Biology subjects

Aggarwal, P.

Publications and source records attributed to Aggarwal, P..

12 recordsLinked to original sources

bioRxiv2026

Oxygen-sensing regulatory architecture structures mammalian diversification

The HIF oxygen-sensing pathway traces to the last metazoan common ancestor [~]800 million years ago and is conventionally viewed as a conserved cellular stress-response module. Whether this ancestral system has contributed to mammalian diversification at macroevolutionary timescales remains unexplored. We analyzed sequence-encoded TF-gene regulatory architecture for 34 transcription factors and 705 genes in 10 oxygen-sensing pathways across 239 mammalian species. Oxygen-sensing regulatory architecture carries strong clade-structured evolutionary signal. The primary axis of variation tracks a fast-slow life history gradient, marked by rewiring of growth-control and tumor suppressor hub genes. A second axis recovers the monotreme-marsupial-placental transition and aligns with the decline in atmospheric O2 from the Permo-Carboniferous maximum toward present-day levels1. Orthogonal axes encode distinct ecological regulatory strategies; two later axes separately resolve HIF-compatible binding-site architecture and dominant TF-family assignment, identifying regulatory strategies associated with powered flight and hibernation. This multidimensional space also informs Petos paradox, suggesting that relative cancer resistance tracks the combination of tumor-suppressor enrichment and coordinated HIF-complex assignment. Together, these results indicate that regulatory configurations arise at major evolutionary transitions and persist coherently across descendant lineages through a punctuated mode of regulatory evolution, providing genomic-level evidence for Simpsons adaptive zones and a mechanism for evolutionary stasis. These findings reframe oxygen sensing as a regulatory hub in mammalian diversification, with stable patterns of TF-family assignment configurations emerging as a structuring force in macroevolution. BriefAncient molecular processes such as oxygen-sensing, whose HIF-pathway dates to the origin of animals [~]800 million years ago, are typically regarded as conserved across lineages. How such deeply ancestral systems have contributed to mammalian diversification remains largely unexplored. By analyzing the oxygen-sensing regulatory architecture (which transcription factors regulate which genes) across 239 mammalian species, we find that oxygen-sensing regulatory rewiring tracks placental evolution, atmospheric O2, life history evolution, ecological specializations, and cancer resistance. Major radiations occupy discrete, heritable configurations established at key phylogenetic transitions and subsequently retained across descendant lineages through near-neutral within-regime drift, revealing regulatory architecture lock-in as a structuring force in macroevolution.

evolutionary biology↗

bioRxiv2025

Recognition and remodelling of nucleosomes and hexasomes by the human INO80 complex

The ATP-dependent INO80 chromatin remodeller slides and repositions nucleosomes to shape and maintain chromatin around gene regulatory elements and replication origins. Recent work uncovered capabilities of yeast and fungal INO80 to bind and slide hexasomes, but whether this is a universal feature is unknown. Here, we show that also human INO80 slides hexasomes as efficiently as H2A and H2A.Z nucleosomes. By determining a variety of structures of human INO80 bound to canonical and H2A.Z nucleosomes as well as hexasomes, we reveal a predominantly topological sensing of nucleosomal species with at least three positions depending on entry DNA unwrapping. INO80 spin-rotates around the wheel like nucleosomal core particle, with the position determined by the Snf2 ATPase that binds the tangentially protruding entry DNA at various degrees of unwrapping. Acidic patch binding by IES2 can differentiate between different nucleosomal species, is important for nucleosome but not hexasome sliding, and can sense unwrapped exit DNA. These findings provide structural and mechanistic insights into how human INO80 remodels diverse chromatin substrates in a topology driven manner.

biochemistry↗

bioRxiv2025

Whole genome analysis identified a cefotaxime-resistant Empedobacter brevis GBW-1 isolate from ground beef encoding a novel metallo-beta-lactamase variant, blaEBR-6

