Investigating the metabolite signature of an altered oral microbiota as a discriminant factor for multiple sclerosis: a pilot study.

In multiple sclerosis (MS), alterations of the gut microbiota lead to inflammation. However, the role of other microbiomes in the body in MS has not been fully elucidated. In a pilot case-controlled study, we carried out simultaneous characterization of faecal and oral microbiota and conducted an in-depth analysis of bacterial alterations associated with MS. Using 16S rRNA sequencing and metabolic inference tools, we compared the oral/faecal microbiota and bacterial metabolism pathways in French MS patients (n = 14) and healthy volunteers (HV, n = 21). A classification model based on metabolite flux balance was established and validated in an independent German cohort (MS n = 12, HV n = 38). Our analysis revealed decreases in diversity indices and oral/faecal compartmentalization, the depletion of commensal bacteria (Aggregatibacter and Streptococcus in saliva and Coprobacter and Roseburia in faeces) and enrichment of inflammation-associated bacteria in MS patients (Leptotrichia and Fusobacterium in saliva and Enterobacteriaceae and Actinomyces in faeces). Several microbial pathways were also altered (the polyamine pathway and remodelling of bacterial surface antigens and energetic metabolism) while flux balance analysis revealed associated alterations in metabolite production in MS (nitrogen and nucleoside). Based on this analysis, we identified a specific oral metabolite signature in MS patients, that could discriminate MS patients from HV and rheumatoid arthritis patients. This signature allowed us to create and validate a discrimination model on an independent cohort, which reached a specificity of 92%. Overall, the oral and faecal microbiomes were altered in MS patients. This pilot study highlights the need to study the oral microbiota and oral health implications in patients with autoimmune diseases on a larger scale and suggests that knowledge of the salivary microbiome could help guide the identification of new pathogenic mechanisms associated with the microbiota in MS patients.

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 4.1, has been subject to fierce debate for its role as a candidate autoantigen in multiple sclerosis. Inwardly rectifying potassium channel 4.1 is expressed in the central nervous system but also in peripheral tissues, raising concerns about the central nervous system-specificity of such autoreactivity. Immunization of C57Bl6/J female mice with the e1 peptide (amino acids 83-120 of Kir4.1) induced anti-e1 immunoglobulin G- and T-cell responses and promoted demyelinating encephalomyelitis with B cell central nervous system enrichment in leptomeninges and T cells/macrophages in central nervous system parenchyma from forebrain to spinal cord, mostly in the white matter. Within our cohort of multiple sclerosis patients (n = 252), 6% exhibited high anti-e1 immunoglobulin G levels in serum as compared to 0.7% in the control cohort (n = 127; P = 0.015). Immunolabelling of inwardly rectifying potassium channel 4.1-expressing white matter glia with the anti-e1 serum from immunized mice increased during murine autoimmune neuroinflammation and in multiple sclerosis white matter as compared with controls. Strikingly, the mouse and human anti-e1 sera labelled astrocytoma cells when N-glycosylation was blocked with tunicamycin. Western blot confirmed that neuroinflammation induces Kir4.1 expression, including its shorter aglycosylated form in murine experimental autoencephalomyelitis and multiple sclerosis. In addition, recognition of inwardly rectifying potassium channel 4.1 using mouse anti-e1 serum in Western blot experiments under unreduced conditions or in cells transfected with the N-glycosylation defective N104Q mutant as compared to the wild type further suggests that autoantibodies target an e1 conformational epitope in its aglycosylated form. These data highlight the e1 sequence of inwardly rectifying potassium channel 4.1 as a valid central nervous system autoantigen with a disease/tissue-specific post-translational antigen modification as potential contributor to autoimmunity in some multiple sclerosis patients.

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. Here, we review current knowledge on non-synonymous single nucleotide polymorphisms (nsSNPs) of human SULTs, focusing on the coded SULT allozymes and molecular mechanisms explaining their variable activity, which is essential for personalized medicine. We discuss the structural and dynamic bases of key amino acid (AA) variants implicated in the impacts on drug metabolism in the case of SULT1A1, as revealed by molecular modeling approaches.

Prevelance and clinical signs of chewing lice in local chickens (Gallus gallus domesticus) in Menoua Division, Western highlands of Cameroon.

