The Critical Turning Points Database : Concept, Methodology and Dataset of an International Transformative Social Innovation Comparison (TRANSIT Working Paper # 10, July 12th 2017)

[Abstract] This working paper presents the TRANSIT open-access online database on Critical Turning Points (CTP) in Transformative Social Innovation. It specifies the contents of the database, comprising qualitative accounts of more than 450 ‘critical’ episodes in the evolution of social innovation initiatives in 27 different countries. Providing the theoretical-methodological context to these data, the paper also describes the theoretical background of the CTP concept and the methodology though which the CTP accounts have been reconstructed through interviews with members of SI initiatives. The paper concludes with reflections on the open access CTP database as a knowledge infrastructure, discussing its significance in terms of mapping, dissemination and framing of social innovation.This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 61316

MIP/Aquaporin 0 Represents a Direct Transcriptional Target of PITX3 in the Developing Lens

The PITX3 bicoid-type homeodomain transcription factor plays an important role in lens development in vertebrates. PITX3 deficiency results in a spectrum of phenotypes from isolated cataracts to microphthalmia in humans, and lens degeneration in mice and zebrafish. While identification of downstream targets of PITX3 is vital for understanding the mechanisms of normal ocular development and human disease, these targets remain largely unknown. To isolate genes that are directly regulated by PITX3, we performed a search for genomic sequences that contain evolutionarily conserved bicoid/PITX3 binding sites and are located in the proximity of known genes. Two bicoid sites that are conserved from zebrafish to human were identified within the human promoter of the major intrinsic protein of lens fiber, MIP/AQP0. MIP/AQP0 deficiency was previously shown to be associated with lens defects in humans and mice. We demonstrate by both chromatin immunoprecipitation and electrophoretic mobility shift assay that PITX3 binds to MIP/AQP0 promoter region in vivo and is able to interact with both bicoid sites in vitro. In addition, we show that wild-type PITX3 is able to activate the MIP/AQP0 promoter via interaction with the proximal bicoid site in cotransfection experiments and that the introduction of mutations disrupting binding to this site abolishes this activation. Furthermore, mutant forms of PITX3 fail to produce the same levels of transactivation as wild-type when cotransfected with the MIP/AQP0 reporter. Finally, knockdown of pitx3 in zebrafish affects formation of a DNA-protein complex associated with mip1 promoter sequences; and examination of expression in pitx3 morphant and control zebrafish revealed a delay in and reduction of mip1 expression in pitx3-deficient embryos. Therefore, our data suggest that PITX3 is involved in direct regulation of MIP/AQP0 expression and that the alteration of MIP/AQP0 expression is likely to contribute to the lens phenotype in cataract patients with PITX3 mutations

Genome-Wide Analysis of the World's Sheep Breeds Reveals High Levels of Historic Mixture and Strong Recent Selection

Genomic structure in a global collection of domesticated sheep reveals a history of artificial selection for horn loss and traits relating to pigmentation, reproduction, and body size

Parámetros genéticos en dos planteles merino de la patagonia

Genetic and phenotypic parameters of body weight, greasy fleece weight, clean yield, clean fleece weight, fiber diameter and coefficient of variation of fiber diameter (CVF) at first shearing were estimated in two Patagonian Merino flocks. The nucleus flock of Pilcaniyeu, used for progeny testing of rams from different bloodlines and the ram breeding flock of Leleque, a traditional Merino stud with a high proportion of home bred sires. All heritabilities, except for CVF, were larger and all genetic correlations with fiber diameter, except for CVF, were smaller in Pilcaniyeu than in Leleque. Parameters for Leleque were in better agreement with published estimates and are suggested for application in traditional ram breeding flocks lacking own data. Results also imply larger expected genetic progress in Pilcaniyeu and the necessity to consider heterogeneity of variance in combined genetic evaluations where Pilcaniyeu operates as a genetic linkage between studs.Se estimaron parámetros genéticos y fenotípicos de peso corporal, peso de vellón sucio, rinde al lavado, peso de vellón limpio, promedio de diámetros de fibra y su coeficiente de variación (CVF) a la primer esquila en dos planteles Merino de la Patagonia. El plantel Pilcaniyeu, utilizado para la evaluación de padres de diferentes cabañas a través de pruebas de progenie y el plantel Leleque, tradicional cabaña de la raza con alta proporción de padres de producción propia. Todas las heredabilidades, salvo CVF, resultaron mayores en Pilcaniyeu y todas las correlaciones genéticas con diámetro de fibra, salvo CVF, resultaron menores que en Leleque. Los parámetros estimados para Leleque coinciden mejor con la literatura y se sugiere su uso en evaluaciones de planteles tradicionales sin parámetros propios. Los resultados también implican mayor progreso genético esperado en Pilcaniyeu y la necesidad de considerar heterogeneidad de varianzas en eventuales evaluaciones genéticas poblacionales en las que un plantel / establecimiento, en nuestro caso Pilcaniyeu, opera como vinculante genético entre planteles

