Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the middle East respiratory syndrome virus.

Coronaviruses raise serious concerns as emerging zoonotic viruses without specific antiviral drugs available. Here we screened a collection of 16671 diverse compounds for anti-human coronavirus 229E activity and identified an inhibitor, designated K22, that specifically targets membrane-bound coronaviral RNA synthesis. K22 exerts most potent antiviral activity after virus entry during an early step of the viral life cycle. Specifically, the formation of double membrane vesicles (DMVs), a hallmark of coronavirus replication, was greatly impaired upon K22 treatment accompanied by near-complete inhibition of viral RNA synthesis. K22-resistant viruses contained substitutions in non-structural protein 6 (nsp6), a membrane-spanning integral component of the viral replication complex implicated in DMV formation, corroborating that K22 targets membrane bound viral RNA synthesis. Besides K22 resistance, the nsp6 mutants induced a reduced number of DMVs, displayed decreased specific infectivity, while RNA synthesis was not affected. Importantly, K22 inhibits a broad range of coronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV), and efficient inhibition was achieved in primary human epithelia cultures representing the entry port of human coronavirus infection. Collectively, this study proposes an evolutionary conserved step in the life cycle of positive-stranded RNA viruses, the recruitment of cellular membranes for viral replication, as vulnerable and, most importantly, druggable target for antiviral intervention. We expect this mode of action to serve as a paradigm for the development of potent antiviral drugs to combat many animal and human virus infections.

Synchronization of two independently moving cameras without feature correspondences

In this work, a method that synchronizes two video sequences is proposed. Unlike previous methods, which require the existence of correspondences between features tracked in the two sequences, and/or that the cameras are static or jointly moving, the proposed approach does not impose any of these constraints. It works when the cameras move independently, even if different features are tracked in the two sequences. The assumptions underlying the proposed strategy are that the intrinsic parameters of the cameras are known and that two rigid objects, with independent motions on the scene, are visible in both sequences. The relative motion between these objects is used as clue for the synchronization. The extrinsic parameters of the cameras are assumed to be unknown. A new synchronization algorithm for static or jointly moving cameras that see (possibly) different parts of a common rigidly moving object is also proposed. Proof-of-concept experiments that illustrate the performance of these methods are presented, as well as a comparison with a state-of-the-art approach.

Arbeitsweisen im Gegenwartstheater

"Arbeitsweisen im Gegenwartstheater", Band 1 der neuen theaterwissenschaftlichen Reihe, ist im April 2015 im Berliner Alexander Verlag erschienen. Die regelmäßig erscheinenden Ausgaben sind als Arbeitsbücher zu den "itw : im dialog"-Symposien des Instituts für Theaterwissenschaft der Universität Bern konzipiert. Die Beiträge des ersten Bandes reflektieren die komplexen und divergenten Erscheinungsformen zeitgenössischen Theaters und nähern sich aus unterschiedlichen Perspektiven der Frage nach den Zusammenhängen von Arbeitsweisen und Ästhetiken: z. B. Kollektivität und Reflexivität im Gegenwartstheater, Formen und Mobilität internationalisierten Theaters, Allianzen zwischen Freier Szene und Stadttheater sowie Autorenregie. Mit Beiträgen von Annemarie Matzke, Barbara Gronau, Sandra Umathum, Philipp Schulte, Karin Nissen-Rizvani und Gesprächen mit Alexandre Devriendt und Joeri Smet (Ontroerend Goed, Gent), Sebastian Brünger (Rimini Protokoll, Berlin), Tomas Schweigen (FADC/Theater Basel), Sabine Harbeke (Autorin/Regisseurin, Zürich).

Prehistoric genomes reveal the genetic foundation and cost of horse domestication

The domestication of the horse revolutionized warfare, trade, and the exchange of people and ideas. This at least 5,500-y-long process, which ultimately transformed wild horses into the hundreds of breeds living today, is difficult to reconstruct from archeological data and modern genetics alone. We therefore sequenced two complete horse genomes, predating domestication by thousands of years, to characterize the genetic footprint of domestication. These ancient genomes reveal predomestic population structure and a significant fraction of genetic variation shared with the domestic breeds but absent from Przewalski’s horses. We find positive selection on genes involved in various aspects of locomotion, physiology, and cognition. Finally, we show that modern horse genomes contain an excess of deleterious mutations, likely representing the genetic cost of domestication.

