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This article sought to analyze the historical evolution, the composition, and the determinants of debt specialization of Brazilian firms traded on Brasil, Bolsa, Balcão (B3) from 2004 to 2019 in aggregate terms and in accordance with their financial constraints. This paper differs from the few studies on this topic carried out in Brazil and in other countries by promoting a discussion on the specialization of the debt structure in a context of financial constraints, as they are a relevant idiosyncrasy of emerging markets, such as in Brazil. The relevance of the study is to identify that debt specialization is a feature of only of financially constrained firms and not of the financially unconstrained ones. The impact of the study lies in a better understanding of why Brazilian firms are reducing their debt specialization, unlike other international evidences, such as the U.S. Descriptive statistics and regressions were estimated using the probit and tobit methods for 246 Brazilian firms between 2004 and 2019. The main result is that financial constrained firms are more likely to specialize their debt structure. Despite this propensity, these companies were the ones that most decreased their debt specialization between 2004 and 2019 (-27.77%), compared to the general sample (-27.5%) and unconstrained firms (-19.48%), revealing a behavior contrary to the U.S. scenario in which companies are increasingly specialists. RESUMO Este artigo buscou analisar a evolução histórica, a composição e os determinantes da especialização de dívida de empresas brasileiras negociadas na Brasil, Bolsa, Balcão (B3), de 2004 a 2019, em termos agregados e de acordo com suas restrições financeiras. Este artigo difere-se dos poucos estudos neste tópico desenvolvidos no Brasil e em outros países por promover uma discussão acerca da especialização da estrutura de dívida em um contexto de restrições financeiras, uma vez que são uma característica relevante de mercados emergentes, como o brasileiro. A relevância deste estudo está em identificar que a especialização da dívida é um atributo apenas de empresas com restrição financeira, e não de empresas sem essas restrições. O impacto deste estudo está no melhor entendimento do motivo de empresas brasileiras estarem reduzindo sua especialização de dívida, diferente de outras evidências internacionais, como as estadunidenses. Foram estimadas estatísticas descritivas e regressões usando o método de probit e de tobit para 246 empresas brasileiras entre 2004 e 2019. O resultado principal é de que empresas com restrições financeiras são mais propensas a especializar sua estrutura de dívida. Apesar dessa propensão, essas empresas foram as que mais diminuíram sua especialização de dívida entre 2004 e 2019 (-27,77%), comparado ao restante da amostra (27,5%) e a empresas sem restrições (-19,48%), revelando um comportamento contrário ao do cenário estadunidense, no qual as empresas são cada vez mais especializadas.

O presente trabalho visa compor um fator constituído por variáveis que caracterizam a expropriação de minoritários e utilizá-lo para identificar a influência da expropriação destes sobre o desempenho de mercado das empresas brasileiras de capital aberto negociadas na Brasil, Bolsa e Balcão (B3). Para isso foi construído um fator representativo da expropriação de acionistas minoritários por meio da Análise Fatorial estimado por meio de Componentes Principais. Posteriormente, foram aplicados modelos de painéis dinâmicos, estimados pelo Método dos Momentos Generalizados para verificar a referida influência. De uma maneira geral, identificou que as variáveis de propriedade e controle bem como o desvio acionário são as melhores proxies representar o fenômeno de expropriação. Por fim, identificou-se que o fator expropriação é negativamente relacionada com o desempenho de mercado, isto é, há uma relação inversa entre o fenômeno de expropriação de acionistas minoritários e o desempenho da empresa.

O presente estudo buscou identificar quais as técnicas de análise financeiras são mais usuais nas empresas de capital aberto brasileiras. Para isso foi aplicado uma survey, tendo como instrumento um questionário composto por 17 construtos e 107 questões abertas e fechadas, no qual foram respondidas por meio de contato direto com os diretores financeiros das empresas negociadas na B3, seja por meio de telefone seja por endereços de e-mail, disponíveis na ficha cadastral na B3. Os principais resultados do artigo apontam que as “Opções reais” é a técnica mais utilizada pelos respondentes e o PayBack a menos utilizada. Este resultado demonstra que as empresas estão cada vez mais especializadas, deixando de usar técnicas simples. Outra questão importante a ser relatada, diz respeito à escala de prioridades quando as empresas precisam obter recursos, confirmando que a lógica do trade-off se sobrepõe a da pecking-order.

