Glycine disrupts myelin, glutamatergic neurotransmission, and redox homeostasis in a neonatal model for non ketotic hyperglycinemia.

Non ketotic hyperglycinemia (NKH) is an inborn error of glycine metabolism caused by mutations in the genes encoding glycine cleavage system proteins. Classic NKH has a neonatal onset, and patients present with severe neurodegeneration. Although glycine accumulation has been implicated in NKH pathophysiology, the exact mechanisms underlying the neurological damage and white matter alterations remain unclear. We investigated the effects of glycine in the brain of neonatal rats and MO3.13 oligodendroglial cells. Glycine decreased myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) in the corpus callosum and striatum of rats on post-natal day (PND) 15. Glycine also reduced neuroglycan 2 (NG2) and N-methyl-d-aspartate receptor subunit 1 (NR1) in the cerebral cortex and striatum on PND15. Moreover, glycine reduced striatal glutamate aspartate transporter 1 (GLAST) content and neuronal nucleus (NeuN), and increased glial fibrillary acidic protein (GFAP) on PND15. Glycine also increased DCFH oxidation and malondialdehyde levels and decreased GSH concentrations in the cerebral cortex and striatum on PND6, but not on PND15. Glycine further reduced viability but did not alter DCFH oxidation and GSH levels in MO3.13 cells after 48- and 72-h incubation. These data indicate that impairment of myelin structure and glutamatergic system and induction of oxidative stress are involved in the neuropathophysiology of NKH.

Simvastatin Differentially Modulates Glial Functions in Cultured Cortical and Hypothalamic Astrocytes Derived from Interferon α/ß Receptor Knockout mice.

Astrocytes have key regulatory roles in central nervous system (CNS), integrating metabolic, inflammatory and synaptic responses. In this regard, type I interferon (IFN) receptor signaling in astrocytes can regulate synaptic plasticity. Simvastatin is a cholesterol-lowering drug that has shown anti-inflammatory properties, but its effects on astrocytes, a main source of cholesterol for neurons, remain to be elucidated. Herein, we investigated the effects of simvastatin in inflammatory and functional parameters of primary cortical and hypothalamic astrocyte cultures obtained from IFNα/ß receptor knockout (IFNα/ßR-/-) mice. Overall, simvastatin decreased extracellular levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), which were related to a downregulation in gene expression in hypothalamic, but not in cortical astrocytes. Moreover, there was an increase in anti-inflammatory interleukin-10 (IL-10) in both structures. Effects of simvastatin in inflammatory signaling also involved a downregulation of cyclooxygenase 2 (COX-2) gene expression as well as an upregulation of nuclear factor κB subunit p65 (NFκB p65). The expression of cytoprotective genes sirtuin 1 (SIRT1) and nuclear factor erythroid derived 2 like 2 (Nrf2) was also increased by simvastatin. In addition, simvastatin increased glutamine synthetase (GS) activity and glutathione (GSH) levels only in cortical astrocytes. Our findings provide evidence that astrocytes from different regions are important cellular targets of simvastatin in the CNS, even in the absence of IFNα/ßR, which was showed by the modulation of cytokine production and release, as well as the expression of cytoprotective genes and functional parameters.

The role of glial cells in Zika virus-induced neurodegeneration.

Zika virus (ZIKV) is a strongly neurotropic flavivirus whose infection has been associated with microcephaly in neonates. However, clinical and experimental evidence indicate that ZIKV also affects the adult nervous system. In this regard, in vitro and in vivo studies have shown the ability of ZIKV to infect glial cells. In the central nervous system (CNS), glial cells are represented by astrocytes, microglia, and oligodendrocytes. In contrast, the peripheral nervous system (PNS) constitutes a highly heterogeneous group of cells (Schwann cells, satellite glial cells, and enteric glial cells) spread through the body. These cells are critical in both physiological and pathological conditions; as such, ZIKV-induced glial dysfunctions can be associated with the development and progression of neurological complications, including those related to the adult and aging brain. This review will address the effects of ZIKV infection on CNS and PNS glial cells, focusing on cellular and molecular mechanisms, including changes in the inflammatory response, oxidative stress, mitochondrial dysfunction, Ca2+ and glutamate homeostasis, neural metabolism, and neuron-glia communication. Of note, preventive and therapeutic strategies that focus on glial cells may emerge to delay and/or prevent the development of ZIKV-induced neurodegeneration and its consequences.

