Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas.

Glucagon-like-peptide-1 (GLP1) analogs may induce thyroid or pancreatic diseases in animals, raising questions about their use in diabetic patients. There is, however, controversy regarding expression of GLP1 receptors (GLP1R) in human normal and diseased thyroid and pancreas. Here, 221 human thyroid and pancreas samples were analyzed for GLP1R immunohistochemistry and compared with quantitative in vitro GLP1R autoradiography. Neither normal nor hyperplastic human thyroids containing parafollicular C cells express GLP1R with either method. Papillary thyroid cancer do not, and medullary thyroid carcinomas rarely express GLP1R. Insulin- and somatostatin-producing cells in the normal pancreas express a high density of GLP1R, whereas acinar cells express them in low amounts. Ductal epithelial cells do not express GLP1R. All benign insulinomas express high densities of GLP1R, whereas malignant insulinomas rarely express them. All ductal pancreatic carcinomas are GLP1R negative, whereas 6/20 PanIN 1/2 and 0/12 PanIN 3 express GLP1R. Therefore, normal thyroid, including normal and hyperplastic C cells, or papillary thyroid cancer are not targets for GLP1 analogs in humans. Conversely, all pancreatic insulin- and somatostatin-producing cells are physiological GLP1 targets, as well as most acini. As normal ductal epithelial cells or PanIN 3 or ductal pancreatic carcinomas do not express GLP1R, it seems unlikely that GLP1R is related to neoplastic transformation in pancreas. GLP1R-positive medullary thyroid carcinomas and all benign insulinomas are candidates for in vivo GLP1R targeting.Modern Pathology advance online publication, 12 September 2014; doi:10.1038/modpathol.2014.113.

Overexpression of EphB4 in the mammary epithelium shifts the differentiation pathway of progenitor cells and promotes branching activity and vascularization

Postnatally, the mammary gland undergoes continuous morphogenesis and thereby is especially prone to malignant transformation. Thus, the maintenance of the epithelium depends on a tight control of stem cell recruitment. We have previously shown that epithelial overexpression of the EphB4 receptor results in defective mammary epithelial development and conferred a metastasizing tumor phenotype on experimental mouse mammary tumors accompanied by a preponderance of progenitor cells. To analyze the effect of EphB4 overexpression on mammary epithelial cell fate, we have used Fluorescence Activated Cell Sorting (FACS) analyses to quantify epithelial sub-populations and repopulation assays of cleared fat pads to investigate their regenerative potential. These experiments revealed that deregulated EphB4 expression leads to an augmentation of bi-potent progenitor cells and to a shift of the differentiation pathway towards the luminal lineage. The analyses of the ductal outgrowths indicated that EphB4 overexpression leads to enforced branching activity, impedes ductal differentiation and stimulates angiogenesis. To elucidate the mechanisms forwarding EphB4 signals, we have compared the expression profile of defined cell populations between EphB4 transgene and wild type mammary glands concentrating on the wnt signaling pathway and on genes implicated in cell migration. With respect to wnt signaling, the progenitor cell population was the most affected, whereas the stem cell-enriched population showed the most pronounced deregulation of migration-associated genes. Thus, the luminal epithelial EphB4 signaling contributes, most likely via wnt signaling, to the regulation of migration and cell fate of early progenitors and is involved in the determination of branching points along the ductal tree.

The research-action interface in sustainable land management in Kyrgyzstan and Tajikistan: Challenges and recommendations

International agencies and programmes introduced sustainable land management (SLM) to Central Asia after the former Soviet Republics became independent in 1991. An aim of early SLM initiatives was to address challenges linked to the transformation of the agricultural sector from a centrally planned economy to a decentralized market economy. This article analyses the knowledge–action interface in Kyrgyzstan and Tajikistan as it relates to SLM. The analysis focuses on the influence of underlying land management concepts by means of a literature review. Contemporary barriers at the research–action interface were identified using participatory appraisal. And a historically contextualized understanding of the effectiveness of interactions between researchers, policy makers and practitioners is based on an analysis of purposefully selected cases. The study concludes that knowledge of different stakeholder groups is often highly disconnected. Interdisciplinary and transdisciplinary studies are rare, and academic research on SLM has subsequently been ineffective at contributing to substantial benefits for society. Further, researchers, policy makers and practitioners in this context must recognize the differences between SLM and what is often referred to as the equivalent Soviet-era concept—rational use of land resources—and the resulting implications of these differences. The authors recommend the following: creating an enabling environment for SLM research through academic institutional reform removing structural constraints, making research outcomes more effective by applying systems approaches that produce evidence for policy makers on the multiple benefits of SLM, helping land users evaluate SLM strategies and investing in the establishment and maintenance of a multi-stakeholder SLM platform that allows dynamic exchange.

