squizofrenia: Neuroinflamação, neurodegeneração ou neurodesenvolvimento? Visão global dos aspectos genéticos

Schizophrenia is a devastating mental illness and its etiology is still largely unknown. Several gene mapping studies suggest that schizophrenia is a complex disorder, with a cumulative impact of variable genetic effects coupled with environmental factors. There is evidence that schizophrenia could be a neurodegenerative, neuroinflammatory or neurodevelopmental disorder. Neuropsychological data indicate neurocognitive functions are relatively stable over time after illness onset, whereas morphological data indicate a degenerative process; potential roles of neuroinflammation in the etiology of psychiatric diseases including schizophrenia have also been suggested. Recent research indicates genetic overlap between schizophrenia and syndromes in which psychopathology manifests in childhood and that are often grouped together as ‘neurodevelopmental disorders’. These findings challenge the etiological basis of current diagnostic categories and, together with evidence for frequent comorbidity, suggest that we should view the functional psychoses as members of a group that result in part from a combination of genetic and environmental effects on brain development and that are associated with specific and general impairments of cognitive function. The objective was to perform a systematic literature review of articles on genetics of schizophrenia relating to neurodegeneration, neuroinflammation and neurodevelopment. After proper filter, we included 40 studies and reviewed each finding and its relevance to the hypotheses. We can conclude that the evidence points to schizophrenia as a neurodevelopmental disease with the direct presence of factors related to neuroinflammation and neurodegeneration.Esquizofrenia é uma doença mental debilitante e sua etiologia é, em sua maior parte, desconhecida. Alguns estudos de mapeamento genético sugerem que esquizofrenia é uma doença complexa, com impacto acumulativo de fatores genéticos variáveis associados a fatores ambientais. Há evidência de que a esquizofrenia poderia ser uma doença neurodegenerativa, neuroinflamatória ou do neurodesenvolvimento. Dados neuropsicológicos indicam que funções cognitivas são relativamente estáveis no decorrer do tempo após o início da doença, enquanto dados morfológicos indicam processos degenerativos; papéis importantes da neuroinflamação na etiologia de doenças psiquiátricas, incluindo esquizofrenia, também foram sugeridos. Pesquisas recentes indicam sobreposição entre esquizofrenia e síndromes cuja fisiopatologia se manifesta na infância e são em geral agrupadas como “doenças do neurodesenvolvimento”. Estes achados desafiam a base etiológica das categorias atuais de diagnóstico e, juntamente com a evidência de comorbidade frequente, sugerem que devemos ver as psicoses como membros do grupo que resulta em parte da combinação de efeitos genéticos e ambientais no desenvolvimento do cérebro e que estão associados a prejuízos específicos e gerais da função cognitiva. O objetivo foi realizar uma revisão sistemática da literatura de trabalhos em genética da esquizofrenia relacionados a neurodegeneração, neuroinflamação e neurodesenvolvimento. Após buscas específicas, incluímos 40 estudos e revisamos cada achado e sua relevância para a hipótese. Nós concluímos que a evidência aponta para esquizofrenia como uma doença do neurodesenvolvimento com presença direta de fatores relacionados a neuroinflamação e neurodegeneração

Influence of lithium in neuron-glia interaction in primary hippocampal cell culturing

Recently, special attention has been given to the possible neuroprotective effects of lithium, especially by the discovery of its regulatory effects on pro and anti-apoptotic proteins. Lithium substantially increases the cytoprotective proteins expression in the central nervous system, both in rat cortex and in human cells of neuronal origin. In addition to neuroprotective actions, it aids in the regeneration of axons in the central nervous system of mammals. Lithium negatively regulates the expression and activity of enzymes that exert important functions in cerebral homeostasis: synaptic plasticity, neurogenesis, andphosphorylation of tau protein. Microglia is known for its importance in neuropathologies. However, under physiological conditions, such immune cells interact actively with neurons, being able to modulate the fate and functions of the synapses. Such ability of microglial cells suggests the consequences of changes in microglial phenotype under pathological conditions, which makes it relevant to understand the interaction between microglial and other developing brain cells and their influence on the formation of neuronal and synaptic networks. The current work aims to identify the main pathway of neuronal-glia integration activated by chronic treatment with lithium (0.02mM; 0.2mM and 2mM) in hippocampal neurons, exploring the use of bioinformatics tools in microarray data. Treatment of primary hippocampal neurons with lithium changed the genes related to different neuroprotection pathwaysat the highest therapeutic dose (2mM). There was dissociation between the therapeutic and sub therapeutic dose of lithium in neuroprotection. Therefore, treatment at therapeutic doses (2mM) modified different signaling pathways when compared to the sub-therapeutic dose (0.02 and 0.2mM)

Association study in Alzheimer’s disease of single nucleotide polymorphisms implicated with coffee consumption

