Biology subjects

Iyengar, S.

Publications and source records attributed to Iyengar, S..

13 recordsLinked to original sources

bioRxiv2026

Neurons entrain and shape an intrinsic arteriole rhythm that distributes blood across the cortical mantle

The cerebral arteriole network distributes blood across cortex through branches whose diameters oscillate near a frequency fvaso ~ 0.1 Hz. We asked whether the spatiotemporal pattern of these vaso-oscillations reflects neuronal entrainment of an intrinsic vascular oscillation. Three findings support this: First, suppressing endothelial hyperpolarization left resting-state oscillations intact but weakened the vascular response to neural activity, showing that vasomotion originates within the arteriole network rather than following neuronal drive. Second, arterioles amplify sensory drive selectively rather than faithfully: neural activity near 0.1 Hz is resonantly enhanced to form a strong peak in the vascular response. Third, neuronal frequency sets spatial reach, and areas compete: when two neighboring cortical areas are driven simultaneously, the one nearer fvaso captures more vascular territory. Neurons therefore entrain an intrinsic vascular rhythm and stimulation frequency governs how vasomotion distributes blood, shapes functional brain images, and may influence interstitial fluid transport.

neuroscience↗

bioRxiv2026

Maximum entropy model reveals frequent brain state switching in psychotic disorders in a multiversal brain function analysis

To design network-based treatments, it is critical to understand dynamic changes in brain networks over time. We comprehensively examined network structure using regional activation-only, pairwise-coactivation-only, and systems-level maximum entropy models (MEM) applied to the Human Connectome Project-Early Psychosis (HCP-EP) resting fMRI data (patients=109, controls=56). The MEM integrates regional activation levels and pairwise correlation-based functional connectivity (FC), providing the potential for better characterization of clinically meaningful brain states and how they change over time. Using the HCP/Glasser atlas to define brain regions within the default mode (DMN) and dorsal attention (DAN) networks, group differences in regional activation, graph measures of FC, and MEM features such as transition rates between minima in an energy landscape along with correlations with cognitive and psychopathological measures were examined. Psychosis was associated with reduced activation in several regions and multiple FC graph metric alterations. MEM demonstrated a wider variety of DMN and DAN activation/deactivation configurations, with more frequent switching between them, more pronounced network configuration differences and higher basin transition rates with reduced basin dwell times suggesting temporally unstable network configurations, meaning the brain cannot rely on any particular configuration for cognitive processing. Activation of only three regions correlated with working memory, but none of the FC metrics did. MEM features, in particular basin transitions and total energy, correlated negatively with working memory. Our findings suggest that MEM provides unique information, specifically attenuated inter-network connectivity with reduced stability of DMN and DAN brain states, to characterize networks as targets and their features as markers for novel treatment development.

neuroscience↗

bioRxiv2025

SPACE: spatially resolved multiomic analysis for high-throughput CRISPR screening in 3D models

Current spatial CRISPR screening technologies are limited by targeted readouts and high costs, restricting the scope of biological discovery. Here we present SPAtial Cell Exploration (SPACE), a spatial CRISPR screening platform that integrates whole-transcriptome profiling ([~]18,000 genes), multiplexed protein detection ([~]68 markers), and CRISPR perturbation mapping at subcellular resolution. SPACE significantly reduces whole-transcriptome profiling costs compared to sequencing methods while preserving spatial context. We demonstrate SPACE by screening 43 CRISPR knockouts (KOs) across [~]100,000 cells in hundreds of cancer-associated fibroblast (CAF)-tumor spheroids, obtaining whole-transcriptome and multiplexed protein readout from the same exact cells. SPACE revealed previously unknown regulatory mechanisms on tumor extracellular matrix (ECM) remodeling, and identified spatially-resolved ligand-receptor interactions and perturbation-specific spatial gene signatures that are not detectable with dissociation-based methods. This scalable, cost-effective platform provides a transformative framework for high-throughput spatial perturbation studies in complex tissue models.

