Biology subjects

Babu, A.

Publications and source records attributed to Babu, A..

18 recordsLinked to original sources

bioRxiv2026

Social ties are maintained through sensory adaptations in green chromides

Sensory systems exhibit considerable plasticity in response to environmental changes, yet the functional implications of such plasticity remain poorly understood, particularly regarding how changes in visual gene expression influence social behaviour. To address this gap, we investigated how visual sensory plasticity relates to conspecific preferences in green chromides (Etroplus suratensis), an Indian cichlid that relies on vision for social preferences towards conspecifics. We first characterized retinal opsin and chromophore-related genes through transcriptomic analysis and subsequently examined behavioural and molecular responses under sequential white- and blue-light environments. We quantified visually mediated conspecific preferences, and the expression of rod and cone opsins and the chromophore-related gene Cyp27c1 at regular intervals. Green chromides retained stable conspecific preferences despite contrasting light environments. Opsins exhibited plasticity, with long wavelength-sensitive opsin (LWS) increasing under blue light, whereas short wavelength-sensitive opsins remained unchanged. Additionally, Cyp27c1 expression declined under blue light, suggesting a potential shift towards increased A1 chromophore utilization. Together, these findings suggest that green chromides undergo multiple molecular modifications under contrasting light environments, whereas maintaining stable social behaviours, demonstrating the cross-talk between the two is not straightforward. Overall, these results highlight that unraveling the underlying proximate mechanisms of behavior is highly intricate, involving multiple pathways, starting from perception (at the retinal level) to post-processing of the stimulus.

ecology↗

bioRxiv2026

Amino acid repeat mosaics shape protein functional landscape

How combinations of functional units such as repeats and motifs within disordered regions influence protein functions remains poorly understood. Here, we investigate how co-occurring amino acid homorepeats of different types within the same protein (HR-mosaics) shape molecular outcomes. Using a novel evolutionary co-occurrence metric, human HR-mosaics were classified as segregated (each HR independently influences distinct outcomes), concerted-disjunct (both HRs jointly shape protein functionality without modulating each other), or concerted-conjunct (both HRs affect functionality through mutual influence). Molecular studies of naturally occurring polyGly-polyPro mosaic in DDX17 and chimeric mosaics of polyAla and polyHis demonstrate that HR-mosaics influence protein abundance, localisation, mobility and interaction landscape. Segregated HR-mosaics expand functional space, concerted-disjunct additionally confer biological context, and concerted-conjunct mosaics further enable rheostatic regulation between HRs. These design principles underscore amino acid type, length and relative positioning of HRs as central architects of HR-mosaic functionality, with implications in protein design and engineering and understanding repeat-associated pathologies.

Systems Biology↗

bioRxiv2026

Monitoring Autonomic Tone During Spinal Cord Neuromodulation Using Wearble AURIS Sensor

The transition of bioelectronic medicine to clinical use is currently limited by a lack of non-invasive sensors capable of measuring autonomic tone during active neuromodulation. Conventional monitoring modalities, such as mean arterial pressure (MAP) and Ag/AgCl chest electrodes, are often invasive, cumbersome, or susceptible to motion artifacts. Here, we present a novel framework employing an in-ear sensor (AURIS) to continuously monitor heart rate variability (HRV) during therapeutic neuromodulation. These sensors utilize a polydimethylsiloxane (PDMS) substrate to ensure biocompatibility and superior conformability. Experiments in a rodent model (n = 3) demonstrate that the AURIS platform achieves gold-standard fidelity, with mean heart rate differences of 6.03 BPM and mean RR interval deltas of 3.18 ms compared to chest electrodes. Sensor agreement was statistically validated using independent t-tests, showing no significant difference between modalities (all p > 0.46). While time-domain shifts trended toward significance, complexity metrics showed robust sequential responses with large effect sizes, including the SD1/SD2 ratio (d = 1.474) and the DFA ratio (d = 1.091). These findings validate a sensor architecture that is durable, accessible, and provides the necessary technical foundation for closed-loop feedback and non-invasive clinical trials.