Evolutionary Genomics and Conservation of the Endangered Przewalski's Horse.

Przewalski's horses (PHs, Equus ferus ssp. przewalskii) were discovered in the Asian steppes in the 1870s and represent the last remaining true wild horses. PHs became extinct in the wild in the 1960s but survived in captivity, thanks to major conservation efforts. The current population is still endangered, with just 2,109 individuals, one-quarter of which are in Chinese and Mongolian reintroduction reserves [1]. These horses descend from a founding population of 12 wild-caught PHs and possibly up to four domesticated individuals [2-4]. With a stocky build, an erect mane, and stripped and short legs, they are phenotypically and behaviorally distinct from domesticated horses (DHs, Equus caballus). Here, we sequenced the complete genomes of 11 PHs, representing all founding lineages, and five historical specimens dated to 1878-1929 CE, including the Holotype. These were compared to the hitherto-most-extensive genome dataset characterized for horses, comprising 21 new genomes. We found that loci showing the most genetic differentiation with DHs were enriched in genes involved in metabolism, cardiac disorders, muscle contraction, reproduction, behavior, and signaling pathways. We also show that DH and PH populations split ∼45,000 years ago and have remained connected by gene-flow thereafter. Finally, we monitor the genomic impact of ∼110 years of captivity, revealing reduced heterozygosity, increased inbreeding, and variable introgression of domestic alleles, ranging from non-detectable to as much as 31.1%. This, together with the identification of ancestry informative markers and corrections to the International Studbook, establishes a framework for evaluating the persistence of genetic variation in future reintroduced populations.

Tracking the origins of Yakutian horses and the genetic basis for their fast adaptation to subarctic environments

Yakutia, Sakha Republic, in the Siberian Far East, represents one of the coldest places on Earth, with winter record temperatures dropping below -70 °C. Nevertheless, Yakutian horses survive all year round in the open air due to striking phenotypic adaptations, including compact body conformations, extremely hairy winter coats, and acute seasonal differences in metabolic activities. The evolutionary origins of Yakutian horses and the genetic basis of their adaptations remain, however, contentious. Here, we present the complete genomes of nine present-day Yakutian horses and two ancient specimens dating from the early 19th century and ∼5,200 y ago. By comparing these genomes with the genomes of two Late Pleistocene, 27 domesticated, and three wild Przewalski's horses, we find that contemporary Yakutian horses do not descend from the native horses that populated the region until the mid-Holocene, but were most likely introduced following the migration of the Yakut people a few centuries ago. Thus, they represent one of the fastest cases of adaptation to the extreme temperatures of the Arctic. We find cis-regulatory mutations to have contributed more than nonsynonymous changes to their adaptation, likely due to the comparatively limited standing variation within gene bodies at the time the population was founded. Genes involved in hair development, body size, and metabolic and hormone signaling pathways represent an essential part of the Yakutian horse adaptive genetic toolkit. Finally, we find evidence for convergent evolution with native human populations and woolly mammoths, suggesting that only a few evolutionary strategies are compatible with survival in extremely cold environments.

Whole-Genome Sequencing of a Canine Family Trio Reveals a FAM83G Variant Associated with Hereditary Footpad Hyperkeratosis

Over 250 Mendelian traits and disorders, caused by rare alleles have been mapped in the canine genome. Although each disease is rare in the dog as a species, they are collectively common and have major impact on canine health. With SNP-based genotyping arrays, genome-wide association studies (GWAS) have proven to be a powerful method to map the genomic region of interest when 10-20 cases and 10-20 controls are available. However, to identify the genetic variant in associated regions, fine-mapping and targeted re-sequencing is required. Here we present a new approach using whole-genome sequencing (WGS) of a family trio without prior GWAS. As a proof-of-concept, we chose an autosomal recessive disease known as hereditary footpad hyperkeratosis (HFH) in Kromfohrl änder dogs. To our knowledge, this is the first time this family trio WGS-approach, has successfully been used to identify a genetic variant that perfectly segregates with a canine disorder. The sequencing of three Kromfohrl änder dogs from a family trio (an affected offspring and both its healthy parents) resulted in an average genome coverage of 9.2X per individual. After applying stringent filtering criteria for candidate causative coding variants, 527 single nucleotide variants (SNVs) and 15 indels were found to be homozygous in the affected offspring and heterozygous in the parents. Using the computer software packages ANNOVAR and SIFT to functionally annotate coding sequence differences and to predict their functional effect, resulted in seven candidate variants located in six different genes. Of these, only FAM83G:c155G>C (p.R52P) was found to be concordant in eight additional cases and 16 healthy Kromfohrl änder dogs.

