Diet, microbiota, and the mucus layer: The guardians of our health

The intestinal tract is an ecosystem in which the resident microbiota lives in symbiosis with its host. This symbiotic relationship is key to maintaining overall health, with dietary habits of the host representing one of the main external factors shaping the microbiome-host relationship. Diets high in fiber and low in fat and sugars, as opposed to Western and high-fat diets, have been shown to have a beneficial effect on intestinal health by promoting the growth of beneficial bacteria, improve mucus barrier function and immune tolerance, while inhibiting pro-inflammatory responses and their downstream effects. On the contrary, diets low in fiber and high in fat and sugars have been associated with alterations in microbiota composition/functionality and the subsequent development of chronic diseases such as food allergies, inflammatory bowel disease, and metabolic disease. In this review, we provided an updated overview of the current understanding of the connection between diet, microbiota, and health, with a special focus on the role of Western and high-fat diets in shaping intestinal homeostasis by modulating the gut microbiota

Endothelial progenitor cell biology in disease and tissue regeneration

Endothelial progenitor cells are increasingly being studied in various diseases ranging from ischemia, diabetic retinopathy, and in cancer. The discovery that these cells can be mobilized from their bone marrow niche to sites of inflammation and tumor to induce neovasculogenesis has afforded a novel opportunity to understand the tissue microenvironment and specific cell-cell interactive pathways. This review provides a comprehensive up-to-date understanding of the physiological function and therapeutic utility of these cells. The emphasis is on the systemic factors that modulate their differentiation/mobilization and survival and presents the challenges of its potential therapeutic clinical utility as a diagnostic and prognostic reagent

Sedimentologic and stratigraphic evolution of the Cacheuta basin: Constraints on the development of the Miocene retroarc foreland basin, south-central Andes

Retroarc foreland basins in contractional arc settings contain evidence of temporal and spatial variations in magmatic activity, deformation, and exhumation along the continental margin and serve as excellent recorders of subduction dynamics through time. The Cacheuta basin, northwestern Mendoza Province, Argentina, is situated within the transition zone between the Pampean flat-slab subduction segment north of 33°S and the normal-dipping slab segment of the Southern Volcanic Zone to the south, and it records a detailed history of Andean orogenic exhumation at this latitude. The integration of sedimentologic, stratigraphic, geochronologic, and sediment provenance data from the Cacheuta basin constrains orogenic exhumation patterns and basin evolution during basin development. Cacheuta basin strata record at least a 12 m.y. period of basin evolution (ca. 20 Ma to younger than 7.5 Ma), based on new geochronology. The timing of initial basin subsidence is constrained by the lowermost sample in the Mariño Formation, which yielded a maximum depositional age of 19.2 ± 0.26 Ma, ∼4 m.y. earlier than previous interpretations. Conglomerate clast counts, thin section petrography, and detrital zircon analyses, coupled with distinct sedimentologic variations, record progressive orogenic exhumation of the Cordillera Principal, Cordillera Frontal, and Precordillera during early to middle Miocene time. Examination of basinal strata demonstrate that uplift of the Cordillera Principal, Cordillera Frontal, and Precordillera, and simultaneous development of the Cacheuta retroarc foreland basin, in the early to mid-Miocene was the result of contractional deformation and crustal thickening during normal subduction-related orogenic processes and did not result from the development of the flat slab in late Miocene time.Fil: Buelow, E. K.. University of Wisconsin; Estados UnidosFil: Suriano, Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Mahoney, J. B.. University of Wisconsin; Estados UnidosFil: Kimbrough, D. L.. San Diego State University; Estados UnidosFil: Mescua, Jose Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Giambiagi, Laura Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; ArgentinaFil: Hoke, Gregory D.. Syracuse University; Estados Unido

Hyperactive ERK and Persistent mTOR Signaling Characterize Vemurafenib Resistance in Papillary Thyroid Cancer Cells

Clinical studies evaluating targeted BRAFV600E inhibitors in advanced thyroid cancer patients are currently underway. Vemurafenib (BRAFV600E inhibitor) monotherapy has shown promising results thus far, although development of resistance is a clinical challenge. The objective of this study was to characterize development of resistance to BRAFV600E inhibition and to identify targets for effective combination therapy. We created a line of BCPAP papillary thyroid cancer cells resistant to vemurafenib by treating with increasing concentrations of the drug. The resistant BCPAP line was characterized and compared to its sensitive counterpart with respect to signaling molecules thought to be directly related to resistance. Expression and phosphorylation of several critical proteins were analyzed by Western blotting and dimerization was evaluated by immunoprecipitation. Resistance to vemurafenib in BCPAP appeared to be mediated by constitutive overexpression of phospho-ERK and by resistance to inhibition of both phospho-mTOR and phospho-S6 ribosomal protein after vemurafenib treatment. Expression of potential alternative signaling molecule, CRAF, was not increased in the resistant line, although formation of CRAF dimers appeared increased. Expression of membrane receptors HER2 and HER3 was greatly amplified in the resistant cancer cells. Papillary thyroid cancer cells were capable of overcoming targeted BRAFV600E inhibition by rewiring of cell signal pathways in response to prolonged vemurafenib therapy. Our study suggests that in vitro culture of cancer cells may be useful in assessing molecular resistance pathways. Potential therapies in advanced thyroid cancer patients may combine vemurafenib with inhibitors of CRAF, HER2/HER3, ERK, and/or mTOR to delay or abort development of resistance