Background There is evidence from animal and in vitro models of the protective effects of caffeine in Alzheimer’s disease. The suggested mechanisms through which caffeine may protect neurons against Alzheimer’s disease pathology include the facilitation of beta-amyloid clearance, upregulation of cholinergic transmission, and increased neuronal plasticity and survival. Epidemiological studies support that Alzheimer’s disease patients consume smaller amounts of coffee beverages throughout their lives as compared to age-matched cognitively healthy individuals. Objective The aim of the present study was to determine whether the negative association between Alzheimer’s disease and coffee consumption may be influenced by a common genetic predisposition, given the fact that the pattern of coffee consumption is determined by both environmental and genetic factors. Method We conducted an in silico search addressing the association between genetic polymorphisms related to coffee consumption and the diagnosis of Alzheimer’s disease. We further investigated the interactions between genes located in regions bearing these polymorphisms. Results Our analysis revealed no evidence for a genetic association (nor interaction between related proteins) involving coffee consumption and Alzheimer’s disease. Discussion The negative association between Alzheimer’s disease and coffee consumption suggested by epidemiological studies is most likely due to environmental factors that are not necessarily regulated by genetic background

Influence of lithium in neuron-glia interaction in hippocampal neurons: preliminary study

Recentemente, especial atenção foi dada aos possíveis efeitos neuroprotetores do lítio, especialmente pela descoberta de seus efeitos regulatórios sobre proteínas pró e anti-apoptóticas. O lítio aumenta substancialmente a expressão de proteínas citoprotetoras no sistema nervoso central, tanto no córtex de ratos quanto em células humanas de origem neuronal. Além de ações neuroprotetoras, auxilia na regeneração de axônios no sistema nervoso central de mamíferos. O lítio regula negativamente a expressão e a atividade de enzimas que exercem funções importantes na homeostase cerebral: plasticidade sináptica, neurogênese e fosforilação da proteína tau. Microglia é conhecida por sua importância na neuropatologia. No entanto, sob condições fisiológicas, tais células imunes interagem ativamente com os neurônios, sendo capazes de modular o destino e as funções das sinapses. Essa capacidade das células microgliais sugere as conseqüências de mudanças no fenótipo microglial sob condições patológicas, o que torna relevante o entendimento da interação entre micróglia e outras células cerebrais em desenvolvimento e sua influência na formação de redes neuronais e sinápticas. O presente trabalho tem como objetivo identificar a principal via de integração neurônio-glia ativada pelo tratamento crônico com lítio em neurônios, explorando o uso de ferramentas de bioinformática em dados de microarray. O tratamento de neurônios hipocampais com lítio alterou os genes relacionados a diferentes vias de neuroproteção na dose terapêutica mais alta. Houve dissociação entre a dose terapêutica e sub-terapêutica de lítio na neuroproteção. Portanto, o tratamento em doses terapêuticas (2mM) modificou diferentes vias de sinalização quando comparado com as doses sub-terapêuticas (0,02 e 0,2mM).Recently, special attention has been given to the possible neuroprotective effects of lithium, especially by the discovery of its regulatory effects on pro and anti-apoptotic proteins. Lithium substantially increases the cytoprotective proteins expression in the central nervous system, both in rat cortex and in human cells of neuronal origin. In addition to neuroprotective actions, it aids in the regeneration of axons in the central nervous system of mammals. Lithium negatively regulates the expression and activity of enzymes that exert important functions in cerebral homeostasis: synaptic plasticity, neurogenesis, and phosphorylation of tau protein. Microglia is known for its importance in neuropathology. However, under physiological conditions, such immune cells interact actively with neurons, being able to modulate the fate and functions of the synapses. Such ability of microglial cells suggests the consequences of changes in microglial phenotype under pathological conditions, which makes it relevant to understand the interaction between microglial and other developing brain cells and their influence on the formation of neuronal and synaptic networks. The current work aims to identify the main pathway of neuronal-glia integration activated by chronic treatment with lithium in neurons, exploring the use of bioinformatics tools in microarray data. Treatment of primary hippocampal neurons with lithium changed the genes related to different neuroprotection pathways at the highest therapeutic dose. There was dissociation between the therapeutic and sub-therapeutic dose of lithium in neuroprotection. Therefore, treatment at therapeutic doses (2mM) modified different signaling pathways when compared to the sub-therapeutic dose (0.02 and 0.2mM)

Fungemia por espécies de Candida em Hospital Pediátrico da cidade de São Paulo, Brasil: estudo no período de 2007 a 2010