While investigating foodstuffs for ESBL-producing Aeromonas species on ampicillin dextrin agar with vancomycin and cefotaxime, a multidrug-resistant Empedobacter brevis strain GBW-1 was identified from ground beef. Phylogenetic analysis supports the interconnectedness of environment, humans and food driving this species evolutionary development. Antimicrobial susceptibility testing demonstrated resistance to gentamicin, carbapenems and third-generation cephalosporins. Whole genome sequencing of this strain detected a 3.74 Mb genome with 32.8% GC content containing 3,780 coding genes. Among these genes, at least three known antimicrobial resistance (AMR) genes were identified with qacG, vanT gene within the vanG cluster, and a novel variant of the metallo-{beta}-lactamase blaEBR-6. This novel homologue, EBR-6, was compared against previously known EBR variants and was found to be closest to EBR-3 with an 84.98% amino acid identity match. Docking software predicted these mutations vary the binding to meropenem. Furthermore, nearly 100 annotated regions associated with mobile genetic elements, including the presence of three, separate tra operons were identified on the genome. Together, these findings implicate the importance of horizontal gene transfer in the acquisition of AMR among the emerging pathogen Empedobacter brevis and further stress its One Health nature. ImportanceAs global trade and commerce continues to create a more interconnected world, the increasing frequency and spread of antimicrobial resistance amongst foodborne bacteria poses a significant challenge to public health. Here, we report the isolation of the multi-drug resistant Empedobacter brevis GBW-1, a bacterial strain harboring resistance against meropenem, third-generation cephalosporins, and gentamicin. Of particular note, this strain displays a novel variant of a metallo-{beta}-lactamase (MBL) gene, blaEBR-6, as well as three distinct tra operons, suggesting enhanced capacity of horizontal gene transfer. These findings highlight how foodborne bacteria may serve as reservoirs and vectors for the further spread of resistance genes, reinforcing the necessity of utilizing a collaborative One Health approach to combat AMR across sectors.

microbiology↗

bioRxiv2024

Transcriptional Variabilities in Human hiPSC-derived Cardiomyocytes: All Genes Are Not Equal and Their Robustness May Foretell Donor's Disease Susceptibility

Human induced pluripotent stem cells (hiPSCs) are frequently used to study disease-associated variations. We characterized transcriptional variability from a hiPSC-derived cardiomyocyte (hiPSC-CM) study of left ventricular hypertrophy (LVH) using donor samples from the HyperGEN study. Multiple hiPSC-CM differentiations over reprogramming events (iPSC generation) across 7 donors were used to assess variabilities from reprogramming, differentiation, and donor LVH status. Variability arising from pathological alterations was assessed using a cardiac stimulant applied to the hiPSC-CMs to trigger hypertrophic responses. We found that for most genes (73.3%[~]85.5%), technical variability was smaller than biological variability. Further, we identified and characterized lists of "noise" genes showing greater technical variability and "signal" genes showing greater biological variability. Together, they support a "genetic robustness" hypothesis of disease-modeling whereby cellular response to relevant stimuli in hiPSC-derived somatic cells from diseased donors tends to show more transcriptional variability. Our findings suggest that hiPSC-CMs can provide a valid model for cardiac hypertrophy and distinguish between technical and disease-relevant transcriptional changes.

genetics↗

bioRxiv2024

Biomimetic fractal topography enhances podocyte maturation in vitro

Cells and tissues in their native environment are organized into intricate fractal structures, which are rarely recapitulated in their culture in vitro. The extent to which fractal patterns that resemble complex topography in vivo influence cell maturation, and the cellular responses to such shape stimulation remain inadequately elucidated. Yet, the application of fractal cues (topographical stimulation via self-similar patterns) as an external input may offer a much-needed solution to the challenge of improving the differentiated cell phenotype in vitro. Here, we established fractality in podocytes, branching highly differentiated kidney cells, and glomerulus structure. Biomimetic fractal patterns derived from glomerular histology were used to generate topographical (2.5-D) substrates for cell culture. Podocytes grown on fractal topography were found to express higher levels of functional markers and exhibit enhanced cell polarity. To track morphological complexities of differentiated podocytes, we employed a fluorescent labelling assay where labelled individual cells are tracked within otherwise optically silent confluent cell monolayer to reveal cell-cell interdigitation. RNAseq analysis suggests enhanced ECM deposition and remodeling in podocytes grown on fractal topography compared to flat surface or non-fractal microcurvature, mediated by YAP signaling. The incorporation of fractal topography into standard tissue culture well plates as demonstrated here may serve as a user-friendly bioengineered platform for high-fidelity cell culture.

bioengineering↗

bioRxiv2022

Sex-Specific Role of Myostatin Signaling in Neonatal Muscle Growth, Denervation Atrophy, and Neuromuscular Contractures

Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that result from impaired longitudinal growth of denervated muscles. This deficit in muscle growth is driven by increased proteasome-mediated protein degradation, suggesting a dysregulation of muscle proteostasis. The myostatin (MSTN) pathway, a prominent muscle-specific regulator of proteostasis, is a putative signaling mechanism by which neonatal denervation could impair longitudinal muscle growth, and thus a potential target to prevent NBPI-induced contractures. Through a mouse model of NBPI, our present study revealed that pharmacologic inhibition of MSTN signaling induces hypertrophy, restores longitudinal growth, and prevents contractures in denervated muscles of female but not male mice, despite inducing hypertrophy of normally innervated muscles in both sexes. Additionally, the MSTN-dependent impairment of longitudinal muscle growth after NBPI in female mice is associated with perturbation of 20S proteasome activity, but not through alterations in canonical MSTN signaling pathways. These findings reveal a sex dimorphism in the regulation of neonatal longitudinal muscle growth and contractures, thereby providing insights into contracture pathophysiology, identifying a potential muscle-specific therapeutic target for contracture prevention, and underscoring the importance of sex as a biological variable in the pathophysiology of neuromuscular disorders.

developmental biology↗

bioRxiv2022

SARS-CoV-2 Omicron Variant Wave in India: Advent, Phylogeny and Evolution

SARS-CoV-2 evolution has continued to generate variants, responsible for new pandemic waves locally and globally. Varying disease presentation and severity has been ascribed to inherent variant characteristics and vaccine immunity. This study analyzed genomic data from 305 whole genome sequences from SARS-CoV-2 patients before and through the third wave in India. Delta variant was responsible for disease in patients without comorbidity(97%), while Omicron BA.2 caused disease primarily in those with comorbidity(77%). Tissue adaptation studies brought forth higher propensity of Omicron variants to bronchial tissue than lung, contrary to observation in Delta variants from Delhi. Study of codon usage pattern distinguished the prevalent variants, clustering them separately, Omicron BA.2 isolated in February grouped away from December strains, and all BA.2 after December acquired a new mutation S959P in ORF1b (44.3% of BA.2 in the study) indicating ongoing evolution. Loss of critical spike mutations in Omicron BA.2 and gain of immune evasion mutations including G142D, reported in Delta but absent in BA.1, and S371F instead of S371L in BA.1 could possibly be due to evolutionary trade-off and explain very brief period of BA.1 in December 2021, followed by complete replacement by BA.2.

genomics↗

bioRxiv2022

MAP1LC3C regulates lysosomal exocytosis and induces zinc reprogramming in renal cancer cells

MAP1LC3C (LC3C) is a member of the microtubule associated family of proteins that are essential in the formation of autophagosomes and lysosomal degradation of cargo. LC3C has tumor suppressing activity and its expression is dependent on kidney cancer tumor suppressors, such as VHL and FLCN. Recently we demonstrated that LC3C autophagy is regulated by noncannonical upstream regulatory complexes and targets for degradation postdivision midbody rings associated with cancer cells stemness. Here we show that loss of LC3C leads to peripheral positioning of the lysosomes and lysosomal exocytosis (LE) in a subset of cells. This process is independent of the autophagic activity of LC3C. Analysis of isogenic cells with low and high LE shows substantial transcriptomic reprogramming with altered expression of Zn-related genes and activity of Polycomb Repressor Complex 2 (PRC2), accompanied by a robust decrease in intracellular Zn. Metabolomic analysis revealed alterations in amino acid steady-state levels. Cells with augmented LE show tumor initiation properties and form aggressive tumors in xenograft models. Immunocytochemistry identified high levels of LAMP1 on the plasma membrane of cancer cells in human ccRCC and reduced levels of Zn, an indication that LE is a frequent event in ccRCC, potentially contributing to the loss of Zn. Overall, these data indicate that an important tumor suppressing activity of LC3C is contributing to the reprogramming of lysosomal activity and Zn metabolism with implication for epigenetic remodeling in a subpopulation of tumor propagating properties of cancer cells.

cell biology↗

bioRxiv2022

Genomic landscape of the DHA1 family in the newly emerged pathogen Candida auris and mapping substrate repertoire of the prominent member CauMdr1