O poder sobre a vida: os corpos regidos pela prática biomédica versus corpos de intensidades / The power over life: bodies governed by biomedical practice versus intensity bodies

Neste artigo, discuto a questão da materialidade organicista do corpo contra um corpo de intensidades. De acordo com Separavich e Canesqui (2010), os estudos de Marcel Mauss (2003 [1934]) e Margaret Mead (2000 [1935]) "revelou que, embora se possa atribuir uma materialidade universal ao corpo, definições, disposições corporais e seus significados são múltiplos. Como resultado dessa heterogeneidade nas formas de conceber corpo, as concepções do que seja saúde e doença também múltiplas tradições" (p. 251). De acordo com Cecil G. Helman (1994) para "os membros de todas as sociedades, o corpo humano é mais do que um simples organismo físico oscilando entre a saúde e a doença. É também o foco de um conjunto de crenças sobre seu significado social e psicológico, estrutura e funcionamento. A expressão 'imagem corporal' é usada para descrever todas as maneiras pelas quais um indivíduo conceitua e experimenta seu próprio corpo, consciente ou inconscientemente" (p. 30), variando com cada sociedade e momento histórico em que se definem: incluem crenças sobre a forma e o tamanho ideal do corpo, crenças sobre sua estrutura e crenças sobre suas funções. Pretendo refletir sobre o corpo, trazendo alguns elementos históricos para chamar a atenção para a ocorrência de certas condições ­ conhecimento médico e outros aspectos sócio-históricos ­ entrelaçada com a produção de práticas e intervenções médicas, no corpo, assim como no governo da vida, com a intenção de chamar a atenção para as práticas médicas integrativas que são a partir de uma visão do corpo de intensidades.

In this article, I discuss the issue of the organicist materiality of the body versus a body of intensities. According to Separavich and Canesqui (2010), the studies of Marcel Mauss (2003 [1934]) and Margaret Mead (2000 [1935]) "revealed that, although a universal materiality can be attributed to the body, definitions, bodily dispositions and their meanings are manifold. As a result of this heterogeneity in the ways of conceiving the body, the conceptions of what health and disease are also have multiple traditions" (p. 251). According to Cecil G. Helman (1994) for "the members of all societies, the human body is more than a simple physical organism oscillating between health and disease. It is also the focus of a set of beliefs about its social and psychological meaning, structure and functioning. The expression 'body image' is used to describe all the ways in which an individual conceptualizes and experiences his own body, consciously or unconsciously" (p. 30), varying with each society and historical moment in which they are defined: they include beliefs about ideal body shape and size, beliefs about its internal structure, and beliefs about its functions. I intend to reflect on the body, bringing some historical elements to draw attention to the occurrence of certain conditions - medical knowledge and other socio-historical aspects - intertwined with the production of medical practices and interventions, in the body, as well as in the government of life, with the intention of drawing attention to integrative medical practices that are based on a vision of the body of intensities.

Dynamics and immunomodulation of cognitive deficits and behavioral changes in non-severe experimental malaria.

Data recently reported by our group indicate that stimulation with a pool of immunogens capable of eliciting type 2 immune responses can restore the cognitive and behavioral dysfunctions recorded after a single episode of non-severe rodent malaria caused by Plasmodium berghei ANKA. Here we explored the hypothesis that isolated immunization with one of the type 2 immune response-inducing immunogens, the human diphtheria-tetanus (dT) vaccine, may revert damages associated with malaria. To investigate this possibility, we studied the dynamics of cognitive deficits and anxiety-like phenotype following non-severe experimental malaria and evaluated the effects of immunization with both dT and of a pool of type 2 immune stimuli in reversing these impairments. Locomotor activity and long-term memory deficits were assessed through the open field test (OFT) and novel object recognition task (NORT), while the anxiety-like phenotype was assessed by OFT and light/dark task (LDT). Our results indicate that poor performance in cognitive-behavioral tests can be detected as early as the 12th day after the end of antimalarial treatment with chloroquine and may persist for up to 155 days post infection. The single immunization strategy with the human dT vaccine showed promise in reversal of long-term memory deficits in NORT, and anxiety-like behavior in OFT and LDT.

