Alzheimer’s Disease as a Membrane Disorder: Spatial Cross-Talk Among Beta-Amyloid Peptides, Nicotinic Acetylcholine Receptors and Lipid Rafts

Biological membranes show lateral and transverse asymmetric lipid distribution. Cholesterol (Chol) localizes in both hemilayers, but in the external one it is mostly condensed in lipid-ordered microdomains (raft domains), together with saturated phosphatidyl lipids and sphingolipids (including sphingomyelin and glycosphingolipids). Membrane asymmetries induce special membrane biophysical properties and behave as signals for several physiological and/or pathological processes. Alzheimer’s disease (AD) is associated with a perturbation in different membrane properties. Amyloid-β (Aβ) plaques and neurofibrillary tangles of tau protein together with neuroinflammation and neurodegeneration are the most characteristic cellular changes observed in this disease. The extracellular presence of Aβ peptides forming senile plaques, together with soluble oligomeric species of Aβ, are considered the major cause of the synaptic dysfunction of AD. The association between Aβ peptide and membrane lipids has been extensively studied. It has been postulated that Chol content and Chol distribution condition Aβ production and posterior accumulation in membranes and, hence, cell dysfunction. Several lines of evidence suggest that Aβ partitions in the cell membrane accumulate mostly in raft domains, the site where the cleavage of the precursor AβPP by β- and γ- secretase is also thought to occur. The main consequence of the pathogenesis of AD is the disruption of the cholinergic pathways in the cerebral cortex and in the basal forebrain. In parallel, the nicotinic acetylcholine receptor has been extensively linked to membrane properties. Since its transmembrane domain exhibits extensive contacts with the surrounding lipids, the acetylcholine receptor function is conditioned by its lipid microenvironment. The nicotinic acetylcholine receptor is present in high-density clusters in the cell membrane where it localizes mainly in lipid-ordered domains. Perturbations of sphingomyelin or cholesterol composition alter acetylcholine receptor location. Therefore, Aβ processing, Aβ partitioning, and acetylcholine receptor location and function can be manipulated by changes in membrane lipid biophysics. Understanding these mechanisms should provide insights into new therapeutic strategies for prevention and/or treatment of AD. Here, we discuss the implications of lipid-protein interactions at the cell membrane level in AD.Fil: Fabiani, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Antollini, Silvia Susana. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentin

Molecular Modulation of Human α7 Nicotinic Receptor by Amyloid-β Peptides

Amyloid β peptide (Aβ) is a key player in the development of Alzheimer’s disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by α7 nicotinic receptors has been shown to be affected by Aβ soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric Aβ1–40 and Aβ1–42 on human α7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV) revealed that in the presence of Aβ α7 undergoes concentration-dependent conformational changes. Exposure of α7 to 100 pM Aβ changes CrV KD towards that of the desensitized state. However, α7 is still reactive to high carbamylcholine (Carb) concentrations. These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both Aβ and Carb. At 100 nM Aβ, α7 adopts a resting-state-like structure which does not respond to Carb, suggesting stabilization of α7 in a blocked state. In real time, we found that Aβ is capable of eliciting α7 channel activity either in the absence or presence of the positive allosteric modulator (PAM) PNU-120596. Activation by Aβ is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high Aβ concentrations, the mean duration of activation episodes elicited by ACh in the presence of PNU-120596 is significantly reduced, an effect compatible with slow open-channel block. We conclude that Aβ directly affects α7 function by acting as an agonist and a negative modulator. Whereas the capability of low concentrations of Aβ to activate α7 could be beneficial, the reduced α7 activity in the presence of higher Aβ concentrations or its long exposure may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD

