Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Synergistic interactions of antibodies in rate of virus neutralization

AbstractAntibodies and antibody combinations are often evaluated only by their potency in inactivating a known quantity of virus in dose–effect assays. However, a crucial additional parameter is the rate at which neutralization takes place, or kinetics. Synergism of certain antibody combinations in dose–effect assays has been previously demonstrated. In the present report, using a battery of murine monoclonal antibodies to herpes simplex virus (HSV), we investigated whether antiviral antibodies can also synergize in neutralization kinetics. To determine whether synergism in dose–effect assays can predict synergism in neutralization rate, the ability of neutralizing antibodies to synergize in neutralization rate (kinetics) was compared to their ability to synergize in dose–effect assays (potency) in cell-free assays. Although certain antibody combinations synergized in both neutralization rate and potency, combinations that did not clearly synergize in potency could still significantly synergize in neutralization rate. Weak neutralizing antibodies could also greatly increase the neutralization rate of more potent antibodies. These results suggest that evaluating antibody combinations in dose–effect assays but not in neutralization kinetics provides a partial picture of neutralizing antibody dynamic interactions and may prevent the identification of certain favorable antibody combinations. These findings also support the importance of establishing defined antibody cocktails for prophylactic and therapeutic purposes. A simple strategy to evaluate antibody interactions in neutralization kinetics is proposed in which a quantitative prediction of additivity is made on the basis of the neutralization rate constants of the individual antibodies in the combination

Environmental flow: assessment perspective in the TDPS system

El concepto de caudal ambiental es considerado actualmente como un insumo imprescindible para los sistemas de gestión integrada de los recursos hídricos. Generalmente se define como la cantidad, calidad y régimen de agua necesarias por cada fase del ciclo hidrológico de un río para asegurar la conservación de su biodiversidad y de su funcionamiento ecológico. Esa necesidad es reconocida en las leyes o normas de numerosos países y en especial en los países de la región andina, aunque las herramientas y la capacidad técnica para evaluar esos caudales aún no fueron desarrolladas para las cuencas hídricas más representativas de la región como lo es el sistema hídrico del TDPS. El concepto o evaluación de caudal ecológico no fue aun desarrollado o experimentado en el sistema hídrico del TDPS. Este trabajo presenta en una primera parte el concepto y las metodologías de evaluación del caudal ecológico. La segunda parte describe la necesidad de incluir esa herramienta en la gestión, a través de elementos de los marcos normativos de Perú y Bolivia y de la información disponible sobre la demanda de agua en el sistema TDPS. Finalmente debido a la falta de información sobre la distribución las especies y su dependencia al hábitat, se propone un plan de estudio biológico para desarrollar una herramienta de evaluación del caudal ecológico a nivel de cuencas internas en el sistema TDPS.Environmental flow is a key concept included in nowadays advocated Integrated Water Resource Management systems. Its general definition corresponds to the water quality and quantity necessary for each hydrological period of a river to insure the conservancy of its biodiversity and ecological functioning. The necessity to take into account the environmental flow concept is recognized in laws of numerous countries, especially in the Andean region. However tools and technical capacities necessary to evaluate the environmental flow are still undeveloped in many of the most representative hydric basins of the region as the TDPS system and for the whole Andean region. This work presents in a first part a definition of the concept and the methodologies used to evaluate the environmental flow. In a second part, elements of the Bolivian and Peruvian laws and of water demands are mentioned, highlighting the need to include this tool in the management system of the TDPS. Finally, due to the scarce availability of species distribution and habitat relationships, a biological study is proposed to develop a tool for the evaluation of the environmental flow at the sub-­‐basin level of the TDPSFil: Pouilly, Marc. Museum National D'histoire Naturelle. Institut de Recherche Pour Le Developpment; FranciaFil: Ibanez, Carla. Universidad Mayor de San Andrés; BoliviaFil: Zepita, Claudia. Universidad Mayor de San Andrés; BoliviaFil: Gutiérrez, Ramiro. Universidad Mayor de San Andrés; BoliviaFil: Aguilera, Gaston. Fundación Miguel Lillo. Dirección de Zoología. Instituto de Vertebrados. Sección Ictiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - Tucumán. Unidad Ejecutora Lillo; ArgentinaFil: Aguirre, Mario. No especifíca

Studie zur Wirkung der direkten Projektfoerderung in den Werkstoff-Programmen Matfo und MaTech des Bundesministeriums fuer Bildung und Forschung - BMBF

SIGLEAvailable from TIB Hannover: F00B1061 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung und Forschung (BMBF), Bonn (Germany)DEGerman

Performance Errors of in Group/ Out Group Stimuli and Valence Association in the Implicit Association Test: Brain Bias of Ingroup Favoritism

International audienceThe goal of this study is to assess the role of membership and valence effects on errors performed in a racial implicit association test indexed by event-related potentials (ERPs). Non-indigenous participants performed an implicit association test (IAT) paradigm emphasizing the feedback of error due to misclassification of ingroup (non-indigenous) and outgroup (indigenous) faces as well as positive and negative words. As expected, participants responded to the compatible task with higher accuracy than to incompatible tasks. This is the first report demonstrating that IAT errors produce electrophysiological ERP modulation. Our results suggest that medial frontal negativity is modulated not only by IAT error of membership and valence classifications but also by IAT compatible and incompatible tasks. These results provide a basis for the future use of the misclassification error in the IAT recorded simultaneously with ERPs in other classic social psychology contexts