Insulin in the Brain: Its Pathophysiological Implications for States Related with Central Insulin Resistance, Type 2 Diabetes and Alzheimer’s Disease

Although the brain has been considered an insulin-insensitive organ, recent reports on the location of insulin and its receptors in the brain have introduced new ways of considering this hormone responsible for several functions. The origin of insulin in the brain has been explained from peripheral or central sources, or both. Regardless of whether insulin is of peripheral origin or produced in the brain, this hormone may act through its own receptors present in the brain. The molecular events through which insulin functions in the brain are the same as those operating in the periphery. However, certain insulin actions are different in the central nervous system, such as hormone-induced glucose uptake due to a low insulin-sensitive GLUT-4 activity, and because of the predominant presence of GLUT-1 and GLUT-3. In addition, insulin in the brain contributes to the control of nutrient homeostasis, reproduction, cognition, and memory, as well as to neurotrophic, neuromodulatory, and neuroprotective effects. Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes mellitus (T2DM), and Alzheimer’s disease (AD). A close association between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients, and some authors have proposed the name “type 3 diabetes” for this association. There are links between AD and T2DM through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein O-GlcNAcylation, formation of amyloid plaques, altered Aβ metabolism, and tau hyperphosphorylation. Advances in the knowledge of preclinical AD and T2DM may be a major stimulus for the development of treatment for preventing the pathogenic events of these disorders, mainly those focused on reducing brain insulin resistance, which is seems to be a common ground for both pathological entities

Role of Nutrient and Energy Sensors in the Development of Type 2 Diabetes

Cell survival depends on the constant challenge to match energy demands with nutrient availability. This process is mediated through a highly conserved network of metabolic fuel sensors that orchestrate both a cellular and whole-body energy balance. A mismatch between cellular energy demand and nutrient availability is a key factor in the development of type 2 diabetes, obesity, metabolic syndrome, and other associated pathologies; thus, understanding the fundamental mechanisms by which cells detect nutrient availability and energy demand may lead to the development of new treatments. This chapter reviews the role of the sensor PASK (protein kinase with PAS domain), analyzing its role in the mechanisms of adaptation to nutrient availability and the metabolic response in different organs (liver, hypothalamus) actively cooperating to control food intake, maintain glycaemia homeostasis, and prevent insulin resistance and weight gain

Elaboración de blogs como herramienta virtual de aprendizaje y trabajo en equipo

Este proyecto de innovación se enmarca dentro de las actividades académicas no presenciales. Se trata de la elaboración de blogs como herramienta virtual de aprendizaje. Los blogs son un recurso de aprendizaje individual o grupal, de gran versatilidad y dinamización del aula. Además, promueve el desarrollo de competencias generales, específicas y transversales que los alumnos deben adquirir durante su formación. Creemos que su aplicación es especialmente interesante en asignaturas como “Bases Celulares de la Genética Humana” impartida en primero de Medicina, donde los alumnos se encuentran con una dificultad añadida a la complejidad de sus fundamentos: unos conceptos complejos con una terminología muy específica para asimilarlos. Los futuros médicos deberán ser capaces, de explicar con un lenguaje sencillo y comprensible a los pacientes la implicación de la genética en las patologías. Consideramos que el uso de blogs está especialmente indicado en este caso para facilitar la adquisición de esta competencia específica, además de apoyar el aprendizaje de parte de los contenidos de la asignatura y promover el trabajo en equipo. Esta herramienta aporta a los alumnos las competencias necesarias para su formación integral como profesional de la salud promoviendo el intercambio colaborativo. Es además, un recurso que puede ser utilizado tanto para la evaluación continua, por parte del profesor durante y a la finalización del diseño del blog, así como para la coevaluación entre los alumnos. Por tanto, esta propuesta facilita el aprendizaje creando espacios para ello. En definitiva, crea oportunidades de aprendizaje

Histone variant MacroH2A1 is downregulated in prostate cancer and influences malignant cell phenotype