Parámetros genéticos en dos planteles merino de la patagoni

Se estimaron parámetros genéticos y fenotípicos de peso corporal, peso de vellón sucio, rinde al lavado, peso de vellón limpio, promedio de diámetros de fibra y su coeficiente de variación (CVF) a la primer esquila en dos planteles Merino de la Patagonia. El plantel Pilcaniyeu, utilizado para la evaluación de padres de diferentes cabañas a través de pruebas de progenie y el plantel Leleque, tradicional cabaña de la raza con alta proporción de padres de producción propia. Todas las heredabilidades, salvo CVF, resultaron mayores en Pilcaniyeu y todas las correlaciones genéticas con diámetro de fibra, salvo CVF, resultaron menores que en Leleque. Los parámetros estimados para Leleque coinciden mejor con la literatura y se sugiere su uso en evaluaciones de planteles tradicionales sin parámetros propios. Los resultados también implican mayor progreso genético esperado en Pilcaniyeu y la necesidad de considerar heterogeneidad de varianzas en eventuales evaluaciones genéticas poblacionales en las que un plantel / establecimiento, en nuestro caso Pilcaniyeu, opera como vinculante genético entre plantele

Protective role of autophagy against Vibrio cholerae cytolysin, a pore-forming toxin from V. cholerae

Autophagy is the unique, regulated mechanism for the degradation of organelles. This intracellular process acts as a prosurvival pathway during cell starvation or stress and is also involved in cellular response against specific bacterial infections. Vibrio cholerae is a noninvasive intestinal pathogen that has been studied extensively as the causative agent of the human disease cholera. V. cholerae illness is produced primarily through the expression of a potent toxin (cholera toxin) within the human intestine. Besides cholera toxin, this bacterium secretes a hemolytic exotoxin termed V. cholerae cytolysin (VCC) that causes extensive vacuolation in epithelial cells. In this work, we explored the relationship between the vacuolation caused by VCC and the autophagic pathway. Treatment of cells with VCC increased the punctate distribution of LC3, a feature indicative of autophagosome formation. Moreover, VCC-induced vacuoles colocalized with LC3 in several cell lines, including human intestinal Caco-2 cells, indicating the interaction of the large vacuoles with autophagic vesicles. Electron microscopy analysis confirmed that the vacuoles caused by VCC presented hallmarks of autophagosomes. Additionally, biochemical evidence demonstrated the degradative nature of the VCC-generated vacuoles. Interestingly, autophagy inhibition resulted in decreased survival of Caco-2 cells upon VCC intoxication. Also, VCC failed to induce vacuolization in Atg5−/− cells, and the survival response of these cells against the toxin was dramatically impaired. These results demonstrate that autophagy acts as a cellular defense pathway against secreted bacterial toxins

SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract

Congenital cataract (CC) is one of the most important causes for blindness or visual impairment in infancy. A substantial proportion of isolated CCs has monogenic causes. The disease is genetically heterogeneous, and all Mendelian modes of inheritance have been reported. We mapped a locus for isolated CC on 19p13.1–q13.2 in a distantly consanguineous German family with two sisters affected by dense white cataracts. Whole-exome sequencing identified a homozygous nonsense variant c.4489C>T (p.(R1497*)) in SIPA1L3 (signal-induced proliferation-associated 1 like 3) in both affected children. SIPA1L3 encodes a GTPase-activating protein (GAP), which interacts with small GTPases of the Rap family via its Rap-GAP-domain. The suggested role of Rap GTPases in cell growth, differentiation and organization of the cytoskeleton in the human lens, and lens-enriched expression of the murine ortholog gene Sipa1l3 in embryonic mice indicates that this gene is crucial for early lens development. Our results provide evidence that sequence variants in human SIPA1L3 cause autosomal recessive isolated CC and give new insight into the molecular pathogenesis underlying human cataracts