Lipid metabolism in astrocytic structure and function

Astrocytes are the most abundant glial cell in the central nervous system and are involved in multiple processes including metabolic homeostasis, blood brain barrier regulation and neuronal crosstalk. Astrocytes are the main storage point of glycogen in the brain and it is well established that astrocyte uptake of glutamate and release of lactate prevents neuronal excitability and supports neuronal metabolic function. However, the role of lipid metabolism in astrocytes in relation to neuronal support has been until recently, unclear. Lipids play a fundamental role in astrocyte function, including energy generation, membrane fluidity and cell to cell signaling. There is now emerging evidence that astrocyte storage of lipids in droplets has a crucial physiological and protective role in the central nervous system. This pathway links β-oxidation in astrocytes to inflammation, signalling, oxidative stress and mitochondrial energy generation in neurons. Disruption in lipid metabolism, structure and signalling in astrocytes can lead to pathogenic mechanisms associated with a range of neurological disorders

Activation of the Keap1/Nrf2 pathway suppresses mitochondrial dysfunction, oxidative stress, and motor phenotypes in C9orf72 ALS/FTD models

Mitochondrial dysfunction is a common feature of C9orf72 amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD); however, it remains unclear whether this is a cause or consequence of the pathogenic process. Analysing multiple aspects of mitochondrial biology across several Drosophila models of C9orf72-ALS/FTD, we found morphology, oxidative stress, and mitophagy are commonly affected, which correlated with progressive loss of locomotor performance. Notably, only genetic manipulations that reversed the oxidative stress levels were also able to rescue C9orf72 locomotor deficits, supporting a causative link between mitochondrial dysfunction, oxidative stress, and behavioural phenotypes. Targeting the key antioxidant Keap1/Nrf2 pathway, we found that genetic reduction of Keap1 or pharmacological inhibition by dimethyl fumarate significantly rescued the C9orf72-related oxidative stress and motor deficits. Finally, mitochondrial ROS levels were also elevated in C9orf72 patient-derived iNeurons and were effectively suppressed by dimethyl fumarate treatment. These results indicate that mitochondrial oxidative stress is an important mechanistic contributor to C9orf72 pathogenesis, affecting multiple aspects of mitochondrial function and turnover. Targeting the Keap1/Nrf2 signalling pathway to combat oxidative stress represents a therapeutic strategy for C9orf72-related ALS/FTD

Structure of Organic Solids at Low Temperature and High Pressure

This tutorial review looks at structural and supramolecular chemistry of molecular solids under extreme conditions, and introduces the instrumentation and facilities that enable single crystal diffraction studies on molecular crystals at both high pressure and low temperature. The equipment used for crystallography under extreme conditions is explored, particularly pressure cells such as the diamond anvil cell, and their mechanism of action, as well as the cryogenic apparatus which allows materials to be cooled to significantly low temperatures. The review also covers recent advances in the structural chemistry of molecular solids under extreme conditions with an emphasis on the use of single crystal crystallography in high pressure and low temperature environments to probe polymorphism and supramolecular interactions

Pareto-based multi-output metamodeling with active learning

When dealing with computationally expensive simulation codes or process measurement data, global surrogate modeling methods are firmly established as facilitators for design space exploration, sensitivity analysis, visualization and optimization. Popular surrogate model types include neural networks, support vector machines, and splines. In addition, the cost of each simulation mandates the use of active learning strategies where data points (simulations) are selected intelligently and incrementally. When applying surrogate models to multi-output systems, the hyperparameter optimization problem is typically formulated in a single objective way. The different response outputs are modeled separately by independent models. Instead, a multi-objective approach would benefit the domain expert by giving information about output correlation, facilitate the generation of diverse ensembles, and enable automatic model type selection for each output on the fly. This paper outlines a multi-objective approach to surrogate model generation including its application to two problems

Hymenopteran parasitoids synthesize ‘honeydew-specific’ oligosaccharides.

1. Many arthropods depend on carbohydrate-rich food sources such as nectar or honeydew. Nevertheless, we often know little about the extent to which various sugar sources contribute to the diet of arthropods. 2. One way to study food use in the field is to analyse guts of collected insects for source-specific compounds. Sugar sources often show distinct differences in their carbohydrate composition. This applies especially to honeydew, the excretion product of phloem-feeding ‘Sternorrhynchae’, which often features a broad range of phloem-feeder synthesized di- and oligosaccharides. 3. Out of these oligosaccharides, melezitose, has been widely used as an indicator of honeydew consumption. The use of melezitose or other honeydew saccharides as ‘signature sugars’ hinges on the assumption that the production of these sugars is unique to honeydew-secreting insects. 4. Here we show that the hymenopteran parasitoids Diadegma semiclausum and D. insulare synthesize the trisaccharides melezitose and erlose as well as the disaccharide maltose when fed sucrose, but not when feeding on an equimolar glucose–fructose mixture. 5. The presence of melezitose, erlose and maltose was confined to the parasitoid's digestive tract, indicating that enzyme activity is restricted to this area. D. semiclausum excrement contained low overall sugar concentrations and low relative levels of melezitose, erlose and maltose. 6. Possible functions of sugar synthesis in these nectar-feeding insects are discussed

Rare and common genetic determinants of mitochondrial function determine severity but not risk of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving selective vulnerability of energy-intensive motor neurons (MNs). It has been unclear whether mitochondrial function is an upstream driver or a downstream modifier of neurotoxicity. We separated upstream genetic determinants of mitochondrial function, including genetic variation within the mitochondrial genome or autosomes; from downstream changeable factors including mitochondrial DNA copy number (mtCN). Across three cohorts including 6,437 ALS patients, we discovered that a set of mitochondrial haplotypes, chosen because they are linked to measurements of mitochondrial function, are a determinant of ALS survival following disease onset, but do not modify ALS risk. One particular haplotype appeared to be neuroprotective and was significantly over-represented in two cohorts of long-surviving ALS patients. Causal inference for mitochondrial function was achievable using mitochondrial haplotypes, but not autosomal SNPs in traditional Mendelian randomization (MR). Furthermore, rare loss-of-function genetic variants within, and reduced MN expression of, ACADM and DNA2 lead to ∼50 % shorter ALS survival; both proteins are implicated in mitochondrial function. Both mtCN and cellular vulnerability are linked to DNA2 function in ALS patient-derived neurons. Finally, MtCN responds dynamically to the onset of ALS independently of mitochondrial haplotype, and is correlated with disease severity. We conclude that, based on the genetic measures we have employed, mitochondrial function is a therapeutic target for amelioration of disease severity but not prevention of ALS