GABA-mediated inhibition of human CD4 T cell functions is enhanced by insulin but impaired by high glucose levels.

Background: γ-aminobutyric acid (GABA), known as the main inhibitory neurotransmitter in the brain, exerts immunomodulatory functions by interaction with immune cells, including T cells. Metabolic programs of T cells are closely linked to their effector functions including proliferation, differentiation, and cytokine production. The physiological molecules glucose and insulin may provide environmental cues and guidance, but whether they coordinate to regulate GABA-mediated T cell immunomodulation is still being examined.

Discovery and Hit-to-Lead Optimization of Benzothiazole Scaffold-Based DNA Gyrase Inhibitors with Potent Activity against and .

We have developed compounds with a promising activity against and , which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor , we identified compound , featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from and , a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of in complex with GyrB24 and ()- in complex with GyrB23 and GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit.

ZEB2 haploinsufficient Mowat-Wilson syndrome induced pluripotent stem cells show disrupted GABAergic transcriptional regulation and function.

Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor . Affected individuals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippocampal degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability.

Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes.

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D.

Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy.

Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures.

Insulin differentially modulates GABA signalling in hippocampal neurons and, in an age-dependent manner, normalizes GABA-activated currents in the tg-APPSwe mouse model of Alzheimer's disease.

Aim: We examined if tonic γ-aminobutyric acid (GABA)-activated currents in primary hippocampal neurons were modulated by insulin in wild-type and tg-APPSwe mice, an Alzheimer's disease (AD) model.

Methods: GABA-activated currents were recorded in dentate gyrus (DG) granule cells and CA3 pyramidal neurons in hippocampal brain slices, from 8 to 10 weeks old (young) wild-type mice and in dorsal DG granule cells in adult, 5-6 and 10-12 (aged) months old wild-type and tg-APPSwe mice, in the absence or presence of insulin, by whole-cell patch-clamp electrophysiology.

Results: In young mice, insulin (1 nmol/L) enhanced the total spontaneous inhibitory postsynaptic current (sIPSC ) density in both dorsal and ventral DG granule cells.

Tonic GABA-activated synaptic and extrasynaptic currents in dentate gyrus granule cells and CA3 pyramidal neurons along the mouse hippocampal dorsoventral axis.

The hippocampus is a medial temporal lobe structure in the brain and is widely studied for its role in memory and learning, in particular, spacial memory and emotional responses. It was thought to be a homogenous structure but emerging evidence shows differentiation along the dorsoventral axis and even microdomains for functional and cellular markers. We have examined in two cell-types of the hippocampal projection neurons, the dentate gyrus (DG) granule cells and CA3 pyramidal neurons, if the GABA-activated tonic current density varied between the dorsal (septal) and the ventral (temporal) poles of the male mouse hippocampus.

GABA Receptor-Mediated Currents and Hormone mRNAs in Cells Expressing More Than One Hormone Transcript in Intact Human Pancreatic Islets.

In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABA receptors (iGABARs).

Application of the stochastic closure theory to the Townsend-Perry constants.

We compare the stochastic closure theory (SCT) to the Townsend-Perry constants as estimated from measurements in the Flow Physic Facility (FPF) at the University of New Hampshire. First, we explain the derivation of the Townsend-Perry constants, which were originally formulated by Meneveau and Marusic, in analogy with a Gaussian distribution. However, this was not supported by the data.

Depression, GABA, and Age Correlate with Plasma Levels of Inflammatory Markers.

Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma samples from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers.

Ataxia in Patients With Bi-Allelic Mutations and Absence of Full-Length NF186.

The etiology of hereditary ataxia syndromes is heterogeneous, and the mechanisms underlying these disorders are often unknown. Here, we utilized exome sequencing in two siblings with progressive ataxia and muscular weakness and identified a novel homozygous splice mutation (c.3020-1G > A) in neurofascin ().

