Analysis of CNS autoimmunity in genetically diverse mice reveals unique phenotypes and mechanisms.

Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE).

Probing the basis of disease heterogeneity in multiple sclerosis using genetically diverse mice.

Unlabelled: Multiple sclerosis (MS) is a complex disease with significant heterogeneity in disease course and progression. Genetic studies have identified numerous loci associated with MS risk, but the genetic basis of disease progression remains elusive. To address this, we leveraged the Collaborative Cross (CC), a genetically diverse mouse strain panel, and experimental autoimmune encephalomyelitis (EAE).

Energy-Efficient Neuromorphic Architectures for Nuclear Radiation Detection Applications.

A comprehensive analysis and simulation of two memristor-based neuromorphic architectures for nuclear radiation detection is presented. Both scalable architectures retrofit a locally competitive algorithm to solve overcomplete sparse approximation problems by harnessing memristor crossbar execution of vector-matrix multiplications. The proposed systems demonstrate excellent accuracy and throughput while consuming minimal energy for radionuclide detection.

Host Genetic Variation Has a Profound Impact on Immune Responses Mediating Control of Viral Load in Chronic Gammaherpesvirus Infection.

Chronic infection with the gammaherpesvirus EBV is a risk factor for several autoimmune diseases, and poor control of EBV viral load and enhanced anti-EBV responses elevate this risk further. However, the role of host genetic variation in the regulation of immune responses to chronic gammaherpesvirus infection and control of viral replication remains unclear. To address this question, we infected C57BL/6J (B6) and genetically divergent wild-derived inbred PWD/PhJ (PWD) mice with murine gammaherpesvirus-68 (MHV-68), a gammaherpesvirus similar to EBV, and determined the effect of latent gammaherpesvirus infection on the CD4 T cell transcriptome.

A genetic locus complements resistance to Bordetella pertussis-induced histamine sensitization.

Histamine plays pivotal role in normal physiology and dysregulated production of histamine or signaling through histamine receptors (HRH) can promote pathology. Previously, we showed that Bordetella pertussis or pertussis toxin can induce histamine sensitization in laboratory inbred mice and is genetically controlled by Hrh1/HRH1. HRH1 allotypes differ at three amino acid residues with P-V-L and L-M-S, imparting sensitization and resistance respectively.

Sex differences in susceptibility to influenza A virus infection depend on host genotype.

Infection with the respiratory pathogen influenza A virus (IAV) causes significant morbidity and mortality each year. While host genotype is thought to contribute to severity of disease, naturally occurring genetic determinants remain mostly unknown. Moreover, more severe disease is seen in women compared with men, but genetic mechanisms underlying this sex difference remain obscure.

Revisiting the edge of chaos: Again?

Does biological computation happen at some sort of "edge of chaos", a dynamical regime somewhere between order and chaos? And if so, is this a fundamental principle that underlies self-organization, evolution, and complex natural and artificial systems that are subjected to adaptation? In this article, we will review the literature on the fundamental principles of computation in natural and artificial systems at the "edge of chaos". The term was coined by Norman Packard in the late 1980s. Since then, the concept of "adaptation to the edge of chaos" was demonstrated and investigated in many fields where both simple and complex systems receive some sort of feedback.

The Cdkn2a gene product p19 alternative reading frame (p19ARF) is a critical regulator of IFNβ-mediated Lyme arthritis.

Type I interferon (IFN) has been identified in patients with Lyme disease, and its abundant expression in joint tissues of C3H mice precedes development of Lyme arthritis. Forward genetics using C3H mice with severe Lyme arthritis and C57BL/6 (B6) mice with mild Lyme arthritis identified the Borrelia burgdorferi arthritis-associated locus 1 (Bbaa1) on chromosome 4 (Chr4) as a regulator of B. burgdorferi-induced IFNβ expression and Lyme arthritis severity.

Reconfigurable perovskite nickelate electronics for artificial intelligence.

Reconfigurable devices offer the ability to program electronic circuits on demand. In this work, we demonstrated on-demand creation of artificial neurons, synapses, and memory capacitors in post-fabricated perovskite NdNiO devices that can be simply reconfigured for a specific purpose by single-shot electric pulses. The sensitivity of electronic properties of perovskite nickelates to the local distribution of hydrogen ions enabled these results.

Interactions between host genetics and gut microbiota determine susceptibility to CNS autoimmunity.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for immune-mediated diseases is an imbalance in the gut microbiome.

Identification of novel loci controlling inflammatory bowel disease susceptibility utilizing the genetic diversity of wild-derived mice.

Inflammatory bowel disease (IBD) is a complex disorder that imposes a growing health burden. Multiple genetic associations have been identified in IBD, but the mechanisms underlying many of these associations are poorly understood. Animal models are needed to bridge this gap, but conventional laboratory mouse strains lack the genetic diversity of human populations.

The sex-specific role of p38 MAP kinase in CNS autoimmunity is regulated by estrogen receptor alpha.

Biological sex is a critical factor in regulating immune function. A striking example of this is the higher prevalence of autoimmune diseases such as multiple sclerosis (MS) and lupus in females compared to males. While many studies have implicated the role of sex hormones such as estrogens and androgens in these sex differences, surprisingly little is known about other molecular pathways that underlie sex differences or interact with sex hormones.

Erratum: Author Correction: A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease).

[This corrects the article DOI: 10.1038/s42003-019-0647-4.].

A natural mouse model reveals genetic determinants of systemic capillary leak syndrome (Clarkson disease).

The systemic capillary leak syndrome (SCLS, Clarkson disease) is a disorder of unknown etiology characterized by recurrent episodes of vascular leakage of proteins and fluids into peripheral tissues, resulting in whole-body edema and hypotensive shock. The pathologic mechanisms and genetic basis for SCLS remain elusive. Here we identify an inbred mouse strain, SJL, which recapitulates cardinal features of SCLS, including susceptibility to histamine- and infection-triggered vascular leak.

Network-Based Functional Prediction Augments Genetic Association To Predict Candidate Genes for Histamine Hypersensitivity in Mice.

Genetic mapping is a primary tool of genetics in model organisms; however, many quantitative trait loci (QTL) contain tens or hundreds of positional candidate genes. Prioritizing these genes for validation is often and biased by previous findings. Here we present a technique for prioritizing positional candidates based on computationally inferred gene function.

Shift-symmetric configurations in two-dimensional cellular automata: Irreversibility, insolvability, and enumeration.

The search for symmetry, as an unusual yet profoundly appealing phenomenon, and the origin of regular, repeating configuration patterns have long been a central focus of complexity science and physics. To better grasp and understand symmetry of configurations in decentralized toroidal architectures, we employ group-theoretic methods, which allow us to identify and enumerate these inputs, and argue about irreversible system behaviors with undesired effects on many computational problems. The concept of so-called "configuration shift-symmetry" is applied to two-dimensional cellular automata as an ideal model of computation.

Tuberculosis and impaired IL-23-dependent IFN-γ immunity in humans homozygous for a common missense variant.

Inherited IL-12Rβ1 and TYK2 deficiencies impair both IL-12- and IL-23-dependent IFN-γ immunity and are rare monogenic causes of tuberculosis, each found in less than 1/600,000 individuals. We show that homozygosity for the common P1104A allele, which is found in about 1/600 Europeans and between 1/1000 and 1/10,000 individuals in regions other than East Asia, is more frequent in a cohort of patients with tuberculosis from endemic areas than in ethnicity-adjusted controls ( = 8.37 × 10; odds ratio, 89.

Fast and Accurate Sparse Coding of Visual Stimuli With a Simple, Ultralow-Energy Spiking Architecture.

Memristive crossbars have become a popular means for realizing unsupervised and supervised learning techniques. In previous neuromorphic architectures with leaky integrate-and-fire neurons, the crossbar itself has been separated from the neuron capacitors to preserve mathematical rigor. In this paper, we sought to design a simplified sparse coding circuit without this restriction, resulting in a fast circuit that approximated a sparse coding operation at a minimal loss in accuracy.

Sex-Specific Gene-by-Vitamin D Interactions Regulate Susceptibility to Central Nervous System Autoimmunity.

Vitamin D3 (VitD) insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis (MS). While low VitD levels strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting the existence of a genetic component. Moreover, VitD supplementation studies in MS so far have not shown a consistent benefit.

Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis.

Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that, in addition to motor, sensory, and cognitive symptoms, also causes constipation, which is poorly understood. Here, we characterize gastrointestinal (GI) dysmotility in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS and evaluate whether autoantibodies target the enteric nervous system (ENS) and cause dysmotility.

Methods: EAE was induced in male SJL and B6 mice.

Genetic Control of Lyme Arthritis by Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-β and Requires Upregulation of Myostatin.

Previously, using a forward genetic approach, we identified differential expression of type I IFN as a positional candidate for an expression quantitative trait locus underlying arthritis-associated locus 1 (). In this study, we show that mAb blockade revealed a unique role for IFN-β in Lyme arthritis development in B6.C3- mice.

Anti-inflammatory roles of p38α MAPK in macrophages are context dependent and require IL-10.

The p38 MAPK pathway was originally identified as a master regulator of proinflammatory cytokine production by myeloid cells. Numerous drugs targeting this kinase showed promise in preclinical models of inflammatory disease, but so far, none have shown efficacy in clinical trials. The reasons behind this are unclear, but may, in part, be explained by emerging anti-inflammatory functions of this kinase or overly refined selectivity of second-generation pharmacologic inhibitors.

Feedforward Chemical Neural Network: An In Silico Chemical System That Learns xor.

Inspired by natural biochemicals that perform complex information processing within living cells, we design and simulate a chemically implemented feedforward neural network, which learns by a novel chemical-reaction-based analogue of backpropagation. Our network is implemented in a simulated chemical system, where individual neurons are separated from each other by semipermeable cell-like membranes. Our compartmentalized, modular design allows a variety of network topologies to be constructed from the same building blocks.

Modeling month-season of birth as a risk factor in mouse models of chronic disease: from multiple sclerosis to autoimmune encephalomyelitis.

Month-season of birth (M-SOB) is a risk factor in multiple chronic diseases, including multiple sclerosis (MS), where the lowest and greatest risk of developing MS coincide with the lowest and highest birth rates, respectively. To determine whether M-SOB effects in such chronic diseases as MS can be experimentally modeled, we examined the effect of M-SOB on susceptibility of C57BL/6J mice to experimental autoimmune encephalomyelitis (EAE). As in MS, mice that were born during the M-SOB with the lowest birth rate were less susceptible to EAE than mice born during the M-SOB with the highest birth rate.

Genetic variation in chromosome Y regulates susceptibility to influenza A virus infection.

Males of many species, ranging from humans to insects, are more susceptible than females to parasitic, fungal, bacterial, and viral infections. One mechanism that has been proposed to account for this difference is the immunocompetence handicap model, which posits that the greater infectious disease burden in males is due to testosterone, which drives the development of secondary male sex characteristics at the expense of suppressing immunity. However, emerging data suggest that cell-intrinsic (chromosome X and Y) sex-specific factors also may contribute to the sex differences in infectious disease burden.