo que en este estudio se evaluó por hibridación in situ la presencia del micro ARN EBER (Epstein Barr-encoded RNAs) de EBV en 71 pacientes con cáncer gástrico que asistieron al Instituto de Cancerología (Incan). Se determinó una prevalencia de 21.1 % (IC 95 % [10.9, 31.3] ) (15 pacientes), mayor que la reportada en otros estudios latinoamericanos. Se determinó asociación significativa entre la expresión del EBER del EBV, y el género masculino OR = 4.9 (IC 95% [1.4, 17.5]) p < .05. Los factores asociados fueron, el padecer diarrea OR 5.7 IC 95 % [1.5, 12.6] p = .008, y la detección del anticuerpos de Helicobacter pylori séricos, OR 7.2 (IC 95 % [1.1, 18.9]) p = .03. Aun cuando la mayoría de los pacientes que expresan el EBER de EBV desarrollaron cáncer gástrico del tipo difuso 66.67 % noexiste asociación significativa p = 0.13 OR = 2.5 (IC 95 % [1.1, 8.2])

Assessing Tn5 and sleeping beauty for transpositional transgenesis by cytoplasmic injection into bovine and ovine zygotes

Transgenic domestic animals represent an alternative to bioreactors for large-scale production of biopharmaceuticals and could also provide more accurate biomedical models than rodents. However, their generation remains inefficient. Recently, DNA transposons allowed improved transgenesis efficiencies in mice and pigs. In this work, Tn5 and Sleeping Beauty (SB) transposon systems were evaluated for transgenesis by simple cytoplasmic injection in livestock zygotes. In the case of Tn5, the transposome complex of transposon nucleic acid and Tn5 protein was injected. In the case of SB, the supercoiled plasmids encoding a transposon and the SB transposase were co-injected. In vitro produced bovine zygotes were used to establish the cytoplasmic injection conditions. The in vitro cultured blastocysts were evaluated for reporter gene expression and genotyped. Subsequently, both transposon systems were injected in seasonally available ovine zygotes, employing transposons carrying the recombinant human factor IX driven by the beta-lactoglobulin promoter. The Tn5 approach did not result in transgenic lambs. In contrast, the Sleeping Beauty injection resulted in 2 lambs (29%) carrying the transgene. Both animals exhibited cellular mosaicism of the transgene. The extraembryonic tissues (placenta or umbilical cord) of three additional animals were also transgenic. These results show that transpositional transgenesis by cytoplasmic injection of SB transposon components can be applied for the production of transgenic lambs of pharmaceutical interest.Instituto de BiotecnologíaFil: Bevacqua, Romina Jimena. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fernández y Martín, Rafael. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Canel, Natalia Gabriela. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario; ArgentinaFil: Gibbons, Alejandro Eduardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche; ArgentinaFil: Texeira, D.I.A. Universidade Estadual do Ceará. Faculdade de Veterinária; BrasilFil: Lange, F. Universidad Maimónides. Laboratorio de Clonación y Transgenesis; ArgentinaFil: Vans Landschoot, Geraldina. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Fil: Lange, F. Universidad Maimónides. Laboratorio de Clonación y Transgenesis; ArgentinaFil: Savy, Virginia. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Briski, Olinda. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Hiriart, María Inés. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Grueso, Esther. Paul-Ehrlich-Institute; AlemaniaFil: Ivics, Zoltán. Paul-Ehrlich-Institute; AlemaniaFil: Taboga, Oscar Alberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Biotecnología; Argentina.Fil: Kues, Wilfried A. Friedrich-Loeffler-Institut; AlemaniaFil: Ferraris, S.R. Universidad Maimónides. Laboratorio de Clonación y Transgenesis; ArgentinaFil: Salamone, Daniel Felipe. Universidad de Buenos Aires. Facultad de Agronomía. Pabellón de Zootecnica. Laboratorio de Biotecnología Animal; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Drug-gene interactions of antihypertensive medications and risk of incident cardiovascular disease: a pharmacogenomics study from the CHARGE consortium

Background Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. Methods Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). Results Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10−8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD

COSNET-a coherent optical subscriber network

A complete coherent multichannel system, designed for application in the local loop, is presented. The concept of a uni- and bidirectional system and its technical realization in a laboratory demonstrator are described. The network control, including frequency management of the bidirectional channels, and network security are discussed. Attention is paid to the scenario for evolution from a narrowband to a complete broadband system. All aspects are integrated in a demonstrator, which is capable of supporting a large number of narrowband and broadband distributive and communicative services. Novel technical solutions for frequency management, data induced polarization switching (DIPS), high-speed encryption, and network signaling are presented

Pandemic (H1N1) 2009 Outbreak on Pig Farm, Argentina

In June–July 2009, an outbreak of pandemic (H1N1) 2009 infection occurred on a pig farm in Argentina. Molecular analysis indicated that the virus was genetically related to the pandemic (H1N1) 2009 influenza virus strain. The outbreak presumably resulted from direct human-to-pig transmission