Transcriptomic analysis of human astrocytes in vitro reveals hypoxia-induced mitochondrial dysfunction, modulation of metabolism, and dysregulation of the immune response

Hypoxia is a feature of neurodegenerative diseases, and can both directly and indirectly impact on neuronal function through modulation of glial function. Astrocytes play a key role in regulating homeostasis within the central nervous system, and mediate hypoxia-induced changes in response to reduced oxygen availability. The current study performed a detailed characterization of hypoxia-induced changes in the transcriptomic profile of astrocytes in vitro. Human astrocytes were cultured under normoxic (5% CO2, 95% air) or hypoxic conditions (1% O2, 5% CO2, 94% N2) for 24 h, and the gene expression profile assessed by microarray analysis. In response to hypoxia 4904 genes were significantly differentially expressed (1306 upregulated and 3598 downregulated, FC ≥ 2 and p ≤ 0.05). Analysis of the significant differentially expressed transcripts identified an increase in immune response pathways, and dysregulation of signalling pathways, including HIF-1 (p = 0.002), and metabolism, including glycolysis (p = 0.006). To assess whether the hypoxia-induced metabolic gene changes observed affected metabolism at a functional level, both the glycolytic and mitochondrial flux were measured using an XF bioanalyser. In support of the transcriptomic data, under physiological conditions hypoxia significantly reduced mitochondrial respiratory flux (p = 0.0001) but increased basal glycolytic flux (p = 0.0313). However, when metabolically stressed, hypoxia reduced mitochondrial spare respiratory capacity (p = 0.0485) and both glycolytic capacity (p = 0.0001) and glycolytic reserve (p < 0.0001). In summary, the current findings detail hypoxia-induced changes in the astrocyte transcriptome in vitro, identifying potential targets for modifying the astrocyte response to reduced oxygen availability in pathological conditions associated with ischaemia/hypoxia, including manipulation of mitochondrial function, metabolism, and the immune response

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses; estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1; further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12; consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12

Impact of global warming on beef cattle production cost in Brazil

Global warming is affecting agribusiness in its economic aspects. Therefore, the prediction of the evolution of Brazilian beef cattle production cost was made using the IPCC forecast scenario for global warming. The methodology consisted of two steps: (i) the development of a fuzzy model that estimated the grazing land capacity (RP) decrease risk as a function of the changes in the average total rain index, air temperature and increase in extension of the dry season; and (ii) the design of an algorithm for predicting the decrease in production as function of the RPfuzzy model, that results in the impact in beef cattle productivity, and consequent increase in production costs. Historical environmental data from important producing counties in the Cerrado were organized and a set of fuzzy Gaussian functions were developed, and three possible settings (optimistic, medium and pessimistic) were considered. The decrease in beef cattle productivity was estimated using the losses in production due to the increase in air temperature and vulnerability of pasture capacity. The boundary settings for the total increase of production cost scenario used the number of animals per area of grazing land, the adoption of grain supplement and its future scenario; and the result output function pointed to a threshold within a variation from an increase in production cost of 80% (optimistic) to 160% (pessimistic). Under the optimistic scenario the total cost of Brazilian beef cattle production in the Cerrado became near to US$2.88 kg-1, while in the pessimistic scenario this cost reached US$ 4.16 kg-1, challenging the international competitiveness of this economic segment.O aquecimento global afeta o agronegócio em seus aspectos econômicos. Foi feita previsão daevolução do custo de produção de carne bovina brasileira usando a predição de aquecimento global do IPCC. A metodologia consistiu de duas etapas: (i) o desenvolvimento de modelo fuzzy que estimou o risco de decréscimo da capacidade de pastagens (RP) em função das mudanças no índice pluviométrico total, na temperatura do ar e na extensão da estação de seca; e (ii) o desenvolvimento de um algoritmo para predição do decréscimo da produção em função de um modelo fuzzy de RP que resulte no impacto na produtividade bovina de corte e conseqüente aumento no custo de produção. Foram organizados os dados históricos de fatores ambientais dos municípios importante produção no Cerrado e um conjunto de funções Gaussianas fuzzy foi desenvolvido e três estimativas possíveis (otimista, média e negativa) foram consideradas. O decréscimo na produtividade do gado foi estimado usando as perdas de produção devido ao acréscimo da temperatura bem como da vulnerabilidade da capacidade de pastagem. O estabelecimento dos limites para o cenário do acréscimo do custo de produção usou o número de unidade animal por área de pastagem, a adoção de suplemento de grãos e o cenário de produção futura; e o resultado da função de saída apontou para uma variação do acréscimo do custo de produção de 80% (otimista) até 160% (pessimista). Sob o cenário otimista, o custo total da produção brasileira de carne bovina no Cerrado chega a US$2,88 kg-1, enquanto no cenário pessimista este custo pode atingir US$ 4,16 kg-1, o que pode comprometer a competitividade internacional do setor