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Familial amyloid polyneuropathy (FAP) is a neurodegenerative disorder whose major hallmark is the deposition of mutated transthyretin (TTR) in the form of amyloid fibrils in the peripheral nervous system (PNS). The exposure of PNS axons to extracellular TTR deposits leads to an axonopathy that culminates in neuronal death. However, the molecular mechanisms underlying TTR-induced neurodegeneration are still unclear, despite the extensive studies in vertebrate models. In this work we used a Drosophila FAP model, based on the expression of the amyloidogenic TTR (V30M) in the fly retina, to uncover genetic interactions with cytoskeleton regulators. We show that TTR interacts with actin regulators and induces cytoskeleton alterations, leading to axonal defects. Moreover, our study pinpoints an interaction between TTRV30M and members of Rho GTPase signaling pathways, the major actin regulators. Based on these findings we propose that actin cytoskeleton alterations may mediate the axonopathy observed in FAP patients, and highlight a molecular pathway, mediated by Rho GTPases, underlying TTR-induced neurodegeneration. We expect this work to prompt novel studies and approaches towards FAP therapy.

Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the intracellular deposition of Tau protein and extracellular deposition of amyloid-β peptide (Aβ). AD is also characterized by neuroinflammation and synapse loss, among others. The S100 family is a group of calcium-binding proteins with intra- and extracellular functions, that are important modulators of inflammatory responses. S100B, which is upregulated in AD patients and the most abundant member of this family, was shown to inhibit in vitro the aggregation and toxicity of Aβ42, acting as a neuroprotective holdase-type chaperone. Although S100B is primarily produced by astrocytes, it is also expressed by various cells, including neurons. In this work, we investigated if S100B neuronal expression is triggered as a response to Aβ toxic species, to provide protection during disease progression. We used the AD mouse model AβPPswe/PS1A246E to show that neuronal S100B levels are significantly higher in 10-month-old animals, and cellular assays to demonstrate that Aβ oligomers significantly increase S100B expression in SH-SY5Y cells, but not monomeric or fibrillar Aβ. Using primary cultures of rat hippocampal neurons, we showed that S100B partially reverts Aβ-induced cofilin-actin rods (synapse disruptors), and rescues the decrease in active synapses and post-synaptic marker (PSD-95), imposed by Aβ peptide. Altogether, these findings establish the neuroprotective activity of S100B in response to proteotoxic stress in cells, highlighting its chaperone function as a crucial factor in understanding proteostasis regulation in the diseased brain and identifying potential therapeutic targets.

Chysodeixis includens and Helicoverpa armigera can negatively impact soybean yield due to defoliation and direct injury on the pods, respectively. Insecticides, such as indoxacarb, are still an important controlling tool to manage these insects. To support Integrated Pest Management (IPM) and Insect Resistance Management (IRM) as well as to reduce product decantation during storage and nozzle clogging in field application, a new indoxacarb formulation (emulsifiable concentrate - EC) was developed to replace the suspension concentrate formulation (SC). The objective of this study was to evaluate the susceptibility and compare the residual effects of two indoxacarb formulations on C. includens and H. armigera on soybean. A dose-response curve and the residual effect from in-field application were obtained using a laboratory strain of both insect pests. Soybean leaflets were collected and dipped into aqueous indoxacarb solutions. The evaluations were performed 96 h after the infestation to calculate the insect mortality percentage and foliar damage. Also, plants were sprayed in the field and leaflets from mid and upper regions of the plants were collected and used to feed third-instar larvae of both species. Results demonstrated that C. includens and H. armigera are similary sensitive to indoxacarb. The residual activity was up to 1 h after application for H. armigera and up to 3 days for C. includens. No difference was observed on this activity between mid and upper regions of the plant. Overall, the enhanced EC formulation is as effective as the SC formulation for the control of both species on soybean.

