Cytosol to Lysosome Transport of Intracellular Antigens During Immune Surveillance

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.The delivery of intracellular substrates such as misfolded proteins and damaged organelles from the cytosol to the lysosome for degradation is crucial for cell survival. Multiple transport pathways including bulk autophagy (microautophagy and macroautophagy) and chaperone‐mediated autophagy (CMA) have been identified to efficiently facilitate this transit of macromolecules from the cytoplasm to acidic vacuolar organelles. While autophagy plays a role in the general housekeeping of cells, it also functions in more specialized processes such as development and differentiation, responses to physiological stress and immunity. The presentation of both exogenous and endogenous antigens (Ag) by major histocompatibility complex (MHC) class II molecules to CD4+ T lymphocytes is critical for the induction of tolerance to self Ag as well as the development of immunity against intracellular pathogens and tumors. Here, we discuss the class II‐mediated presentation of several endogenous Ag, dependent on either macroautophagy or CMA for their transport from the cytosol to endosomal/lysosomal compartments. Thus, the various pathways of autophagy as routes of cytoplasmic Ag delivery to lysosomes have significant implications for the MHC class II‐mediated immune response to intracellular pathogens and cancer

The Pink Tax

https://youtu.be/vWq0H5gJsSU - Interview Video Hosted on YouTube, CC available via YouTube auto-generate.Advertisin

Efficacy of B-Trees in an Information Storage and Retrieval Environment

This study investigates the efficacy of B-trees in an information storage and retrieval environment. A practical information storage and retrieval system is developed and used to test the performance of B-trees.Computing and Information Science

Mass Media in Society

Panel Chair: Lisa Vazzi Student Presenters: Sarah Mathis, Camila Garcia, Douglas Laman, Amanda Crotzer, and Veronica Nicole Liang Sarah Mathis “The Effects of Media on Women’s Body Image” Camila Garcia “Positive Advantages of Mass Communication” Douglas Laman “Autism, Actually: A Look at Representation of Autism in Pop Culture” Amanda Crotzer “Thruth in Advertising: Targeting Children in and Age of Privatized Media Consumption

T Cell Receptor Engagement Leads to Phosphorylation of Clathrin Heavy Chain during Receptor Internalization

T cell receptor (TCR) internalization by clathrin-coated vesicles after encounter with antigen has been implicated in the regulation of T cell responses. We demonstrate that TCR internalization after receptor engagement and TCR signaling involves inducible phosphorylation of clathrin heavy chain (CHC) in both CD4+ and CD8+ human T cells. Studies with mutant Jurkat T cells implicate the Src family kinase Lck as the responsible enzyme and its activity in this process is influenced by the functional integrity of the downstream signaling molecule ZAP-70. CHC phosphorylation positively correlates with ligand-induced TCR internalization in both CD4+ and CD8+ T cells, and CHC phosphorylation as a result of basal Lck activity is also implicated in constitutive TCR endocytosis by CD4+ T cells. Remarkably, irreversible CHC phosphorylation in the presence of pervanadate reduced both constitutive and ligand-induced TCR internalization in CD4+ T cells, and immunofluorescence studies revealed that this inhibition affected the early stages of TCR endocytosis from the plasma membrane. Thus, we propose that CHC phosphorylation and dephosphorylation are involved in TCR internalization and that this is a regulatory mechanism linking TCR signaling to endocytosis

Progress in smooth particle hydrodynamics

Smooth Particle Hydrodynamics (SPH) is a meshless, Lagrangian numerical method for hydrodynamics calculations where calculational elements are fuzzy particles which move according to the hydrodynamic equations of motion. Each particle carries local values of density, temperature, pressure and other hydrodynamic parameters. A major advantage of SPH is that it is meshless, thus large deformation calculations can be easily done with no connectivity complications. Interface positions are known and there are no problems with advecting quantities through a mesh that typical Eulerian codes have. These underlying SPH features make fracture physics easy and natural and in fact, much of the applications work revolves around simulating fracture. Debris particles from impacts can be easily transported across large voids with SPH. While SPH has considerable promise, there are some problems inherent in the technique that have so far limited its usefulness. The most serious problem is the well known instability in tension leading to particle clumping and numerical fracture. Another problem is that the SPH interpolation is only correct when particles are uniformly spaced a half particle apart leading to incorrect strain rates, accelerations and other quantities for general particle distributions. SPH calculations are also sensitive to particle locations. The standard artificial viscosity treatment in SPH leads to spurious viscosity in shear flows. This paper will demonstrate solutions for these problems that they and others have been developing. The most promising is to replace the SPH interpolant with the moving least squares (MLS) interpolant invented by Lancaster and Salkauskas in 1981. SPH and MLS are closely related with MLS being essentially SPH with corrected particle volumes. When formulated correctly, JLS is conservative, stable in both compression and tension, does not have the SPH boundary problems and is not sensitive to particle placement. The other approach to solving SPH problems, pioneered by Randles and Libersky, is to use a different SPH equation and to renormalize the kernel gradient sums. Finally the authors present results using the SPH statistical fracture model (SPHSFM). It has been applied to a series of ball on plate impacts performed by Grady and Kipp. A description of the model and comparison with the experiments will be given