bioengineering↗

bioRxiv2024

Aberrant Transitional Alveolar Epithelial Cells Promote Pathogenic Activation of Lung Fibroblasts in Preclinical Fibrosis Modeling

Pulmonary fibrosis (PF) is a chronic progressive lung disease histopathologically characterized by fibrotic remodeling and the presence of pathological epithelial and mesenchymal cell populations in the distal lung parenchyma. Within the epithelial compartment, a subset of alveolar type 2 cells (AT2s) enter and persist in an aberrant transitional state. Whether and how these aberrant transitional cells participate in lung fibrosis is not known. To address this, we exploited the SftpcC121G mouse model, where we previously demonstrated that chronic expression of a PF-associated point mutation (C121G) in the AT2-specific surfactant protein C (Sftpc) gene results in spontaneous and progressive fibrosis driven by intrinsic AT2 dysfunction. We utilized single cell RNA sequencing to demonstrate the emergence of pathologic epithelial and mesenchymal cells in the SftpcC121G murine lung fibrosis model, including aberrant transitional alveolar epithelial cells as well as transitional and fibrotic fibroblasts. Aberrant transitional alveolar epithelial cells share similar transcriptional profiles to human aberrant basaloid cells, including the upregulation of profibrotic gene markers (Fn1, Ctgf, Tgfb2, Pdgfb, Spp1), and develop a unique interactome with pathogenic lung fibroblasts. We developed a method to reliably flow sort aberrant transitional alveolar epithelial cells, and we highlight their ability to cause fibrotic activation of fibroblasts in ex vivo organoid assays and using conditioned supernatant, suggesting a profibrotic secretome. We conclude that aberrant transitional alveolar epithelial cells actively contribute to fibrotic lung remodeling through pathogenic activation of alveolar fibroblasts.

cell biology↗

bioRxiv2024

A longitudinal atlas of post-viral lung regeneration reveals persistent injury-associated cell states

Functional regeneration of the lungs gas exchange surface following injury requires the coordination of a complex series of cell behaviors within the alveolar niche. Using a multi-modal approach, we have mapped the temporal sequencing of mouse lung regeneration after acute viral injury, demonstrating that this response is asynchronously phased across different cellular compartments. This longitudinal atlas of regeneration has produced a catalogue of new cell states that reflect transient and persistent transcriptional alterations in daughter cells as they transit across axes of differentiation. These new cell states include an injury-induced capillary endothelial cell (iCAP) that arises after injury, persists indefinitely, and shares transcriptional hallmarks with both developing lung endothelium and the endothelial aberrations found in degenerative human lung diseases. This comprehensive atlas of lung regeneration provides a foundational resource to understand the complexity of the cellular and molecular responses to injury, reveals the critical importance of capillary endothelium in maintaining and rebuilding the alveolar niche after injury, and correlates these responses to those found in development and human lung diseases.

cell biology↗

bioRxiv2024

Impaired AMPK Control of Alveolar Epithelial Cell Metabolism Promotes Pulmonary Fibrosis

Alveolar epithelial type II (AT2) cell dysfunction is implicated in the pathogenesis of familial and sporadic idiopathic pulmonary fibrosis (IPF). We previously described that expression of an AT2 cell exclusive disease-associated protein isoform (SP-CI73T) in murine and patient-specific induced pluripotent stem cell (iPSC)-derived AT2 cells leads to a block in late macroautophagy and promotes time-dependent mitochondrial impairments; however, how a metabolically dysfunctional AT2 cell results in fibrosis remains elusive. Here using murine and human iPSC-derived AT2 cell models expressing SP-CI73T, we characterize the molecular mechanisms governing alterations in AT2 cell metabolism that lead to increased glycolysis, decreased mitochondrial biogenesis, disrupted fatty acid oxidation, accumulation of impaired mitochondria, and diminished AT2 cell progenitor capacity manifesting as reduced AT2 self-renewal and accumulation of transitional epithelial cells. We identify deficient AMP-kinase signaling as a key upstream signaling hub driving disease in these dysfunctional AT2 cells and augment this pathway to restore alveolar epithelial metabolic function, thus successfully alleviating lung fibrosis in vivo.