Alpha-Synuclein (αSyn), a protein highly enriched in neurons where it preferentially localizes at the pre-synapse, has been in the spotlight because its intraneuronal aggregation is a central phenomenon in Parkinson’s disease. However, the consequences of αSyn accumulation to neuronal function are not fully understood. Considering the crucial role of actin on synaptic function and the fact that dysregulation of this cytoskeleton component is emerging in neurodegenerative disorders, the impact of αSyn on actin is a critical point to be addressed. In this review we explore the link between αSyn and actin and its significance for physiology and pathology. We discuss the relevance of αSyn-actin interaction for synaptic function and highlight the actin-depolymerizing protein cofilin-1 as a key player on αSyn-induced actin dysfunction in Parkinson’s disease.

Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrP C ) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.

Melon fortification with calcium by impregnation techniques using a vacuum and/or ultrasound and drying were combined to obtain a snack product. For the impregnation step, samples were immersed in a 2 g 100 mL−1 calcium chloride solution at 25 °C. The samples were dried at 60 °C and an air velocity of 2 m s−1. The influence of the impregnation method on drying kinetics, mass variation, calcium content, water activity, color, and texture was evaluated. All dried samples had reduced water activity. The vacuum impregnated (VI) melons presented higher mass gain and drying time. It resulted in the highest calcium incorporation, increasing up to 13 times the calcium concentration of the samples. The samples dried after submitted to VI showed the greatest differences in color and hardness. However, VI was the most effective technique for calcium incorporation, being the only one capable of producing fortified dried melon.

Introduction Zika virus (ZIKV) caused an outbreak in Brazil, in 2015, being associated to microcephaly. ZIKV has a strong neurotropism leading to death of infected cells in different brain regions, including the hippocampus, a major site for neurogenesis. The neuronal populations of the brain are affected differently by ZIKV from Asian and African ancestral lineages. However, it remains to be investigated whether subtle variations in the ZIKV genome can impact hippocampus infection dynamics and host response. Objective This study evaluated how two Brazilian ZIKV isolates, PE243 and SPH2015, that differ in two specific missense amino acid substitutions, one in the NS1 protein and the other in the NS4A protein, affect the hippocampal phenotype and transcriptome. Methods Organotypic hippocampal cultures (OHC) from infant Wistar rats were infected with PE243 or SPH2015 and analyzed in time series using immunofluorescence, confocal microscopy, RNA-Seq and RT-qPCR. Results Unique patterns of infection and changes in neuronal density in the OHC were observed for PE243 and SPH2015 between 8 and 48 h post infection (p.i.). Phenotypic analysis of microglia indicated that SPH2015 has a greater capacity for immune evasion. Transcriptome analysis of OHC at 16 h p.i. disclosed 32 and 113 differentially expressed genes (DEGs) in response to infection with PE243 and SPH2015, respectively. Functional enrichment analysis suggested that infection with SPH2015 activates mostly astrocytes rather than microglia. PE243 downregulated biological process of proliferation of brain cells and upregulated those associated with neuron death, while SPH2015 downregulated processes related to neuronal development. Both isolates downregulated cognitive and behavioral development processes. Ten genes were similarly regulated by both isolates. They are putative biomarkers of early hippocampus response to ZIKV infection. At 5, 7, and 10 days p.i., neuronal density of infected OHC remained below controls, and mature neurons of infected OHC showed an increase in the epigenetic mark H3K4me3, which is associated to a transcriptionally active state. This feature is more prominent in response to SPH2015. Conclusion Subtle genetic diversity of the ZIKV affects the dynamics of viral dissemination in the hippocampus and host response in the early stages of infection, which may lead to different long-term effects in neuronal population.