cell biology↗

bioRxiv2025

What's next for Indian Ornithology? 101 key research questions

India has a rich history of ornithology, and bird research in this field has expanded considerably in recent decades, spurred by a growing number of birdwatchers and ornithologists. Despite this progress, critical gaps remain. This paper highlights key areas where further research is needed and identifies pressing questions that will shape Indian ornithology in the coming years. Drawing from diverse inputs, we present a curated list of 101 research questions spanning across the various disciplines in ornithology - Natural History, Physiology and Disease Ecology, Behaviour, Population and Community Ecology, Habitat Ecology, Macroecology and Biogeography, Population Genetics and Evolution, Applied/Economic Ornithology and Conservation. The list was compiled through a multi-stage process, starting with a public open call for questions, followed by review and curation by a smaller panel of subject specialists. Each question was independently scored by a panel of experts based on three criteria: generality, novelty, and relevance. To account for variation in scoring styles, scores were normalised using Z-scores. The top 101 research questions were then selected based on these standardised scores. Each question is accompanied by an annotation that describes the significance of the question, and highlights opportunities to address it. While our list of research questions highlights significant research priorities, it is not intended to be exhaustive. Rather, it reflects the perspectives of those involved in its curation, who deemed these questions particularly relevant and impactful towards advancing Indian ornithology. We expect these questions to spark new project ideas among students, researchers, and citizen scientists, while guiding funders, managers, and policymakers toward priority research areas.

ecology↗

bioRxiv2024

Opioid Modulation of Differential Gene Expression and Neuronal Differentiation in the Ventricular-Subventricular Zone of Adult Male Zebra Finches

1The endogenous opioid system modulates diverse functions including pain, physiological functions and motivation. We had earlier demonstrated an increase in cell proliferation in the neurogenic niche of adult male zebra finches, following administration of the general opioid antagonist, naloxone. Since the mechanisms underlying opioid modulation of neurogenesis are poorly understood, we have investigated the molecular mechanisms underlying cell proliferation differentiation induced by the opioid system. Systemic naloxone or vehicle administration in adult male birds was followed by a whole transcriptome microarray assay of the ventricular-subventricular zone (V-SVZ). The analysis revealed 26 differentially expressed transcripts (expression fold change [≥] 1.5), encoding genes important for neuronal functions. The transcriptomics analysis using microarray identified a significant increase in the expression of precursor miRNA tgu-mir-124-201 transcript following inhibition of opioid receptors by naloxone. Our results suggested that the administration of naloxone triggers an increase in the expression of the pro-differentiating microRNA, miR-124, in the brains of adult zebra finches. Using quantitative real-time PCR, we found that the expression of miR-124-3p was higher in the V-SVZ of naloxone-treated versus control birds. Furthermore, the density of neuroblasts was higher in the ventral V-SVZ adjacent to the striatal nucleus Area X, but not in the V-SVZ above the pallial nucleus, HVC, both of which are involved in singing. Since miR-124 targets signalling pathways important for neuronal proliferation and differentiation, our findings suggest that microRNA-124 may be involved in the increase in neurogenesis in adult songbirds induced by altering opioid modulation.

neuroscience↗

bioRxiv2023

Changes in the Dopaminergic circuitry and Adult Neurogenesis linked to Reinforcement Learning in Corvids

The caudolateral nidopallium (NCL, an analogue of the prefrontal cortex) is known to be involved in learning, memory, and discrimination in crows, whereas the involvement of other brain regions in these phenomena are unknown. However, recent studies on pigeons have demonstrated that besides NCL, basal ganglia-thalamocortical loops connected to this region play are also crucial for learning. The present study demonstrates that besides NCL, other parts of the caudal nidopallium (NC), avian basal ganglia, and intriguingly, vocal control regions in house crows (Corvus splendens), are involved in visual discrimination. We have also found that training on the visual discrimination task can be correlated to neurite pruning in mature dopaminoceptive neurons and immature doublecortin-positive neurons in the NC of house crows. Furthermore, there is an increase in the incorporation of new neurons throughout NC and the medial striatum which can also be linked to learning. For the first time, our results demonstrate that a combination of structural changes in mature and immature neurons and adult neurogenesis are linked to learning in corvids.