Longterm Increased S100B Enhances Hippocampal Progenitor Cell Proliferation in a Transgenic Mouse Model.

(1) The neurotrophic protein S100B is a marker of brain injury and has been associated with neuroregeneration. In S100Btg mice rendering 12 copies of the murine S100B gene we evaluated whether S100B may serve as a treatment option. (2) In juvenile, adult, and one-year-old S100Btg mice (female and male; n = 8 per group), progenitor cell proliferation was quantified in the subgranular zone (SGZ) and the granular cell layer (GCL) of the dentate gyrus with the proliferative marker Ki67 and BrdU (50 mg/kg). Concomitant signaling was quantified utilizing glial fibrillary acidic protein (GFAP), apolipoprotein E (ApoE), brain-derived neurotrophic factor (BDNF), and the receptor for advanced glycation end products (RAGE) immunohistochemistry. (3) Progenitor cell proliferation in the SGZ and migration to the GCL was enhanced. Hippocampal GFAP was reduced in one-year-old S100Btg mice. ApoE in the hippocampus and frontal cortex of male and BDNF in the frontal cortex of female S100Btg mice was reduced. RAGE was not affected. (4) Enhanced hippocampal neurogenesis in S100Btg mice was not accompanied by reactive astrogliosis. Sex- and brain region-specific variations of ApoE and BDNF require further elucidations. Our data reinforce the importance of this S100Btg model in evaluating the role of S100B in neuroregenerative medicine.

Methylmalonic acid induces inflammatory response and redox homeostasis disruption in C6 astroglial cells: potential glioprotective roles of melatonin and resveratrol.

Methylmalonic acidemia is a neurometabolic disorder biochemically characterized by the accumulation of methylmalonic acid (MMA) in different tissues, including the central nervous system (CNS). In this sense, it has been shown that high levels of this organic acid have a key role in the progressive neurological deterioration in patients. Astroglial cells actively participate in a wide range of CNS functions, such as antioxidant defenses and inflammatory response. Considering the role of these cells to maintain brain homeostasis, in the present study, we investigated the effects of MMA on glial parameters, focusing on redox homeostasis and inflammatory process, as well as putative mediators of these events in C6 astroglial cells. MMA decreased cell viability, glutathione levels, and antioxidant enzyme activities, increased inflammatory response, and changed the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NFκB), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and adenosine receptors, suggesting that these transcriptional factors and proteins may underlie the glial responses induced by MMA. Moreover, we also demonstrated the protective roles of melatonin and resveratrol against MMA-induced inflammation and decrease in glutathione levels. In summary, our findings support the hypothesis that astroglial changes are associated with pathogenesis of methylmalonic acidemia. In addition, we showed that these cells might be potential targets for preventive/therapeutic strategies by using molecules, such as melatonin and resveratrol, which mediated glioprotection in this inborn error of metabolism.

Scientific production and most researched diseases in the Biological Sciences postgraduate programs in Brazil / Produção científica e doenças mais pesquisadas nos programas de pós-graduação em Ciências Biológicas no Brasil

This macro-level scientometrics study aimed to analyze the similarities and differences in the scientific communication patterns of the Brazilian postgraduate programs (BPPs) belonging to the Biological Sciences II field (BS2), as defined by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Also, it was identified the most researched diseases and it was discussed their relationship with the needs of Brazilian public health considering the burden of disease (Disability-Adjusted Life Year - DALY, Brazil) estimated by the World Health Organization (WHO). Thus, the scientific production of the BS2's sub-areas Biophysics, Biochemistry, Pharmacology, Physiology, and Morphology was evaluated from 2013 to 2016, through considering the citation impact, Impact Factor (Journal Citation Reports), and scientific collaboration. Data collected included formal information provided to CAPES by all BPPs through the Plataforma Sucupira as well as metadata from Web of Science documents. In addition, were employed the standardized Medical Subject Headings (PubMed) for the analysis of researched diseases. We concluded that the patterns of scientific communication in Biophysics, Biochemistry, Pharmacology, Physiology, and Morphology were predominantly different. Thus, there is a need to consider specificities among the five sub-areas in the evaluation process performed by CAPES. Different approaches are revealed by identifying the most frequently researched diseases and explaining the contributions of each sub-area for Brazilian public health.