An outbreak of Arthroderma vanbreuseghemii dermatophytosis at a veterinary school associated with an infected horse

We report a case of an outbreak of inflammatory dermatophytoses caused by Arthroderma vanbreuseghemii (formally Trichophyton mentagrophytes pro parte) that involved an infected horse, the owner and at least 20 students, staff and stablemen at a veterinary school in Bern (Switzerland) that presented highly inflammatory dermatitis of the body and the face. Transmission from human to human was also recorded as one patient was the partner of an infected person. Both the phenotypic characteristics and ITS sequence of the dermatophytes isolated from the horse and patients were identical, consistent with the conclusion that the fungus originated from the horse. Three infected persons had not been in direct contact with the horse. Although direct transmission from human to human cannot be ruled out, fomites were most likely the source of infection for these three patients. Inspection of the literature at the end of the nineteenth and beginning of the twentieth century revealed that this dermatophyte was frequently transmitted from horses to humans in contact with horses (stablemen, coachmen, carters and artillery soldiers). The rarity of the present case report at the present time is likely related to the transformation of civilisation from the nineteenth century to nowadays in Europe with the change of horse husbandry. In addition, the inadequate immune response of the horse and the high number of people in contact with it at the equine clinic may explain the exceptional aspect of this case report.

Signal transduction of {\it HER-2\/}/{\it neu\/} receptor tyrosine kinase

Overexpression and/or amplification of HER2/neu is frequently detected in many human cancers. Activation of p185 tyrosine kinase can be achieved by point mutation, overexpression, deletion, and heterodimerization with other class I receptors. In this study I investigated the signal transduction pathways mediating the oncogenic signal of the point mutation-activated rat p185. I demonstrated that tyrosine phosphorylation of Shc and formation of Shc/Grb2 complex correlated to the transformation of NIH3T3 cells caused by the point mutation-activated rat HER2/neu. Furthermore, I observed that association with Shc was severely impaired by deletion of most of the major autophosphorylation sites of the point-mutated p185. The truncated p185 product, however, fully retained its ability to transform NIH3T3 cells, induce Shc tyrosine phosphorylation and Shc/Grb2 complex formation. These results suggest that tyrosine phosphorylation of Shc which allows formation of Shc/Grb2 complex may play an important role in cell transformation induced by the point mutation-activated p185, and that stable binding to mutant p185 may not be necessary for Shc to mediate this signaling pathway.^ Recent studies have suggested that formation of the complex containing Sos, Grb2 and Shc is important in coupling receptor tyrosine kinases to the Ras signaling pathway. To clarify the role of this trimer in the oncogenic signaling of the activated p185, I set out to interfere with the protein-protein interactions in Shc/Grb2/Sos complex by introducing Grb2 mutants with deletions in either amino- ($\Delta$N-Grb2) or carboxyl- ($\Delta$C-Grb2) terminal SH3 domains into B104-1-1 cells derived from NIH3T3 cells that express the point mutation-activated HER-2/neu. I found that the transformed phenotypes of the B104-1-1 cells were largely reversed by expression of the $\Delta$N-Grb2. The effect of the $\Delta$C-Grb2 on phenotypic reversion was much weaker. Biochemical analysis showed that the $\Delta$N-Grb2 was able to associate Shc but not the activated p185 nor Sos, while the $\Delta$C-Grb2 bound to Shc, the activated p185, and Sos. The p185-mediated Ras activation was severely inhibited by the $\Delta$N-Grb2 but not the $\Delta$C-Grb2. Taken together, these data demonstrate that interruption of the interaction between Shc and the endogenous Grb2 by the $\Delta$N-Grb2 is able to impair the oncogenic signaling of the mutation-activated p185, indicating that (i) the $\Delta$N-Grb2 functions as a strong dominant-negative mutant, (ii) Shc/Grb2/Sos pathway plays a major role in mediating the oncogenic signal of the mutation-activated p185. Unlike the $\Delta$N-Grb2, the $\Delta$C-Grb2 appears to be a relatively weak dominant-negative mutant, probably due to its ability to largely fulfill the biological functions of the wild-type Grb2. ^