neuroscience↗

bioRxiv2023

NULISA: a novel proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing

The blood proteome holds great promise for precision medicine but poses substantial challenges due to the low abundance of most plasma proteins and the vast dynamic range across the proteome. We report a novel proteomic technology - NUcleic acid Linked Immuno-Sandwich Assay (NULISA) - that incorporates a dual capture and release mechanism to suppress the assay background and improves the sensitivity of the proximity ligation assay by over 10,000-fold to the attomolar level. It utilizes pairs of antibodies conjugated to DNA oligonucleotides that enable immunocomplex purification and generate reporter DNA containing target- and sample-specific barcodes for a next-generation sequencing-based, highly multiplexed readout. A 200-plex NULISA targeting 124 cytokines and chemokines and 80 other immune response-related proteins demonstrated superior sensitivity for detecting low-abundance proteins and high concordance with other immunoassays. The ultrahigh sensitivity allowed the detection of previously difficult-to-detect, but biologically important, low-abundance biomarkers in patients with autoimmune diseases and COVID-19. Fully automated NULISA addresses longstanding challenges in proteomic analysis of liquid biopsies and makes broad and in-depth proteomic analysis accessible to the general research community and future diagnostic applications.

genomics↗

bioRxiv2022

Stem cell heterogeneity and reiteration of developmental signaling underlie melanocyte regeneration in zebrafish

Tissue-resident stem cells are present in many adult organs, where they are important for organ homeostasis and repair in response to injury. However, the signals that activate these cells and the mechanisms governing how these cells self-renew or differentiate are highly context-dependent and incompletely understood, particularly in non-hematopoietic tissues. In the skin, melanocyte stem cells (McSCs) are responsible for replenishing mature pigmented melanocytes. In mammals, these cells reside in the hair follicle bulge and bulb niches where they are activated during homeostatic hair follicle turnover and following melanocyte destruction, as occurs in vitiligo and other skin hypopigmentation disorders. Recently, we identified adult McSCs in the zebrafish. To elucidate mechanisms governing McSC self-renewal and differentiation we analyzed individual transcriptomes from thousands of melanocyte lineage cells during the regeneration process. We identified transcriptional signatures for McSCs, deciphered transcriptional changes and intermediate cell states during regeneration, and analyzed cell-cell signaling changes to discover mechanisms governing melanocyte regeneration. We identified KIT signaling via the RAS/MAPK pathway as a regulator of McSC direct differentiation. Analysis of the scRNAseq dataset also revealed a population of mitfa/aox5 co-expressing cells that divides following melanocyte destruction, likely corresponding to cells that undergo self-renewal. Our findings show how activation of different subpopulations of mitfa-positive cells underlies self-renewal and differentiation to properly reconstitute the melanocyte pigmentary system following injury.

cell biology↗

bioRxiv2021

Evaluating Network Threshold Selection for Structural and Functional Brain Connectomes

