A TGFβ-ECM-Integrin signalling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease

: The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor-β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery

Comparte la felicidad, educando sobre sexualidad con ciudadanos y ciudadanas habitantes de calle

Curso de Especial InterésLos habitantes de calle (en adelante CHC) se han convertido en una problemática social debido a la desarticulación, violencia y pobreza de la sociedad colombiana. A partir de esta situación se diseñó y elaboró la cartilla “Comparte la felicidad, educando sobre sexualidad con Ciudadanos y Ciudadanas Habitantes de calle” que aborda los cuatro holones de la sexualidad: Vinculación afectiva, erotismo, género y reproductividad, con el objetivo de promover la salud sexual y reproductiva, y la prevención de Infecciones de transmisión sexual, incluido el VIH/SIDA. Para identificar el contenido de la cartilla se realizó una entrevista estructurada de la cual se obtuvo la información a incluir en la cartilla, posteriormente validada en la unidad OASIS.Curso de Especial Interés1. Resumen 2. Justificación 3. Marco teórico 4. Objetivos de la investigación 5. Métodología 6. Estudio de mercado 7. Resultados 8. Discusión 9. Conclusiones 10. Recomendaciones 11. Referencias 12. ApéndicesPregradoPsicólog

A Comprehensive Case Study of Macrosegregation in a Steel Ingot

This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s11663-015-0386-yA case study is presented that examines the macrosegregation and grain structure present in a 12-tonne steel ingot, which was cast for experimental purposes. Details of the casting procedure were well documented and the resulting ingot was characterized using a number of techniques that measured chemical segregation, shrinkage, and porosity. The formation of the porosity and segregation patterns is discussed in reference to the particular grain structure observed in the ingot. It is hoped that this case study can be used as a tool for the validation of future macromodels.This work was undertaken as part of a Project sponsored by Rolls-Royce Power Nuclear plc in collaboration with Sheffield Forgemasters International

Exacerbated inflammatory cellular immune response characteristics of HAM/TSP is observed in a large proportion of HTLV-I asymptomatic carriers

BACKGROUND: A small fraction of Human T cell Leukemia Virus type-1 (HTLV-I) infected subjects develop a severe form of myelopathy. It has been established that patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) show an exaggerated immune response when compared with the immunological response observed in HTLV-I asymptomatic carriers. In this study the immunological responses in HAM/TSP patients and in HTLV-I asymptomatic carriers were compared using several immunological assays to identify immunological markers associated with progression from infection to disease. METHODS: Immunoproliferation assays, cytokine levels of unstimulated cultures, and flow cytometry analysis were used to evaluate the studied groups. Nonparametric tests (Mann-Whitney U test and Wilcoxon matched-pairs signed ranks) were used to compare the difference between the groups. RESULTS: Although both groups showed great variability, HAM/TSP patients had higher spontaneous lymphoproliferation as well as higher IFN-γ levels in unstimulated supernatants when compared with asymptomatic carriers. Flow cytometry studies demonstrated a high frequency of inflammatory cytokine (IFN-γ and TNF-α) producing lymphocytes in HAM/TSP as compared to the asymptomatic group. This difference was accounted for mainly by an increase in CD8 cell production of these cytokines. Moreover, the HAM/TSP patients also expressed an increased frequency of CD28-/CD8+ T cells. Since forty percent of the asymptomatic carriers had spontaneous lymphoproliferation and IFN-γ production similar to HAM/TSP patients, IFN-γ levels were measured eight months after the first evaluation in some of these patients to observe if this was a transient or a persistent situation. No significant difference was observed between the means of IFN-γ levels in the first and second evaluation. CONCLUSIONS: The finding that a large proportion of HTLV-I carriers present similar immunological responses to those observed in HAM/TSP, strongly argues for further studies to evaluate these parameters as markers of HAM/TSP progression

Comprehensive resequence analysis of a 97 kb region of chromosome 10q11.2 containing the MSMB gene associated with prostate cancer