Representações de adolescentes acerca da consulta ginecológica

Objetivo: Analisar as representações sociais de adolescentes acerca da consulta ginecológica e a influência dessas representações na procura pela consulta. Método: Estudo qualitativo descritivo fundamentado na Teoria das Representações Sociais, realizado com 50 adolescentes que cursavam o último ano do ensino fundamental. Os dados foram colhidos entre abril e maio de 2010 por meio de Evocações e Grupo Focal. Utilizou-se o software EVOC e análise contextual no tratamento dos mesmos. Resultados: Os elementos medo e constrangedor, constantes no núcleo central, podem justificar a baixa frequência de adolescentes nas consultas. No sistema periférico o termo vergonha reforça normas socioculturais vigentes, enquanto prevenção, associado a aprender sobre sexo e esclarecer dúvidas, permitem vislumbrar uma função educativa. Depoimentos obtidos nos grupos focais exemplificam e reforçam esses achados. Conclusão: Para uma educação em saúde efetiva, os profissionais, especialmente enfermeiros, precisam esclarecer os jovens, em nível individual e coletivo, sobre seus direitos à privacidade, sigilo, além de enfocar a consulta ginecológica como medida promotora da saúde sexual e reprodutiva.
Objetivo: Analizar las representaciones sociales de adolescentes acerca de la consulta ginecológica y la influencia de estas representaciones en la demanda por la consulta mencionada. Método: Estudio cualitativo, descriptivo basado en la Teoría de las Representaciones Sociales, realizado con 50 adolescentes que cursaban el último año de la escuela primaria. Los datos fueron recolectados entre abril y mayo del 2010 por medio de Evocaciones y Grupo Focal. Se utilizó el software EVOC y el análisis contextual en el tratamiento de los datos. Resultados: Los elementos miedo y vergüenza, constantes en el núcleo central, pueden explicar la baja frecuencia de adolescentes en las consultas. En el sistema periférico el término vergüenza refuerza normas socio-culturales vigentes, mientras que, prevención, asociado al aprendizaje sobre sexo y aclaración de dudas, nos permiten vislumbrar una función educativa. Declaraciones obtenidas en los grupos focales ejemplifican y refuerzan estos hallazgos. Conclusión: Para una educación en la salud eficaz, los profesionales, especialmente enfermeros, necesitan aclarar a los jóvenes, en el nivel individual y colectivo, sobre sus derechos a la intimidad y la confidencialidad, además de enfocar la consulta ginecológica como una medida de promoción de la salud sexual y reproductiva.Objective: To analyze the social representation of adolescents about gynecological consultation and the influence of those in searching for consultations. Method: Qualitative descriptive study based on the Social Representations Theory, conducted with 50 adolescents in their last year of middle school. The data was collected between April and May of 2010 by Evocations and a Focal Group. The software EVOC and contextual analysis were used in the data treatment. Results: The elements fear and constraint, constant in the central nucleus, can justify the low frequency of adolescents in consultations. The term embarrassment in the peripheral system reinforce current sociocultural norms, while prevention, associated with learning about sex and clarifying doubts, allows to envision an educative function. Obtained testimonies in the focal groups exemplify and reinforce those findings. Conclusion: For an effective health education, professionals, including nurses, need to clarify the youth individually and collectively about their rights to privacy, secrecy, in addition to focus the gynecological consultation as a promotion measure to sexual and reproductive health

Helminth Coinfection Does Not Affect Therapeutic Effect of a DNA Vaccine in Mice Harboring Tuberculosis

From 14 diseases considered by WHO as Neglected Tropical Diseases, four involve helminth infections, such as schistosomiasis and soil-transmitted helminthiasis. Toxocariasis is a soil-transmitted worm highly prevalent in many developing countries, while schistosomiasis causes an annual mortality of 14,000 deaths per year, with 200–300 million infected people and 10% at risk of infection worldwide. Additionally, tuberculosis (TB) remains one of the leading causes of morbidity and mortality in many settings, particularly in the world's poorest countries. Mycobacteria and helminths are co-endemic and induce opposing patterns of immune responses in the host, recognized as Th1 and Th2 respectively. These co-existing patterns could be associated with the failure of TB vaccines. In this sense, we investigated the inflammatory and immune response in a coinfection model with T. canis or S. mansoni and M. tuberculosis analyzing the effects of an immunotherapy that has previously shown efficacy in experimental TB. This immunotherapy is based on a DNA vaccine that codifies a mycobacterial heat shock protein (hsp65), which can prevent TB in a prophylactic and also therapeutic setting. In this work, we show that helminth coinfection does not abrogate the therapeutic effects of DNAhsp65 vaccine against TB