Autophagy in the Thymic Epithelium Is Dispensable for the Development of Self-Tolerance in a Novel Mouse Model

The thymic epithelium plays critical roles in the positive and negative selection of T cells. Recently, it was proposed that autophagy in thymic epithelial cells is essential for the induction of T cell tolerance to self antigens and thus for the prevention of autoimmune diseases. Here we have tested this hypothesis using mouse models in which autophagy was blocked specifically in epithelial cells expressing keratin 14 (K14), including the precursor of thymic epithelial cells. While the thymic epithelial cells of mice carrying the floxed Atg7 gene (ATG7 f/f) showed a high level of autophagy, as determined by LC3 Western blot analysis and fluorescence detection of the recombinant green fluorescent protein (GFP)-LC3 reporter protein on autophagosomes, autophagy in the thymic epithelium was efficiently suppressed by deletion of the Atg7 gene using the Cre-loxP system (ATG7 f/f K14-Cre). Suppression of autophagy led to the massive accumulation of p62/sequestosome 1 (SQSTM1) in thymic epithelial cells. However, the structure of the thymic epithelium as well as the organization and the size of the thymus were not altered in mutant mice. The ratio of CD4 to CD8-positive T cells, as well as the frequency of activated (CD69+) CD4 T cells in lymphoid organs, did not differ between mice with autophagy-competent and autophagy-deficient thymic epithelium. Inflammatory infiltrating cells, potentially indicative of autoimmune reactions, were present in the liver, lung, and colon of a similar fraction of ATG7 f/f and ATG7 f/f K14-Cre mice. In contrast to previously reported mice, that had received an autophagy-deficient thymus transplant, ATG7 f/f K14-Cre mice did not suffer from autoimmunity-induced weight loss. In summary, the results of this study suggest that autophagy in the thymic epithelium is dispensable for negative selection of autoreactive T cells

Common Traits Spark the Mitophagy/Xenophagy Interplay

Selective autophagy contributes to the wellbeing of eukaryotic cells by recycling cellular components, disposing damaged organelles, and removing pathogens, amongst others. Both the quality control process of selective mitochondrial autophagy (Mitophagy) and the defensive process of intracellular pathogen-engulfment (Xenophagy) are facilitated via protein assemblies which have shared molecules, a prime example being the Tank-Binding Kinase 1 (TBK1). TBK1 plays a central role in the immunity response driven by Xenophagy and was recently shown to be an amplifying mechanism in Mitophagy, bring to attention the potential cross talk between the two processes. Here we draw parallels between Xenophagy and Mitophagy, speculating on the inhibitory mechanisms of specific proteins (e.g., the 18 kDa protein TSPO), how the preferential sequestering toward one of the two pathways may undermine the other, and in this way impair cellular response to pathogens and cellular immunity. We believe that an in depth understanding of the commonalities may present an opportunity to design novel therapeutic strategies targeted at both the autonomous and non-autonomous processes of selective autophagy

Chikungunya virus-induced autophagy delays caspase-dependent cell death

Autophagy is an important survival pathway and can participate in the host response to infection. Studying Chikungunya virus (CHIKV), the causative agent of a major epidemic in India, Southeast Asia, and southern Europe, we reveal a novel mechanism by which autophagy limits cell death and mortality after infection. We use biochemical studies and single cell multispectral assays to demonstrate that direct infection triggers both apoptosis and autophagy. CHIKV-induced autophagy is mediated by the independent induction of endoplasmic reticulum and oxidative stress pathways. These cellular responses delay apoptotic cell death by inducing the IRE1α–XBP-1 pathway in conjunction with ROS-mediated mTOR inhibition. Silencing of autophagy genes resulted in enhanced intrinsic and extrinsic apoptosis, favoring viral propagation in cultured cells. Providing in vivo evidence for the relevance of our findings, Atg16L(HM) mice, which display reduced levels of autophagy, exhibited increased lethality and showed a higher sensitivity to CHIKV-induced apoptosis. Based on kinetic studies and the observation that features of apoptosis and autophagy were mutually exclusive, we conclude that autophagy inhibits caspase-dependent cell death but is ultimately overwhelmed by viral replication. Our study suggests that inducers of autophagy may limit the pathogenesis of acute Chikungunya disease

Dynamics of Membrane Trafficking Downstream of B and T Cell Receptor Engagement: Impact on Immune Synapses

The onset of an adaptive immune response requires the activation of T and B lymphocytes by antigen-presenting cells, through a specialized form of intercellular communication, known as the immunological synapse (IS). In B lymphocytes the IS promotes efficient recognition and acquisition of membrane-bound Ags, while in T cells, it modulates the T cell response upon exposure to peptide-major histocompatibility complexes. In this review, we highlight the similarities that determine B and T cell activation, focusing on immune receptor downstream signaling events that lead to synapse formation. We stress the notion that polarization of T and B lymphocytes characterized by global changes in cytoskeleton and membrane trafficking modulates synapse structure and function, thus determining lymphocyte effector functions and fate