Interferon-γ potentiates GABA receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons.

The neural transmission and plasticity can be differentially modulated by various elements of the immune system. Interferon-γ (IFN-γ) is a "pro-inflammatory" cytokine mainly produced by T lymphocytes, activates its corresponding receptor and plays important roles under both homeostatic and inflammatory conditions. However, the impact of IFN-γ on the γ-aminobutyric acid (GABA)-mediated currents in the hippocampus, a major brain region involved in the cognitive function, has not been investigated.

Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment.

Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the α-subunit of the neuronal sodium channel Na1.1. The syndrome is characterized by age-related progression of seizures, cognitive decline and movement disorders.

Predicting impacts of chemicals from organisms to ecosystem service delivery: A case study of insecticide impacts on a freshwater lake.

Assessing and managing risks of anthropogenic activities to ecological systems is necessary to ensure sustained delivery of ecosystem services for future generations. Ecological models provide a means of quantitatively linking measured risk assessment endpoints with protection goals, by integrating potential chemical effects with species life history, ecological interactions, environmental drivers and other potential stressors. Here we demonstrate how an ecosystem modeling approach can be used to quantify insecticide-induced impacts on ecosystem services provided by a lake from toxicity data for organism-level endpoints.

Expression of calcium release-activated and voltage-gated calcium channels genes in peripheral blood mononuclear cells is altered in pregnancy and in type 1 diabetes.

Calcium (Ca2+) is an important ion in physiology and is found both outside and inside cells. The intracellular concentration of Ca2+ is tightly regulated as it is an intracellular signal molecule and can affect a variety of cellular processes. In immune cells Ca2+ has been shown to regulate e.

Predicting impacts of chemicals from organisms to ecosystem service delivery: A case study of endocrine disruptor effects on trout.

We demonstrate how mechanistic modeling can be used to predict whether and how biological responses to chemicals at (sub)organismal levels in model species (i.e., what we typically measure) translate into impacts on ecosystem service delivery (i.

GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4 T Cells and Is Immunosuppressive in Type 1 Diabetes.

The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4 T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals.

Functional Characterization of Native, High-Affinity GABA Receptors in Human Pancreatic β Cells.

In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABA receptors in human islet β cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels.

Parameter dependence of high-frequency nonlinear oscillations and intrinsic chaos in short GaAs/(Al, Ga)As superlattices.

We explore the design parameter space of short (5-25 period), n-doped, Ga/(Al,Ga)As semiconductor superlattices (SSLs) in the sequential resonant tunneling regime. We consider SSLs at cool (77 K) and warm (295 K) temperatures, simulating the electronic response to variations in (a) the number of SSL periods, (b) the contact conductivity, and (c) the strength of disorder (aperiodicities). Our analysis shows that the chaotic dynamical phases exist on a number of sub-manifolds of codimension zero within the design parameter space.

Insulin enhances GABA receptor-mediated inhibitory currents in rat central amygdala neurons.

Insulin, a pancreatic hormone, can access the central nervous system, activate insulin receptors distributed in selective brain regions and affect various cellular functions such as neurotransmission. We have previously shown that physiologically relevant concentration of insulin potentiates the GABA receptor-mediated tonic inhibition and reduces excitability of rat hippocampal CA1 neurons. The central nucleus of the amygdala (CeA) comprises heterogeneous neuronal populations that can respond to hormonal stimulus.

Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism.

Background: γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons.

Effects of fish movement assumptions on the design of a marine protected area to protect an overfished stock.

Marine Protected Areas (MPA) are important management tools shown to protect marine organisms, restore biomass, and increase fisheries yields. While MPAs have been successful in meeting these goals for many relatively sedentary species, highly mobile organisms may get few benefits from this type of spatial protection due to their frequent movement outside the protected area. The use of a large MPA can compensate for extensive movement, but testing this empirically is challenging, as it requires both large areas and sufficient time series to draw conclusions.