molecular biology↗

bioRxiv2023

Disruption of Prostaglandin F2α Receptor Signaling Attenuates Fibrotic Remodeling and Alters Fibroblast Population Dynamics in A Preclinical Murine Model of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2, and its cognate receptor FPr (Ptfgr) are implicated as a TGF{beta}1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (IER -SftpcI73T) expressing a disease-associated missense mutation in the surfactant protein C (Sftpc) gene. Tamoxifen treated IER -Sftpc I73T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. IER -Sftpc I73T mice crossed to a Ptgfr null (FPr-/-) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr+/+ cohorts. IER -Sftpc I73T /FPr-/- mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2/ FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2 signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

molecular biology↗

bioRxiv2023

A Resource of Gene Expression Data from a Multiethnic Population Cohort of Induced Pluripotent Cell-Derived Cardiomyocytes

Induced pluripotent stem cells (iPSCs), upon differentiation into somatic cell types, offer the ability to model the genetic states of tissues in the individuals from whom the iPSCs were derived.1 A prior study used a multiethnic cohort of healthy individuals to derive iPSCs and iPSC-hepatocytes and perform gene expression and expression quantitative trait locus (eQTL) analyses, identifying causal genes and variants linked to blood lipid levels.2 We sought to use this cohort of iPSC lines to generate a similar resource with iPSC-cardiomyocytes (iPSC-CMs) and make the results available to the community.

genomics↗

bioRxiv2023

TGFβ controls alveolar type 1 epithelial cell plasticity and alveolar matrisome gene transcription

Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease increasing in incidence which disrupts lung health throughout the lifespan. The TGF{beta} superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that Tgfbr2 is critical for AT1 cell fate maintenance and function. Loss of Tgfbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analysis reveal the necessity of Tgfbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF{beta} signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF{beta} signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome.

cell biology↗

bioRxiv2023

Generation of human alveolar epithelial type I cells from pluripotent stem cells

In the distal lung, alveolar epithelial type I cells (AT1s) comprise the vast majority of alveolar surface area and are uniquely flattened to allow the diffusion of oxygen into the capillaries. This structure along with a quiescent, terminally differentiated phenotype has made AT1s particularly challenging to isolate or maintain in cell culture. As a result, there is a lack of established models for the study of human AT1 biology, and in contrast to alveolar epithelial type II cells (AT2s), little is known about the mechanisms regulating their differentiation. Here we engineer a human in vitro AT1 model system through the directed differentiation of induced pluripotent stem cells (iPSC). We first define the global transcriptomes of primary adult human AT1s, suggesting gene-set benchmarks and pathways, such as Hippo-LATS-YAP/TAZ signaling, that are enriched in these cells. Next, we generate iPSC-derived AT2s (iAT2s) and find that activating nuclear YAP signaling is sufficient to promote a broad transcriptomic shift from AT2 to AT1 gene programs. The resulting cells express a molecular, morphologic, and functional phenotype reminiscent of human AT1 cells, including the capacity to form a flat epithelial barrier which produces characteristic extracellular matrix molecules and secreted ligands. Our results indicate a role for Hippo-LATS-YAP signaling in the differentiation of human AT1s and demonstrate the generation of viable AT1-like cells from iAT2s, providing an in vitro model of human alveolar epithelial differentiation and a potential source of human AT1s that until now have been challenging to viably obtain from patients.