Este estudo cientométrico de nível macro teve como objetivo analisar as semelhanças e as diferenças nos padrões de comunicação científica dos programas de pós-graduação brasileiros (PPGs) da área de Ciências Biológicas II, avaliados pela Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). Além disso, foram identificadas as doenças mais pesquisadas e foi discutido sua relação com as necessidades de saúde pública brasileira, considerando a carga de doenças (Disability-Adjusted Life Year - DALY, Brasil) estimada pela Organização Mundial da Saúde (OMS). Assim, a produção científica das subáreas Biofísica, Bioquímica, Farmacologia, Fisiologia e Morfologia da área de Ciências Biológicas II foi avaliada de 2013 a 2016, considerando o impacto de citações, o Fator de Impacto (Journal Citation Reports) e a colaboração científica. Os dados coletados incluíram informações declaradas à CAPES por todos os PPGs por meio da Plataforma Sucupira, bem como metadados de documentos da Web of Science. Além disso, foram utilizados os cabeçalhos de Medical Subject Headings (PubMed) para a análise das doenças pesquisadas. Concluímos que os padrões de comunicação científica entre as subáreas Biofísica, Bioquímica, Farmacologia, Fisiologia e Morfologia foram predominantemente diferentes. Assim, é necessário considerar as especificidades entre as cinco subáreas no processo de avaliação realizado pela CAPES. Diferentes abordagens são reveladas a partir da identificação das doenças mais pesquisadas e da explicação das contribuições de cada subárea para a saúde pública brasileira.

Teste de Progresso: ausência de alunos de Medicina é sugestiva de mau desempenho acadêmico / Progress Test: medical student absenteeism is suggestive of poor academic performance

Resumo: Introdução: Não se sabe se a ausência de estudantes de Medicina ao Teste de Progresso (TP) se dá de forma aleatória ou por alguma característica sistemática deles, o que poderia influenciar a representatividade dos resultados obtidos pelos participantes. Objetivo: Este estudo teve como objetivos comparar os índices de desempenho acadêmico, no curso de Medicina da UFSC, dos alunos presentes e ausentes ao TP em 2019; propor uma maneira de estimar, a partir desses índices, quais seriam as notas dos faltantes se tivessem participado do TP; e identificar fatores associados à ausência ao TP. Método: Foram comparadas as médias dos índices de desempenho acadêmico, globais e nas diferentes fases (semestres) dos grupos de alunos presentes e ausentes ao TP, utilizando teste t de Student para amostras independentes. Por meio de uma técnica de regressão linear, foram imputadas as prováveis notas no TP ao grupo de alunos ausentes. Resultado: As médias globais dos três indicadores acadêmicos foram significativamente menores nos alunos ausentes ao TP (p variando de < 0,03 a < 0,0001); em dez das 11 fases (semestres) analisadas do curso, os indicadores acadêmicos dos faltosos foram piores do que dos presentes. A imputação de notas no TP aos ausentes permitiu verificar que existe correlação (R = 0,62) entre a porcentagem destes e a diferença de notas entre os grupos que realizaram e os que faltaram ao TP. Entre os alunos do gênero masculino, 25,8% não fizeram o TP, enquanto no gênero feminino foram 16,6% (diferença com p < 0,01). Conclusão: A ausência de alunos ao TP não se dá de forma aleatória. Entre os faltosos, há uma tendência sistemática de existirem alunos com piores índices de desempenho acadêmico. O uso de imputação múltipla de dados evidencia uma correlação entre a porcentagem de faltosos e a diferença na média da nota no TP, desse grupo, comparada à média da nota dos participantes. A proporção de homens que faltaram ao TP foi significativamente maior do que a de mulheres.