Ectoparasite infestations are a major concern in local poultry sector as they cause body weight loss, drop in laying performance and disease transmission. Thus, a study was conducted from April to June 2021 to assess the prevalence and clinical signs of ectoparasites in backyard chickens in Menoua, West region of Cameroon. Ectoparasites were investigated on 400 local chickens. Results showed that out of 400 chickens, 133 (33.3%) were infested with at least one species of ectoparasite. Two chewing lice including Menopon gallinae (26.3%) and Goniocotes gallinae (4.5%) and one blood-feeding louse including Menacanthus stramineus (16.0%) were identified. The prevalence was significantly associated with the sampling site (p < 0.05), with the highest prevalence recorded in Balessing (49.5%), followed by Foreke (38.8%) and Bamendou (27.1%). There was a positive and significant correlation between M. gallinae and M. stramineus (r = 0.329, p < 0.05)), M. gallinae and G. gallinae (r = 0.199, p < 0.05), M. stramineus and G. gallinae (r = 0.103, p < 0.05). Single infestation was the most frequent (19.0%) followed by double infestation which consist of M. gallinae and M. stramineus (9.5%), M. gallinae and G. gallinae (3%), and M. stramineus and G. gallinae (1.5%). The infested chickens exhibited some degree of restlessness, frequent grooming of the feathers associated with skin irritation, itching and mechanical damage on the skin. The skin lesions were localized on the cloaca, thigh, wing, neck and chest areas of the body; petechiae as well as whitish scabs were observed on the lesions. The feathers were ruffled, and the bases of some of the feathers were gnawed as a result of lice bites. In conclusion, chewing lice occur in local chickens in Menoua Division, inducing severe clinical signs. Thus, commercial poultry farms (raising exotic breeds) with access to free range chickens (local chickens) in Menoua Division are exposed to lice infestations from these local chickens. Further investigations are required in the dry season in order to be well acquainted with ectoparasites occurring in the local chickens in the area.

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. We developed an original machine learning approach for the prediction of drug-like molecules inhibiting CYP2C9. We created new predictive models by integrating CYP2C9 protein structure and dynamics knowledge, an original selection of physicochemical properties of CYP2C9 inhibitors, and machine learning modeling. We tested the machine learning models on publicly available data and demonstrated that our models successfully predicted CYP2C9 inhibitors with an accuracy, sensitivity and specificity of approximately 80%. We experimentally validated the developed approach and provided the first identification of the drugs vatalanib, piriqualone, ticagrelor and cloperidone as strong inhibitors of CYP2C9 with IC values <18 µM and sertindole, asapiprant, duvelisib and dasatinib as moderate inhibitors with IC50 values between 40 and 85 µM. Vatalanib was identified as the strongest inhibitor with an IC50 value of 0.067 µM. Metabolism assays allowed the characterization of specific metabolites of abemaciclib, cloperidone, vatalanib and tarafenacin produced by CYP2C9. The obtained results demonstrate that such a strategy could improve the prediction of drug-drug interactions in clinical practice and could be utilized to prioritize drug candidates in drug discovery pipelines.

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. The natural ligands interacting with SULTs were further compared to other natural products for which interactions with SULTs were not known. Various descriptors of the molecular structures were calculated and analyzed. Statistical methods (ANOVA, PCA, and clustering) were used to explore the chemical space of the studied compounds. Similarity search between the compounds in the different groups was performed with the ROCS software. The interactions with SULTs were additionally analyzed by docking into different experimental and modeled conformations of SULT1A1. Natural products with potentially strong interactions with SULTs were outlined. Our results contribute to a better understanding of chemical space and interactions of natural compounds with SULT enzymes and help to outline new potential ligands of these enzymes.

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. MDeNM allowed exploring an extended conformational space of PAPS-bound SULT1A1, which has not been achieved up to now by using classical MD. The generated ensembles combined with docking of 132 SULT1A1 ligands shed new light on substrate and inhibitor binding mechanisms. Unexpectedly, our simulations and analyses on binding of the substrates estradiol and fulvestrant demonstrated that large conformational changes of the PAPS-bound SULT1A1 could occur independently of the co-factor movements that could be sufficient to accommodate large substrates as fulvestrant. Such structural displacements detected by the MDeNM simulations in the presence of the co-factor suggest that a wider range of drugs could be recognized by PAPS-bound SULT1A1 and highlight the utility of including MDeNM in protein-ligand interactions studies where major rearrangements are expected.