IntroductionStructural and functional brain connectomes built using macroscale data collected through magnetic resonance imaging (MRI) may contain noise that contributes to false-positive edges, which can obscure structure-function relationships with implications for data interpretation. Thresholding procedures are routinely applied in practice to optimize network density by removing low-signal edges, but there is limited consensus regarding the appropriate selection of thresholds. We compare existing methods and propose a novel alternative objective function thresholding (OFT) method. MethodsThe performance of thresholding approaches, including a percolation-based approach and an objective function-based approach, is assessed by (a) computing the normalized mutual information (NMI) of community structure between a known network and a simulated, perturbed networks to which various forms of thresholding have been applied, and (b) comparing the density and the clustering coefficient (CC) between the baseline and thresholded networks. ResultsIn our analysis, the proposed objective function-based threshold exhibits the best performance in terms of high similarity between the underlying networks and their perturbed, thresholded counterparts, as quantified by NMI and CC analysis on the simulated functional networks. DiscussionExisting network thresholding methods yield widely different results when graph metrics are computed. Thresholding based on the objective function appears to maintain a set of edges such that the resulting network shares the community structure and clustering features present in the original network. This outcome provides proof-of-principle evidence that thresholding based on the objective function could offer a useful approach to reducing the network density of functional connectivity data. Impact StatementNetwork thresholding refers to removing edges between node pairs in a functional network that have weak edge-weights that may arise from unwanted variability or noise. Since edge-weight cutoffs used to generate a binary network can be sensitive to thresholding, we introduce a novel thresholding algorithm. We find that when applied to networks derived via perturbations, namely through simulated functional connectivity of a known network, this approach yields a binary network that is more similar to the known network compared to using existing thresholding approaches. Thus, our algorithm is a competitive candidate for use in thresholding of brain connectome.

neuroscience↗

bioRxiv2021

Design, synthesis, and characterization of mG2P026 as a high contrast PET imaging ligand for metabotropic glutamate receptor 2

An array of triazolopyridines based on JNJ-46356479 (6) were synthesized as potential PET imaging ligands for metabotropic glutamate receptor 2 (mGluR2) in the brain. The selected candidates 8-11 featured an enhanced positive allosteric modulator (PAM) activity (37-fold max.) and an apparent mGluR2 agonist activity (25-fold max.) compared to compound 6. Radiolabeling of compounds 8 and 9 (also named mG2P026) was achieved via the Cu(I)-mediated radiofluorination in the automated TRACERLabTM FXF-N platform. Both [18F]8 and [18F]9 were obtained with satisfactory radiochemical yields (> 5%, non-decay corrected), high molar activity (> 180 GBq/mol), and excellent chemical and radiochemical purities (> 98%). Preliminary characterization of [18F]8 and [18F]9 in rats confirmed their excellent brain permeability with [18F]9 showing better brain heterogeneity and favorable binding kinetics. Pretreatment with different classes of PAMs enhanced the radioactivity uptake for both [18F]8 and [18F]9 at the regions of interest by 20.3-40.9% and 16.7-81.6%, respectively, due to their pharmacological effects. Further evaluation of [18F]9 in a nonhuman primate confirmed its superior brain heterogeneity in mapping mGlu2 receptors and its higher specific binding than [18F]6. Pretreatment with 0.5 mg/kg BINA led (2) to an enhanced brain uptake of [18F]9 by 3% in high tracer uptake regions that was consistent with the rat studies. Therefore, [18F]9 has the potential to be translated for human studies.

neuroscience↗

bioRxiv2021

Synthesis and characterization of 5-(2-fluoro-4-pyridine-7-carboxamide as a PET imaging ligand for metabotropic glutamate receptor 2

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for the treatment of several neuropsychiatric disorders and conditions. The role of mGluR2 function in etiology could be unveiled by in vivo imaging using positron emission tomography (PET). In this regard, 5-(2- fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7- carboxamide ([11C]13), a potent negative allosteric modulator (NAM), was developed to support this endeavor. Radioligand [11C]13 was synthesized via the O-[11C]methylation of phenol 24 with a high molar activity of 212 {+/-} 76 GBq/{micro}mol (n = 5) and excellent radiochemical purity (> 99%). PET imaging of [11C]13 in rats demonstrated its superior brain heterogeneity, particularly in the regions of striatum, thalamus, hippocampus, and cortex. Accumulation of [11C]13 in these regions of interest (ROIs) was reduced with pretreatment of mGluR2 NAMs, VU6001966 (9) and MNI-137 (26), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [11C]13 selectively accumulated in mGluR2-rich regions, especially in different cortical areas, putamen, thalamus, and hippocampus, and resulted in high-contrast brain images. The regional total volume of distribution (VT) estimates of [11C]13 decreased by 14% after the pretreatment with 9. Therefore, [11C]13 is a potential candidate for translational PET imaging studies of mGluR2 function.

