Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity

Torsion pairs and rigid objects in tubes

We classify the torsion pairs in a tube category and show that they are in bijection with maximal rigid objects in the extension of the tube category containing the Pruefer and adic modules. We show that the annulus geometric model for the tube category can be extended to the larger category and interpret torsion pairs, maximal rigid objects and the bijection between them geometrically. We also give a similar geometric description in the case of the linear orientation of a Dynkin quiver of type A.Comment: 25 pages, 13 figures. Paper shortened. Minor errors correcte

Normierung der Testbatterie COGBAT bei Jugendlichen im Alter von 12 bis 15 Jahren

Das Jugendalter stellt eine wichtige Phase in der Entwicklung der Verarbeitungsgeschwindigkeit, der Aufmerksamkeit, des Gedächtnisses und der exekutiven Funktionen dar. Im Rahmen einer Normierungsstudie der kognitiven Basistestung (COGBAT) für das Jugendalter wurden Testwerte bei n = 269 Jugendlichen im Alter von 12 bis 15 Jahren erhoben und mit den Normen der Altersgruppe der 16- bis 30-Jährigen verglichen. Zusätzlich wurde überprüft, inwiefern sich diese Testergebnisse in der subjektiven Einschätzung zur Leistungsfähigkeit (FLei) und Psychopathologie (SDQ) abbilden lassen. Im Jugendalter zeigte sich ein starker Zuwachs in der kognitiven Flexibilität, der Verarbeitungs- und Reaktionsgeschwindigkeit sowie der Inhibitions- und Planungsfähigkeit. Ein bedeutsamer Geschlechtsunterschied fand sich in der Inhibition, mit stärkeren Leistungen bei Mädchen als bei Jungen. Zwischen den Testergebnissen und den subjektiven Einschätzungen zeigten sich keine Zusammenhänge

On quiver Grassmannians and orbit closures for representation-finite algebras

We show that Auslander algebras have a unique tilting and cotilting module which is generated and cogenerated by a projective-injective; its endomorphism ring is called the projective quotient algebra. For any representation- nite algebra, we use the projective quotient algebra to construct desingularizations of quiver Grassmannians, orbit closures in representation varieties, and their desingularizations. This generalizes results of Cerulli Irelli, Feigin and Reineke

Технология синтеза и очистки гликолида

Данная работа посвящена технологии получения и очистки гликолида, как мономера для биоразлагаемых полимеров. Основные потери продукта происходят на стадии получения и очистки мономера. Потери составляют порядка 50-60 %. Целью данной работы является выбор оптимального пути и очистки гликолида. В данной работе проведён и представлен всесторонний литературный обзор по методам получения гликолевой кислоты, гликолида, очистки и полимеризации гликолида. Сравнивались различные катализаторы на стадиях поликонденсации, деполимеризации и полимеризации гликолида. В работе описаны характеристики сырья, описаны способы получения, очистки и полимеризации гликолида. Изложены методики анализа гликолида.This paper is devoted to the technology of production and purification of glycolide as a monomer for biodegradable polymers. The main product losses occur at the stage of monomer production and purification. Losses are about 50-60%. The purpose of this work is to choose the optimal path and purification of glycolide. In this paper, we conducted and presented a comprehensive literature review on methods for producing glycolic acid, glycolide, and purification and polymerization of glycolide. Different catalysts were compared at the stages of glycolide polycondensation, depolymerization, and polymerization. The work describes the characteristics of the raw materials, describes the methods of production, purification, and polymerization of glycolide

MALT1 is an intrinsic regulator of regulatory T cells.

peer reviewedRegulatory T cells (Tregs) are crucial for the maintenance of immunological self-tolerance and their absence or dysfunction can lead to autoimmunity. However, the molecular pathways that govern Treg biology remain obscure. In this study, we show that the nuclear factor-κB signalling mediator mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is an important novel regulator of both Tregs originating in the thymus ('natural' or nTregs) and Tregs induced to differentiate from naive thymocyte helper (Th) cells in the periphery ('induced' or iTregs). Our examination of mice deficient for MALT1 revealed that these mutants have a reduced number of total Tregs. In young Malt1-/- mice, nTregs are totally absent and iTreg are diminished in the periphery. Interestingly, total Treg numbers increase in older Malt1-/- mice as well as in Malt1-/- mice subjected to experimentally induced inflammation. iTregs isolated from WT and Malt1-/- mice were indistinguishable with respect to their ability to suppress the activities of effector T cells, but Malt1-/- iTregs expressed higher levels of Toll-like receptor (TLR) 2. Treatment of WT and Malt1-/- Th cells in vitro with the TLR2 ligand Pam3Cys strongly enhanced the induction and proliferation of Malt1-/- iTregs. Our data suggest that MALT1 supports nTreg development in the thymus but suppresses iTreg induction in the periphery during inflammation. Our data position MALT1 as a key molecule that contributes to immune tolerance at steady-state while facilitating immune reactivity under stress conditions