Imaging Study by Mass Spectrometry of the Spatial Variation of Cellulose and Hemicellulose Structures in Corn Stalks.

The study used mass spectrometry imaging (MSI) to map the distribution of enzymatically degraded cell wall polysaccharides in maize stems for two genotypes and at several stages of development. The context was the production of biofuels, and the overall objective was to better describe the structural determinants of recalcitrance of grasses in bioconversion. The selected genotypes showed contrasting characteristics in bioconversion assays as well as in their lignin deposition pattern. We compared the pattern of cell wall polysaccharide degradation observed by MSI following the enzymatic degradation of tissues with that of lignin deposition. Several enzymes targeting the main families of wall polysaccharides were used. In the early stages of development, cellulose and mixed-linked ß-glucans appeared as the main polysaccharides degraded from the walls, while heteroxylan products were barely detected, suggesting subsequent deposition of heteroxylans in the walls. At all stages and for both genotypes, enzymatic degradation occurred preferentially in nonlignified walls for all structural families of polysaccharides studied here. However, our results showed heterogeneity in the distribution of heteroxylan products according to their chemical structure: arabinosylated products were mostly represented in the pith center, while glucuronylated products were found at the pith periphery. The conclusions of our work are in agreement with those of previous studies. The MSI approach presented here is unique and attractive for addressing the histological and biochemical aspects of biomass recalcitrance to conversion, as it allows for a simultaneous interpretation of cell wall degradation and lignification patterns at the scale of an entire stem section.

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. However, there is little information to date concerning the microorganisms producing α1,3-Gal in the human gut microbiome. Here, available α1,3-Galactosyltransferase (GT) gene sequences from gut bacteria were selectively quantified for the first time in the gut microbiome shotgun sequences of 163 adult individuals from three published population-based metagenomics analyses. We showed that most of the gut microbiome of adult individuals contained a small set of bacteria bearing α1,3-GT genes. These bacteria belong mainly to the Enterobacteriaceae family, including Escherichia coli, but also to Pasteurellaceae genera, Haemophilus influenza and Lactobacillus species. α1,3-Gal antigens and α1,3-GT activity were detected in healthy stools of individuals exhibiting α1,3-GT bacterial gene sequences in their shotgun data.

Immuno-Guided Laser-Capture Microdissection of Glial Cells for mRNA Analysis.

Laser-capture microdissection (LCM) allows for retrieval of specific cell populations in situ. By combining immunofluorescent labeling with LCM, mRNAs can be probed by qRT-PCR for determining in situ gene expression during health and disease. This approach permits obtaining and analyzing histologically enriched cell populations in a tissue that can be hardly obtained from other methods such as white matter astrocytes from rodents or any individual cell population from archival human or rodent brain tissues. Herein, we present our methodology of laser-captured mouse spinal cord white matter astrocytes, which can be adapted for any cell type in CNS tissue and low RNAse containing tissues. The methods presented with an emphasis on tips and advices include the cryostat section preparation from snap-frozen tissue, an adapted immunofluorescent labeling, a brief overview of LCM using a UV-based technology with polyethylene membrane glass slides, procedures for direct use of RNA from lysis buffer vs. column-based purified RNA, RNA quality/quantity assessment, the reverse transcription and preamplification steps used before real-time qPCR analysis.

An intermediate level of CD161 expression defines a novel activated, inflammatory, and pathogenic subset of CD8+ T cells involved in multiple sclerosis.