Migraine is a common neurological disorder impairing the quality of life of patients. The condition requires, as an acute or prophylactic line of intervention, the frequent use of drugs acting on the central nervous system (CNS). The long-term impact of these medications on cognition and neurodegeneration has never been consistently assessed. The paper reviews pharmacological migraine treatments and discusses their biological and clinical effects on the CNS. The different anti-migraine drugs show distinct profiles concerning neurodegeneration and the risk of cognitive deficits. These features should be carefully evaluated when prescribing a pharmacological treatment as many migraineurs are of scholar or working age and their performances may be affected by drug misuse. Thus, a reconsideration of therapy guidelines is warranted. Furthermore, since conflicting results have emerged in the relationship between migraine and dementia, future studies must consider present and past pharmacological regimens as potential confounding factors.

Brain aging and aging-related neurodegenerative disorders are posing a significant challenge for health systems worldwide. To date, most of the therapeutic efforts aimed at counteracting dementiarelated behavioral and cognitive impairment have been focused on addressing putative determinants of the disease, such as β-amyloid or tau. In contrast, relatively little attention has been paid to pharmacological interventions aimed at restoring or promoting the synaptic plasticity of the aging brain. The review will explore and discuss the most recent molecular, structural/functional, and behavioral evidence that supports the use of non-pharmacological approaches as well as cognitive-enhancing drugs to counteract brain aging and early-stage dementia.

A atividade agropecuária está sujeita a diversas mudanças que variam desde as climáticas, os efeitos políticos, as pestes e doenças e; também; os efeitos financeiros e econômicos. No que tange aos últimos, podem-se elencar como sendo agentes mudanças governamentais, estrutura de preços, relação oferta/demanda e sazonalidade de preços. Diante desse contexto, o objetivo deste trabalho foi o de analisar o comportamento de curto prazo da volatilidade presente nas commodities açúcar, café, farelo de soja, óleo de soja brasileira frente ao mundo, e vice-versa com o intuito de investigar se as alterações de preços de cada uma destas commodities estão relacionadas com as variações mundiais e brasileiras. A fim de atingir este objetivo, o estudo fez uso dos modelos GARCH, GJR e EGARCH para determinar qual destes se ajustava melhor ao modelo. Para determinar o comportamento de curto prazo, o estudo fez uso do modelo de vetores autorregressivos (VAR) nas commodities par a par. Observou-se que, para o mercado mundial, a commodity que tem maior volatilidade associada é o café, e no Brasil, o açúcar. Sob o prisma do comportamento de curto prazo das volatilidades, observou-se que o açúcar é o mais sazonal, com influências de volatilidade em até 14 defasagens. Para o café e o farelo de soja, notou-se que o mercado mundial não sofre influência do brasileiro, e o brasileiro tem influência direta do mercado mundial. Para o óleo de soja e a soja em grão, observou-se a presença de volatilidade unidirecional, isto é, os mercados não têm relação entre si, o que indica que para estes dois últimos mercados, os riscos associados estão presentes apenas em seus mercados.

Alzheimer's disease (AD) is a neurodegenerative condition driven by multifactorial etiology. Mild cognitive impairment (MCI) is a transitional condition between healthy aging and dementia. No reliable biomarkers are available to predict the conversion from MCI to AD.To evaluate the use of machine learning (ML) on a wealth of data offered by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Alzheimer's Disease Metabolomics Consortium (ADMC) database in the prediction of the MCI to AD conversion.We implemented an ML-based Random Forest (RF) algorithm to predict conversion from MCI to AD. Data related to the study population (587 MCI subjects) were analyzed by RF as separate or combined features and assessed for classification power. Four classes of variables were considered: neuropsychological test scores, AD-related cerebrospinal fluid (CSF) biomarkers, peripheral biomarkers, and structural magnetic resonance imaging (MRI) variables.The ML-based algorithm exhibited 86% accuracy in predicting the AD conversion of MCI subjects. When assessing the features that helped the most, neuropsychological test scores, MRI data, and CSF biomarkers were the most relevant in the MCI to AD prediction. Peripheral parameters were effective when employed in association with neuropsychological test scores. Age and sex differences modulated the prediction accuracy. AD conversion was more effectively predicted in females and younger subjects.Our findings support the notion that AD-related neurodegenerative processes result from the concerted activity of multiple pathological mechanisms and factors that act inside and outside the brain and are dynamically affected by age and sex.

