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BackgroundChronic sympathetic stimulation drives desensitization and downregulation of β1 adrenergic receptor (β1AR) in heart failure. We aim to explore the differential downregulation subcellular pools of β1AR signaling in the heart.Methods and resultsWe applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice. We applied confocal and proximity ligation assay to examine β1AR association with L-type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and Förster resonance energy transfer-based biosensors to probe subcellular β1AR-PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced β1AR protein levels, receptor association with L-type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta/cell, 29.65 saline versus 14.17 isoproterenol, P

Autism spectrum disorders and developmental coordination disorders are both associated with sensorimotor impairments, yet their nature and specificity remain unknown. In order to clearly distinguish the specificity between the two disorders, children with autism spectrum disorder or developmental coordination disorder presenting the same degree of motor impairment, thus homogeneous profiles, were examined in a reach-to-displace paradigm, which allows the integrity of two main aspects of motor control (anticipation/feedforward control and movement correction/feedback control) to be separately interrogated. We manipulated children's previous knowledge of the weight of the object they were to displace: when known, participants could anticipate the consequences of the weight when reaching for the object, prior to contact with it, thus allowing for feedforward control. Conversely, when unknown prior to contact, participants had to cope with the object weight in the displacing phase of the movement, and use feedback control. Results revealed a preserved feedforward control, but an impaired movement execution (atypical slowness) in children with developmental coordination disorder, while children with autism spectrum disorder displayed the opposite pattern with an impaired feedforward control, but a preserved feedback one. These findings shed light on how specific motor impairments might differently characterize developmental disorders and call for motor rehabilitation programmes adapted to each population.

Abstract Background In recent years, significant efforts have been directed towards the research and development of disease-modifying therapies for dementia. These drugs focus on prodromal (mild cognitive impairment, MCI) and/or early stages of Alzheimer’s disease (AD). Literature evidence indicates that a considerable proportion of individuals with MCI do not progress to dementia. Identifying individuals at higher risk of developing dementia is essential for appropriate management, including the prescription of new disease-modifying therapies expected to become available in clinical practice in the near future. Methods The ongoing INTERCEPTOR study is a multicenter, longitudinal, interventional, non-therapeutic cohort study designed to enroll 500 individuals with MCI aged 50–85 years. The primary aim is to identify a biomarker or a set of biomarkers able to accurately predict the conversion from MCI to AD dementia within 3 years of follow-up. The biomarkers investigated in this study are neuropsychological tests (mini-mental state examination (MMSE) and delayed free recall), brain glucose metabolism ([18F]FDG-PET), MRI volumetry of the hippocampus, EEG brain connectivity, cerebrospinal fluid (CSF) markers (p-tau, t-tau, Aβ1-42, Aβ1-42/1–40 ratio, Aβ1-42/p-Tau ratio) and APOE genotype. The baseline visit includes a full cognitive and neuropsychological evaluation, as well as the collection of clinical and socio-demographic information. Prognostic models will be developed using Cox regression, incorporating individual characteristics and biomarkers through stepwise selection. Model performance will be evaluated in terms of discrimination and calibration and subjected to internal validation using the bootstrapping procedure. The final model will be visually represented as a nomogram. Discussion This paper contains a detailed description of the statistical analysis plan to ensure the reproducibility and transparency of the analysis. The prognostic model developed in this study aims to identify the population with MCI at higher risk of developing AD dementia, potentially eligible for drug prescriptions. The nomogram could provide a valuable tool for clinicians for risk stratification and early treatment decisions. Trial registration ClinicalTrials.gov NCT03834402. Registered on February 8, 2019

