Metabolic Features of Brain Function with Relevance to Clinical Features of Alzheimer and Parkinson Diseases

Brain metabolism is comprised in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since the brain primarily relies on metabolism of glucose, ketone bodies, and amino acids, aspects of these metabolic processes in these disorders—and particularly how these altered metabolic pro- cesses are related to oxidative and/or nitrosative stress and the resulting damaged targets—are re- viewed in this paper. Greater understanding of the decreased functions in brain metabolism in AD and PD is posited to lead to potentially important therapeutic strategies to address both of these disorders, which cause relatively long-lasting decreased quality of life in patients

Metabolic Features of Brain Function with Relevance to Clinical Features of Alzheimer and Parkinson Diseases

Brain metabolism is comprised in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Since the brain primarily relies on metabolism of glucose, ketone bodies, and amino acids, aspects of these metabolic processes in these disorders—and particularly how these altered metabolic processes are related to oxidative and/or nitrosative stress and the resulting damaged targets—are reviewed in this paper. Greater understanding of the decreased functions in brain metabolism in AD and PD is posited to lead to potentially important therapeutic strategies to address both of these disorders, which cause relatively long-lasting decreased quality of life in patients

COMPARING HABITATS Reframing comparison in the “post-disciplinary” era

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A Shearless microfluidic device detects a role in mechanosensitivity for awcon neuron in Caenorhabditis elegans

AWC olfactory neurons are fundamental for chemotaxis toward volatile attractants in Caenorhabditis elegans. Here, it is shown that AWC(ON) responds not only to chemicals but also to mechanical stimuli caused by fluid flow changes in a microfluidic device. The dynamics of calcium events are correlated with the stimulus amplitude. It is further shown that the mechanosensitivity of AWC(ON) neurons has an intrinsic nature rather than a synaptic origin, and the calcium transient response is mediated by TAX-4 cGMP-gated cation channel, suggesting the involvement of one or more "odorant" receptors in AWC(ON) mechano-transduction. In many cases, the responses show plateau properties resembling bistable calcium dynamics where neurons can switch from one stable state to the other. To investigate the unprecedentedly observed mechanosensitivity of AWC(ON) neurons, a novel microfluidic device is designed to minimize the fluid shear flow in the arena hosting the nematodes. Animals in this device show reduced neuronal activation of AWC(ON) neurons. The results observed indicate that the tangential component of the mechanical stress is the main contributor to the mechanosensitivity of AWC(ON). Furthermore, the microfluidic platform, integrating shearless perfusion and calcium imaging, provides a novel and more controlled solution for in vivo analysis both in micro-organisms and cultured cells

C. elegans-based chemosensation strategy for the early detection of cancer metabolites in urine samples

Chemosensory receptors play a crucial role in distinguishing the wide range of volatile/soluble molecules by binding them with high accuracy. Chemosensation is the main sensory modality in organisms lacking long-range sensory mechanisms like vision/hearing. Despite its low number of sensory neurons, the nematode Caenorhabditis elegans possesses several chemosensory receptors, allowing it to detect about as many odorants as mammals. Here, we show that C. elegans displays attraction towards urine samples of women with breast cancer, avoiding control ones. Behavioral assays on animals lacking AWC sensory neurons demonstrate the relevance of these neurons in sensing cancer odorants: calcium imaging on AWC increases the accuracy of the discrimination (97.22%). Also, chemotaxis assays on animals lacking GPCRs expressed in AWC allow to identify receptors involved in binding cancer metabolites, suggesting that an alteration of a few metabolites is sufficient for the cancer discriminating behavior of C. elegans, which may help identify a fundamental fingerprint of breast cancer

The J2-Immortalized Murine Macrophage Cell Line Displays Phenotypical and Metabolic Features of Primary BMDMs in Their M1 and M2 Polarization State

Macrophages are immune cells that are important for the development of the defensive front line of the innate immune system. Following signal recognition, macrophages undergo activation toward specific functional states, consisting not only in the acquisition of specific features but also of peculiar metabolic programs associated with each function. For these reasons, macrophages are often isolated from mice to perform cellular assays to study the mechanisms mediating immune cell activation. This requires expensive and time-consuming breeding and housing of mice strains. To overcome this issue, we analyzed an in-house J2-generated immortalized macrophage cell line from BMDMs, both from a functional and metabolic point of view. By assaying the intracellular and extracellular metabolism coupled with the phenotypic features of immortalized versus primary BMDMs, we concluded that classically and alternatively immortalized macrophages display similar phenotypical, metabolic and functional features compared to primary cells polarized in the same way. Our study validates the use of this immortalized cell line as a suitable model with which to evaluate in vitro how perturbations can influence the phenotypical and functional features of murine macrophages