Cycle-finite module categories

We describe the structure of module categories of finite dimensional algebras over an algebraically closed field for which the cycles of nonzero nonisomorphisms between indecomposable finite dimensional modules are finite (do not belong to the infinite Jacobson radical of the module category). Moreover, geometric and homological properties of these module categories are exhibited

Erratum: Modeling psychiatric disorders: from genomic findings to cellular phenotypes

Major programs in psychiatric genetics have identified >150 risk loci for psychiatric disorders. These loci converge on a small number of functional pathways, which span conventional diagnostic criteria, suggesting a partly common biology underlying schizophrenia, autism and other psychiatric disorders. Nevertheless, the cellular phenotypes that capture the fundamental features of psychiatric disorders have not yet been determined. Recent advances in genetics and stem cell biology offer new prospects for cell-based modeling of psychiatric disorders. The advent of cell reprogramming and induced pluripotent stem cells (iPSC) provides an opportunity to translate genetic findings into patient-specific in vitro models. iPSC technology is less than a decade old but holds great promise for bridging the gaps between patients, genetics and biology. Despite many obvious advantages, iPSC studies still present multiple challenges. In this expert review, we critically review the challenges for modeling of psychiatric disorders, potential solutions and how iPSC technology can be used to develop an analytical framework for the evaluation and therapeutic manipulation of fundamental disease processes

The Slab Puzzle of the Alpine‐Mediterranean Region: Insights from a new, High‐Resolution, Shear‐Wave Velocity Model of the Upper Mantle

Mediterranean tectonics since the Lower Cretaceous has been characterized by a multi‐phase subduction and collision history with temporally and spatially‐variable, small‐scale plate configurations. A new shear‐wave velocity model of the Mediterranean upper mantle (MeRE2020), constrained by a very large set of over 200,000 broadband (8‐350 s), inter‐station, Rayleigh‐wave, phase‐velocity curves, illuminates the complex structure and fragmentation of the subducting slabs. Phase‐velocity maps computed using these measurements were inverted for depth‐dependent, shear‐wave velocities using a stochastic particle‐swarm‐optimization algorithm (PSO). The resulting three‐dimensional (3‐D) model makes possible an inventory of slab segments across the Mediterranean. Fourteen slab segments of 200‐800 km length along‐strike are identified. We distinguish three categories of subducted slabs: attached slabs reaching down to the bottom of the model; shallow slabs of shorter length in down‐dip direction, terminating shallower than 300 km depth; and detached slab segments. The location of slab segments are consistent with and validated by the intermediate‐depth seismicity, where it is present. The new high‐resolution tomography demonstrates the intricate relationships between slab fragmentation and the evolution of the relatively small and highly curved subduction zones and collisional orogens characteristic of the Mediterranean realm

A Single-Cell Model for Synaptic Transmission and Plasticity in Human iPSC-Derived Neurons

Synaptic dysfunction is associated with many brain disorders, but robust human cell models to study synaptic transmission and plasticity are lacking. Instead, current in vitro studies on human neurons typically rely on spontaneous synaptic events as a proxy for synapse function. Here, we describe a standardized in vitro approach using human neurons cultured individually on glia microdot arrays that allow single-cell analysis of synapse formation and function. We show that single glutamatergic or GABAergic forebrain neurons differentiated from human induced pluripotent stem cells form mature synapses that exhibit robust evoked synaptic transmission. These neurons show plasticity features such as synaptic facilitation, depression, and recovery. Finally, we show that spontaneous events are a poor predictor of synaptic maturity and do not correlate with the robustness of evoked responses. This methodology can be deployed directly to evaluate disease models for synaptic dysfunction and can be leveraged for drug development and precision medicine. This multisite study by Meijer et al. establishes a standardized in vitro approach to study synapse formation and function in single iPSC-derived human neurons. They validate this approach for GABA and glutamatergic human neurons. The methodology is scalable and suitable for compound screening and disease modeling