BACKGROUND AND AIM: Direct-acting antivirals (DAAs) have revolutionised the management of chronic hepatitis C. We analysed the use of different generations of DAAs over time in Switzerland and investigated factors predictive of treatment failure. METHODS: This retrospective study was conducted within the framework of the Swiss Association for the Study of the Liver and the Swiss Hepatitis C Cohort Study; it included all patients with chronic hepatitis C treated with DAAs between January 2015 and December 2019 at eight Swiss referral centres. RESULTS: A total of 3088 patients were included; 57.3% were male, and the median age was 54 years. Liver cirrhosis was present in 23.9% of the cohort, 87.8% of whom were compensated. The overall sustained virological response (SVR) rate (defined as undetectable HCV RNA at week 12 after the first course of DAA-based treatment) was 96.2%, with an increase over time. The rate of treatment failure dropped from 8.3% in 2015 to 2.5% in 2019. Multivariable analysis revealed that female sex, the use of the latest generation of pangenotypic DAA regimens, Caucasian origin, and genotype (gt) 1 were associated with SVR, whereas the presence of active hepatocellular carcinoma (HCC), gt 3, and increasing liver stiffness were associated with treatment failure. Notably, the presence of active HCC during treatment increased the risk of DAA failure by a factor of almost thirteen. CONCLUSIONS: SVR rates increased over time, and the highest success rates were identified after the introduction of the latest generation of pangenotypic DAA regimens. Active HCC, gt 3 and increasing liver stiffness were associated with DAA failure.

Background Chronic sympathetic stimulation drives desensitization and downregulation of β1 adrenergic receptor (β1AR) in heart failure. We aim to explore the differential downregulation subcellular pools of β1AR signaling in the heart. Methods and Results We applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice. We applied confocal and proximity ligation assay to examine β1AR association with L‐type calcium channel, ryanodine receptor 2, and SERCA2a ((Sarco)endoplasmic reticulum calcium ATPase 2a) and Förster resonance energy transfer‐based biosensors to probe subcellular β1AR‐PKA (protein kinase A) signaling in ventricular myocytes. Chronic infusion of isoproterenol led to reduced β1AR protein levels, receptor association with L‐type calcium channel and ryanodine receptor 2 measured by proximity ligation (puncta/cell, 29.65 saline versus 14.17 isoproterenol, P

Abstract p140Cap is an adaptor protein involved in assembling multi-protein complexes regulating several cellular processes. p140Cap acts as a tumor suppressor in breast cancer (BC) and neuroblastoma patients, where its expression correlates with a better prognosis. The role of p140Cap in tumor metabolism remains largely unknown. Here we study the role of p140Cap in the modulation of the mevalonate (MVA) pathway in BC cells. The MVA pathway is responsible for the biosynthesis of cholesterol and non-sterol isoprenoids and is often deregulated in cancer. We found that both in vitro and in vivo, p140Cap cells and tumors show an increased flux through the MVA pathway by positively regulating the pace-maker enzyme of the MVA pathway, the 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), via transcriptional and post-translational mechanisms. The higher cholesterol synthesis is paralleled with enhanced cholesterol efflux. Moreover, p140Cap promotes increased cholesterol localization in the plasma membrane and reduces lipid rafts-associated Rac1 signalling, impairing cell membrane fluidity and cell migration in a cholesterol-dependent manner. Finally, p140Cap BC cells exhibit decreased cell viability upon treatments with statins, alone or in combination with chemotherapeutic at low concentrations in a synergistic manner. Overall, our data highlight a new perspective point on tumor suppression in BC by establishing a previously uncharacterized role of the MVA pathway in p140Cap expressing tumors, thus paving the way to the use of p140Cap as a potent biomarker to stratify patients for better tuning therapeutic options.

Abstract The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function. Mechanistically, p140Cap inhibition of β-Catenin depends on its ability to localize in and stabilize the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Clinical studies in women show that low p140Cap expression correlates with reduced presence of tumor-infiltrating lymphocytes and more aggressive tumor types in a large cohort of real-life female breast cancer patients, highlighting the potential of p140Cap as a biomarker for therapeutic intervention targeting the β-Catenin/ Tumor-initiating cells /G-CSF/ polymorphonuclear myeloid-derived suppressor cell axis to restore an efficient anti-tumor immune response.