CD18 Regulates Monocyte Hematopoiesis and Promotes Resistance to Experimental Schistosomiasis

Infection with Schistosoma mansoni causes a chronic parasitic disease that progress to severe liver and gastrointestinal damage, and eventually death. During its development into mammalian hosts, immature schistosomula transit through the lung vasculature before they reach the liver to mature into adult worms. A low grade inflammatory reaction is induced during this process. However, molecules that are required for efficient leukocyte accumulation in the lungs of S. mansoni-infected subjects are unknown. In addition, specific leukocyte subsets that mediate pulmonary response during S. mansoni migration through the lung remain to be elucidated. β2 integrins are fundamental regulators of leukocyte trans-endothelial migration and function. Therefore, we investigated their role during experimental schistosomiasis. Mice that express low levels of CD18 (the common β2 integrin subunit) and wild type C57BL/6 mice were subcutaneously infected with S. mansoni cercariae. Cellular profiles of lungs and livers were evaluated in different time points after infection by flow cytometry. Low levels of CD18 affected the accumulation of patrolling Ly6Clow, intermediate Ly6Cinter monocytes, monocyte-derived macrophages and monocyte-derived dendritic cells in the lungs 7 days after infection. This correlated with increased TNF-α levels. Strikingly, low CD18 expression resulted in monocytopenia both in the peripheral blood and bone marrow during acute infection. After 48 days, S. mansoni worm burdens were higher in the hepatic portal system of CD18low mice, which also displayed reduced hepatic accumulation of patrolling Ly6Clow and intermediate Ly6Cinter, but not inflammatory Ly6Chigh monocytes. Higher parasite burden resulted in increased granulomatous lesions in the liver, increased egg deposition and enhanced mortality. Overall, our data point for a fundamental role of CD18 for monocyte hematopoiesis during infection, which promotes an efficient host response against experimental schistosomiasis

La conflictividad social en clave local. Un ejercicio de ponderación sobre los hechos de rebelión en la Mar del Plata actual (Argentina, 2011-2016)

En el artículo propuesto se presenta un avance de la investigación en curso sobre la conflictividad social en las comunidades portuarias del sudeste bonaerense durante el período 2011-2016. Analizamos el caso de la ciudad puerto de Mar del Plata. En primer lugar, se da cuenta de los distintos clivajes emergentes en los hechos de rebelión, dividiéndolos en dos grandes grupos: los hechos impulsados por personificaciones de la relación capital-trabajo y los hechos emprendidos por personificaciones que se producen por fuera de la relación capital-trabajo. En un segundo lugar, se ensaya una ponderación de los conflictos con el objetivo de arriesgar una caracterización e interpretación global de la dinámica conflictual en aquellos años. La base empírica para dicho ejercicio es el registro normalizado que de la conflictividad social se viene realizando en el marco del Seminario de Investigación Sobre el Movimiento de la Sociedad (SISMOS), cuya fuente de información es el diario local La Capital.En l'article proposat es presenta un avanç de la investigacio en curs sobre la conflictivitat social a les comunitats portua ries del sud-est de Buenos Aires durant el perí ode 2011-2016. Hi analitzem el cas de la ciutat port de Mar del Plata. En primer lloc, es dona compte dels diferents clivatges emergents en els fets de rebel·lio , que es divideixen en dos grans grups: els fets impulsats per personificacions de la relacio capital-treball i els fets empresos per personificacions que es produeixen fora de la relacio capital-treball. En segon lloc, s’hi assaja una ponderacio dels conflictes amb l'objectiu d'arriscar una caracteritzacio i interpretacio global de la dina mica conflictual d’aquells anys. La base empí rica per a aquest exercici e s el registre normalitzat que de la conflictivitat social es realitza en el marc del Seminari d’Investigacio Sobre el Moviment de la Societat (SISMOS), la font d'informacio del qual e s el diari local La CapitalIn this article we present a preview of an ongoing investigation on social conflict situations in the port communities of southeast Buenos Aires in the period 2011-2016. We examine the case of the port city of Mar del Plata. Firstly, we present the several cleavages emerging in the conflicts and divide them in two large groups: capital-labour conflicts and conflicts which happen outside the capital-labour relations. In the second place, we attempt an analysis of the conflicts in order to propose a characterization and global interpretation of conflict dynamics in those years. The empirical base of this exercise is the normalized record of social conflict situations that we are preparing within the Research Seminar on the Movement of Society (SISMOS), whose source of information is the local newspaper La CapitalFil: Nieto, Alejandro Agustín. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Laitano, María Guillermina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Rabino, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Nogueira, Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Nogueira, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Andreozzi, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Becher, Pablo Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Fabiani, Luis Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Sánchez, Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Teijón, Ivana Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Marioli, Eliana Margarita. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; ArgentinaFil: Pironi, Emmanuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; ArgentinaFil: Okada, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata; Argentina. Universidad Nacional de Mar del Plata. Facultad de Humanidades. Departamento de Historia. Centro de Estudios Históricos; Argentin

