Mu opioid receptors expressed in striatal D2 medium spiny neurons have divergent contributions to cocaine and morphine reward.

While our understanding of the neurobiological mechanisms underlying cocaine and opiate reward has historically been dopamine-focused, evidence from genetic and pharmacological approaches indicates that µ-opioid receptors (MORs) in the striatum are important contributors. Within the striatum, MORs are expressed in both dopamine D1-receptor and D2-receptor expressing GABAergic medium spiny neurons (MSNs), as well as in interneurons and various afferents. Thus, it remains unclear how these distinct MOR populations regulate drug reward.

BIN1 regulates actin-membrane interactions during IRSp53-dependent filopodia formation.

Amphiphysin 2 (BIN1) is a membrane and actin remodeling protein mutated in congenital and adult centronuclear myopathies. Here, we report an unexpected function of this N-BAR domain protein BIN1 in filopodia formation. We demonstrated that BIN1 expression is necessary and sufficient to induce filopodia formation.

Building pyramids against the evolutionary emergence of pathogens.

Mutations allowing pathogens to escape host immunity promote the spread of infectious diseases in heterogeneous host populations and can lead to major epidemics. Understanding the conditions that slow down this evolution is key for the development of durable control strategies against pathogens. Here, we use theory and experiments to compare the efficacy of three strategies for the deployment of resistance: (i) a strategy where the host population contains two single-resistant genotypes, (ii) a strategy where the host carries a double-resistant genotype, (iii) a strategy where the host population is a mix of a single-resistant genotype and a double-resistant genotype.

A vesicular Warburg effect: Aerobic glycolysis occurs on axonal vesicles for local NAD+ recycling and transport.

In neurons, fast axonal transport (FAT) of vesicles occurs over long distances and requires constant and local energy supply for molecular motors in the form of adenosine triphosphate (ATP). FAT is independent of mitochondrial metabolism. Indeed, the glycolytic machinery is present on vesicles and locally produces ATP, as well as nicotinamide adenine dinucleotide bonded with hydrogen (NADH) and pyruvate, using glucose as a substrate.

Endogenous opioid system modulates conditioned cocaine reward in a sex-dependent manner.

Cocaine predictive cues and contexts exert powerful control over behaviour and can incite cocaine seeking and taking. This type of conditioned behaviour is encoded within striatal circuits, and these circuits and behaviours are, in part, regulated by opioid peptides and receptors expressed in striatal medium spiny neurons. We previously showed that augmenting levels of the opioid peptide enkephalin in the striatum facilitates acquisition of cocaine conditioned place preference (CPP), while opioid receptor antagonists attenuate expression of cocaine CPP.

Aglycosylated extracellular loop of inwardly rectifying potassium channel 4.1 (KCNJ10) provides a target for autoimmune neuroinflammation.

Multiple sclerosis is an autoimmune disease of the central nervous system. Yet, the autoimmune targets are still undefined. The extracellular e1 sequence of KCNJ10, the inwardly rectifying potassium channel 4.

Immune Profiling Reveals the T-Cell Effect of Ocrelizumab in Early Relapsing-Remitting Multiple Sclerosis.

Background And Objectives: Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, is highly efficient in patients with relapsing-remitting multiple sclerosis (RR-MS). We assessed early cellular immune profiles and their association with disease activity at treatment start and under therapy, which may provide new clues on the mechanisms of action of OCR and on the disease pathophysiology.

Methods: A first group of 42 patients with an early RR-MS, never exposed to disease-modifying therapy, was included in 11 centers participating to an ancillary study of the ENSEMBLE trial (NCT03085810) to evaluate the effectiveness and safety of OCR.

Huntingtin regulates calcium fluxes in skeletal muscle.

The expression of the Huntingtin protein, well known for its involvement in the neurodegenerative Huntington's disease, has been confirmed in skeletal muscle. The impact of HTT deficiency was studied in human skeletal muscle cell lines and in a mouse model with inducible and muscle-specific HTT deletion. Characterization of calcium fluxes in the knock-out cell lines demonstrated a reduction in excitation-contraction (EC) coupling, related to an alteration in the coupling between the dihydropyridine receptor and the ryanodine receptor, and an increase in the amount of calcium stored within the sarcoplasmic reticulum, linked to the hyperactivity of store-operated calcium entry (SOCE).

Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature.

Background And Objectives: Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS.

Pharmacogenetics of human sulfotransferases and impact of amino acid exchange on Phase II drug metabolism.

Sulfotransferases (SULTs) are Phase II drug-metabolizing enzymes (DMEs) catalyzing the sulfation of a variety of endogenous compounds, natural products, and drugs. Various drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDS) can inhibit SULTs, affecting drug-drug interactions. Several polymorphisms have been identified for SULTs that might be crucial for interindividual variability in drug response and toxicity or for increased disease risk.

Competition and coevolution drive the evolution and the diversification of CRISPR immunity.

The diversity of resistance challenges the ability of pathogens to spread and to exploit host populations. Yet, how this host diversity evolves over time remains unclear because it depends on the interplay between intraspecific competition among host genotypes and coevolution with pathogens. Here we study experimentally the effect of coevolving phage populations on the diversification of bacterial CRISPR immunity across space and time.

Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9.