Abstract: Introduction: It is not known whether the absence of medical students at the Progress Test (PT) is random event or if it due to some systematic characteristic of the students, which could influence the representativeness of the results obtained by the participants. Objectives: 1) to compare the academic performance indexes, in UFSC Medical School, of students who were present and absent from the PT in 2019; 2) to propose a way to estimate, based on these indexes, what the absentee's grades would be if they had participated in the PT; 3) to identify factors associated with absence from the PT. Method: The averages of academic performance indexes, overall and in the different phases (semesters) in the groups of students who were present and absent from the PT, were compared using Student's t test for independent samples. Using a linear regression technique, the probable PT scores were assigned to the group of absent students. Results: The global averages of the three academic indicators were significantly lower in students absent from the PT (p ranging from < 0.03 to < 0.0001); in 10 of the 11 analyzed course phases (semesters), the academic indicators of absentees were worse than those present at the test. The attribution of PT grades to the absentees allowed us to verify that there is a correlation (R=0.62) between the percentage of these students and the difference in grades between the groups that took and those that did not take the PT. Among male students, 25.8% did not attend the PT, while among female students the number of absentees was 16.6% (difference with p <0.01). Conclusions: The absence of students at the PT does not occur randomly. Among the absentees, there is a systematic tendency to have students with worse academic performance. The use of multiple imputation of data demonstrate a correlation between the percentage of absentees and the difference in the average of grades in the PT of this group, compared to the average of the participants' grades. The proportion of male students who missed the PT was significantly higher than that of female students.

Functional Recovery Caused by Human Adipose Tissue Mesenchymal Stem Cell-Derived Extracellular Vesicles Administered 24 h after Stroke in Rats.

Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood-brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

Amyloid-ß Processing in Aged S100B Transgenic Mice Is Sex Dependent.

(1) Background: Calcium-binding protein S100B is involved in neuroregeneration but has also been associated with neurodegeneration. These contrasting effects may result from concentration or duration of exposure. We investigated the effect of long-term increased S100B levels on amyloid-ß processing in one-year-old transgenic (tg) mice with 12 copies of the murine S100B gene with specific consideration of sex and specific brain regions. (2) Methods: S100B and amyloid-ß 42 (Aß42) were quantified in serum, cerebrospinal fluid (CSF), adipose tissue, and different brain regions by ELISA in wild-type (wt) and S100Btg mice (each n = 7 per group). Thioflavin T (ThT) and Aß immunostaining were performed for visualization of Aß deposition. (3) Results: S100B in serum, CSF, and brain was significantly increased in S100Btg mice of both sexes. Aß42 was significantly increased in the hippocampus of male S100Btg mice (p = 0.0075), and the frontal cortex of female S100Btg mice (p = 0.0262). ThT and Aß immunostaining demonstrated Aß deposition in different brain regions in S100Btg mice of both sexes and female wt. (4) Conclusion: Our data validate this experimental model for studying the role of S100B in neurodegeneration and indicate that Aß processing is sex-dependent and brain region-specific, which deserves further investigation of signaling pathways and behavioral responses.

Immune system challenge improves recognition memory and reverses malaria-induced cognitive impairment in mice.

The immune system plays a role in the maintenance of healthy neurocognitive function. Different patterns of immune response triggered by distinct stimuli may affect nervous functions through regulatory or deregulatory signals, depending on the properties of the exogenous immunogens. Here, we investigate the effect of immune stimulation on cognitive-behavioural parameters in healthy mice and its impact on cognitive sequelae resulting from non-severe experimental malaria. We show that immune modulation induced by a specific combination of immune stimuli that induce a type 2 immune response can enhance long-term recognition memory in healthy adult mice subjected to novel object recognition task (NORT) and reverse a lack of recognition ability in NORT and anxiety-like behaviour in a light/dark task that result from a single episode of mild Plasmodium berghei ANKA malaria. Our findings suggest a potential use of immunogens for boosting and recovering recognition memory that may be impaired by chronic and infectious diseases and by the effects of ageing.

Post-weaning social isolation impairs purinergic signaling in rat brain.