Growth regulatory role of R -PTPmu in normal and neoplastic epithelial cells

Cellular oncogenes and tumor suppressor genes regulate cellular adhesion and proliferation, two important events in malignant transformation. Even though receptor-like protein tyrosine phosphatases (R-PTPs) can influence these events, their role in malignant transformation has not been studied. The major goal of this study was to determine whether downregulation of R-PTP$\mu$ expression in lung epithelial cells is associated with or causal to neoplastic transformation. Examination of R-PTP$\mu$ expression in normal and carcinoma cells demonstrated that lung epithelial cells expressed R-PTP$\mu$ whereas lung carcinoma cells did not, and that incubation with TGF-$\alpha$ and HGF induced a two fold increase in R-PTP$\mu$ mRNA expression. To associate the expression of R-PTP$\mu$ with neoplastic transformation, we transfected lung epithelial cells with the H-ras oncogene. Transformation resulted in the activation of the MAPK signal transduction pathway, the hyperphosphorylation of c-met, and the production of HGF. Upon analysis of R-PTP$\mu$ expression, we observed a significant decrease in R-PTP$\mu$ mRNA and protein levels suggesting that transformation can directly or indirectly downregulate the expression of R-PTP$\mu.$ TGF-$\beta$ reversed the H-ras transformed phenotype, an event directly correlated with upregulation of R-PTP$\mu.$ To provide a casual relationship between R-PTP$\mu$ and cessation of tumor cell growth, we transfected carcinoma cells with the wild type R-PTP$\mu$ cDNA. Transiently expressing cells were selected by FACS using the mAb 3D7 and plated into individual wells. Carcinoma cells positive for R-PTP$\mu$ expression did not grow into colonies whereas non-R-PTP$\mu$ expressing carcinoma cells did, suggesting that expression of R-PTP$\mu$ arrested cell growth. To better understand the growth arrest induced by R-PTP$\mu$, we transfected the H-ras transformed lung epithelial cell line (MvLu-1-ras) with R-PTP$\mu$ (MvLu-1-ras/R-PTP$\mu$). Examination of growth factor receptor phosphorylation revealed significant inhibition of c-met and EGF-R. Furthermore, these cells underwent apoptosis in the absence of serum. Taken together the data demonstrate that the downregulation of R-PTP$\mu$ expression is an important step in neoplastic transformation of lung epithelial cells and that its presence can induce apoptosis and inhibit the signaling of c-met and EGF-R, two major growth factor receptors in lung carcinoma. In conclusion, the expression of R-PTP$\mu$ is inversely correlated with neoplastic transformation, growth and survival of tumor cells. ^

Functional studies of a LIM -homeodomain transcription factor lmx1b in murine mid -hindbrain and limb development

This thesis is centered on applying molecular genetics to study pattern formation during animal development. More specifically, this thesis describes the functional studies of a LIM-homeodomain gene called lmx1b during murine embryogenesis. Lmx1b expression is restricted to the mid-hindbrain junction as well as to the dorsal mesenchyme of the limb, suggesting important functions during mid-hindbrain and limb development. To test these possibilities, lmx1b homozygous mutant mice were generated and their limb and CNS phenotypes examined. Lmx1b homozygous mutant mice exhibit a large reduction of mid-hindbrain structures, and that their limbs are symmetrical along the dorsal-ventral axis as the result of a dorsal to ventral transformation. Taken together, these studies define essential functions for lmx1b in mid-hindbrain patteming and in dorsal limb cell fate determination. However, the molecular mechanisms which accounts for these phenotypes are unknown, and whether lmx1b has same or distinctive functions during the mid-hindbrain and limb development is also unclear. ^ Recently, insight into molecular mechanisms of mid-hindbrain patterning and limb development has resulted from the identification of several factors with restricted expression patterns within these regions. These include the secreted factors wnt-1, fgf-8, wnt-7a and the transcription factors pax-2, and en-1. Targeted disruption of any of these genes in mice suggests that these genes might be involved in similar regulatory pathways. Analysis of the expression of these genes in lmx1b mutants demonstrates that lmxlb is not required for the initiation, but is required to maintain their expression at the mid-hindbrain junction. Thus, lmxlb is not required for specifying mid-hindbrain cell fates, rather, it functions to ensure the establishment or maintenance of a proper organizing center at the mid-hindbrain junction. Interestingly, lmxlb functions cell non-autonomously in chimera analysis, which indicates that lmx1b might regulate the expression of secreted factors such as wnt-1 and/or fgf-8 in the organizing center. In contrast, lmx1b functions cell autonomously in the dorsal limb to govern dorsal ventral limb development and its expression is regulated by with wnt-7a and en-1. However, single and double mutant analysis suggest that all three genes have partially overlapping functions as well as independent functions. The results point toward a complicated network of cross-talks among all three limb axes. ^