Several lines of evidence support a key role for CD8+ T cells in central nervous system tissue damage of patients with multiple sclerosis. However, the precise phenotype of the circulating CD8+ T cells that may be recruited from the peripheral blood to invade the CNS remains largely undefined to date. It has been suggested that IL-17 secreting CD8 (Tc17) T cells may be involved, and in humans these cells are characterized by the expression of CD161. We focused our study on a unique and recently described subset of CD8 T cells characterized by an intermediate expression of CD161 as its role in neuroinflammation has not been investigated to date. The frequency, phenotype, and function of CD8+ T cells with an intermediate CD161 expression level were characterized ex-vivo, in vitro, and in situ using RNAseq, RT-PCR, flow cytometry, TCR sequencing, and immunohistofluorescence of cells derived from healthy volunteers (n = 61), MS subjects (n = 90), as well as inflammatory (n = 15) and non-inflammatory controls (n = 6). We report here that CD8+CD161int T cells present characteristics of effector cells, up-regulate cell-adhesion molecules and have an increased ability to cross the blood-brain barrier and to secrete IL-17, IFNγ, GM-CSF, and IL-22. We further demonstrate that these cells are recruited and enriched in the CNS of MS subjects where they produce IL-17. In the peripheral blood, RNAseq, RT-PCR, high-throughput TCR repertoire analyses, and flow cytometry confirmed an increased effector and transmigration pattern of these cells in MS patients, with the presence of supernumerary clones compared to healthy controls. Our data demonstrate that intermediate levels of CD161 expression identifies activated and effector CD8+ T cells with pathogenic properties that are recruited to MS lesions. This suggests that CD161 may represent a biomarker and a valid target for the treatment of neuroinflammation.

Quantum size effect on charges and phonons ultrafast dynamics in atomically controlled nanolayers of topological insulators Bi2Te3.

Heralded as one of the key elements for next generation spintronics devices, topological insulators (TIs) are now step by step envisioned as nanodevices like charge-to-spin current conversion or as Dirac fermions based nanometer Schottky diode for example. However, reduced to few nanometers, TIs layers exhibit a profound modification of the electronic structure and the consequence of this quantum size effect on the fundamental carriers and phonons ultrafast dynamics has been poorly investigated so far. Here, thanks to a complete study of a set of high quality molecular beam epitaxy grown nanolayers, we report the existence of a critical thickness of around ~6 nm, below which a spectacular reduction of the carrier relaxation time by a factor of ten is found in comparison to bulk Bi2 Te3 In addition, we also evidence an A1g optical phonon mode softening together with the appearance of a thickness dependence of the photoinduced coherent acoustic phonons signals. This drastic evolution of the carriers and phonons dynamics might be due an important electron-phonon coupling evolution due to the quantum confinement. These properties have to be taken into account for future TIs-based spintronic devices.

Neuropathologic, phenotypic and functional analyses of Mucosal Associated Invariant T cells in Multiple Sclerosis.

BACKGROUND: The involvement of Mucosal Associated Invariant T (MAIT) cells, which are anti-microbial semi-invariant T cells, remains elusive in Multiple Sclerosis (MS). OBJECTIVE: Deciphering the potential involvement of MAIT cells in the MS inflammatory process. METHODS: By flow cytometry, blood MAIT cells from similar cohorts of MS patients and healthy volunteers (HV) were compared for frequency, phenotype, activation potential after in vitro TCR engagement by bacterial ligands and transmigration abilities through an in vitro model of blood-brain barrier. MS CNS samples were also studied by immunofluorescent staining and quantitative PCR. RESULTS AND CONCLUSION: Blood MAIT cells from relapsing-remitting MS patients and HV presented similar frequency, ex vivo effector phenotype and activation abilities. MAIT cells represented 0.5% of the total infiltrating T cells on 39 MS CNS lesions. This is low as compared to blood frequency (p<0.001), but consistent with their low transmigration rate. Finally, transcriptional over-expression of MR1 - which presents cognate antigens to MAIT cells - and of the activating cytokines IL-18 and IL-23 was evidenced in MS lesions, suggesting that the CNS microenvironment is suited to activate the few infiltrating MAIT cells. Taken together, these data place MAIT cells from MS patients as minor components of the inflammatory pathological process.

RORγt+ cells selectively express redundant cation channels linked to the Golgi apparatus.