The membrane protein TREM2 (Triggering Receptor Expressed on Myeloid cells 2) regulates key microglial functions including phagocytosis and chemotaxis. Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer’s disease (AD). Because abnormalities in Ca2+ signaling have been observed in several AD models, we investigated TREM2 regulation of Ca2+ signaling in human induced pluripotent stem cell-derived microglia (iPSC-microglia) with genetic deletion of TREM2. We found that iPSC-microglia lacking TREM2 (TREM2 KO) show exaggerated Ca2+ signals in response to purinergic agonists, such as ADP, that shape microglial injury responses. This ADP hypersensitivity, driven by increased expression of P2Y12 and P2Y13 receptors, results in greater release of Ca2+ from the endoplasmic reticulum (ER) stores, which triggers sustained Ca2+ influx through Orai channels and alters cell motility in TREM2 KO microglia. Using iPSC-microglia expressing the genetically encoded Ca2+ probe, Salsa6f, we found that cytosolic Ca2+ tunes motility to a greater extent in TREM2 KO microglia. Despite showing greater overall displacement, TREM2 KO microglia exhibit reduced directional chemotaxis along ADP gradients. Accordingly, the chemotactic defect in TREM2 KO microglia was rescued by reducing cytosolic Ca2+ using a P2Y12 receptor antagonist. Our results show that loss of TREM2 confers a defect in microglial Ca2+ response to purinergic signals, suggesting a window of Ca2+ signaling for optimal microglial motility.

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, 'aged' neurons display dysregulation of [Ca2+]ilevels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Alzheimer's disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances.

The cause of Alzheimer’s disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ.

Alzheimer’s Disease (AD) is a type of dementia very common in the elderly. A growing body of recent evidence has linked AD pathogenesis to Copper (Cu) dysmetabolism in the body. In fact, a subset of patients affected either by AD or by its prodromal form known as Mild Cognitive Impairment (MCI) have been observed to be unable to maintain a proper balance of Cu metabolism and distribution and are characterized by the presence in their serum of increased levels of Cu not bound to ceruloplasmin (non-ceruloplasmin Cu). Since serum non-ceruloplasmin Cu is a biomarker of Wilson's Disease (WD), a well-known condition of Cu-driven toxicosis, in this review, we propose that in close analogy with WD, the assessment of non-ceruloplasmin Cu levels can be exploited as a cost-effective stratification and susceptibility/risk biomarker for the identification of some AD/MCI individuals. The approach can also be used as an eligibility criterion for clinical trials aiming at investigating Cu-related interventions against AD/MCI.

Alzheimer’s disease (AD) is a neurodegenerative condition driven by a multifactorial etiology. We employed a machine learning (ML) based algorithm and the wealth of information offered by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to investigate the relative contribution of clinically relevant factors for identifying subjects affected by Mild Cognitive Impairment (MCI), a transitional status between healthy aging and dementia. Our ML-based Random Forest (RF) algorithm did not help predict clinical outcomes and the AD conversion of MCI subjects. On the other hand, non-converting (ncMCI) subjects were correctly classified and predicted. Two neuropsychological tests, the FAQ and ADAS13, were the most relevant features used for the classification and prediction of younger, under 70, ncMCI subjects. Structural MRI data combined with systemic parameters and the cardiovascular status were instead the most critical factors for the classification of over 70 ncMCI subjects. Our results support the notion that AD is not an organ-specific condition and results from pathological processes inside and outside the Central Nervous System.