Minerals, native metals, and intermetallides in bottom sediments of the Markov Deep, Mid-Atlantic Ridge

Bottom sediments of the Markov Deep contain rather large (>0.1 mm) grains of native minerals and intermetallides of noble and nonferrous metals that can be concentrated in placers. Intermetallides of Pt and Fe are likely to be derivates of the gold-hematite-barite assemblage that forms at late (low-depth) stages of hydrothermal massive sulfide formation. Mineral association of native forms of lead, tin, and copper with Zn-bearing copper may be related to hydrothermal transformation of ultrabasic and basic rocks accompanied by massive sulfide copper mineralization. The association of these minerals of native elements in bottom sediments can also serve as a prospecting guide for sulfide mineralization both at the Sierra Leone site, in particular, and on the seafloor, in general.

Los extranjeros de Buenos Aires en los albores del siglo XIX : Algunos rasgos de su composición

Para el período colonial tardío, Buenos Aires era una ciudad diferente del resto de Hispanoamérica, tanto en términos de su cultura como en sus manifestaciones sociales y en su crecimiento poco común. Bastaron poco más de tres décadas para que la pequeña aldea se transformara en una pujante ciudad hispanoamericana. La clave de esta transformación estuvo dada a lo largo de todo el siglo XVIII, dado que éste fue un período de profundos cambios político-sociales y Buenos Aires no fue la excepción. La ciudad comenzó a cambiar en todos sus aspectos. En primer lugar el conflicto de la España Borbónica con Inglaterra y Portugal llevó a introducir cambios profundos en la política española para el control estricto de las colonias en los bordes del imperio. La creación del Virreinato del Río de la Plata en 1776 y la extensión de la ordenanza de libre comercio dos años más tarde otorgaron un gran empuje a la ciudad. De este modo, Buenos Aires pasó a ser un activo polo de atracción tanto para los migrantes internos como para los externos del imperio español. Estos motivos provocaron mutaciones a nivel político, social y arquitectónico, dando lugar a un crecimiento único para una ciudad hispanoamericana entre 1750 y 1810

Communication and enhancement of Italian cultural heritage by Google

Tras liderar la investigación e indización de la información por cerca de una década, el motor de búsqueda Google se ha convertido en un sistema económico que influye nuestro mundo contemporáneo, contribuyendo grandemente a la transformación de nuestro mundo en un único globo virtual. En años recientes, Google ha comenzado a ofrecer a los usuarios globales aplicaciones o software que son usados para nuestra herencia cultural. Este software se resalta aquí en su potencial, desde un punto de vista económico, cultural y turístico. Tratamos de describir lo más importante del software de Google (como Google Maps, Google Street View, Google Earth, Google SketchUp, Google Books y Google Art Project), con el mayor y más evidente impacto en los sectores culturales y turísticos. Este ensayo muestra la digitalización y promoción de la herencia cultural italiana en Google, a través de sus programas informáticos (por ejemplo, Google Street View que ha llevado al uso de vistas tridimensionales remotas de algunos de los más importantes monumentos y sitios arqueológicos de Italia; el uso de Google SketchUp ha llevado al diseño de reconstrucción tridimensional del histórico centro de la ciudad de L'Aquila, devastada luego del terremoto de abril de 2009 y nunca reconstruida), y a través de diversos programas asociados específicos con el Ministerio Italiano de Cultura

Los extranjeros de Buenos Aires en los albores del siglo XIX : Algunos rasgos de su composición

Para el período colonial tardío, Buenos Aires era una ciudad diferente del resto de Hispanoamérica, tanto en términos de su cultura como en sus manifestaciones sociales y en su crecimiento poco común. Bastaron poco más de tres décadas para que la pequeña aldea se transformara en una pujante ciudad hispanoamericana. La clave de esta transformación estuvo dada a lo largo de todo el siglo XVIII, dado que éste fue un período de profundos cambios político-sociales y Buenos Aires no fue la excepción. La ciudad comenzó a cambiar en todos sus aspectos. En primer lugar el conflicto de la España Borbónica con Inglaterra y Portugal llevó a introducir cambios profundos en la política española para el control estricto de las colonias en los bordes del imperio. La creación del Virreinato del Río de la Plata en 1776 y la extensión de la ordenanza de libre comercio dos años más tarde otorgaron un gran empuje a la ciudad. De este modo, Buenos Aires pasó a ser un activo polo de atracción tanto para los migrantes internos como para los externos del imperio español. Estos motivos provocaron mutaciones a nivel político, social y arquitectónico, dando lugar a un crecimiento único para una ciudad hispanoamericana entre 1750 y 1810