Pemphigus is a life-threatening autoimmune blistering disease affecting skin and mucous membranes. Despite its etiopathogenesis remains largely unknown, several trigger and predisposing factors have been reported. Pemphigus is caused by autoantibodies that target desmoglein 1 and desmoglein 3, impacting desmosome function. However, circulating autoantibodies are often the consequence of a precipitating factor that occurs in predisposed individuals. This review aims to describe and discuss almost all trigger and predisposing factors reported as possible or probable cause of the disease. Among the reported trigger factors that may induce or exacerbate pemphigus, we have found of particular interest: drug intake (especially thiol- and phenol-containing compounds), vaccines, infections, as well as some reports about pregnancy, radiations, emotional stress, pesticides and physical trauma. Moreover, we discuss the possible role of food intake in pemphigus onset and particular attention is given to dietary factors containing thiol, phenol and tannin compounds. A trigger factor is “the straw that breaks the camel’s back,” and often acts together with predisposing factors. Here we discuss how pemphigus onset may be influenced by genetic susceptibility and comorbidities like thyroid diseases, malignancies and other autoimmune disorders.To identify other hitherto unknown trigger and predisposing factors, well designed prospective studies are needed. In this context, future research should explore their connection with the aim to advance our understanding of pemphigus pathogenesis.

This paper explores the intimate connections that exist between the psychological phenomena of internal attention and mental automatism. The article does not regard attention as a psychological process made up of cognitive components, rather it takes into consideration the internal dimension that is shared by the meditative state as it is maintained by J. Krishnamurti in his public lectures. Some connections between the Weltanschauung of J. Krishnamurti and those of the pre-socratic “sofoi“ (“wise philosophers” or “knowledge seekers”) are here highlighted, due to their being cultural, psychological and intangible worlds that connect the east with the west, with special regard to Heidegger’s philosophy. The article investigates attentive processes and goes on to examine some clinical examples taken from experiments of hysteria induced somnambulism and from experiments of hypnosis through which the author explores both the notion of mental automatism and that of affective type autonomous complex, as they appeared in Janet’s and Jung’s works. The analysis is concluded with exemplary clinical anecdotes that show how reflexive attention can lead to consciousness where automatism would otherwise reign and therefore make one able to abandon the predominant psychological complex responsible for psychopathological blocks.

Abstract L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic.

Background: Acute kidney injury (AKI) after transcatheter aortic valve implantation (TAVI) is a frequent complication associated with adverse outcomes and mortality. Various scores have been developed to predict this complication in the coronary setting. However, none have ever been tested in a large TAVI population. This study aimed to evaluate the power of four different scores in predicting AKI after TAVI. Methods: Overall, 1535 consecutive TAVI patients from the observational multicentric “Magna Graecia” TAVI registry were included in the analysis. Of the study population, 235 (15.31%) developed AKI early. The Mehran, William Beaumont Hospital, CR4EATME3AD3, and ACEF scores were calculated retrospectively. Results: The patients who developed TAVI-related AKI had significantly higher absolute values of all risk scores than those who did not. The receiver-operating characteristic analysis also showed a significant correlation between these four scores and AKI, but without a significant difference among all of them (p value = 0.176). Nevertheless, based on their area under the curve values (≤0.604 for all), none had adequate diagnostic accuracy in predicting TAVI-related AKI. Importantly, multivariate analysis identified myocardial revascularization close to the TAVI procedure and implantation of self-expanding prostheses, as well as atrial fibrillation, low-osmolar contrast media administration, corrected contrast medium volume, and any transfusion (p value