Retinoid-related orphan receptor gamma t (RORγt) is a master transcription factor central to type 17 immunity involving cells such as T helper 17, group 3 innate lymphoid cells or IL-17-producing γδ T cells. Here we show that the intracellular ion channel TMEM176B and its homologue TMEM176A are strongly expressed in these RORγt(+) cells. We demonstrate that TMEM176A and B exhibit a similar cation channel activity and mainly colocalise in close proximity to the trans-Golgi network. Strikingly, in the mouse, the loss of Tmem176b is systematically associated with a strong upregulation of Tmem176a. While Tmem176b single-deficiency has no effect on the course of experimental autoimmune encephalomyelitis, T cell or DSS-induced colitis, it significantly reduces imiquimod-induced psoriasis-like skin inflammation. These findings shed light on a potentially novel specific process linked to post-Golgi trafficking for modulating the function of RORγt(+) cells and indicate that both homologues should be simultaneously targeted to clearly elucidate the role of this intracellular ion flow.

Integrated structure- and ligand-based in silico approach to predict inhibition of cytochrome P450 2D6.

MOTIVATION: Cytochrome P450 (CYP) is a superfamily of enzymes responsible for the metabolism of drugs, xenobiotics and endogenous compounds. CYP2D6 metabolizes about 30% of drugs and predicting potential CYP2D6 inhibition is important in early-stage drug discovery. RESULTS: We developed an original in silico approach for the prediction of CYP2D6 inhibition combining the knowledge of the protein structure and its dynamic behavior in response to the binding of various ligands and machine learning modeling. This approach includes structural information for CYP2D6 based on the available crystal structures and molecular dynamic simulations (MD) that we performed to take into account conformational changes of the binding site. We performed modeling using three learning algorithms--support vector machine, RandomForest and NaiveBayesian--and we constructed combined models based on topological information of known CYP2D6 inhibitors and predicted binding energies computed by docking on both X-ray and MD protein conformations. In addition, we identified three MD-derived structures that are capable all together to better discriminate inhibitors and non-inhibitors compared with individual CYP2D6 conformations, thus ensuring complementary ligand profiles. Inhibition models based on classical molecular descriptors and predicted binding energies were able to predict CYP2D6 inhibition with an accuracy of 78% on the training set and 75% on the external validation set.

Transcript analysis of laser capture microdissected white matter astrocytes and higher phenol sulfotransferase 1A1 expression during autoimmune neuroinflammation.

BACKGROUND: Astrocytes, the most abundant cell population in mammal central nervous system (CNS), contribute to a variety of functions including homeostasis, metabolism, synapse formation, and myelin maintenance. White matter (WM) reactive astrocytes are important players in amplifying autoimmune demyelination and may exhibit different changes in transcriptome profiles and cell function in a disease-context dependent manner. However, their transcriptomic profile has not yet been defined because they are difficult to purify, compared to gray matter astrocytes. Here, we isolated WM astrocytes by laser capture microdissection (LCM) in a murine model of multiple sclerosis to better define their molecular profile focusing on selected genes related to inflammation. Based on previous data indicating anti-inflammatory effects of estrogen only at high nanomolar doses, we also examined mRNA expression for enzymes involved in steroid inactivation. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL6 mice with MOG35-55 immunization. Fluorescence activated cell sorting (FACS) analysis of a portion of individual spinal cords at peak disease was used to assess the composition of immune cell infiltrates. Using custom Taqman low-density-array (TLDA), we analyzed mRNA expression of 40 selected genes from immuno-labeled laser-microdissected WM astrocytes from lumbar spinal cord sections of EAE and control mice. Immunohistochemistry and double immunofluorescence on control and EAE mouse spinal cord sections were used to confirm protein expression in astrocytes. RESULTS: The spinal cords of EAE mice were infiltrated mostly by effector/memory T CD4+ cells and macrophages. TLDA-based profiling of LCM-astrocytes identified EAE-induced gene expression of cytokines and chemokines as well as inflammatory mediators recently described in gray matter reactive astrocytes in other murine CNS disease models. Strikingly, SULT1A1, but not other members of the sulfotransferase family, was expressed in WM spinal cord astrocytes. Moreover, its expression was further increased in EAE. Immunohistochemistry on spinal cord tissues confirmed preferential expression of this enzyme in WM astrocytic processes but not in gray matter astrocytes. CONCLUSIONS: We described here for the first time the mRNA expression of several genes in WM astrocytes in a mouse model of multiple sclerosis. Besides expected pro-inflammatory chemokines and specific inflammatory mediators increased during EAE, we evidenced relative high astrocytic expression of the cytoplasmic enzyme SULT1A1. As the sulfonation activity of SULT1A1 inactivates estradiol among other phenolic substrates, its high astrocytic expression may account for the relative resistance of this cell population to the anti-neuroinflammatory effects of estradiol. Blocking the activity of this enzyme during neuroinflammation may thus help the injured CNS to maintain the anti-inflammatory activity of endogenous estrogens or limit the dose of estrogen co-regimens for therapeutical purposes.