The interplay between bacterial virulence factors and the host innate immune response in pneumococcal meningitis (PM) can result in uncontrolled neuroinflammation, which is known to induce apoptotic death of progenitor cells and post-mitotic neurons in the hippocampal dentate gyrus, resulting in cognitive impairment. Vitamin B12 attenuates hippocampal damage and reduces the expression of some key inflammatory genes in PM, by acting as an epidrug that promotes DNA methylation, with increased production of S-adenosyl-methionine, the universal donor of methyl. Eleven-day-old rats were infected with via intracisternal injection and then administered either vitamin B12 or a placebo. After 24 hours of infection, the animals were euthanized, and apoptosis in the hippocampal dentate gyrus, microglia activation, and the inflammatory infiltrate were quantified in one brain hemisphere. The other hemisphere was used for RNA-Seq and RT-qPCR analysis. In this study, adjuvant therapy with B12 was found to modulate the hippocampal transcriptional signature induced by PM in infant rats, mitigating the effects of the disease in canonical pathways related to the recognition of pathogens by immune cells, signaling via NF-kB, production of pro-inflammatory cytokines, migration of peripheral leukocytes into the central nervous system, and production of reactive species. Phenotypic analysis revealed that B12 effectively inhibited microglia activation in the hippocampus and reduced the inflammatory infiltrate in the central nervous system of the infected animals. These pleiotropic transcriptional effects of B12 that lead to neuroprotection are partly regulated by alterations in histone methylation markings. No adverse effects of B12 were predicted or observed, reinforcing the well-established safety profile of this epidrug. B12 effectively mitigates the impact of PM on pivotal neuroinflammatory pathways. This leads to reduced microglia activation and inflammatory infiltrate within the central nervous system, resulting in the attenuation of hippocampal damage. The anti-inflammatory and neuroprotective effects of B12 involve the modulation of histone markings in hippocampal neural cells.

ResumoEstudo transversal com o objetivo de analisar as associações entre as condições de saúde e a inadequação do consumo de frutas e hortaliças (FH) de 1.255 homens e mulheres atendidos em Unidades Básicas de Saúde de Belo Horizonte (MG). A coleta de dados contemplou o consumo de FH, a situação socioeconômica e as condições de saúde. Os resultados foram apresentados em razão de prevalência (RP) e intervalo de confiança de 95% (IC 95%). Verificou-se 77,5% (IC 95%: 75,1%-79,8%) de inadequação do consumo de FH (< 5 porções diárias) e esta foi superior entre os homens (83,8%, IC 95%: 79,0%-88,5% vs. mulheres: 76%, IC 95%: 73,4%-78,6%). Para as mulheres, o consumo inadequado de FH foi maior entre aquelas com percepção muito ruim da qualidade de sua saúde (RP: 1,37; IC 95%: 1,19-1,59) e entre as que consideraram a sua alimentação não saudável (RP: 1,15; IC 95%: 1,07-1,24). Para os homens, o consumo inadequado de FH foi superior entre os que referiram de 2 a 4 visitas ao médico no ano anterior à entrevista (RP: 1,21; IC 95%: 1,06-1,37). Concluiu-se que o consumo de FH na amostra encontra-se aquém das recomendações e que as condições de saúde se associaram de maneira distinta entre os sexos. ABSTRACTThis cross-sectional study sought to analyze the associations between health conditions and the inadequate consumption of fruit and vegetables (FV) of 1,255 men and women attended in Primary Healthcare Units in Belo Horizonte (State of Minas Gerais). Data collection included FV consumption, socioeconomic status and health conditions. Results are presented by prevalence ratio (PR) with a confidence interval of 95% (CI 95%). A 77.5% (CI 95%: 75.1%-79.8%) of inadequacy of consumption (< 5 daily servings) was found and it was more prevalent among men (83.8%, CI 95%: 79.0%-88.5% than among women: 76.0%, CI 95%: 73.4%-78.6%). For women, the inadequate consumption of FV was higher among those with poor perception of health quality (PR: 1.37; CI 95%: 1.19-1.59) and among those who consider their dietary habits as being unhealthy (PR: 1.15; CI 95%: 1.07-1.24). For men, the inadequate consumption was higher between individuals that reported 2 to 4 visits to the doctor in the year prior to the interview (PR: 1.21; CI 95%: 1.06-1.21). The conclusions showed that the consumption of FV among the population under study is below the recommendations and the health conditions are associated differently for each gender.

Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrP ) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.