Genome-wide association studies of prostate cancer have identified single nucleotide polymorphism (SNP) markers in a region of chromosome 10q11.2, harboring the microseminoprotein-β (MSMB) gene. Both the gene product of MSMB, the prostate secretory protein 94 (PSP94) and its binding protein (PSPBP), have been previously investigated as serum biomarkers for prostate cancer progression. Recent functional work has shown that different alleles of the significantly associated SNP in the promoter of MSMB found to be associated with prostate cancer risk, rs10993994, can influence its expression in tumors and in vitro studies. Since it is plausible that additional variants in this region contribute to the risk of prostate cancer, we have used next-generation sequencing technology to resequence a ~97-kb region that includes the area surrounding MSMB (chr10: 51,168,025–51,265,101) in 36 prostate cancer cases, 26 controls of European origin, and 8 unrelated CEPH individuals in order to identify additional variants to investigate in functional studies. We identified 241 novel polymorphisms within this region, including 142 in the 51-kb block of linkage disequilibrium (LD) that contains rs10993994 and the proximal promoter of MSMB. No sites were observed to be polymorphic within the exons of MSMB

Soil bacterial and fungal communities across a pH gradient in an arable soil

Soils collected across a long-term liming experiment (pH 4.0-8.3), in which variation in factors other than pH have been minimized, were used to investigate the direct influence of pH on the abundance and composition of the two major soil microbial taxa, fungi and bacteria. We hypothesized that bacterial communities would be more strongly influenced by pH than fungal communities. To determine the relative abundance of bacteria and fungi, we used quantitative PCR (qPCR), and to analyze the composition and diversity of the bacterial and fungal communities, we used a bar-coded pyrosequencing technique. Both the relative abundance and diversity of bacteria were positively related to pH, the latter nearly doubling between pH 4 and 8. In contrast, the relative abundance of fungi was unaffected by pH and fungal diversity was only weakly related with pH. The composition of the bacterial communities was closely defined by soil pH; there was as much variability in bacterial community composition across the 180-m distance of this liming experiment as across soils collected from a wide range of biomes in North and South America, emphasizing the dominance of pH in structuring bacterial communities. The apparent direct influence of pH on bacterial community composition is probably due to the narrow pH ranges for optimal growth of bacteria. Fungal community composition was less strongly affected by pH, which is consistent with pure culture studies, demonstrating that fungi generally exhibit wider pH ranges for optimal growth. The ISME Journal (2010) 4, 1340-1351; doi: 10.1038/ismej.2010.58; published online 6 May 2010&nbsp

Oxygen: A Fundamental Property Regulating Pelagic Ecosystem Structure in the Coastal Southeastern Tropical Pacific

Background: In the southeastern tropical Pacific anchovy (Engraulis ringens) and sardine (Sardinops sagax) abundance have recently fluctuated on multidecadal scales and food and temperature have been proposed as the key parameters explaining these changes. However, ecological and paleoecological studies, and the fact that anchovies and sardines are favored differently in other regions, raise questions about the role of temperature. Here we investigate the role of oxygen in structuring fish populations in the Peruvian upwelling ecosystem that has evolved over anoxic conditions and is one of the world's most productive ecosystems in terms of forage fish. This study is particularly relevant given that the distribution of oxygen in the ocean is changing with uncertain consequences. Methodology/Principal Findings: A comprehensive data set is used to show how oxygen concentration and oxycline depth affect the abundance and distribution of pelagic fish. We show that the effects of oxygen on anchovy and sardine are opposite. Anchovy flourishes under relatively low oxygen conditions while sardine avoid periods/areas with low oxygen concentration and restricted habitat. Oxygen consumption, trophic structure and habitat compression play a fundamental role in fish dynamics in this important ecosystem. Conclusions/Significance: For the ocean off Peru we suggest that a key process, the need to breathe, has been neglected previously. Inclusion of this missing piece allows the development of a comprehensive conceptual model of pelagic fish populations and change in an ocean ecosystem impacted by low oxygen. Should current trends in oxygen in the ocean continue similar effects may be evident in other coastal upwelling ecosystems