Deletion of Lactate Dehydrogenase-A Impairs Oncogene-Induced Mouse Hepatocellular Carcinoma Development

Hepatocellular carcinoma (HCC) is a multistep process whereby abnormally proliferating cancer cells undergo extensive metabolic reprogramming. Metabolic alterations in hepatocarcinogenesis depend on the activation of specific oncogenes, thus partially explaining HCC heterogeneity. c-Myc oncogene overexpression, frequently observed in human HCCs, leads to a metabolic rewiring toward a Warburg phenotype and production of lactate, resulting in the acidification of the extracellular space, favoring the emergence of an immune-permissive tumor microenvironment. Here, we investigated whether Ldha genetic ablation interferes with metabolic reprogramming and HCC development in the mouse

The recurrent pathogenic Pro890Leu substitution in CLTC causes a generalized defect in synaptic transmission in Caenorhabditis elegans

De novo CLTC mutations underlie a spectrum of early-onset neurodevelopmental phenotypes having developmental delay/intellectual disability (ID), epilepsy, and movement disorders (MD) as major clinical features. CLTC encodes the widely expressed heavy polypeptide of clathrin, a major component of the coated vesicles mediating endocytosis, intracellular trafficking, and synaptic vesicle recycling. The underlying pathogenic mechanism is largely unknown. Here, we assessed the functional impact of the recurrent c.2669C > T (p.P890L) substitution, which is associated with a relatively mild ID/MD phenotype. Primary fibroblasts endogenously expressing the mutated protein show reduced transferrin uptake compared to fibroblast lines obtained from three unrelated healthy donors, suggesting defective clathrin-mediated endocytosis. In vitro studies also reveal a block in cell cycle transition from G0/G1 to the S phase in patient's cells compared to control cells. To demonstrate the causative role of the p.P890L substitution, the pathogenic missense change was introduced at the orthologous position of the Caenorhabditis elegans gene, chc-1 (p.P892L), via CRISPR/Cas9. The resulting homozygous gene-edited strain displays resistance to aldicarb and hypersensitivity to PTZ, indicating defective release of acetylcholine and GABA by ventral cord motor neurons. Consistently, mutant animals show synaptic vesicle depletion at the sublateral nerve cords, and slightly defective dopamine signaling, highlighting a generalized deficit in synaptic transmission. This defective release of neurotransmitters is associated with their secondary accumulation at the presynaptic membrane. Automated analysis of C. elegans locomotion indicates that chc-1 mutants move slower than their isogenic controls and display defective synaptic plasticity. Phenotypic profiling of chc-1 (+/P892L) heterozygous animals and transgenic overexpression experiments document a mild dominant-negative behavior for the mutant allele. Finally, a more severe phenotype resembling that of chc-1 null mutants is observed in animals harboring the c.3146 T > C substitution (p.L1049P), homologs of the pathogenic c.3140 T > C (p.L1047P) change associated with a severe epileptic phenotype. Overall, our findings provide novel insights into disease mechanisms and genotype-phenotype correlations of CLTC-related disorders

Measuring and comparing the carbon footprints of different procurement models for primary school meals:Analysis of cases across five European countries

Sustainable Public Food Procurement (PFP) represents a key game changer for food systems transformation. It can influence both food consumption and food production patterns. It can deliver multiple social, economic and environmental benefits towards sustainable food systems for healthy diets. This publication aims to contribute to the improved understanding, dissemination and use of PFP as a development tool in particular in the case of school meals programmes. In Volume 1, researchers, policymakers and development partners can find evidence on how PFP can be used as a development tool and deliver multiple benefits for multiple beneficiaries. It argues that PFP can provide a market for local and smallholder farmers, promote the conservation and sustainable use of agrobiodiversity, and improve the nutrition and health of children and communities. Volume 2 of this publication, available at https://doi.org/10.4060/cb7969en, presents further analysis of the instruments, enablers and barriers for PFP implementation. It also provides case studies with local, regional and national experiences from Africa, Asia, Europe and North and South America