Early life stressors, such as social isolation (SI), can disrupt brain development contributing to behavioral and neurochemical alterations in adulthood. Purinergic receptors and ectonucleotidases are key regulators of brain development in embryonic and postnatal periods, and they are involved in several psychiatric disorders, including schizophrenia. The extracellular ATP drives purinergic signaling by activating P2X and P2Y receptors and it is hydrolyzed by ectonucleotidases in adenosine, which activates P1 receptors. The purpose of this study was to investigate if SI, a rodent model used to replicate abnormal behavior relevant to schizophrenia, impacts purinergic signaling. Male Wistar rats were reared from weaning in group-housed or SI conditions for 8 weeks. SI rats exhibited impairment in prepulse inhibition and social interaction. SI presented increased ADP levels in cerebrospinal fluid and ADP hydrolysis in the hippocampus and striatum synaptosomes. Purinergic receptor expressions were upregulated in the prefrontal cortex and downregulated in the hippocampus and striatum. A2A receptors were differentially expressed in SI prefrontal cortex and the striatum, suggesting distinct roles in these brain structures. SI also presented decreased ADP, adenosine, and guanosine levels in the cerebrospinal fluid in response to D-amphetamine. Like patients with schizophrenia, uric acid levels were prominently increased in SI rats after D-amphetamine challenge. We suggest that the SI-induced deficits in prepulse inhibition might be related to the SI-induced changes in purinergic signaling. We provide new evidence that purinergic signaling is markedly affected in a rat model relevant to schizophrenia, pointing out the importance of purinergic system in psychiatry conditions.

Zika Virus Envelope Domain III Recombinant Protein Delivered With Saponin-Based Nanoadjuvant From Quillaja brasiliensis Enhances Anti-Zika Immune Responses, Including Neutralizing Antibodies and Splenocyte Proliferation.

Nanoadjuvants that combine immunostimulatory properties and delivery systems reportedly bestow major improvements on the efficacy of recombinant, protein-based vaccines. Among these, self-assembled micellar formulations named ISCOMs (immune stimulating complexes) show a great ability to trigger powerful immunological responses against infectious pathogens. Here, a nanoadjuvant preparation, based on saponins from Quillaja brasiliensis, was evaluated together with an experimental Zika virus (ZIKV) vaccine (IQB80-zEDIII) and compared to an equivalent vaccine with alum as the standard adjuvant. The preparations were administered to mice in two doses (on days zero and 14) and immune responses were evaluated on day 28 post-priming. Serum levels of anti-Zika virus IgG, IgG1, IgG2b, IgG2c, IgG3 were significantly increased by the nanoadjuvant vaccine, compared to the mice that received the alum-adjuvanted vaccine or the unadjuvanted vaccine. In addition, a robust production of neutralizing antibodies and in vitro splenocyte proliferative responses were observed in mice immunized with IQB80-zEDIII nanoformulated vaccine. Therefore, the IQB80-zEDIII recombinant preparation seems to be a suitable candidate vaccine for ZIKV. Overall, this study identified saponin-based delivery systems as an adequate adjuvant for recombinant ZIKV vaccines and has important implications for recombinant protein-based vaccine formulations against other flaviviruses and possibly enveloped viruses.

Rapid size-exclusion high performance liquid chromatography method for the quality control of amyloid-ß oligomers.

Amyloid-ß (Aß) dysmetabolism is thought to be the main trigger for neurodegenerative events in Alzheimer's disease (AD). In particular, soluble Aß oligomers (AßOs) are proposed as key mediators of synaptic and cognitive dysfunction in AD. Over the past few decades, AßOs prepared from synthetic Aß have been widely applied in vitro and in vivo, the so-called chemical models of AD, uncovering their multiple neurotoxic mechanisms. However, the lack of a reliable quality control (QC) for synthetic AßOs may reflect poor experimental reproducibility. In keeping with this, we optimized and validated a rapid and reproducible SECHPLC method using fluorescence detection for the QC of synthetic AßOs. Our analytical method offers an unprecedent alternative to improve the reproducibility of AD chemical models.

In-depth quantitative proteomic characterization of organotypic hippocampal slice culture reveals sex-specific differences in biochemical pathways.

