A role for von Hippel-Lindau protein in pancreatic beta-cell function.

ObjectiveThe Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing. In humans, a germline mutation in the VHL gene leads to the von Hippel-Lindau disease, a familial syndrome characterized by benign and malignant tumors of the kidney, central nervous system, and pancreas.Research design and methodsWe use Cre-lox recombination to eliminate Vhlh in adult mouse pancreatic beta-cells. Morphology of mutant islets is assessed by immunofluorescence analysis. To determine the functional state of Vhlh(-/-) islets, insulin secretion is measured in vivo and in vitro, and quantitative PCR is used to identify changes in gene expression.ResultsLoss of VHL in beta-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for beta-cell specification and development, it is critical for beta-cell function. Insulin production is normal in beta-cells lacking VHL; however, insulin secretion in the presence of high concentrations of glucose is impaired. Furthermore, the loss of VHL leads to dysregulation of glycolytic enzymes, pointing to a perturbation of the intracellular energy homeostasis.ConclusionsWe show that loss of VHL in beta-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in beta-cell function. We believe that the beta-cell-specific Vhlh-deficient mice might be a useful tool as a "genetic hypoxia" model, to unravel the possible link between hypoxia signaling and impairment of beta-cell function

Multi-domain ferroelectricity as a limiting factor for voltage amplification in ferroelectric field-effect transistors

We revise the possibility of having an amplified surface potential in ferroelectric field-effect transistors pointed out by [S. Salahuddin and S. Datta, Nano Lett. 8, 405 (2008)]. We show that the negative-capacitance regime that allows for such an amplification is actually bounded by the appearance of multi-domain ferroelectricity. This imposes a severe limit to the maximum step-up of the surface potential obtainable in the device. We indicate new device design rules taking into account this scenario.Comment: 4 pages, 3 figure

AIP and MEN1 mutations and AIP immunohistochemistry in pituitary adenomas in a tertiary referral center.

Background: Pituitary adenomas have a high disease burden due to tumor growth/ invasion and disordered hormonal secretion. Germline mutations in genes such as MEN1 and AIP are associated with early onset of aggressive pituitary adenomas that can be resistant to medical therapy. Aims: We performed a retrospective screening study using published risk criteria to assess the frequency of AIP and MEN1 mutations in pituitary adenoma patients in a tertiary referral center. Methods: Pituitary adenoma patients with pediatric/adolescent onset, macroadenomas occurring ≤30 years of age, familial isolated pituitary adenoma (FIPA) kindreds and acromegaly or prolactinoma cases that were uncontrolled by medical therapy were studied genetically. We also assessed whether immunohistochemical staining for AIP (AIP-IHC) in somatotropinomas was associated with somatostatin analogs (SSA) response. Results: Fifty-five patients met the study criteria and underwent genetic screening for AIP/MEN1 mutations. No mutations were identified and large deletions/duplications were ruled out using MLPA. In a cohort of sporadic somatotropinomas, low AIP-IHC tumors were significantly larger (P = 0.002) and were more frequently sparsely granulated (P = 0.046) than high AIP-IHC tumors. No significant relationship between AIP-IHC and SSA responses was seen. Conclusions: Germline mutations in AIP/MEN1 in pituitary adenoma patients are rare and the use of general risk criteria did not identify cases in a large tertiary-referral setting. In acromegaly, low AIP-IHC was related to larger tumor size and more frequent sparsely granulated subtype but no relationship with SSA responsiveness was seen. The genetics of pituitary adenomas remains largely unexplained and AIP screening criteria could be significantly refined to focus on large, aggressive tumors in young patients

Extremal rotating black holes in Einsteinian cubic gravity

We obtain new solutions of Einsteinian cubic gravity coupled to a Maxwell field that describe the near-horizon geometry of charged and rotating black holes. We show that the AdS2×S2 near-horizon geometry of Reissner-Nordström black holes receives no corrections, but deviations with respect to the extremal Kerr-Newman solution appear as we turn on the angular momentum. We construct the profile of these corrected geometries using both numerical methods and slowly spinning expansions, but we also find additional solutions that do not reduce to AdS2×S2 geometries in any limit and that do not have a counterpart in Einstein gravity. Quite remarkably, we are able to obtain closed-form exact expressions for the area and Wald's entropy of all of these solutions, and using this result, we analyze the phase space of extremal back holes in this theory. To the best of our knowledge, this is the first time the entropy of a rotating black hole in higher-order gravity has been exactly computedP. A. C. was mostly funded by Fundación la Caixa through a “la Caixa–Severo Ochoa” International predoctoral grant. In the last stages of this project P. A. C. was supported by the Katholieke Universiteit Leuven (KU Leuven) grant “Bijzonder Onderzoeksfonds C16/16/005—Horizons in hoge-energie fysica.” D. P. is funded by a “Centro de Excelencia Internacional Universidad Autonoma de Madrid (UAM)/ Consejo Superior de Investigaciones Cientificas (CSIC)” Formacion Personal Investigador (FPI) predoctoral grant. P. A. C. and D. P. were further supported by the Ministerio de Economía y Competitividad (MINECO)/Fondo Europeo de Desarrollo Regional (FEDER), European Union (EU) Grant No. PGC2018-095205-B-I00, and by the “Centro de Excelencia Severo Ochoa” Program Grant No. SEV2016-059