The last decade has witnessed the rise of extremely threatening healthcare-associated multidrug resistant non-albicans Candida (NAC) species, Candida auris. Thus, understanding the molecular basis of antifungal resistance has emerged as the single most important goal amongst the research community. Since besides target alterations, efflux mechanisms contribute maximally to antifungal resistance, it is imperative to investigate their contributions in this pathogen. Of note, within the Major Facilitator Superfamily (MFS) of efflux pumps, Drug/H+ antiporter family 1 (DHA1) has been established as a predominant contributor towards xenobiotic efflux. Our study provides a complete landscape of DHA1 transporters encoded in the genome of C. auris. This study identifies 14 DHA1 transporters encoded in the genome of the pathogen. We also construct deletion and heterologous overexpression strains for the most important DHA1 drug transporter, viz., CauMdr1 to map the spectrum of its substrates. While the knockout strain did not show any significant changes in the resistance patterns against the majority of the tested substrates, the ortholog when overexpressed in a minimal background S. cerevisiae strain, AD1-8u-, showed significant enhancement in the Minimum inhibitory concentrations (MICs) against a large panel of antifungal molecules. Altogether, the present study provides a comprehensive template for investigating the role of DHA1 members of C. auris in antifungal resistance mechanisms.

microbiology↗

bioRxiv2021

Robust Brain State Decoding using Bidirectional Long Short Term Memory Networks in functional MRI

Decoding brain states of the underlying cognitive processes via learning discriminative feature representations has recently gained a lot of interest in brain imaging studies. Particularly, there has been an impetus to encode the dynamics of brain functioning by analyzing temporal information available in the fMRI data. Long-short term memory (LSTM), a class of machine learning model possessing a "memory" component, is increasingly being observed to perform well in various applications with dynamic temporal behavior, including brain state decoding. Because of the dynamics and inherent latency in fMRI BOLD responses, future temporal context is crucial. However, it is neither encoded nor captured by the conventional LSTM model. This paper performs robust brain state decoding via information encapsulation from both the past and future instances of fMRI data via bi-directional LSTM. This allows for explicitly modeling the dynamics of BOLD response without any delay adjustment. The two hidden activations of forward and reverse directions in bi-LSTM are collated to build the "memory" of the model and are used to robustly predict the brain states at every time instance. Working memory data from the Human Connectome Project (HCP) is utilized for validation and was observed to perform 18% better than its unidirectional counterpart in terms of accuracy in predicting the brain states.

scientific communication and education↗

bioRxiv2020

Structural analysis of Sub16 sedolisin of Trichophyton rubrum reveals a flexible nature of its pro domain

Trichophyton rubrum is one of the leading causes of superficial skin infections worldwide. It is a keratinolytic fungus specialized in colonization of keratinized tissue of skin, hair and nails for long periods of time. The fungus encodes a wide repertoire of secreted proteases in its genome that not only aid in nutrient acquisition but also establishment of infection on the host. The proteases are synthesized in prepro form that requires removal of the prosegment for activation. In order to gain insights into the structural association of the pro domain with the catalytic domain, we investigate the structural features of the pro domain of the secreted sedolisin member Sub16 of T. rubrum. Our results show that the pro domain of Sub16 may have inherent flexibility in the absence of the associated catalytic domain which is stabilized in complex with catalytic domain. This is the first report of structural investigation on a stand-alone pro domain of sedolisin family of subtilases that will help in design of further structural studies of this protein.

biophysics↗

bioRxiv2017

Dynamic Phase Synchrony based Ranked Spatio-Temporal Clustering for Tracking Time-Resolved Functional Brain Networks

Of late, there has been a growing interest in studying brain networks, particularly, for understanding spontaneous temporal changes in functional brain networks. Recently, phase synchrony based methods have been proposed to track instantaneous time-resolved functional connectivity without any need of windowing the data. This paper extends one such recently used phase synchrony measure in two steps. First, multiple temporal models are built from four-mode tensor that are further clustered to detect dynamic brain network communities. This clustering is based on spatio-temporal data and hence, is named as Spatio-Temporal Clustering (STC). Second, a method is proposed to rank all the communities allowing the proposed model to deal with multiple communities of differing time evolution. This helps in the comparison of network communities, especially, when available communities are too dense to provide relevant information for comparison. The ranking of communities allows for the dimensionality reduction of communities, while still maintaining the key brain networks. Intrinsic time-varying functional connectivity has been investigated for large scale brain networks, including default-mode network (DMN), visual network (VN), cognitive control network (CCN), auditory network (AN), etc. The proposed method provides a new complementary tool to investigate dynamic network states at a high temporal resolution and is tested on resting-state functional MRI data of 26 typically developing controls (TDC) and 35 autism spectrum disorder (ASD) subjects. Simulation results demonstrate that ASD subjects have altered dynamic brain networks compared to TDC.

neuroscience↗