Excitotoxicity is a form of neuronal death characterized by the sustained activation of N-methyl-D-aspartate receptors (NMDARs) triggered by the excitatory neurotransmitter glutamate. NADPH-diaphorase neurons [also known as nNOS (+) neurons] are a subpopulation of aspiny interneurons, largely spared following excitotoxic challenges. Unlike nNOS (-) cells, nNOS (+) neurons fail to generate reactive oxygen species in response to NMDAR activation, a key divergent step in the excitotoxic cascade. However, additional mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death have not been explored. Using functional, genetic, and molecular analysis in striatal cultures, we demonstrate that nNOS (+) neurons possess distinct NMDAR properties. These specific features are primarily driven by the peculiar redox milieu of this subpopulation. In addition, we found that nNOS (+) neurons exposed to a pharmacological maneuver set to mimic chronic excitotoxicity alter their responses to NMDAR-mediated challenges. These findings suggest the presence of mechanisms providing long-term dynamic regulation of NMDARs that can have critical implications in neurotoxic settings.

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be counteracted. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a pleiotropic class of sphingolipids, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored. In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor of thede novoceramide biosynthesis, on the aging phenotype of cortical neurons cultured for 22 days, a setting employed as anin vitromodel of senescence. Our findings indicate that, compared to control cultures, ‘aged’ neurons display dysregulation of [Ca2+]ilevels, mitochondrial dysfunction, increased generation of reactive oxygen species (ROS), altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS positively affected the senescent phenotype, a result associated with recovery of neuronal [Ca2+]isignaling and reduction of mitochondrial dysfunction and ROS generation. The results suggest that thede novoceramide biosynthesis represents a critical intermediate in the molecular and functional cascade leading to neuronal senescence and identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Although aging is considered to be an unavoidable event, recent experimental evidence suggests that the process can be delayed, counteracted, if not completely interrupted. Aging is the primary risk factor for the onset and development of neurodegenerative conditions like Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Intracellular calcium (Ca2+i) dyshomeostasis, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are critical factors that contribute to senescence-related processes. Ceramides, a class of sphingolipids involved in a wide array of biological functions, are important mediators of cellular senescence, but their role in neuronal aging is still largely unexplored.In this study, we investigated the effects of L-cycloserine (L-CS), an inhibitor ofde novoceramide biosynthesis, on the aging phenotype of cortical neurons that have been maintained in culture for 22 days, a setting employed as anin vitromodel of cellular senescence. Our findings indicate that ‘aged’ neurons display, when compared to control cultures, overt dysregulation of cytosolic and subcellular [Ca2+]ilevels, mitochondrial dysfunction, increased reactive oxygen species generation, altered synaptic activity as well as the activation of neuronal death-related molecules. Treatment with L-CS (30 µM) positively affected the senescent phenotype, a result accompanied by recovery of neuronal [Ca2+]isignaling, and reduction of mitochondrial dysfunction and reactive oxygen species generation.The results suggest that thede novoceramide biosynthesis may represent a critical intermediate in the molecular and functional cascade leading to neuronal senescence. Our findings also identify ceramide biosynthesis inhibitors as promising pharmacological tools to decrease age-related neuronal dysfunctions.

Alzheimer's disease (AD) is one of the most common forms of dementia. Despite a wealth of knowledge on the molecular mechanisms involved in AD, current treatments have mainly focused on targeting amyloid β (Aβ) production, but have failed to show significant effects and efficacy. Therefore, a critical reconsideration of the multifactorial nature of the disease is needed. AD is a complex multifactorial disorder in which, along with Aβ and tau, the convergence of polygenic, epigenetic, environmental, vascular, and metabolic factors increases the global susceptibility to the disease and shapes its course. One of the cofactors converging on AD is the dysregulation of brain metals. In this review, we focus on the role of AD-related neurodegeneration and cognitive decline triggered by the imbalance of two endogenous metals: copper and zinc.

Zinc (Zn2+) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn2+levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn2+affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn2+levels, we employed the Zn2+(and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signalling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn2+was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine densityin vivo.Our study highlights the importance of choosing “when”, “where”, and “how much” in the modulation of brain Zn2+levels. Our findings confirm the importance of targeting Zn2+as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn2+availability upon the early stages of development.

