Biology subjects

Iyer, K.

Publications and source records attributed to Iyer, K..

6 recordsLinked to original sources

bioRxiv2026

SIRPA suppresses integrin-dependent virus endocytosis

New World arenaviruses (NWAs) that cause viral hemorrhagic fever, such as Junin virus, have few therapeutic options. Entry of these viruses into cells is mediated by binding to cell surface receptors, followed by endocytosis and trafficking to a low pH compartment. We showed previously that Signal Regulatory Protein Alpha (SIRPA), a critical cell surface receptor that inhibits macrophage phagocytic activity, decreases internalization by NWAs as well as other pathogenic RNA viruses that traffic to low pH compartments. Here we demonstrate that proteins involved in the SIRPA/integrin signaling axis, including Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), src family kinases (SFKs), particularly FYN, focal adhesion kinase (FAK), and alpha-integrin play a role in viral endocytosis and that SIRPA inhibits virus entry through blocking this pathway. In addition to defining a role for integrins in viral entry, these studies also provide additional insight into SIRPAs interference in processes dependent on integrin signaling, including phagocytosis. Moreover, using drugs that block the integrin signaling pathway in vitro and in vivo, we show that there are additional steps that may be targeted therapeutically for inhibiting infection by RNA viruses that traffic to acidic compartments.

cell biology↗

bioRxiv2023

Modulations of right hemisphere connectivity in young children relates to the perception of spoken words

The early school years shape a young brains capability to comprehend and contextualize words within milliseconds of exposure. Parsing word sounds (phonological interpretation) and word recognition (enabling semantic interpretation) are integral to this process. Yet little is known about the causal mechanisms of cortical activity during these early developmental stages. In this study, we aimed to explore these causal mechanisms via dynamic causal modelling of event-related potentials (ERPs) acquired from 30 typically developing children (ages 6 to 8 years) as they completed a spoken word-picture matching task. Source reconstruction of high-density electroencephalography (128 channels) was used to ascertain differences in whole-brain cortical activity during semantically "congruent" and "incongruent" conditions. Source activations analyzed during the N400 ERP window identified significant regions-of-interest (pFWE<.05) localized primarily in the right hemisphere when contrasting congruent and incongruent word-picture stimuli. Dynamic causal models (DCMs) were tested on source activations in the fusiform gyrus (rFusi), inferior parietal lobule (rIPL), inferior temporal gyrus (rITG) and superior frontal gyrus (rSFG). DCM results indicated that a fully connected bidirectional model with self-(inhibiting) connections over rFusi, rIPL and rSFG provided the highest model evidence, based on exceedance probabilities derived from Bayesian statistical inferences. Connectivity parameters of rITG and rSFG regions from the winning DCM were negatively correlated with behavioural measures of receptive vocabulary and phonological memory (pFDR<.05), such that lower scores on these assessments corresponded with increased connectivity between temporal pole and anterior frontal regions. The findings suggest that children with lower language processing skills required increased recruitment of right hemisphere frontal/temporal areas during task performance.

neuroscience↗

bioRxiv2021

Microbiota links to neural dynamics supporting threat processing

There is growing recognition that the composition of the gut microbiota influences behaviour, including responses to threat. The cognitive-interoceptive appraisal of threat-related stimuli relies on dynamic neural computations between the anterior insular (AIC) and the dorsal anterior cingulate (dACC) cortices. If, to what extent, and how microbial consortia influence the activity of this cortical threat processing circuitry is unclear. We addressed this question by combining a threat processing task, neuroimaging, 16S rRNA profiling, and computational modelling in healthy participants. Results showed interactions between high-level ecological indices with threat-related AIC-dACC neural dynamics. At finer taxonomic resolutions, the abundance of Ruminococcus was differentially linked to connectivity between, and activity within the AIC and dACC during threat updating. Functional inference analysis provides a strong rationale to motivate future investigations of microbiota-derived metabolites in the observed relationship with threat-related brain processes.