No contexto das recentes reformas educacionais foi promulgada a resolução CNE/CP 02/2019, que define as Diretrizes Curriculares Nacionais para a Formação de Professores, substituindo as antigas Diretrizes (Resolução CNE/CP 02/2015), demandando das Instituições de Ensino Superior a reformulação dos projetos pedagógicos dos cursos de licenciatura. O presente artigo busca traçar uma análise comparativa entre as duas diretrizes, entendendo os contextos sociais, econômicos e políticos de sua implementação, expondo suas similaridades e diferenças, além de possíveis consequências da modificação no perfil formativo dos novos professores. O estudo aqui realizado aponta que, de modo geral, as diretrizes atuais são mais prescritivas e padronizantes em relação às suas antecessoras, além de não trazer elementos acerca da formação continuada e pouco dizer sobre a questão da valorização profissional docente. Considerando tais características e o contexto pouco democrático de sua implementação, a resolução atual pode ser encarada como um retrocesso no seio das políticas públicas educacionais brasileiras.

IntroductionFrontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two phenotypes of the same neurodegenerative disease, the FTD-ALS spectrum. What determines the development of one rather than the other phenotype is still unknown. Based on the clinical observation that patients’ personality seems to differ between the two phenotypes, i.e., ALS patients tend to display kind, prosocial behaviors whereas FTD patients tend to present anti-social behaviors, and that these traits are often reported as pre-existing the disease onset by caregivers, we set up to study experimentally patients’ personality in their premorbid life.MethodsWe first tested for differences between groups, then tested the association between premorbid personality and current functional organization of the brain. Premorbid personality of a cohort of forty patients, 27 FTD and 13 ALS, was explored through the NEO Personality Inventory 3 (NEO-PI-3), which analyses the five main personality factors, completed by the caregiver with reference to patient’s personality 20 years before symptoms onset (premorbid). A subgroup of patients underwent a brain MRI including structural and resting-state functional MRI (rsfMRI).ResultsA significant difference between FTD and ALS in premorbid personality emerged in the Openness (133.92 FTD vs. 149.84 ALS, p = 0.01) and Extraversion (136.55 FTD vs. 150.53 ALS, p = 0.04) factors. This suggests that ALS patients had been, in their premorbid life, more open to new experiences, more sociable and optimistic than FTD patients. They also showed greater functional connectivity than both FTD and a control group in the Salience resting state network, over and above differences in gray matter atrophy. Finally, there was a positive correlation between premorbid Openness and functional connectivity in the Salience network across all patients, suggesting a possible association between premorbid personality and current functional organization of the brain, irrespective of the degree of atrophy.DiscussionOur proof-of-concept results suggest that premorbid personality may eventually predispose to the development of one, rather than the other, phenotype in the FTD-ALS spectrum.

This article aims to introduce the impacts of the courser’s postgraduate requirements on the postgraduate Quality of Life (QL), infer possible impacts and suggestions for referrals. This is an excerpt from an investigation that focused on the training of teachers for higher education, from different angles, approaching results from a qualitative and quantitative perspective. It had as participants a sample (27.12% of the universe) of students entering a postgraduate program in Science and Mathematics Teaching, a reference in the area. The constitution of the data was made at the end of 2019 based on a questionnaire WHOQOL-BREF, validated by the World Health Organization, and by field notes constituted in one offered disciplined. Checked that the QL of the participants: which can be considered a median, close to 60 points (1 to 100); with men's indicators smaller than those offering women's; most had of them felt pain and were using medication and presented difficulties in carrying out daily activities; productivism, the time elements factor, among others, are part of the stressors elements. It is argued that hat programs/universities that monitor these movements need to articulate with the regulatory agencies, improve rating criteria instruments and use welcoming activities targeting students, minimizing stressors in the environment

Background: Dementia is a neurological syndrome characterized by severe cognitive impairment with functional impact on everyday life. It can be classified as young onset dementia (EOD) in case of symptom onset before 65, and late onset dementia (LOD). The purpose of this study is to assess the risk of dementia due to light pollution, and specifically outdoor artificial light at night (LAN). Methods: Using a case-control design, we enrolled dementia patients newly-diagnosed in the province of Modena in the period 2017–2019 and a referent population from their caregivers. We geo-referenced the address of residence on the date of recruitment, provided it was stable for the previous five years. We assessed LAN exposure through 2015 nighttime luminance satellite images from the Visible Infrared Imaging Radiometer Suite (VIIRS). Using a logistic regression model adjusted for age, sex, and education, we calculated the risk of dementia associated with increasing LAN exposure, namely using