Pension funds, when they acquire common shares of companies in the capital markets, start to participate more actively in the decision-making of boards of directors and, through their representatives, in the monitoring of managers. The aim of this study is to determine whether pension funds are good monitors. This is done by identifying the influence of the control structure of pension funds over the financial performance and the market value of Brazilian public companies. Using dynamical models of linear and non-linear regressions estimated by GMM-Sys in an unbalanced panel from 1995 to 2015, it is shown that pension funds do not play a good monitoring role, as the control structure of these funds is negatively related to the financial performance of a company or, in other words, the higher the stake, the worse the performance of the company. A possible reason for this is that pension funds invest in the capital markets for portfolio diversification, are not concerned with specific decision-making in companies and have few monitoring skills, thus generating conflicts that go against the objective of maximizing the value of the company. Also, the study identifies the fact that investors give a higher value to the shares of firms in which domestic public funds have investments, even without proof that such funds improve the profitability of companies. Resumo Os fundos de pensão, ao adquirirem ações ordinárias de empresas no mercado de capitais, começam a participar mais ativamente nas tomadas de decisão dos conselhos de administração e no monitoramento dos gestores através de seus representantes. Devido a essa questão, o presente estudo buscou verificar se os fundos de pensão são bons monitores através da identificação da influência da estrutura de controle destes no desempenho financeiro e no valor de mercado das empresas de capital aberto brasileiras. Utilizando modelos dinâmicos de regressões lineares e não lineares múltiplas, estimadas pelo GMM-Sys, em um painel não balanceado de 1995 a 2015, foi evidenciado que os fundos de pensão não desempenham um bom papel de monitoramento, já que a estrutura de controle destes fundos possui uma relação inversa com o resultado financeiro tanto interno quanto de mercado, ou seja, quanto maior a participação acionária, menor é o desempenho das empresas. Esse resultado foi encontrado, possivelmente, pois os fundos de pensão investem no mercado de capitais para diversificação de portfólio, não estando preocupados com tomadas de decisão específicas nas empresas, gerando, assim, falta de habilidades de monitoramento adequadas, provocando conflitos que vão contra o objetivo de maximização de valor das empresas. Também, foi identificado que os investidores valorizam as ações de firmas investidas por fundos públicos domésticos, mesmo sem comprovação que tais fundos melhoram a rentabilidade das empresas.

Backgroundpreclinical, clinical, and epidemiological evidence support the notion that Alzheimer’s disease(AD) is a multifactorial condition in which, along with β-amyloid (Aβ) and tau-related pathology, the synergistic activity of genetic, environmental, vascular, metabolic, and inflammatory factors promote the onset and progression of the disease. Epidemiological evidence indicate that glucose intolerance, deficits in insulin secretion or type 2 diabetes mellitus (T2DM) participate in increasing the risk of developing cognitive impairment or dementia. A pivotal role in the process is played by insulin as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a GLP-1R agonist, characterized by an extended half-life, employed in T2DM. However, exenatide has also been shown to affect the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models of brain aging and neurodegeneration.Methodsin this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. To that aim, we investigated the effects of 3-month exenatide treatment in 3xTg-AD mice challenged for six months with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, levels of Aβ and tau pathology as well as changes in cognitive performances.Findings and interpretationresults of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD.

The risk for Alzheimer’s disease (AD) is associated with the presence of the 𝜀4 allele of Apolipoprotein E (APOE) gene and, recently, with a novel genetic variant of the RNF219 gene. This study aimed at evaluating interactions between APOE-𝜀4 and RNF219/G variants in the modulation of behavioral and cognitive features of two cohorts of patients suffering from mild cognitive impairment (MCI) or AD. We enrolled a total of 173 female MCI or AD patients (83 MCI; 90 AD). Subjects were screened with a comprehensive set of neuropsychological evaluations and genotyped for the APOE and RNF219 polymorphic variants. Analysis of covariance was performed to assess the main and interaction effects of APOE and RNF219 genotypes on the cognitive and behavioral scores. The analysis revealed that the simultaneous presence of APOE-𝜀4 and RNF219/G variants results in significant effects on specific neuropsychiatric scores in MCI and AD patients. In MCI patients, RNF219 and APOE variants worked together to impact the levels of anxiety negatively. Similarly, in AD patients, the RNF219 variants were found to be associated with increased anxiety levels. Our data indicate a novel synergistic activity APOE and RNF219 in the modulation of behavioral traits of female MCI and AD patients.