Background: Prostate cancer (PCa), a major cause of cancer-related morbidity and mortality worldwide and mostly asymptomatic at earliest stages, is characterized by disruption of genetic and epigenetic balance. A better understanding of how those mechanisms orchestrate disease might improve diagnostic and prognostic tools, allowing for improvements in treatment efficacy. Replacement of canonical histones, an epigenetic mechanism, is highly conserved among species and altered expression of histones variants (e.g., MacroH2A1) has been associated with tumorigenesis. H2AFY gene encodes two isoforms of H2A histone variant MacroH2A1: MacroH2A1.1 and MacroH2A1.2. Specifically, MacroH2A1.1 isoform inhibits cell proliferation and promotes cellular differentiation. Because the contribution of this histone variant to carcinogenesis has been reported in several cancer types, but not for PCa, we aimed to investigate the contribution of MacroH2A1 for prostate carcinogenesis. Methods: MacroH2A1, MacroH2A1.1 and MacroH2A1.2 isoforms and the corresponding splicing regulators transcript levels were evaluated by RT-qPCR, in a tissue cohort composed by PCa, prostatic intraepithelial neoplasia (PIN) and normal prostate cases. Knockdown for MacroH2A1 and MacroH2A1.1 was performed through lentiviral transduction in DU145 cells, and MacroH2A1.1 overexpression was achieved in LNCaP cells by plasmid transfection, followed by functional assays. Biological and/or experimental replicates were performed when necessary, and specific statistical tests were applied to perform data analysis. Results: MacroH2A1.1 transcript levels were downregulated in PIN and primary PCa compared to normal prostate tissues. The same was found for QKI, a MacroH2A1.1's splicing regulator. Moreover, lower MacroH2A1.1 and QKI expression levels associated with less differentiated tumors (Gleason score ≥ 7). Interestingly, MacroH2A1.1, but more impressively DDX17 (AUC = 0.93; p < 0.0001) and QKI (AUC = 0.94; p < 0.0001), accurately discriminated cancerous from noncancerous prostate tissues. Furthermore, in PCa cell lines, total MacroH2A1 knockdown augmented malignant features, whereas MacroH2A1.1 overexpression impressively attenuated the malignant phenotype. Conclusions: Overall, our data, derived from primary PCa tissues and cell lines, anticipate a tumor suppressive role for MacroH2A1, particularly for the MacroH2A1.1 isoform, in prostate carcinogenesis

Direct Measurement of Nuclear Dependence of Charged Current Quasielastic-like Neutrino Interactions using MINERvA

Charged-current $\nu_{\mu}$ interactions on carbon, iron, and lead with a final state hadronic system of one or more protons with zero mesons are used to investigate the influence of the nuclear environment on quasielastic-like interactions. The transfered four-momentum squared to the target nucleus, $Q^2$, is reconstructed based on the kinematics of the leading proton, and differential cross sections versus $Q^2$ and the cross-section ratios of iron, lead and carbon to scintillator are measured for the first time in a single experiment. The measurements show a dependence on atomic number. While the quasielastic-like scattering on carbon is compatible with predictions, the trends exhibited by scattering on iron and lead favor a prediction with intranuclear rescattering of hadrons accounted for by a conventional particle cascade treatment. These measurements help discriminate between different models of both initial state nucleons and final state interactions used in the neutrino oscillation experiments

First evidence of coherent K+K^{+} meson production in neutrino-nucleus scattering

Neutrino-induced charged-current coherent kaon production, $\nu_{\mu}A\rightarrow\mu^{-}K^{+}A$, is a rare, inelastic electroweak process that brings a $K^+$ on shell and leaves the target nucleus intact in its ground state. This process is significantly lower in rate than neutrino-induced charged-current coherent pion production, because of Cabibbo suppression and a kinematic suppression due to the larger kaon mass. We search for such events in the scintillator tracker of MINERvA by observing the final state $K^+$, $\mu^-$ and no other detector activity, and by using the kinematics of the final state particles to reconstruct the small momentum transfer to the nucleus, which is a model-independent characteristic of coherent scattering. We find the first experimental evidence for the process at $3\sigma$ significance.Comment: added ancillary file with information about the six kaon candidate

Single neutral pion production by charged-current νˉμ\bar{\nu}_\mu interactions on hydrocarbon at ⟨Eν⟩=\langle E_\nu \rangle = 3.6 GeV

Single neutral pion production via muon antineutrino charged-current interactions in plastic scintillator (CH) is studied using the \minerva detector exposed to the NuMI low-energy, wideband antineutrino beam at Fermilab. Measurement of this process constrains models of neutral pion production in nuclei, which is important because the neutral-current analog is a background for $\bar{\nu}_e$ appearance oscillation experiments. The differential cross sections for $\pi^0$ momentum and production angle, for events with a single observed $\pi^0$ and no charged pions, are presented and compared to model predictions. These results comprise the first measurement of the $\pi^0$ kinematics for this process.Comment: 6 pages, 5 figures, submitted to Physics Letters