Near-horizon geometries and black hole thermodynamics in higher-derivative AdS5_5 supergravity

Higher-derivative corrections in the AdS/CFT correspondence allow us to capture finer details of the dual CFT and to explore the holographic dictionary beyond the infinite N and strong coupling limits. Following an effective field theory approach, we investigate extremal AdS black hole solutions in five-dimensional supergravity with higher-derivative corrections. We provide a general analysis of near-horizon geometries of rotating extremal black holes and show how to obtain their corresponding charges and chemical potentials. We discuss the near-horizon solutions of the two-derivative theory, which we write using a novel parametrization that eases our computation of the higher-derivative corrections. The charges and thermodynamic properties of the black hole are computed while clarifying the ambiguities in their definitions. The charges and potentials turn out to satisfy a near-horizon version of the first law of thermodynamics whose interpretation we make clear. In the supersymmetric case, the results are shown to match the field theory prediction as well as previous results obtained from the on-shell action.Comment: 41 pages and 1 figure; ancillary Mathematica notebook with corresponding higher derivative result

The extremal Kerr entropy in higher-derivative gravities

We investigate higher derivative corrections to the extremal Kerr black hole in the context of heterotic string theory with $\alpha'$ corrections and of a cubic-curvature extension of general relativity. By analyzing the near-horizon extremal geometry of these black holes, we are able to compute the Iyer-Wald entropy as well as the angular momentum via generalized Komar integrals. In the case of the stringy corrections, we obtain the physically relevant relation $S(J)$ at order $\alpha'^2$. On the other hand, the cubic theories, which are chosen as Einsteinian cubic gravity plus a new odd-parity density with analogous features, possess special integrability properties that enable us to obtain exact results in the higher-derivative couplings. This allows us to find the relation $S(J)$ at arbitrary orders in the couplings and even to study it in a non-perturbative way. We also extend our analysis to the case of the extremal Kerr-(A)dS black hole.Comment: 33 pages+appendices, one figur

La ruta de señalización WNT en la determinación de progenitores pancreáticos

1 página. IX Jornadas Andaluzas Salud Investiga. Cádiz 20-22 octubre, 2010.Nuestro laboratorio trata de determinar los mecanismos moleculares implicados en la formación de los distintos tipos celulares pancreáticos adultos a partir de células progenitoras. Este conocimiento es fundamental para comprender las bases de enfermedades tan terribles como el cáncer pancreático. Además, es absolutamente necesario para el desarrollo de protocolos de formación in vitro de células beta productoras de insulina, una atractiva estrategia terapéutica para la diabetes. A este respecto, el papel de la ruta de señalización embrionaria Wnt parece ser importante ya que estudios previos han demostrado que la activación de esta ruta es necesaria para la formación de células pancreáticas a partir de células embrionarias. En nuestro proyecto nos hemos planteado determinar el efecto de la ruta Wnt sobre la formación de páncreas sobreactivando dicha ruta en progenitores pancreáticos en el ratón.Peer reviewe

Loss of pancreas upon activated Wnt signaling is concomitant with emergence of gastrointestinal identity

Organ formation is achieved through the complex interplay between signaling pathways and transcriptional cascades. The canonical Wnt signaling pathway plays multiple roles during embryonic development including patterning, proliferation and differentiation in distinct tissues. Previous studies have established the importance of this pathway at multiple stages of pancreas formation as well as in postnatal organ function and homeostasis. In mice, gain-of-function experiments have demonstrated that activation of the canonical Wnt pathway results in pancreatic hypoplasia, a phenomenon whose underlying mechanisms remains to be elucidated. Here, we show that ectopic activation of epithelial canonical Wnt signaling causes aberrant induction of gastric and intestinal markers both in the pancreatic epithelium and mesenchyme, leading to the development of gut-like features. Furthermore, we provide evidence that β -catenin-induced impairment of pancreas formation depends on Hedgehog signaling. Together, our data emphasize the developmental plasticity of pancreatic progenitors and further underscore the key role of precise regulation of signaling pathways to maintain appropriate organ boundaries

The effect of experience and instructions on learned attentional biases

Afiliaciones: Instituto de Investigación Biomédica de Málaga (IBIMA), University of Malaga, Spain Primary Care and Public Health Sciences, King’s College London, UK School of Psychology, UNSW Australia, Sydney, AustraliaIt has been shown that selective attention is allocated to the best available predictor of an outcome, which is known as learned predictiveness. Mitchell et al. (2012) have shown that instructions about the ‘relevance’ of each stimulus can influence (and even reverse) the learned predictiveness attentional bias, suggesting that propositional reasoning plays a crucial role in this phenomenon. Our experiment further explores the effects of instructions on this learned attentional bias. As a difference with previous work, we measured attentional capture through spatial cueing effects, which have been found to rely on rapid attentional processes (Le Pelley et al., 2013). Participants responded faster to events presented in the spatial location cued by stimuli that had previously been trained as predictive through trial-by-trial learning. However, verbal instructions regarding relevance failed to speed up participants’ responses or to modulate the effect of learned predictiveness on spatial cueing. These results suggest that predictive stimuli produce an attentional bias which is not (always) under voluntary control.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech