Update on T cells in the virally infected brain: Friends and foes

PURPOSE OF REVIEW: The present review will outline neuroprotective and neurotoxic effects of central nervous system (CNS) infiltrating T cells during viral infections. Evidence demonstrating differential roles for antiviral effector and resident memory T-cell subsets in virologic control and immunopathology in the CNS will be discussed. Potential therapeutic targets emanating from a growing understanding of T-cell-initiated neuropathology that impacts learning and memory will also be delineated. RECENT FINDINGS: The critical role for T cells in preventing and clearing CNS infections became incontrovertible during the era of acquired immunodeficiency syndrome. Recent studies have further defined differential roles of T-cell subsets, including resident memory T cells (Trm), in antiviral immunity and, unexpectedly, in postinfectious cognitive dysfunction. Mechanisms of T-cell-mediated effects include differential innate immune signaling within neural cells that are virus-specific. SUMMARY: T-cell cytokines that are essential for cell-mediated virologic control during neurotropic viral infections have recently been identified as potential targets to prevent post-infection memory disorders. Further identification of T-cell subsets, their antigen specificity, and postinfection localization of Trm will enhance the efficacy of immunotherapies through minimization of immunopathology

Gravitational Collapse and Fragmentation in Molecular Clouds with Adaptive Mesh Refinement

We describe a powerful methodology for numerical solution of 3-D self-gravitational hydrodynamics problems with extremely high resolution. Our method utilizes the technique of local adaptive mesh refinement (AMR), employing multiple grids at multiple levels of resolution. These grids are automatically and dynamically added and removed as necessary to maintain adequate resolution. This technology allows for the solution of problems in a manner that is both more efficient and more versatile than other fixed and variable resolution methods. The application of AMR to simulate the collapse and fragmentation of a molecular cloud, a key step in star formation, is discussed. Such simulations involve many orders of magnitude of variation in length scale as fragments form. In this paper we briefly describe the methodology and present an illustrative application for nonisothermal cloud collapse. We describe the numerical Jeans condition, a criterion for stability of self-gravitational hydrodynamics problems. We show the first well-resolved nonisothermal evolutionary sequence beginning with a perturbed dense molecular cloud core that leads to the formation of a binary system consisting of protostellar cores surrounded by distinct protostellar disks. The scale of the disks, of order 100 AU, is consistent with observations of gaseous disks surrounding single T-Tauri stars and debris disks surrounding systems such as $\beta$ Pictoris.Comment: 10 pages, 6 figures (color postscript). To appear in the proceedings of Numerical Astrophysics 1998, Tokyo, March 10-13, 199

Gravity and Electromagnetism in Noncommutative Geometry

We present a unified description of gravity and electromagnetism in the framework of a $Z_2$ noncommutative differential calculus. It can be considered as a ``discrete version" of Kaluza-Klein theory, where the fifth continuous dimension is replaced by two discrete points. We derive an action which coincides with the dimensionally reduced one of the ordinary Kaluza-Klein theory.Comment: 1 + 11 pages, Report # SU-4240-566, Few misprints have been correcte

Introduction to the Workshop

Public health administrators are forced to consider efficiency as a criterion in their choice of preventive programs because of the numerous programs to choose from, restricted budgets, and declining caries experience in children. Interest in cost effectiveness in dental prevention has risen considerably since the initial conference on this issue at the University of Michigan in 1978. This article introduces the goals of the workshop, the nature of the work groups, and the data they will use.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66042/1/j.1752-7325.1989.tb02083.x.pd

Chiral spinors and gauge fields in noncommutative curved space-time

The fundamental concepts of Riemannian geometry, such as differential forms, vielbein, metric, connection, torsion and curvature, are generalized in the context of non-commutative geometry. This allows us to construct the Einstein-Hilbert-Cartan terms, in addition to the bosonic and fermionic ones in the Lagrangian of an action functional on non-commutative spaces. As an example, and also as a prelude to the Standard Model that includes gravitational interactions, we present a model of chiral spinor fields on a curved two-sheeted space-time with two distinct abelian gauge fields. In this model, the full spectrum of the generalized metric consists of pairs of tensor, vector and scalar fields. They are coupled to the chiral fermions and the gauge fields leading to possible parity violation effects triggered by gravity.Comment: 50 pages LaTeX, minor corrections and references adde

Single-cell RNA transcriptome analysis of CNS immune cells reveals CXCL16/CXCR6 as maintenance factors for tissue-resident T cells that drive synapse elimination

BACKGROUND: Emerging RNA viruses that target the central nervous system (CNS) lead to cognitive sequelae in survivors. Studies in humans and mice infected with West Nile virus (WNV), a re-emerging RNA virus associated with learning and memory deficits, revealed microglial-mediated synapse elimination within the hippocampus. Moreover, CNS-resident memory T (T METHODS: Here, we examined immune cells within the murine WNV-recovered forebrain using single-cell RNA sequencing to identify putative ligand-receptor pairs involved in intercellular communication between T cells and microglia. Clustering and differential gene analyses were followed by protein validation and genetic and antibody-based approaches utilizing an established murine model of WNV recovery in which microglia and complement promote ongoing hippocampal synaptic loss. RESULTS: Profiling of host transcriptome immune cells at 25 days post-infection in mice revealed a shift in forebrain homeostatic microglia to activated subpopulations with transcriptional signatures that have previously been observed in studies of neurodegenerative diseases. Importantly, CXCL16/CXCR6, a chemokine signaling pathway involved in T CONCLUSIONS: We provide a comprehensive assessment of the role of CXCL16/CXCR6 as an interaction link between microglia and CD

Perivascular Expression and Potent Vasoconstrictor Effect of Dynorphin A in Cerebral Arteries

BACKGROUND: Numerous literary data indicate that dynorphin A (DYN-A) has a significant impact on cerebral circulation, especially under pathophysiological conditions, but its potential direct influence on the tone of cerebral vessels is obscure. The aim of the present study was threefold: 1) to clarify if DYN-A is present in cerebral vessels, 2) to determine if it exerts any direct effect on cerebrovascular tone, and if so, 3) to analyze the role of κ-opiate receptors in mediating the effect. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical analysis revealed the expression of DYN-A in perivascular nerves of rat pial arteries as well as in both rat and human intraparenchymal vessels of the cerebral cortex. In isolated rat basilar and middle cerebral arteries (BAs and MCAs) DYN-A (1-13) and DYN-A (1-17) but not DYN-A (1-8) or dynorphin B (DYN-B) induced strong vasoconstriction in micromolar concentrations. The maximal effects, compared to a reference contraction induced by 124 mM K(+), were 115±6% and 104±10% in BAs and 113±3% and 125±9% in MCAs for 10 µM of DYN-A (1-13) and DYN-A (1-17), respectively. The vasoconstrictor effects of DYN-A (1-13) could be inhibited but not abolished by both the κ-opiate receptor antagonist nor-Binaltorphimine dihydrochloride (NORBI) and blockade of G(i/o)-protein mediated signaling by pertussis toxin. Finally, des-Tyr(1) DYN-A (2-13), which reportedly fails to activate κ-opiate receptors, induced vasoconstriction of 45±11% in BAs and 50±5% in MCAs at 10 µM, which effects were resistant to NORBI. CONCLUSION/SIGNIFICANCE: DYN-A is present in rat and human cerebral perivascular nerves and induces sustained contraction of rat cerebral arteries. This vasoconstrictor effect is only partly mediated by κ-opiate receptors and heterotrimeric G(i/o)-proteins. To our knowledge our present findings are the first to indicate that DYN-A has a direct cerebral vasoconstrictor effect and that a dynorphin-induced vascular action may be, at least in part, independent of κ-opiate receptors

Two-dimensional Vortices in Superconductors

Superconductors have two key characteristics. They expel magnetic field and they conduct electrical current with zero resistance. However, both properties are compromised in high magnetic fields which can penetrate the material and create a mixed state of quantized vortices. The vortices move in response to an electrical current dissipating energy which destroys the zero resistance state\cite{And64}. One of the central problems for applications of high temperature superconductivity is the stabilization of vortices to ensure zero electrical resistance. We find that vortices in the anisotropic superconductor Bi$_{2}$Sr$_{2}$CaCu$_{2}$O$_{8+\delta}$ (Bi-2212) have a phase transition from a liquid state, which is inherently unstable, to a two-dimensional vortex solid. We show that at high field the transition temperature is independent of magnetic field, as was predicted theoretically for the melting of an ideal two-dimensional vortex lattice\cite{Fis80,Gla91}. Our results indicate that the stable solid phase can be reached at any field as may be necessary for applications involving superconducting magnets\cite{Has04,Sca04,COHMAG}. The vortex solid is disordered, as suggested by previous studies at lower fields\cite{Lee93,Cub93}. But its evolution with increasing magnetic field displays unexpected threshold behavior that needs further investigation.Comment: 5 pages and 4 figures. submitted to Nature Physic

A computational exploration of resilience and evolvability of protein–protein interaction networks

Protein-protein interaction (PPI) networks represent complex intra-cellular protein interactions , and the presence or absence of such interactions can lead to biological changes in an organism. Recent network-based approaches have shown that a phenotype's PPI network's resilience to environmental perturbations is related to its placement in the tree of life; though we still do not know how or why certain intra-cellular factors can bring about this resilience. Here, we explore the influence of gene expression and network properties on PPI networks' resilience. We use publicly available data of PPIs for E. coli, S. cerevisiae, and H. sapiens, where we compute changes in network resilience as new nodes (proteins) are added to the networks under three node addition mechanisms-random, degree-based, and gene-expression-based attachments. By calculating the resilience of the resulting networks, we estimate the effectiveness of these node addition mechanisms. We demonstrate that adding nodes with gene-expression-based preferential attachment (as opposed to random or degree-based) preserves and can increase the original resilience of PPI network in all three species, regardless of gene expression distribution or network structure. These findings introduce a general notion of prospective resilience, which highlights the key role of network structures in understanding the evolvability of phenotypic traits