Modulation of insulin-dependent signaling is emerging as a valuable therapeutic tool to target neurodegeneration. In the brain, the activation of insulin receptors promotes cell growth, neuronal repair, and protection. Altered brain insulin signaling participates in the cognitive decline seen in Alzheimer's disease patients and the aging brain. Glucagon-like peptide-1 (GLP-1) regulates insulin secretion and, along with GLP-1 analogues, enhances neurotrophic signaling and counteracts cognitive deficits in preclinical models of neurodegeneration. Moreover, recent evidence indicates that GLP-1 modulates the activity of the brain-derived neurotrophic factor (BDNF). In this study, in adult wild-type mice, here employed as a model of mid-life brain aging, we evaluated the effects of a 2-month treatment with exenatide, a GLP-1 analogue. We found that exenatide promotes the enhancement of long-term memory performances. Biochemical and imaging analyses show that the drug promotes the activation of the BDNF-TrkB neurotrophic axis and inhibits apoptosis by decreasing p75NTR-mediated signaling. The study provides preclinical evidence for the use of exenatide to delay age-dependent cognitive decline.

The present work sought to identify the influence of the control structure on the accounting and market performance of listed and delisted Brazilian companies traded only on B3 as compared to those with a double listing with the US (ADRs). For this purpose, linear regressions were applied by GMM-Sys with unbalanced panel data. It was evidenced that for companies traded only on B3, the control structure is negatively related to efficiency while listed and positively related when delisting occurs, prevailing shareholder conflict. This context is inverse to that found in the analysis of ADRs, where the control structure is positively related to efficiency while listed and negatively related when delisting occur, proving that, in this case, agency conflicts prevail. This study confirms that the effects of US Commom Law also affect Brazilian companies that are traded in the US.

NMDA receptor (NMDAR) overstimulation by glutamate promotes massive calcium (Ca2+) entry and initiates a cascade of events leading to the overproduction of Reactive Oxygen Species (ROS), mitochondrial dysfunction, intraneuronal zinc (Zn2+) mobilization, and, ultimately, neuronal demise (Choi 1992). This glutamate-driven form of neuronal death has been described as excitotoxicity (Olney 1969). NADPH-diaphorase neurons [nNOS (+) neurons] are a subpopulation of nitric-oxide synthase-overexpressing interneurons that is spared from the NMDAR-mediated neuronal death (Koh and Choi, 1988). The mechanisms underlying the reduced vulnerability of nNOS (+) neurons to NMDAR-driven neuronal death are still largely unexplored. In the talk, we will discuss the mechanisms that are involved in the reduced vulnerability of nNOS (+) neurons. Differences between nNOS (+) and nNOS (-) neurons as far as changes in intracellular Ca2+ levels, mitochondrial functioning, ROS production as well as the intraneuronal accumulation of Zn2+ were investigated. We found that nNOS (+) neurons differ from nNOS (-) cells by lacking the production of a significant amount of ROS in response to NMDAR activation. The absence of NMDA-driven oxidative stress shown by the nNOS (+) neurons abolished the neurotoxic accumulation of Zn2+. Exposure of nNOS (-) neurons to NMDA in the presence of TPEN (a Zn2+ chelator)mimicked the behavior of the nNOS (+) subpopulation and preserved the nNOS (-) population from the excitotoxic damage. These results indicate that Zn2+ mobilization is the mandatory step of the excitotoxic cascade. These findings identify the intraneuronal accumulation of Zn2+ as a therapeutic target for the treatment of excitotoxic prone neurological conditions.&nbsp

Aims: Abnormal metal accumulation is associated with Alzheimer’s disease and plays a relevant role in affecting amyloid-β (Aβ) peptide aggregation and neurotoxicity. Material & Methods: In the present study, employing a microarray analysis of 35,129 genes, we analyzed gene expression profile changes due to exposure to Aβ1-42 –Zn or Aβ1-42 –Cu complexes in neuronal-like cells (SH-SY5Y). Results: Microarray data indicated that Aβ–Zn or Aβ–Cu complexes selectively alter expression of genes mainly related to cell death, inflammatory responses, cytoprotective mechanisms and apoptosis. Conclusions: Taken together, these findings indicate that Aβ1–42 –Zn or Aβ1–42 –Cu show some commonalities in affecting Alzheimer’s disease-related target functions. The overall modulatory activity on these genes supports the idea of a possible net effect resulting in the activation of pathways that counteract toxic effects of Aβ–Zn or Aβ–Cu.