Expanded CD8 T-cell sharing between periphery and CNS in multiple sclerosis.

OBJECTIVE: In multiple sclerosis (MS), central nervous system (CNS), cerebrospinal fluid (CSF), and blood display TCR clonal expansions of CD8(+) T cells. These clones have been assumed - but never demonstrated - to be similar in the three compartments. Addressing this key question is essential to infer the implication of peripheral clonally expanded CD8(+) T cells in the disease. METHODS: For the first time, TCR Vß repertoire from paired blood (purified CD8(+) and CD4(+) T cells), CSF and CNS (22 lesions, various inflammatory and demyelination statuses) samples from three MS patients was studied using complementary determining region 3 (CDR3) spectratyping and high-throughput sequencing. In parallel, blood and CNS clonally expanded CD8(+) T cells were characterized by fluorescent staining. RESULTS: TCR Vß repertoire analysis revealed strong sharing of predominant T-cell clones between CNS lesions, CSF, and blood CD8(+) T cells. In parallel, we showed that blood oligoclonal CD8(+) T cells exhibit characteristics of pathogenic cells, as they displayed a bias toward a memory phenotype in MS patients, with increased expression of CCR5, CD11a and Granzyme B (GZM-B) compared to non oligoclonal counterparts. CNS-infiltrating T cells were mainly CD8 expressing CD11a and GZM-B. INTERPRETATION: This study highlights the predominant implication of CD8(+) T cells in MS pathophysiology and demonstrates that potentially aggressive CD8(+) T cells can be easily identified and characterized from blood and CSF samples.

Sex steroids and neuroprotection in spinal cord injury: a review of preclinical investigations.

Spinal cord injury (SCI) is a debilitating condition that affects motor, sensory and autonomic functions. Subsequent to the first mechanical trauma, secondary events, which include inflammation and glial activation, exacerbate tissue damage and worsen functional deficits. Although these secondary injury mechanisms are amenable to therapeutic interventions, the efficacy of current approaches is inadequate. Further investigations are necessary to implement new therapies that can protect neural cells and attenuate some of the detrimental effects of inflammation while promoting regeneration. Studies on different animal models of SCI indicated that sex steroids, especially 17ß-estradiol and progesterone, exert neuroprotective, anti-apoptotic and anti-inflammatory effects, ameliorate tissue sparing and improve functional deficits in SCI. As sex steroid receptors are expressed in a variety of cells including neurons, glia and immune system-related cells which infiltrate the injury epicenter, sex steroids could impact multiple processes simultaneously and in doing so, influence the outcomes of SCI. However, the translation of these pre-clinical findings into the clinical setting presents challenges such as the narrow therapeutic time window of sex steroid administration, the diversity of treatment regimens that have been employed in animal studies and the lack of sufficient information regarding the persistence of the effects in chronic SCI. The current review will summarize some of the major findings in this field and will discuss the challenges associated with the implementation of sex steroids as a promising treatment in human SCI.

Associations between inhibitory control, respiratory sinus arrhythmia, and externalizing problems in early childhood.

Polyvagal theory provides a framework for understanding connections between children's autonomic regulation, cognitive functioning, and behavioral adjustment. Parasympathetic regulation has been associated with executive functions and externalizing problems (EP), and children with EP demonstrate deficits in inhibition of prepotent responding, or inhibitory control (IC). We examined parasympathetic regulation of cardiac reactivity during two IC tasks in 144 children (M = 5.61 years, SD = 1.09) ranging from low to clinical levels of EP. Overall children with more EP evidenced greater RSA suppression during IC tasks than did children with fewer EP, and degree of RSA suppression also moderated associations between IC performance and EP. Only for children who showed stronger RSA suppression was accuracy of IC response inversely associated with EP, and latency of response for one task positively associated with EP. This study provides insight into the role of parasympathetic mechanisms in children's cognitive regulation of impulsive and aggressive behaviors.