Structural results on convexity relative to cost functions

Mass transportation problems appear in various areas of mathematics, their solutions involving cost convex potentials. Fenchel duality also represents an important concept for a wide variety of optimization problems, both from the theoretical and the computational viewpoints. We drew a parallel to the classical theory of convex functions by investigating the cost convexity and its connections with the usual convexity. We give a generalization of Jensen's inequality for cost convex functions.Comment: 10 page

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone–brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental–physical co-morbidity trias of alcohol abuse—depression/anxiety—bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental–physical co-morbidity trias

Single-nucleus transcriptome analysis reveals disease- and regeneration-associated endothelial cells in white matter vascular dementia.

BackgroundVascular dementia (VaD) is the accumulation of vascular lesions in the subcortical white matter of the brain. These lesions progress and there is no direct medical therapy.AimsTo determine the specific cellular responses in VaD so as to provide molecular targets for therapeutic development.Materials and methodsSingle-nucleus transcriptome analysis was performed in human periventricular white matter (PVWM) samples of VaD and normal control (NC) subjects.ResultsDifferential analysis shows that cell type-specific transcriptomic changes in VaD are associated with the disruption of specific biological processes, including angiogenesis, immune activation, axonal injury and myelination. Each cell type in the neurovascular unit within white matter has a specific alteration in gene expression in VaD. In a central cell type for this disease, subcluster analysis of endothelial cells (EC) indicates that VaD contains a disease-associated EC subcluster that expresses genes associated with programmed cell death and a response to protein folding. Two other subpopulations of EC in VaD express molecular systems associated with regenerative processes in angiogenesis, and in axonal sprouting and oligodendrocyte progenitor cell maturation.ConclusionThis comprehensive molecular profiling of brain samples from patients with VaD reveals previously unknown molecular changes in cells of the neurovascular niche, and an attempt at regeneration in injured white matter

NPC1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP46A1 activation

NPC is a neurodegenerative disorder characterized by cholesterol accumulation in endolysosomal compartments. It is caused by mutations in the gene encoding NPC1, an endolysosomal protein mediating intracellular cholesterol trafficking. Cognitive and psychiatric alterations are hallmarks in NPC patients pointing to synaptic defects. However, the role of NPC1 in synapses has not been explored. We show that NPC1 is present in the postsynaptic compartment and is locally translated during LTP. A mutation in a region of the NPC1 gene commonly altered in NPC patients reduces NPC1 levels at synapses due to enhanced NPC1 protein degradation. This leads to shorter postsynaptic densities, increased synaptic cholesterol and impaired LTP in NPC1nmf164 mice with cognitive deficits. NPC1 mediates cholesterol mobilization and enables surface delivery of CYP46A1 and GluA1 receptors necessary for LTP, which is defective in NPC1nmf164 mice. Pharmacological activation of CYP46A1 normalizes synaptic levels of cholesterol, LTP and cognitive abilities, and extends life span of NPC1nmf164 mice. Our results unveil NPC1 as a regulator of cholesterol dynamics in synapses contributing to synaptic plasticity, and provide a potential therapeutic strategy for NPC patients

Oxidative Stress and Histopathological Changes in Gills and Kidneys of <i>Cyprinus carpio</i> following Exposure to Benzethonium Chloride, a Cationic Surfactant

One cationic surfactant with a wide spectrum of microbiocidal activity is benzethonium chloride (BEC). Despite being widely used, the toxicity data on vertebrate organisms are limited. Therefore, we aimed to evaluate within this study the acute toxicity of BEC on the gills and kidneys of Cyprinus carpio (European carp). An alteration of the antioxidant enzymes activities (glutathione reductase, glutathione peroxidase and glutathione S-transferase) was noticed after 96 h of exposure, along with an elevation of lipid peroxidation and decreased concentration of reduced glutathione, which confirmed that BEC was able to induce toxicity to these tissues. These metabolic effects were correlated with unspecific structural changes observed in gills and kidneys, having moderate degree of severity (such as an increase of melanomacrophages aggregation incidence and cytoplasm vacuolation of goblet cells in collecting tubules) and generally being compatible with life for the exposure time studied. The most severe structural effects were observed in gills after 96 h, noticing a lamellar aneurysm, hemorrhages and lamellar epithelium disruption due to the blood vessels and pillar cells damages and increased blood flow inside the lamellae. By our research we can confirm the utility of biochemical and histological analyses in the fish organs as tools for monitoring the water quality and ecotoxicological potential of chemicals