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

All you need is coffe

Cholinergic deficit is regarded as an important factor responsible for Alzheimer’s disease symptoms. Two molecular targets for the treatment of this disease are acetylcholinesterase (AChE) and nic otinic receptor (nAChR). Caffeine (CAFF) acts as a non-competitive inhibitor of AChE but its mechanism of action on nAChR is still un known. To this end, we first explored if CAFF influences the nAChR conformational state using the AChR conformational-sensitive probe crystal violet (CrV) and AChR-rich membranes from T. californica. CAFF induced changes in the KD value of CrV in a concentra tion-dependent manner taking the nAChR to a state close to the desensitized one. In the presence of α-bungarotoxin, a specific nA ChR competitive antagonist, high concentrations of CAFF increased the KD value of CrV, compatible with a competition for the CrV site in the channel pore. The same effect was seen with galantamine, an AChE inhibitor and partial agonist of nAChR. To understand the molecular mechanism underlying the conformational changes of the nAChR, we expressed adult muscle or neuronal a7 nAChRs in BOSC cells, and performed single channel recordings with different CAFF concentrations in the presence or absence of ACh. At low concentrations (1-300 µM), CAFF activated muscle and a7 nAChRs, and the activation profile was independent of CAFF concentration. On the other hand, at high CAFF concentrations (up to 20 mM), the mean open duration decreased, the relative area of the briefer closed component and the cluster duration increased, and a flick ering behavior was observed, these suggesting that CAFF acts as an open channel blocker. Thus, we here demonstrate a dual effect of CAFF on muscle and a7 nAChRs, behaving as a weak agonist at low concentrations and as a negative modulator at high concen trations. Our results bring new information about the mechanism of modulation of pharmacology targets for the design of new therapies for the intervention in neurological diseases.Fil: Fabiani, Camila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Corradi, Jeremias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; ArgentinaFil: Antollini, Silvia Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaLXII Reunión Científica de la Sociedad Argentina de Investigación Clínica; LIII Reunión Anual de la Sociedad Argentina de Investigación Bioquímica y Biología Molecular; LXV Reunión Anual de la Sociedad Argentina de Inmunología; Reunión de la Sociedad Argentina de Andrología; XLVI Reunión Anual de la Sociedad Argentina de Biofísica ; XLIX Reunión Anual de la Sociedad Argentina de Farmacología Experimental; Reunión Anual de la Sociedad Argentina de Fisiología; Reunión de la Sociedad Argentina de Hematología y XXIX Reunión Anual de la Sociedad Argentina de ProtozoologíaBuenos AiresArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de Investigación Bioquímica y Biología MolecularSociedad Argentina de InmunologíaSociedad Argentina de AndrologiaSociedad Argentina de BiofísicaSociedad Argentina de BiologiaSociedad Argentina de Farmacologia ExperimentalSociedad Argentina de FisiologiaSociedad Argentina de HematologiaSociedad Argentina de Protozoologi