E-Cadherin Destabilization Accounts for the Pathogenicity of Missense Mutations in Hereditary Diffuse Gastric Cancer

E-cadherin is critical for the maintenance of tissue architecture due to its role in cell-cell adhesion. E-cadherin mutations are the genetic cause of Hereditary Diffuse Gastric Cancer (HDGC) and missense mutations represent a clinical burden, due to the uncertainty of their pathogenic role. In vitro and in vivo, most mutations lead to loss-of-function, although the causal factor is unknown for the majority. We hypothesized that destabilization could account for the pathogenicity of E-cadherin missense mutations in HDGC, and tested our hypothesis using in silico and in vitro tools. FoldX algorithm was used to calculate the impact of each mutation in E-cadherin native-state stability, and the analysis was complemented with evolutionary conservation, by SIFT. Interestingly, HDGC patients harbouring germline E-cadherin destabilizing mutants present a younger age at diagnosis or death, suggesting that the loss of native-state stability of E-cadherin accounts for the disease phenotype. To elucidate the biological relevance of E-cadherin destabilization in HDGC, we investigated a group of newly identified HDGC-associated mutations (E185V, S232C and L583R), of which L583R is predicted to be destabilizing. We show that this mutation is not functional in vitro, exhibits shorter half-life and is unable to mature, due to premature proteasome-dependent degradation, a phenotype reverted by stabilization with the artificial mutation L583I (structurally tolerated). Herein we report E-cadherin structural models suitable to predict the impact of the majority of cancer-associated missense mutations and we show that E-cadherin destabilization leads to loss-of-function in vitro and increased pathogenicity in vivo

Impact of recycling and lateral sediment input on grain size fining trends – implications for reconstructing tectonic and climate forcings in ancient sedimentary systems

Grain size trends in basin stratigraphy are thought to preserve a rich record of the climatic and tectonic controls on landscape evolution. Stratigraphic models assume that over geological timescales, the downstream profile of sediment deposition is in dynamic equilibrium with the spatial distribution of tectonic subsidence in the basin, sea level and the flux and calibre of sediment supplied from mountain catchments. Here, we demonstrate that this approach in modelling stratigraphic responses to environmental change is missing a key ingredient: the dynamic geomorphology of the sediment routing system. For three large alluvial fans in the Iglesia basin, Argentine Andes we measured the grain size of modern river sediment from fan apex to toe and characterise the spatial distribution of differential subsidence for each fan by constructing a 3D model of basin stratigraphy from seismic data. We find, using a self-similar grain size fining model, that the profile of grain size fining on all three fans cannot be reproduced given the subsidence profile measured and for any sediment supply scenario. However, by adapting the self-similar model, we demonstrate that the grain size trends on each fan can be effectively reproduced when sediment is not only sourced from a single catchment at the apex of the system, but also laterally, from tributary catchments and through fan surface recycling. Without constraint on the dynamic geomorphology of these large alluvial systems, signals of tectonic and climate forcing in grain size data are masked and would be indecipherable in the geological record. This has significant implications for our ability to make sensitive, quantitative reconstructions of external boundary conditions from the sedimentary record

The MAJORANA DEMONSTRATOR: A Search for Neutrinoless Double-beta Decay of Germanium-76

The {\sc Majorana} collaboration is searching for neutrinoless double beta decay using $^{76}$Ge, which has been shown to have a number of advantages in terms of sensitivities and backgrounds. The observation of neutrinoless double-beta decay would show that lepton number is violated and that neutrinos are Majorana particles and would simultaneously provide information on neutrino mass. Attaining sensitivities for neutrino masses in the inverted hierarchy region, $15 - 50$ meV, will require large, tonne-scale detectors with extremely low backgrounds, at the level of $\sim$1 count/t-y or lower in the region of the signal. The {\sc Majorana} collaboration, with funding support from DOE Office of Nuclear Physics and NSF Particle Astrophysics, is constructing the {\sc Demonstrator}, an array consisting of 40 kg of p-type point-contact high-purity germanium (HPGe) detectors, of which $\sim$30 kg will be enriched to 87% in $^{76}$Ge. The {\sc Demonstrator} is being constructed in a clean room laboratory facility at the 4850' level (4300 m.w.e.) of the Sanford Underground Research Facility (SURF) in Lead, SD. It utilizes a compact graded shield approach with the inner portion consisting of ultra-clean Cu that is being electroformed and machined underground. The primary aim of the {\sc Demonstrator} is to show the feasibility of a future tonne-scale measurement in terms of backgrounds and scalability.Comment: Proceedings for the MEDEX 2013 Conferenc