Evaluation of Sub-Lethal Toxicity of Benzethonium Chloride in Cyprinus carpio Liver

Benzenthonium chloride (BEC, Hyamine 1622) is a quaternary ammonium surfactant with cationic properties widely used in cleaning, sanitation, and medical products that can become harmful to humans and also to the environment. This study aimed to evaluate its acute effects on Cyprinus carpio fish in terms of oxidative stress and morphological changes on hepatic tissue in order to show the sub-lethal toxicity of BEC. Fish were exposed to 1 mg/L BEC for 24, 48, and 96 h, and the liver samples were collected. The most significant changes were noticed after 96 h of exposure when the entire antioxidant enzyme system was affected. The activities of catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase decreased by 44%, 31%, 30%, and 45%, respectively, compared to control. Glucose-6-phosphate dehydrogenase activity decreased by 29% after 96 h of control, inducing a reduction of NADPH formation which decreased by half the level of reduced glutathione, the main non-enzymatic antioxidant. These effects correlated with the raised value of lipid peroxidation after 96 h and the morphology changes on hepatic tissue, such as cytoplasmic vacuolization and nuclear hypertrophy that could affect the normal function of the liver. All of these results showed acute toxicity of BEC on C. carpio after 96 h of exposure, causing oxidative stress response at the hepatic level

SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production

<p>Macroautophagy/autophagy defects have been identified as critical factors underlying the pathogenesis of neurodegenerative diseases. The roles of the bioactive signaling lipid sphingosine-1-phosphate (S1P) and its catabolic enzyme SGPL1/SPL (sphingosine phosphate lyase 1) in autophagy are increasingly recognized. Here we provide in vitro and in vivo evidence for a previously unidentified route through which SGPL1 modulates autophagy in neurons. SGPL1 cleaves S1P into ethanolamine phosphate, which is directed toward the synthesis of phosphatidylethanolamine (PE) that anchors LC3-I to phagophore membranes in the form of LC3-II. In the brains of SGPL1^fl/fl/Nes mice with developmental neural specific SGPL1 ablation, we observed significantly reduced PE levels. Accordingly, alterations in basal and stimulated autophagy involving decreased conversion of LC3-I to LC3-II and increased BECN1/Beclin-1 and SQSTM1/p62 levels were apparent. Alterations were also noticed in downstream events of the autophagic-lysosomal pathway such as increased levels of lysosomal markers and aggregate-prone proteins such as APP (amyloid β [A4] precursor protein) and SNCA/α-synuclein. In vivo profound deficits in cognitive skills were observed. Genetic and pharmacological inhibition of SGPL1 in cultured neurons promoted these alterations, whereas addition of PE was sufficient to restore LC3-I to LC3-II conversion, and control levels of SQSTM1, APP and SNCA. Electron and immunofluorescence microscopy showed accumulation of unclosed phagophore-like structures, reduction of autolysosomes and altered distribution of LC3 in SGPL1^fl/fl/Nes brains. Experiments using EGFP-mRFP-LC3 provided further support for blockage of the autophagic flux at initiation stages upon SGPL1 deficiency due to PE paucity. These results emphasize a formerly overlooked direct role of SGPL1 in neuronal autophagy and assume significance in the context that autophagy modulators hold an enormous therapeutic potential in the treatment of neurodegenerative diseases.</p