Candidemia remains a major cause of morbidity and mortality in the health care environment. The epidemiology of Candida infection is changing, mainly in relation to the number of episodes caused by species C. non-albicans. The overall objective of this study was to evaluate the frequency of yeasts of the genus Candida, in a four-year period, isolated from blood of pediatric patients hospitalized in a public hospital of the city of São Paulo, Brazil. In this period, yeasts from blood of 104 patients were isolated and, the identified species of Candida by phenotypic and genotypic methods were: C. albicans (39/104), C. tropicalis (25/104), C. parapsilosis (23/104), Pichia anomala (6/104), C. guilliermondii (5/104), C. krusei (3/104), C. glabrata (2/104) and C. pararugosa (1/104). During the period of the study, a higher frequency of isolates of C. non-albicans (63.55%) (p = 0.0286) was verified. In this study we verified the increase of the non-albicans species throughout the years (mainly in 2009 and 2010). Thus, considering the peculiarities presented by Candida species, a correct identification of species is recommended to lead to a faster diagnosis and an efficient treatment.Candidemia permance como a maior causa de morbidade e mortalidade em ambiente hospitalar. A epidemiologia de infecções por Candida vem se alterando, principalmente em relação ao número de episódios causados por espécies não-albicans. Este estudo teve como objetivo avaliar a frequência, em um período de quatro anos, de leveduras do gênero Candida isoladas de sangue de pacientes pediátricos internados em hospital público da cidade de São Paulo, Brasil. Neste período foram isoladas leveduras de sangue de 104 pacientes, e as espécies de Candida identificadas, por métodos fenotípicos e genotípicos, foram: C. albicans (39/104), C. tropicalis (25/104), C. parapsilosis (23/104), Pichia anomala (6/104), C. guilliermondii (5/104), C. krusei (3/104), C. glabrata (2/104) e C. pararugosa (1/104). Em todo período do estudo foi observada maior frequência de isolamento de C. não-albicans (63,55%) (p = 0,0286). Neste estudo verificou-se aumento das espécies não-albicans ao longo dos anos (principalmente em 2009 e 2010), assim, ressalta-se que correta identificação em nível de espécie é recomendável, para que isso acarrete diagnóstico rápido e tratamento eficaz

HOXB7 mRNA is overexpressed in pancreatic ductal adenocarcinomas and its knockdown induces cell cycle arrest and apoptosis

Background\ud Human homeobox genes encode nuclear proteins that act as transcription factors involved in the control of differentiation and proliferation. Currently, the role of these genes in development and tumor progression has been extensively studied. Recently, increased expression of HOXB7 homeobox gene (HOXB7) in pancreatic ductal adenocarcinomas (PDAC) was shown to correlate with an invasive phenotype, lymph node metastasis and worse survival outcomes, but no influence on cell proliferation or viability was detected. In the present study, the effects arising from the knockdown of HOXB7 in PDAC cell lines was investigated.\ud \ud Methods\ud Real time quantitative PCR (qRT-PCR) (Taqman) was employed to assess HOXB7 mRNA expression in 29 PDAC, 6 metastatic tissues, 24 peritumoral tissues and two PDAC cell lines. siRNA was used to knockdown HOXB7 mRNA in the cell lines and its consequences on apoptosis rate and cell proliferation were measured by flow cytometry and MTT assay respectively.\ud \ud Results\ud Overexpression of HOXB7 mRNA was observed in the tumoral tissues and in the cell lines MIA PaCa-2 and Capan-1. HOXB7 knockdown elicited (1) an increase in the expression of the pro-apoptotic proteins BAX and BAD in both cell lines; (2) a decrease in the expression of the anti-apoptotic protein BCL-2 and in cyclin D1 and an increase in the number of apoptotic cells in the MIA PaCa-2 cell line; (3) accumulation of cell in sub-G1 phase in both cell lines; (4) the modulation of several biological processes, especially in MIA PaCa-2, such as proteasomal ubiquitin-dependent catabolic process and cell cycle.\ud \ud Conclusion\ud The present study confirms the overexpression of HOXB7 mRNA expression in PDAC and demonstrates that decreasing its protein level by siRNA could significantly increase apoptosis and modulate several biological processes. HOXB7 might be a promising target for future therapies.This study was supported in part by a FAPESP grant 2010/01421-1

Pervasive gaps in Amazonian ecological research

Biodiversity loss is one of the main challenges of our time,1,2 and attempts to address it require a clear un derstanding of how ecological communities respond to environmental change across time and space.3,4 While the increasing availability of global databases on ecological communities has advanced our knowledge of biodiversity sensitivity to environmental changes,5–7 vast areas of the tropics remain understudied.8–11 In the American tropics, Amazonia stands out as the world’s most diverse rainforest and the primary source of Neotropical biodiversity,12 but it remains among the least known forests in America and is often underrepre sented in biodiversity databases.13–15 To worsen this situation, human-induced modifications16,17 may elim inate pieces of the Amazon’s biodiversity puzzle before we can use them to understand how ecological com munities are responding. To increase generalization and applicability of biodiversity knowledge,18,19 it is thus crucial to reduce biases in ecological research, particularly in regions projected to face the most pronounced environmental changes. We integrate ecological community metadata of 7,694 sampling sites for multiple or ganism groups in a machine learning model framework to map the research probability across the Brazilian Amazonia, while identifying the region’s vulnerability to environmental change. 15%–18% of the most ne glected areas in ecological research are expected to experience severe climate or land use changes by 2050. This means that unless we take immediate action, we will not be able to establish their current status, much less monitor how it is changing and what is being lostinfo:eu-repo/semantics/publishedVersio

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO