Search bioRxiv⌕ Search

Biology subjects

Silva, A. A.

Publications and source records attributed to Silva, A. A..

3 recordsLinked to original sources

Primate superior colliculus is engaged in abstract higher-order cognition

Categorization is a fundamental cognitive process by which the brain assigns stimuli to behaviorally meaningful groups. Investigations of visual categorization in primates have identified a hierarchy of cortical areas that are involved in the transformation of sensory information into abstract category representations. However, categorization behaviors are ubiquitous across diverse animal species, even those without a neocortex, motivating the possibility that subcortical regions may contribute to abstract cognition in primates. One candidate structure is the superior colliculus (SC), an evolutionarily conserved midbrain region that, although traditionally thought to mediate only reflexive spatial orienting, is involved in cognitive tasks that require spatial orienting. Here, we reveal a novel role of the primate SC in abstract, higher-order visual cognition. We compared neural activity in the SC and the posterior parietal cortex (PPC), a region previously shown to causally contribute to category decisions, while monkeys performed a visual categorization task in which they report their decisions with a hand movement. The SC exhibits stronger and shorter-latency category encoding than the PPC, and inactivation of the SC markedly impairs monkeys category decisions. These results extend SCs established role in spatial orienting to abstract, non-spatial cognition.

neuroscience↗

Genetic deletion and pharmacologic inhibition of FcER1 reduces renal injury in mouse models of diabetic nephropathy.

FcER1 forms a high affinity multimeric cell-surface receptor for the Fc region of immunoglobulin E (IgE) and controls the activation of mast cells and basophils. Antigen binding and cross-linking of FcER1 associated IgE induces several downstream signaling pathways that result in diverse outcomes. Canonical signaling through IgE-FcER1 has been related to allergic responses, however, recent studies have identified that their function in mast cell and basophils contribute to other pathogenic conditions such as cancer and diabetes. Previous studies have demonstrated that FcER1 protein is upregulated in advanced diabetic kidney disease (DKD) making it a targetable molecule for the treatment of DKD. This study presents evidence that loss of FcER1 signaling reduces proteinuria and renal injury in two pre-clinical mouse models of diabetes. Mice deficient for fcer1 are protected from streptozotocin mediated induction of proteinuria and display reduced fibrosis and mast cell infiltration in kidney. Furthermore, inhibition of FcER1 signaling with an antibody directed against the {gamma}-subunit reduces proteinuria in a spontaneous model of type II diabetes. Our results show significant reduction of proteinuria and tissue damage in pre-clinical DKD models demonstrating the potential of FcER1 inhibitory approaches for developing new therapies in DKD.

immunology↗

Utilizing a PTPN22 gene signature to predict response to targeted therapies in rheumatoid arthritis

Despite the development of several targeted therapies for rheumatoid arthritis (RA), there is still no reliable drug-specific predictor to assist rheumatologists in selecting the most effective targeted therapy for each patient. Recently, a gene signature caused by impaired induction of PTPN22 in anti-CD3 stimulated peripheral blood mononuclear cells (PBMC) was observed in healthy at-risk individuals. However, the downstream target genes of PTPN22 and the molecular mechanisms regulating its expression are still poorly understood. Here we report that the PTPN22 gene signature is also present in PBMC from patients with active RA and can be reversed after effective treatment. The expression of PTPN22 correlates with that of more than 1000 genes in Th cells of anti-CD3 stimulated PBMC of healthy donors and is inhibited by TNF or CD28 signals, but not IL-6, through distinct mechanisms. In addition, the impaired induction of PTPN22 in PBMC of patients with active RA can be normalized in vitro by several targeted therapies. More importantly, the in vitro normalization of PTPN22 expression correlates with clinical response to the targeted therapies in a longitudinal RA cohort. Thus, in vitro normalization of PTPN22 expression by targeted therapies can potentially be used to predict clinical response in a drug-specific manner.

immunology↗