Cytochrome P450 2C9 (CYP2C9) is a major drug-metabolizing enzyme that represents 20% of the hepatic CYPs and is responsible for the metabolism of 15% of drugs. A general concern in drug discovery is to avoid the inhibition of CYP leading to toxic drug accumulation and adverse drug-drug interactions. However, the prediction of CYP inhibition remains challenging due to its complexity.

Computational Analysis of Chemical Space of Natural Compounds Interacting with Sulfotransferases.

The aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their chemical structures and properties were compared to those of compounds of non-natural (synthetic) origin, known to interact with SULTs.

Insights into the substrate binding mechanism of SULT1A1 through molecular dynamics with excited normal modes simulations.

Sulfotransferases (SULTs) are phase II drug-metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to a substrate. It has been previously suggested that a considerable shift of SULT structure caused by PAPS binding could control the capability of SULT to bind large substrates. We employed molecular dynamics (MD) simulations and the recently developed approach of MD with excited normal modes (MDeNM) to elucidate molecular mechanisms guiding the recognition of diverse substrates and inhibitors by SULT1A1.

Distribution of Bacterial α1,3-Galactosyltransferase Genes in the Human Gut Microbiome.

Because of a loss-of-function mutation in the GGTA1 gene, humans are unable to synthetize α1,3-Galactose (Gal) decorated glycans and develop high levels of circulating anti-α1,3-Galactose antibodies (anti-Gal Abs). Anti-Gal Abs have been identified as a major obstacle of organ xenotransplantation and play a role in several host-pathogen relationships including potential susceptibility to infection. Anti-Gal Abs are supposed to stem from immunization against the gut microbiota, an assumption derived from the observation that some pathogens display α1,3-Gal and that antibiotic treatment decreases the level of anti-Gal.

Allele-Specific CRISPR/Cas9 Correction of a Heterozygous DNM2 Mutation Rescues Centronuclear Myopathy Cell Phenotypes.

Genome editing with the CRISPR/Cas9 technology has emerged recently as a potential strategy for therapy in genetic diseases. For dominant mutations linked to gain-of-function effects, allele-specific correction may be the most suitable approach. In this study, we tested allele-specific inactivation or correction of a heterozygous mutation in the Dynamin 2 (DNM2) gene that causes the autosomal dominant form of centronuclear myopathies (CNMs), a rare muscle disorder belonging to the large group of congenital myopathies.

Chemosystematics Using Cuticular Compounds: A Powerful Tool to Separate Species in Mediterranean Dung Beetles (Coleoptera: Geotrupidae).

The use of chemical characters to infer a phylogeny is known to be promising to ascertain phylogenetic relationships in controversial groups. Dung beetle classifications containing the Geotrupidae family, based on morphological characters and genes, are debated with respect to the subfamilies, such as the Bolboceratids. In our study, we used different approaches to generate and compare the Geotrupidae phylogenies based on genetics and chemotaxonomy.

Variability in the durability of CRISPR-Cas immunity.

The durability of host resistance is challenged by the ability of pathogens to escape the defence of their hosts. Understanding the variability in the durability of host resistance is of paramount importance for designing more effective control strategies against infectious diseases. Here, we study the durability of various clustered regularly interspaced short palindromic repeats-Cas (CRISPR-Cas) alleles of the bacteria Streptococcus thermophilus against lytic phages.

Amphiphysin 2 modulation rescues myotubular myopathy and prevents focal adhesion defects in mice.

Centronuclear myopathies (CNMs) are severe diseases characterized by muscle weakness and myofiber atrophy. Currently, there are no approved treatments for these disorders. Mutations in the phosphoinositide 3-phosphatase myotubularin (MTM1) are responsible for X-linked CNM (XLCNM), also called myotubular myopathy, whereas mutations in the membrane remodeling Bin/amphiphysin/Rvs protein amphiphysin 2 [bridging integrator 1 (BIN1)] are responsible for an autosomal form of the disease.

Avian malaria alters the dynamics of blood feeding in Culex pipiens mosquitoes.

Background: Some Plasmodium species have the ability to modify the behaviour of their mosquito vectors. This is thought to be an adaptive strategy that maximizes the parasite's transmission.

Methods: The effect of Plasmodium relictum infections on the blood feeding behaviour of Culex pipiens quinquefasciatus mosquitoes was monitored.

Timing malaria transmission with mosquito fluctuations.

Temporal variations in the activity of arthropod vectors can dramatically affect the epidemiology and evolution of vector-borne pathogens. Here, we explore the "Hawking hypothesis", which states that these pathogens may evolve the ability to time investment in transmission to match the activity of their vectors. First, we use a theoretical model to identify the conditions promoting the evolution of time-varying transmission strategies in pathogens.

Evolutionary emergence of infectious diseases in heterogeneous host populations.

The emergence and re-emergence of pathogens remains a major public health concern. Unfortunately, when and where pathogens will (re-)emerge is notoriously difficult to predict, as the erratic nature of those events is reinforced by the stochastic nature of pathogen evolution during the early phase of an epidemic. For instance, mutations allowing pathogens to escape host resistance may boost pathogen spread and promote emergence.

Complete avian malaria parasite genomes reveal features associated with lineage-specific evolution in birds and mammals.

Avian malaria parasites are prevalent around the world and infect a wide diversity of bird species. Here, we report the sequencing and analysis of high-quality draft genome sequences for two avian malaria species, and We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes. Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian species, and using amino acid divergence between species, we estimate the avian- and mammalian-infective lineages diverged in the order of 10 million years ago.