The Swiss Primary Hypersomnolence and Narcolepsy Cohort study (SPHYNCS): Study protocol for a prospective, multicentre cohort observational study

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL. The primary aim is to validate new and reappraise well-known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3-year recruitment phase. Healthy controls and patients with EDS due to severe sleep-disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long-term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagnosis, better prognosis and personalized management of CDH

Memory CD8+ T Cells Balance Pro- and Anti-inflammatory Activity by Reprogramming Cellular Acetate Handling at Sites of Infection.

Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite-acetate-induces distinct immunometabolic programs within the same cell type

Genome-Wide Association Analysis of Autoantibody Positivity in Type 1 Diabetes Cases

The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A)

Engineered hexavalent Fc proteins with enhanced Fc-gamma receptor avidity provide insights into immune-complex interactions

Tania Rowley et al. present multivalent Fc molecules with enhanced avidity for Fc gamma receptors in order to improve the treatment of autoantibody-mediated human diseases. They found several key amino acids involved in Fc receptor binding interactions

Slow Dissociation of a Charged Ligand: Analysis of the Primary Quinone QA Site of Photosynthetic Bacterial Reaction Centers

Reaction centers (RCs) are integral membrane proteins that undergo a series of electron transfer reactions during the process of photosynthesis. In the QA site of RCs from Rhodobacter sphaeroides, ubiquinone-10 is reduced, by a single electron transfer, to its semiquinone. The neutral quinone and anionic semiquinone have similar affinities, which is required for correct in situ reaction thermodynamics. A previous study showed that despite similar affinities, anionic quinones associate and dissociate from the QA site at rates ≈104 times slower than neutral quinones indicating that anionic quinones encounter larger binding barriers (Madeo, J.; Gunner, M. R. Modeling binding kinetics at the QA site in bacterial reaction centers. Biochemistry2005, 44, 10994–11004). The present study investigates these barriers computationally, using steered molecular dynamics (SMD) to model the unbinding of neutral ground state ubiquinone (UQ) and its reduced anionic semiquinone (SQ–) from the QA site. In agreement with experiment, the SMD unbinding barrier for SQ– is larger than for UQ. Multi Conformational Continuum Electrostatics (MCCE), used here to calculate the binding energy, shows that SQ– and UQ have comparable affinities. In the QA site, there are stronger binding interactions for SQ– compared to UQ, especially electrostatic attraction to a bound non-heme Fe2+. These interactions compensate for the higher SQ– desolvation penalty, allowing both redox states to have similar affinities. These additional interactions also increase the dissociation barrier for SQ– relative to UQ. Thus, the slower SQ– dissociation rate is a direct physical consequence of the additional binding interactions required to achieve a QA site affinity similar to that of UQ. By a similar mechanism, the slower association rate is caused by stronger interactions between SQ– and the polar solvent. Thus, stronger interactions for both the unbound and bound states of charged and highly polar ligands can slow their binding kinetics without a conformational gate. Implications of this for other systems are discussed

Relationship between Exercise Capacity and Brain Size in Mammals

A great deal of experimental research supports strong associations between exercise, cognition, neurogenesis and neuroprotection in mammals. Much of this work has focused on neurogenesis in individual subjects in a limited number of species. However, no study to date has examined the relationship between exercise and neurobiology across a wide range of mammalian taxa. It is possible that exercise and neurobiology are related across evolutionary time. To test this hypothesis, this study examines the association between exercise and brain size across a wide range of mammals.Controlling for associations with body size, we examined the correlation between brain size and a proxy for exercise frequency and capacity, maximum metabolic rate (MMR; ml O(2) min(-1)). We collected brain sizes and MMRs from the literature and calculated residuals from the least-squares regression line describing the relationship between body mass and each variable of interest. We then analyzed the correlation between residual brain size and residual MMR both before and after controlling for phylogeny using phylogenetic independent contrasts. We found a significant positive correlation between maximum metabolic rate and brain size across a wide range of taxa.These results suggest a novel hypothesis that links brain size to the evolution of locomotor behaviors in a wide variety of mammalian species. In the end, we suggest that some portion of brain size in nonhuman mammals may have evolved in conjunction with increases in exercise capacity rather than solely in response to selection related to cognitive abilities

The Four types of Tregs in malignant lymphomas

Regulatory T cells (Tregs) are a specialized subpopulation of CD4+ T cells, which act to suppress the activation of other immune cells. Tregs represent important modulators for the interaction between lymphomas and host microenvironment. Lymphomas are a group of serious and frequently fatal malignant diseases of lymphocytes. Recent studies revealed that some lymphoma T cells might adopt a Treg profile. Assessment of Treg phenotypes and genotypes in patients may offer prediction of outcome in many types of lymphomas including diffuse large B-cell lymphoma, follicular lymphoma, cutaneous T cell lymphoma, and Hodgkin's lymphoma. Based on characterized roles of Tregs in lymphomas, we can categorize the various roles into four groups: (a) suppressor Tregs; (b) malignant Tregs; (c) direct tumor-killing Tregs; and (d) incompetent Tregs. The classification into four groups is significant in predicting prognosis and designing Tregs-based immunotherapies for treating lymphomas. In patients with lymphomas where Tregs serve either as suppressor Tregs or malignant Tregs, anti-tumor cytotoxicity is suppressed thus decreased numbers of Tregs are associated with a good prognosis. In contrast, in patients with lymphomas where Tregs serve as tumor-killing Tregs and incompetent Tregs, anti-tumor cytotoxicity is enhanced or anti-autoimmune Tregs activities are weakened thus increased numbers of Tregs are associated with a good prognosis and reduced numbers of Tregs are associated with a poor prognosis. However, the mechanisms underlying the various roles of Tregs in patients with lymphomas remain unknown. Therefore, further research is needed in this regard as well as the utility of Tregs as prognostic factors and therapy strategies in different lymphomas

Geometric and Electronic Structures of the NiI and Methyl−NiIII Intermediates of Methyl-Coenzyme M Reductase†

ABSTRACT: Methyl-coenzyme M reductase (MCR) catalyzes the terminal step in the formation of biological methane from methyl-coenzyme M (Me-SCoM) and coenzyme B (CoBSH). The active site in MCR contains a Ni-F430 cofactor, which can exist in different oxidation states. The catalytic mechanism of methane formation has remained elusive despite intense spectroscopic and theoretical investigations. On the basis of spectroscopic and crystallographic data, the first step of the mechanism is proposed to involve a nucleophilic attack of the NiI active state (MCRred1) on Me-SCoM to form a NiIII-methyl intermediate, while computational studies indicate that the first step involves the attack of NiI on the sulfur of Me-SCoM, forming a CH3 radical and a NiII-thiolate species. In this study, a combination of Ni K-edge X-ray absorption spectroscopic (XAS) studies and density functional theory (DFT) calculations have been performed on the NiI (MCRred1), NiII (MCRred1-silent), and NiIII-methyl (MCRMe) states of MCR to elucidate the geometric and electronic structures of the different redox states. Ni K-edge EXAFS data are used to reveal a five-coordinate active site with an open upper axial coordination site in MCRred1. Ni K-pre-edge and EXAFS data and time-dependent DFT calculations unambiguously demonstrate the presence of a long Ni-C bond (∼2.04 Å) in the NiIII-methyl state of MCR. The formation and stability of this species support mechanism I, and the Ni-C bond length suggests a homolytic cleavage of the NiIII-methyl bon

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology