Exploring cellular markers of metabolic syndrome in peripheral blood mononuclear cells across the neuropsychiatric spectrum

Recent evidence suggests that comorbidities between neuropsychiatric conditions and metabolic syndrome may precede and even exacerbate long-term side-effects of psychiatric medication, such as a higher risk of type 2 diabetes and cardiovascular disease, which result in increased mortality. In the present study we compare the expression of key metabolic proteins, including the insulin receptor (CD220), glucose transporter 1 (GLUT1) and fatty acid translocase (CD36), on peripheral blood mononuclear cell subtypes from patients across the neuropsychiatric spectrum, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions (n = 25/condition), relative to typical controls (n = 100). This revealed alterations in the expression of these proteins that were specific to schizophrenia. Further characterization of metabolic alterations in an extended cohort of first-onset antipsychotic drug-naïve schizophrenia patients (n = 58) and controls (n = 63) revealed that the relationship between insulin receptor expression in monocytes and physiological insulin sensitivity was disrupted in schizophrenia and that altered expression of the insulin receptor was associated with whole genome polygenic risk scores for schizophrenia. Finally, longitudinal follow-up of the schizophrenia patients over the course of antipsychotic drug treatment revealed that peripheral metabolic markers predicted changes in psychopathology and the principal side effect of weight gain at clinically relevant time points. These findings suggest that peripheral blood cells can provide an accessible surrogate model for metabolic alterations in schizophrenia and have the potential to stratify subgroups of patients with different clinical outcomes or a greater risk of developing metabolic complications following antipsychotic therapy

Temporal proteomic profiling of postnatal human cortical development.

Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR < 5%). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation, and disease

Hydrodynamic transport functions from quantum kinetic theory

Starting from the quantum kinetic field theory [E. Calzetta and B. L. Hu, Phys. Rev. D37, 2878 (1988)] constructed from the closed-time-path (CTP), two-particle-irreducible (2PI) effective action we show how to compute from first principles the shear and bulk viscosity functions in the hydrodynamic-thermodynamic regime. For a real scalar field with $\lambda \Phi ^{4}$ self-interaction we need to include 4 loop graphs in the equation of motion. This work provides a microscopic field-theoretical basis to the ``effective kinetic theory'' proposed by Jeon and Yaffe [S. Jeon and L. G. Yaffe, Phys. Rev. D53, 5799 (1996)], while our result for the bulk viscosity reproduces their expression derived from linear response theory and the imaginary-time formalism of thermal field theory. Though unavoidably involved in calculations of this sort, we feel that the approach using fundamental quantum kinetic field theory is conceptually clearer and methodically simpler than the effective kinetic theory approach, as the success of the latter requires clever rendition of diagrammatic resummations which is neither straightforward nor failsafe. Moreover, the method based on the CTP-2PI effective action illustrated here for a scalar field can be formulated entirely in terms of functional integral quantization, which makes it an appealing method for a first-principles calculation of transport functions of a thermal non-abelian gauge theory, e.g., QCD quark-gluon plasma produced from heavy ion collisions.Comment: 25 pages revtex, 11 postscript figures. Final version accepted for publicatio

Molecular Sex Differences in Human Serum

Background: Sex is an important factor in the prevalence, incidence, progression, and response to treatment of many medical conditions, including autoimmune and cardiovascular diseases and psychiatric conditions. Identification of molecular differences between typical males and females can provide a valuable basis for exploring conditions differentially affected by sex. Methodology/Principal Findings: Using multiplexed immunoassays, we analyzed 174 serum molecules in 9 independent cohorts of typical individuals, comprising 196 males and 196 females. Sex differences in analyte levels were quantified using a meta-analysis approach and put into biological context using k-means to generate clusters of analytes with distinct biological functions. Natural sex differences were established in these analyte groups and these were applied to illustrate sexually dimorphic analyte expression in a cohort of 22 males and 22 females with Asperger syndrome. Reproducible sex differences were found in the levels of 77 analytes in serum of typical controls, and these comprised clusters of molecules enriched with distinct biological functions. Analytes involved in fatty acid oxidation/hormone regulation, immune cell growth and activation, and cell death were found at higher levels in females, and analytes involved in immune cell chemotaxis and other indistinct functions were higher in males. Comparison of these naturally occurring sex differences against a cohort of people with Asperger syndrome indicated that a cluster of analytes that had functions related to fatty acid oxidation/hormone regulation was associated with sex and the occurren

Galaxy and Apollo as a biologist-friendly interface for high-quality cooperative phage genome annotation

In the modern genomic era, scientists without extensive bioinformatic training need to apply high-power computational analyses to critical tasks like phage genome annotation. At the Center for Phage Technology (CPT), we developed a suite of phage-oriented tools housed in open, user-friendly web-based interfaces. A Galaxy platform conducts computationally intensive analyses and Apollo, a collaborative genome annotation editor, visualizes the results of these analyses. The collection includes open source applications such as the BLAST+ suite, InterProScan, and several gene callers, as well as unique tools developed at the CPT that allow maximum user flexibility. We describe in detail programs for finding Shine-Dalgarno sequences, resources used for confident identification of lysis genes such as spanins, and methods used for identifying interrupted genes that contain frameshifts or introns. At the CPT, genome annotation is separated into two robust segments that are facilitated through the automated execution of many tools chained together in an operatio

O(N) Quantum fields in curved spacetime

For the O(N) field theory with lambda Phi^4 self-coupling, we construct the two-particle-irreducible (2PI), closed-time-path (CTP) effective action in a general curved spacetime. From this we derive a set of coupled equations for the mean field and the variance. They are useful for studying the nonperturbative, nonequilibrium dynamics of a quantum field when full back reactions of the quantum field on the curved spacetime, as well as the fluctuations on the mean field, are required. Applications to phase transitions in the early Universe such as the Planck scale or in the reheating phase of chaotic inflation are under investigation.Comment: 31 pages, 2 figures, uses RevTeX 3.1, LaTeX 2e, AMSfonts 2.2, graphics 0.6; To appear in Phys. Rev. D (7/15/97

Non-equilibrium dynamics of a thermal plasma in a gravitational field

We introduce functional methods to study the non-equilibrium dynamics of a quantum massless scalar field at finite temperature in a gravitational field. We calculate the Close Time Path (CTP) effective action and, using its formal equivalence with the influence functional, derive the noise and dissipation kernels of the quantum open system in terms of quantities in thermodynamical equilibrium. Using this fact, we formally prove the existence of a Fluctuation-Dissipation Relation (FDR) at all temperatures between the quantum fluctuations of the plasma in thermal equilibrium and the energy dissipated by the external gravitational field. What is new is the identification of a stochastic source (noise) term arising from the quantum and thermal fluctuations in the plasma field, and the derivation of a Langevin-type equation which describes the non-equilibrium dynamics of the gravitational field influenced by the plasma. The back reaction of the plasma on the gravitational field is embodied in the FDR. From the CTP effective action the contribution of the quantum scalar field to the thermal graviton polarization tensor can also be derived and it is shown to agree with other techniques, most notably, Linear Response Theory (LRT). We show the connection between the LRT, which is applicable for near-equilibrium conditions and the functional methods used in this work which are useful for fully non-equilibrium conditions.Comment: Final version published in Phys. Rev.

Drug discovery for psychiatric disorders using high-content single-cell screening of signaling network responses ex vivo

There is a paucity of efficacious new compounds to treat neuropsychiatric disorders. We present a novel approach to neuropsychiatric drug discovery based on high-content characterization of druggable signaling network responses at the single-cell level in patient-derived lymphocytes ex vivo. Primary T lymphocytes showed functional responses encompassing neuropsychiatric medications and central nervous system ligands at established (e.g., GSK-3?) and emerging (e.g., CrkL) drug targets. Clinical application of the platform to schizophrenia patients over the course of antipsychotic treatment revealed therapeutic targets within the phospholipase C?1-calcium signaling pathway. Compound library screening against the target phenotype identified subsets of L-type calcium channel blockers and corticosteroids as novel therapeutically relevant drug classes with corresponding activity in neuronal cells. The screening results were validated by predicting in vivo efficacy in an independent schizophrenia cohort. The approach has the potential to discern new drug targets and accelerate drug discovery and personalized medicine for neuropsychiatric conditions

Exploring cellular markers of metabolic syndrome in peripheral blood mononuclear cells across the neuropsychiatric spectrum

Recent evidence suggests that comorbidities between neuropsychiatric conditions and metabolic syndrome may precede and even exacerbate long-term side-effects of psychiatric medication, such as a higher risk of type 2 diabetes and cardiovascular disease, which result in increased mortality. In the present study we compare the expression of key metabolic proteins, including the insulin receptor (CD220), glucose transporter 1 (GLUT1) and fatty acid translocase (CD36), on peripheral blood mononuclear cell subtypes from patients across the neuropsychiatric spectrum, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions (n = 25/condition), relative to typical controls (n = 100). This revealed alterations in the expression of these proteins that were specific to schizophrenia. Further characterization of metabolic alterations in an extended cohort of first-onset antipsychotic drug-naïve schizophrenia patients (n = 58) and controls (n = 63) revealed that the relationship between insulin receptor expression in monocytes and physiological insulin sensitivity was disrupted in schizophrenia and that altered expression of the insulin receptor was associated with whole genome polygenic risk scores for schizophrenia. Finally, longitudinal follow-up of the schizophrenia patients over the course of antipsychotic drug treatment revealed that peripheral metabolic markers predicted changes in psychopathology and the principal side effect of weight gain at clinically relevant time points. These findings suggest that peripheral blood cells can provide an accessible surrogate model for metabolic alterations in schizophrenia and have the potential to stratify subgroups of patients with different clinical outcomes or a greater risk of developing metabolic complications following antipsychotic therapy.This work was supported by grants from the Stanley Medical Research Institute (SMRI); the Engineering and Physical Sciences Research Council UK (EPSRC); the Dutch Government-funded Virgo consortium (ref. FES0908); the Netherlands Genomics Initiative (ref. 050-060-452); the European Union FP7 funding scheme: Marie Curie Actions Industry Academia Partnerships and Pathways (ref. 286334, PSYCH-AID project); SAF2016-76046-R and SAF2013-46292-R (MINECO) and PI16/00156 (isciii and FEDER)