The DESCARTES-Nantes survey of kidney transplant recipients displaying clinical operational tolerance identifies 35 new tolerant patients and 34 almost tolerant patients.

BACKGROUND Kidney recipients maintaining a prolonged allograft survival in the absence of immunosuppressive drugs and without evidence of rejection are supposed to be exceptional. The ERA-EDTA-DESCARTES working group together with Nantes University launched a European-wide survey to identify new patients, describe them and estimate their frequency for the first time. METHODS Seventeen coordinators distributed a questionnaire in 256 transplant centres and 28 countries in order to report as many 'operationally tolerant' patients (TOL; defined as having a serum creatinine <1.7 mg/dL and proteinuria <1 g/day or g/g creatinine despite at least 1 year without any immunosuppressive drug) and 'almost tolerant' patients (minimally immunosuppressed patients (MIS) receiving low-dose steroids) as possible. We reported their number and the total number of kidney transplants performed at each centre to calculate their frequency. RESULTS One hundred and forty-seven questionnaires were returned and we identified 66 TOL (61 with complete data) and 34 MIS patients. Of the 61 TOL patients, 26 were previously described by the Nantes group and 35 new patients are presented here. Most of them were noncompliant patients. At data collection, 31/35 patients were alive and 22/31 still TOL. For the remaining 9/31, 2 were restarted on immunosuppressive drugs and 7 had rising creatinine of whom 3 resumed dialysis. Considering all patients, 10-year death-censored graft survival post-immunosuppression weaning reached 85% in TOL patients and 100% in MIS patients. With 218 913 kidney recipients surveyed, cumulative incidences of operational tolerance and almost tolerance were estimated at 3 and 1.5 per 10 000 kidney recipients, respectively. CONCLUSIONS In kidney transplantation, operational tolerance and almost tolerance are infrequent findings associated with excellent long-term death-censored graft survival.

[Spontaneous retropharyngeal hematoma with fatal outcome]

Halsschmerz, Dysphagie und Dyspnoe sind die häufigsten Symptomen, aufgrund derer Patienten einen Arzt aufsuchen. Hierbei handelt es sich um unspezifische Symptome mit vielfältigen Ursachen. Mögliche im Retropharyngealraum lokalisierte Pathologien sind in der überwiegenden Anzahl der Fälle selbst limitierend oder durch medikamentöse Therapien beherrschbar (Bsp.: Pharyngitis, Tonsillitis, Seitenstrangangina). Deutlich seltener sind im Spatium retropharyngeum lokalisierte Abszesse, Neoplasien (Bsp.: Lipome, Neurofibrome, Liposarkome) oder Hämatome (Schmäl F et al. HNO 2002; 50: 418 – 423). Letztlich können auch degenerative Veränderungen der Wirbelsäule, eine ektop verlaufende Arteria carotis interna oder seltene Manifestationen von Systemerkrankungen (Bsp.: Sarkoidose) zu einer unterschiedlich stark ausgeprägten Vorwölbung der Pharynxhinterwand und Einengung der Luft- und Speiseröhre führen. Anhand des vorliegenden Falls wird die klinische Präsentation sowie die radiologische Diagnose eines retropharyngealen Hämatoms diskutiert und die anatomische Beziehung der Halskompartimente mit besonderem Fokus auf den Retropharyngealraum dargestellt.

Las razas : algunos aspectos del problema ; conferencia pronunciada en la Biblioteca del Jockey Club, el día 25 de Junio de 1936

Tomas Amadeo

Antropología de las relaciones transnacionales en las regiones de frontera. Hegemonía y resistencia en el Sistema Mundo (2010/2012) “HANUIN VIII”.. 16H312