neuroscience↗

bioRxiv2020

CRIMSON: An Open-Source Software Framework for Cardiovascular Integrated Modelling and Simulation

In this work, we describe the CRIMSON (CardiovasculaR Integrated Modelling and SimulatiON) software environment. CRIMSON provides a powerful, customizable and user-friendly system for performing three-dimensional and reduced-order computational haemodynamics studies via a pipeline which involves: 1) segmenting vascular structures from medical images; 2) constructing analytic arterial and venous geometric models; 3) performing finite element mesh generation; 4) designing, and 5) applying boundary conditions; 6) running incompressible Navier-Stokes simulations of blood flow with fluid-structure interaction capabilities; and 7) post-processing and visualizing the results, including velocity, pressure and wall shear stress fields. A key aim of CRIMSON is to create a software environment that makes powerful computational haemodynamics tools accessible to a wide audience, including clinicians and students, both within our research laboratories and throughout the community. The overall philosophy is to leverage best-in-class open source standards for medical image processing, parallel flow computation, geometric solid modelling, data assimilation, and mesh generation. It is actively used by researchers in Europe, North and South America, Asia, and Australia. It has been applied to numerous clinical problems; we illustrate applications of CRIMSON to real-world problems using examples ranging from pre-operative surgical planning to medical device design optimization. CRIMSON binaries for Microsoft Windows 10, documentation and example input files are freely available for download from www.crimson.software, and the source code with compilation instructions is available on GitHub https://github.com/carthurs/CRIMSONFlowsolver (CRIMSON Flowsolver) under the GPL v3.0 license, and https://github.com/carthurs/CRIMSONGUI (CRIMSON GUI), under the AGPL v3.0 license. Support is available on the CRIMSON Google Groups forum, located at https://groups.google.com/forum/#!forum/crimson-users.

bioengineering↗

bioRxiv2019

SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity

Fine control of protein stoichiometry at synapses underlies brain function and plasticity. How proteostasis is controlled independently for each type of synaptic protein in a synapse-specific and activity-dependent manner remains unclear. Here we show that SUSD4, a complement-related transmembrane protein, binds the AMPA receptor subunit GLUA2 and controls its activity-dependent degradation. Several proteins with known roles in the regulation of AMPA receptor turnover, in particular ubiquitin ligases of the NEDD4 subfamily, are identified as SUSD4 binding partners. SUSD4 is expressed by many neuronal populations starting at the time of synapse formation. Loss-of-function of Susd4 in the mouse prevents long-term depression at cerebellar synapses, and leads to impairment in motor coordination adaptation and learning. Our findings reveal that activity-dependent synaptic plasticity relies on a transmembrane CCP domain-containing protein that regulates the degradation of specific substrates. This mechanism potentially accounts for the role of SUSD4 mutations in neurodevelopmental diseases.

neuroscience↗

bioRxiv2019

Genome Sequencing Unveils a New Regulatory Landscape of Platelet Reactivity

Exaggerated platelet aggregation at the site of vascular injury is the underlying pathophysiology of thrombotic diseases. Here, we conduct the largest whole genome sequencing (WGS) effort to uncover the genetic determinants of platelet aggregation. Leveraging 3,855 NHLBI Trans-Omics for Precision Medicine (TOPMed) individuals deeply phenotyped for platelet aggregation, we identify 18 loci using single-variant approaches. This includes the novel RGS18 locus encoding a myeloerythroid lineage-specific regulator of G-protein signaling that co-localizes with eQTL signatures for RGS18 expression in platelets. A gene-based approach focusing on deleterious coding variants identifies the SVEP1 gene, previously shown to be associated with coronary artery disease, as a novel determinant of platelet aggregation. Finally, in an integrative approach leveraging epigenetic data on megakaryocytes, we find strong association between rare variants mapping to a super enhancer region for PEAR1. This is a novel finding implicating the importance of rare variants with regulatory potential in a previously documented GWAS-identified locus.

genomics↗