neuroscience↗

bioRxiv2021

Ancestral diversity improves discovery and fine-mapping of genetic loci for anthropometric traits - the Hispanic/Latino Anthropometry Consortium

Hispanic/Latinos have been underrepresented in genome-wide association studies (GWAS) for anthropometric traits despite notable anthropometric variability with ancestry proportions, and a high burden of growth stunting and overweight/obesity in Hispanic/Latino populations. This address this knowledge gap, we analyzed densely-imputed genetic data in a sample of Hispanic/Latino adults, to identify and fine-map common genetic variants associated with body mass index (BMI), height, and BMI-adjusted waist-to-hip ratio (WHRadjBMI). We conducted a GWAS of 18 studies/consortia as part of the Hispanic/Latino Anthropometry (HISLA) Consortium (Stage 1, n=59,769) and validated our findings in 9 additional studies (HISLA Stage 2, n=9,336). We conducted a trans-ethnic GWAS with summary statistics from HISLA Stage 1 and existing consortia of European and African ancestries. In our HISLA Stage 1+2 analyses, we discovered one novel BMI locus, as well two novel BMI signals and another novel height signal, each within established anthropometric loci. In our trans-ethnic meta- analysis, we identified three additional novel BMI loci, one novel height locus, and one novel WHRadjBMI locus. We also identified three secondary signals for BMI, 28 for height, and two for WHRadjBMI. We replicated >60 established anthropometric loci in Hispanic/Latino populations at genome-wide significance--representing up to 30% of previously-reported index SNP anthropometric associations. Trans-ethnic meta-analysis of the three ancestries showed a small-to-moderate impact of uncorrected population stratification on the resulting effect size estimates. Our novel findings demonstrate that future studies may also benefit from leveraging differences in linkage disequilibrium patterns to discover novel loci and additional signals with less residual population stratification.

genetics↗

bioRxiv2020

Cell size homeostasis is maintained by a circuitry involving a CDK4-determined target size that programs the cell size-dependent activation of p38

While molecules that promote the growth of animal cells have been identified, the following question remains: How are growth promoting pathways regulated to specify a characteristic size for each of the different cell types? In 1975, Hartwell and Nurse suggested that in eukaryotes, cell size is determined by size checkpoints - mechanisms that restrict cell cycle progression from cells that are smaller than their target size. Curiously, such checkpoint mechanisms imply a conceptual distinction between a cells actual size and cells target size. In the present study, we materialize this conceptual distinction by describing experimental assays that discriminately quantify a cells target size value. With these assays, we show that a cells size and target size are distinct phenotypes that are subject to different upstream regulators. While mTORC1 promotes growth in cell size, our data suggests that a cells target size value is regulated by other pathways including FGFR3, ROCK2, and CDK4. For example, while rapamycin (an mTORC1 inhibitor) decreases cell size, rapamycin does not change the target size that is required for the G1/S transition. The CDK4/Rb pathway has been previously proposed as a putative regulator of target size. Yet, in lacking experimental means that discriminate perturbations of cell growth from perturbations that reprogram target size, such claims on target size were not validated. To investigate the functions of CDK4 in target size determination, we used genetic and chemical means to dial higher and lower levels of CDK4 activity. These measurements identified functions of CDK4 on target size that are distinct from other G1 CDKs. Using C. elegans, we further demonstrate that these influences of CDK4 on size determination function in vivo. Finally, we propose a model whereby mTORC1, p38, and CDK4 cooperate in a manner that is analogous to the function of a thermostat. While mTORC1 promotes cellular growth as prompted by p38, CDK4 is analogous to the thermostat dial that sets the critical target size associated with cell size homeostasis.

cell biology↗