La presente investigación forma parte de un ciclo integrado por siete investigaciones precedentes, cuyas referencias están incluidas en el apartado de antecedentes. Dichas investigaciones cuentan con los informes de avance y finales aprobados. Su objetivo principal es conocer y describir la complejidad de la región de frontera estudiada (Triple Frontera entre Argentina, Brasil y Paraguay) ), el núcleo duro de las relaciones directas, y las acciones propias, que desde la región, protagonizan organizaciones y movimientos sociales en relación a las cada vez mas intensas amenazas de intervención militar/”humanitaria”, por parte del poder hegemónico de Estados Unidos y la intensificación de los controles estatales nacionales que responden a las presiones internacionales. ¿Qué lugar ocupa en las estrategias de la hegemonía imperial esta región? y ¿cuales son las respuestas locales tanto en acciones como en representaciones?. El proyecto posee las siguientes sub-áreas con sus respectivos coordinadores a) Centro de estudios de la población paraguaya en Argentina (CEDAPPA); b) Centro de Estudios de Antropología y Derecho (mediante un convenio de cooperación e investigadores adscriptos) y c) Área de estudios de Historia Regional El presente proyecto es la novena etapa de una secuencia que incluye ocho proyectos precedentes del programa de incentivos. Todos, menos el último, fueron bianuales y el octavo, que finalizó en el 2012, trianual. La nómina completa de estos proyectos es la siguiente: Proyectos pertenecientes al Programa de Incentivos: "Integración Regional Fronteriza: sectores vulnerables frente al impacto global. Políticas y acciones alternativas" UNaM, Sec. de Investigación FHCS. 1994-96.Informes de avance y final aprobados. Código: H-16-001 “Hanuin I” (“Hacer nuestra la integración”) En este proyecto se adoptó este nombre general que luego se repitió en toda la secuencia y que proviene de un lema formulado en un encuentro de movimientos sociales de los cuatro países del MERCOSUR.. “Estrategias de una red de movimientos sociales argentinos, brasileños y paraguayos en el marco de la integración regional fronteriza. Factores de cohesión y de conflicto”. Sec. de Invs. y Posgrado, 1996/1998.Informes de avance y final aprobados. Código: H-16-033, “Hanuin II”. “Los movimientos sociales en la integración regional. Relaciones transfronterizas de solidaridad y lucha. La cuestión agraria integral. Secretaría de Investigación y Postgrado, FHYCS, UNaM.1999-2000 Código: H-16-034, “Hanuin III”. “Interacciones transfronterizas, procesos socioculturales emergentes en el contexto de la integración. Los movimientos sociales ante el impacto del Mercosur. (Arg., Br. y Par.) (2001-2002). Código: H-16- 035 “Hanuin IV”. 4 “Procesos transfronterizos complejos: El caso de la Triple Frontera. Movimientos y organizaciones sociales, grupos “bajo sospecha”, control y políticas públicas. (2003-2005). Código: H-16- 135., “Hanuin V”. “Hegemonías y resistencias en el sistema mundo. Estados y procesos transfronterizos. El caso de la Triple frontera. (2006-2007) Código: H-16-198. Incluye el proyecto de Voluntariado CEDAPA. Convenio entre la UNaM (FHYCS) y la Comisión de Verdad y Justicia del Paraguay “Hanuin VI”. “Antropología de los procesos transfronterizos: La Triple Frontera en el sistema mundo. Complejidad y resistencia regional” Incluye el proyecto de Voluntariado CEDAPA. Convenio entre la UNaM (FHYCS) y la Comisión de Verdad y Justicia del Paraguay. (2008-2009). 16-H-245. “Hanuin VII”. “ Antropología de las relaciones transnacionales en las regiones de frontera. Hegemonía y resistencia en el sistema mundo” Incluye el proyecto CEDAPPA, Historia Regional, convenio con el CEDEAD. (2010-2012) “Hanuin VIII”,cod. 16-H-312 La inclusión de esta iformación procura ofrecer a los posibles evaluadores datos sobre la secuencia que hoy finaliza su etapa 2010-2012, pero que se continuará en el proyecto Hanuin IX que ya fue presentado. Tambien se abre una nueva instancia con la formulación de un programa que convierte a los subproyectos en proyectos.. Dicho programa lleva por título: “Investigaciónes interdisciplinarias sobre las regiones de frontera. Estado, sistemas socioculturales y terrorios” (2013/15). Una de las conclusiones del proyecto que reseñamos, fue presisamente, la necesidad de ampliar las líneas de investigación con equipos de mayor autonomía que puedan, además, atender las exigencias de creciente incorporación de auxiliares, becarios, tesistas, investigadores adscriptos o invitados.