Se presenta un panorama histórico de la trayectoria científica y académica de, al menos, dos disciplinas que desde fines del siglo XIX trataron conjuntamente la cuestión de los paleoambientes y su transformación a partir de la presencia humana. Esta práctica inter y multidisciplinaria fue consolidándose en el Museo de La Plata como la línea de investigación zooarqueológica que hoy tiene gran desarrollo no solo en el país, sino en el mundo. En esta extensa historia académica, las ideas propuestas por Florentino Ameghino hasta las de la actualidad han sido puestas a prueba continuamente. La meta es exponer los principales conceptos vistos desde la producción interdisciplinaria de biólogos y arqueólogos en las regiones pampeana y patagónica.

Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, and this heterogeneity is a crucial determinant of malignant progression and response to treatments. In addition to genetic diversity and plasticity of cancer cells, the tumor microenvironment contributes to tumor heterogeneity shaping the physical and biological surroundings of the tumor. The activity of certain types of immune, endothelial or mesenchymal cells in the microenvironment can change the effectiveness of cancer therapies via a plethora of different mechanisms. Therefore, deciphering the interactions between the distinct cell types, their spatial organization and their specific contribution to tumor growth and drug sensitivity is still a major challenge. Dissecting intra-tumor heterogeneity is currently an urgent need to better define breast cancer biology and to develop therapeutic strategies targeting the microenvironment as helpful tools for combined and personalized treatment. In this review, we analyze the mechanisms by which the tumor microenvironment affects the characteristics of tumor heterogeneity that ultimately result in drug resistance, and we outline state of the art preclinical models and emerging technologies that will be instrumental in unraveling the impact of the tumor microenvironment on resistance to therapies.

ObjectivesVirtual reality (VR) offers an ecological setting and the possibility of altered visual feedback during head movements useful for vestibular research and treatment of vestibular disorders. There is however no data quantifying vestibulo-ocular reflex (VOR) during head impulse test (HIT) in VR. The main objective of this study is to assess the feasibility and performance of eye and head movement measurements of healthy subjects in a VR environment during high velocity horizontal head rotation (VR-HIT) under a normal visual feedback condition. The secondary objective is to establish the feasibility of VR-HIT recordings in the same group of normal subjects but under altered visual feedback conditions.DesignTwelve healthy subjects underwent video HIT using both a standard setup (vHIT) and VR-HIT. In VR, eye and head positions were recorded by using, respectively, an imbedded eye tracker and an infrared motion tracker. Subjects were tested under four conditions, one reproducing normal visual feedback and three simulating an altered gain or direction of visual feedback. During these three altered conditions the movement of the visual scene relative to the head movement was decreased in amplitude by 50% (half), was nullified (freeze) or was inverted in direction (inverse).ResultsEye and head motion recording during normal visual feedback as well as during all 3 altered conditions was successful. There was no significant difference in VOR gain in VR-HIT between normal, half, freeze and inverse conditions. In the normal condition, VOR gain was significantly but slightly (by 3%) different for VR-HIT and vHIT. Duration and amplitude of head impulses were significantly greater in VR-HIT than in vHIT. In all three altered VR-HIT conditions, covert saccades were present in approximatively one out of four trials.ConclusionOur VR setup allowed high quality recording of eye and head data during head impulse test under normal and altered visual feedback conditions. This setup could be used to investigate compensation mechanisms in vestibular hypofunction, to elicit adaptation of VOR in ecological settings or to allow objective evaluation of VR-based vestibular rehabilitation.

IntroductionOccult hepatitis B infection (OBI) is a condition where replication-competent hepatitis B virus-DNA (HBV-DNA) is present in the liver, with or without HBV-DNA in the blood [