Communication and enhancement of Italian cultural heritage by Google

Tras liderar la investigación e indización de la información por cerca de una década, el motor de búsqueda Google se ha convertido en un sistema económico que influye nuestro mundo contemporáneo, contribuyendo grandemente a la transformación de nuestro mundo en un único globo virtual. En años recientes, Google ha comenzado a ofrecer a los usuarios globales aplicaciones o software que son usados para nuestra herencia cultural. Este software se resalta aquí en su potencial, desde un punto de vista económico, cultural y turístico. Tratamos de describir lo más importante del software de Google (como Google Maps, Google Street View, Google Earth, Google SketchUp, Google Books y Google Art Project), con el mayor y más evidente impacto en los sectores culturales y turísticos. Este ensayo muestra la digitalización y promoción de la herencia cultural italiana en Google, a través de sus programas informáticos (por ejemplo, Google Street View que ha llevado al uso de vistas tridimensionales remotas de algunos de los más importantes monumentos y sitios arqueológicos de Italia; el uso de Google SketchUp ha llevado al diseño de reconstrucción tridimensional del histórico centro de la ciudad de L'Aquila, devastada luego del terremoto de abril de 2009 y nunca reconstruida), y a través de diversos programas asociados específicos con el Ministerio Italiano de Cultura

Los extranjeros de Buenos Aires en los albores del siglo XIX : Algunos rasgos de su composición

Para el período colonial tardío, Buenos Aires era una ciudad diferente del resto de Hispanoamérica, tanto en términos de su cultura como en sus manifestaciones sociales y en su crecimiento poco común. Bastaron poco más de tres décadas para que la pequeña aldea se transformara en una pujante ciudad hispanoamericana. La clave de esta transformación estuvo dada a lo largo de todo el siglo XVIII, dado que éste fue un período de profundos cambios político-sociales y Buenos Aires no fue la excepción. La ciudad comenzó a cambiar en todos sus aspectos. En primer lugar el conflicto de la España Borbónica con Inglaterra y Portugal llevó a introducir cambios profundos en la política española para el control estricto de las colonias en los bordes del imperio. La creación del Virreinato del Río de la Plata en 1776 y la extensión de la ordenanza de libre comercio dos años más tarde otorgaron un gran empuje a la ciudad. De este modo, Buenos Aires pasó a ser un activo polo de atracción tanto para los migrantes internos como para los externos del imperio español. Estos motivos provocaron mutaciones a nivel político, social y arquitectónico, dando lugar a un crecimiento único para una ciudad hispanoamericana entre 1750 y 1810

Communication and enhancement of Italian cultural heritage by Google

Tras liderar la investigación e indización de la información por cerca de una década, el motor de búsqueda Google se ha convertido en un sistema económico que influye nuestro mundo contemporáneo, contribuyendo grandemente a la transformación de nuestro mundo en un único globo virtual. En años recientes, Google ha comenzado a ofrecer a los usuarios globales aplicaciones o software que son usados para nuestra herencia cultural. Este software se resalta aquí en su potencial, desde un punto de vista económico, cultural y turístico. Tratamos de describir lo más importante del software de Google (como Google Maps, Google Street View, Google Earth, Google SketchUp, Google Books y Google Art Project), con el mayor y más evidente impacto en los sectores culturales y turísticos. Este ensayo muestra la digitalización y promoción de la herencia cultural italiana en Google, a través de sus programas informáticos (por ejemplo, Google Street View que ha llevado al uso de vistas tridimensionales remotas de algunos de los más importantes monumentos y sitios arqueológicos de Italia; el uso de Google SketchUp ha llevado al diseño de reconstrucción tridimensional del histórico centro de la ciudad de L'Aquila, devastada luego del terremoto de abril de 2009 y nunca reconstruida), y a través de diversos programas asociados específicos con el Ministerio Italiano de Cultura

Mineral and chemical compositions of authigenic carbonates from the northern Deryugin Basin, Sea of Okhotsk

Mineral and chemical compositions of authigenic carbonates are studied by several methods in a sediment core collected in the axial zone of the Deryugin riftogenic basin. Manganese carbonates (kutnahorite, rhodochrosite) associated with manganiferous calcite, manganiferous pyrite, and nontronite are firstly identified in the Sea of Okhotsk. Manganese carbonates in Holocene diatomaceous ooze were presumably formed due to diagenetic transformation of sedimentary manganese hydroxides, organic matter, and biogenic silica, while those found in the underlying turbidites precipitated owing to the intermittent influx of endogenic fluids migrating along sand interbeds.