Sex differences in the brain of mammals range from neuroarchitecture through cognition to cellular metabolism. The hippocampus, a structure mostly associated with learning and memory, presents high vulnerability to neurodegeneration and aging. Therefore, we explored basal sex-related differences in the proteome of organotypic hippocampal slice culture, a major in vitro model for studying the cellular and molecular mechanisms related to neurodegenerative disorders. Results suggest a greater prevalence of astrocytic metabolism in females and significant neuronal metabolism in males. The preference for glucose use in glycolysis, pentose phosphate pathway and glycogen metabolism in females and high abundance of mitochondrial respiration subunits in males support this idea. An overall upregulation of lipid metabolism was observed in females. Upregulation of proteins responsible for neuronal glutamate and GABA synthesis, along with synaptic associated proteins, were observed in males. In general, the significant spectrum of pathways known to predominate in neurons or astrocytes, together with the well-known neuronal and glial markers observed, revealed sex-specific metabolic differences in the hippocampus. TEM qualitative analysis might indicate a greater presence of mitochondria at CA1 synapses in females. These findings are crucial to a better understanding of how sex chromosomes can influence the physiology of cultured hippocampal slices and allow us to gain insights into distinct responses of males and females on neurological diseases that present a sex-biased incidence.

IMXQB-80: A Quillaja brasiliensis saponin-based nanoadjuvant enhances Zika virus specific immune responses in mice.

Vaccine adjuvants are compounds that enhance/prolong the immune response to a co-administered antigen. Saponins have been widely used as adjuvants for many years in several vaccines - especially for intracellular pathogens - including the recent and somewhat revolutionary malaria and shingles vaccines. In view of the immunoadjuvant potential of Q. brasiliensis saponins, the present study aimed to characterize the QB-80 saponin-rich fraction and a nanoadjuvant prepared with QB-80 and lipids (IMXQB-80). In addition, the performance of such adjuvants was examined in experimental inactivated vaccines against Zika virus (ZIKV). Analysis of QB-80 by DI-ESI-ToF by negative ion electrospray revealed over 29 saponins that could be assigned to known structures existing in their congener Q. saponaria, including the well-studied QS-21 and QS-7. The QB-80 saponins were a micrOTOF able to self-assembly with lipids in ISCOM-like nanoparticles with diameters of approximately 43 nm, here named IMXQB-80. Toxicity assays revealed that QB-80 saponins did present some haemolytical and cytotoxic potentials; however, these were abrogated in IMXQB-80 nanoparticles. Regarding the adjuvant activity, QB-80 and IMXQB-80 significantly enhanced serum levels of anti-Zika virus IgG and subtypes (IgG1, IgG2b, IgG2c) as well as neutralized antibodies when compared to an unadjuvanted vaccine. Furthermore, the nanoadjuvant IMXQB-80 was as effective as QB-80 in stimulating immune responses, yet requiring fourfold less saponins to induce the equivalent stimuli, and with less toxicity. These findings reveal that the saponin fraction QB-80, and particularly the IMXQB-80 nanoadjuvant, are safe and capable of potentializing immune responses when used as adjuvants in experimental ZIKV vaccines.

Zika virus-induced brain malformations in chicken embryos.

BACKGROUND: Zika virus (ZIKV) was confirmed to be related to microcephaly in 2016. However, there is still a need for understanding the embryonic morphological changes induced by ZIKV and when they occur. Here, chicken embryos were chosen as experimental model of ZIKV to evaluate virus-associated morphological alterations that might take place during embryonic development. METHODS: A screening with different viral doses was conducted in embryos at HH Stage 10-12 (E1.5) as well as a follow up of the first 5 days postinfection (dpi) was performed to observe the main morphologic changes post ZIKV infection. RESULTS: ZIKV exposed embryos presented a higher prevalence of mortality and defects such as brain malformation when compared to controls. Moreover, we observed that the phenotypes become more evident at 4dpi, when the viral load quantification reaches a peak. CONCLUSIONS: We found that ZIKV exposed embryos presented a high prevalence of mortality and central nervous system (CNS) abnormalities in a dose-dependent manner. The phenotype was more evident 4 days postinfection, when the viral load quantification reached a peak.