Biology subjects

Horowitz, A.

Publications and source records attributed to Horowitz, A..

3 recordsLinked to original sources

bioRxiv2018

Murine MPDZ-Linked Hydrocephalus is Caused by Hyperpermeability of the Choroid Plexus

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast-medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straight-forward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus.

neuroscience↗

bioRxiv2018

A Framework for Cortical Layer Composition Analysis using Low Resolution T1 MRI Images

The layer composition of the cerebral cortex represents a unique anatomical fingerprint of brain development, function, connectivity and pathology. Historically the cortical layers were investigated solely ex-vivo using histological means, but recent magnetic resonance imaging (MRI) studies suggest that T1 relaxation images can be utilized to separate the layers. Despite technological advancements in the field of high resolution MRI, accurate estimation of whole brain layer composition has remained limited due to partial volume effects, leaving some layers far beyond the image resolution. In this study we offer a simple and accurate method for layer composition analysis, resolving partial volume effects and cortical curvature heterogeneity. We use a low resolution echo planar imaging inversion recovery (EPI IR) MRI scan protocol that provides fast acquisition (~12 minutes) and enables extraction of multiple T1 relaxation time components per voxel, which are assigned to types of brain tissue and utilized to extract the subvoxel composition of each T1 layer. While previous investigation of the layers required the estimation of cortical normals or smoothing of layer widths (similar to VBM), here we developed a sphere-based approach to explore the inner mesoscale architecture of the cortex. Our novel algorithm conducts spatial analysis using volumetric sampling of a system of virtual spheres dispersed throughout the entire cortical space. The methodology offers a robust and powerful framework for quantification and visualization of the layers on the cortical surface, providing a basis for quantitative investigation of their role in cognition, physiology and pathology.

neuroscience↗

bioRxiv2018

Anti-α4β7 therapy targets lymphoid aggregates in the gastrointestinal tract of HIV-1 infected individuals

Herein, we present the first human study of anti-4{beta}7 therapy in a cohort of HIV-1 infected subjects with mild inflammatory bowel disease. 4{beta}7+ gut homing CD4+ T cells are early viral targets and contribute to HIV-1 pathogenesis, likely by seeding the gastrointestinal (GI) tract with HIV. Although, simianized anti-4{beta}7 monoclonal antibodies (Mab) have shown promise in preventing or attenuating the disease course of SIV in Non-Human Primate studies, the mechanisms of drug action remain elusive and the impact on HIV-1 persistence remains unanswered. By sampling the immune inductive and effector sites of the GI tract, we have discovered that anti-4{beta}7 therapy led to a significant and unexpected attenuation of lymphoid aggregates, most notably in the terminal ileum. Given that lymphoid aggregates serve as important sanctuary sites for establishing and maintaining viral reservoirs, their attrition by anti-4{beta}7 therapy has important implications for HIV-1 therapeutics and eradication efforts, and defines a rational basis for the continued evaluation of anti-4{beta}7 therapy in HIV-1 infection.\n\nOne Sentence SummaryAnti-4{beta}7 integrin therapy results in attrition of lymphoid aggregates within the gastrointestinal tract of HIV-1 infected individuals

immunology↗