cell biology↗

bioRxiv2022

Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration

Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange with the external environment. Little is known about the transcriptional and signaling factors that drive pulmonary endothelial cell (EC) proliferation and subsequent regeneration of pulmonary capillaries, as well as their response to stress. Here, we show that the transcription factor Atf3 is essential for the regenerative response of the mouse pulmonary endothelium after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in endothelial development, differentiation, and migration. During lung alveolar regeneration, this EC population expands and increases expression of genes involved in angiogenesis, blood vessel development, and cellular response to stress. Importantly, endothelial cell-specific loss of Atf3 results in defective alveolar regeneration, in part through increased apoptosis and decreased proliferation in the endothelium. This leads to the general loss of alveolar endothelium and persistent morphological changes to the alveolar niche, including an emphysema-like phenotype with enlarged alveolar airspaces lined with regions that lack vascular investment. Taken together, these data implicate Atf3 as an essential component of the vascular response to acute lung injury that is required for successful lung alveolar regeneration.

cell biology↗

bioRxiv2022

Temporal and spatial staging of lung alveolar regeneration is determined by the grainyhead transcription factor Tfcp2l1

Alveolar epithelial type 2 (AT2) cells harbor the facultative progenitor capacity in the lung alveolus to drive regeneration after lung injury. Using single cell transcriptomics, software-guided segmentation of tissue damage, and in vivo lineage tracing, we have identified the grainyhead transcription factor Tfcp2l1 as a key regulator of this regenerative process. Tfcp2l1 expression is initiated late in lung development and restricted to the AT2 cell population in the postnatal lung. Loss of Tfcp2l1 in adult AT2 cells decreased self-renewal and enhanced AT2-AT1 differentiation during active tissue regeneration. Conversely, Tfcp2l1 blunts the proliferative response to inflammatory signaling during the early acute phase after injury. This ability of Tfcp2l1 to temporally regulate the balance of AT2 self-renewal and differentiation is spatially restricted to zones undergoing active alveolar regeneration. Single-cell transcriptomics and lineage tracing reveal that Tfcp2l1 regulates cell fate dynamics by balancing the traffic across the AT2-AT1 differentiation axis and restricting the inflammatory program in AT2 cells. Organoid modeling shows that these cell fate dynamics are controlled by Tfcp2l1 regulation of IL-1 receptor expression and activity in AT2 cells. Together, these studies reveal the critical importance of properly staging lung alveolar regeneration and the integral role of Tfcp2l1 plays in balancing epithelial cell self-renewal and differentiation in this process.

cell biology↗

bioRxiv2022

Guided construction of single cell reference for human and mouse lung

Accurate cell type identification is a key and rate-limiting step in single cell data analysis. Single cell references with comprehensive cell types, reproducible and functional validated cell identities, and common nomenclatures are much needed by the research community to optimize automated cell type annotation and facilitate data integration, sharing, and collaboration. In the present study, we developed a novel computational pipeline to utilize the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples and constructed "LungMAP CellRef" and "LungMAP CellRef Seed" for both normal human and mouse lungs. "CellRef Seed" has an equivalent prediction power and produces consistent cell annotation as does "CellRef" but improves computational efficiency and simplifies its utilization for fast automated cell type annotation and online visualization. This atlas set incorporates 48 human and 40 mouse well-defined lung cell types catalogued from diverse anatomic locations and developmental time points. Using independent datasets, we demonstrated the utility of our CellRefs for automated cell type annotation analysis of both normal and disease lungs. User-friendly web interfaces were developed to support easy access and maximal utilization of the LungMAP CellRefs. LungMAP CellRefs are freely available to the pulmonary research community through fast interactive web interfaces to facilitate hypothesis generation, research discovery, and identification of cell type alterations in disease conditions.

bioinformatics↗

bioRxiv2022

ALS sensitive spinal motor neurons enter a degenerative downward spiral of impaired splicing and proteostasis

Despite clear therapeutic potential, the mechanisms that confer differential neuronal sensitivity are not well understood. During Amyotrophic Lateral Sclerosis (ALS), sensitive spinal motor neurons (SpMN) die while a subset of rostral cranial motor neurons (CrMN) survive. In this work, we optimized a protocol to differentiate CrMNs and SpMNs from human induced pluripotent stem cells (iPSCs) by direct programming and positional patterning. Human iCrMNs are more resistant than iSpMNs to proteotoxic stress and rely on the proteasome to maintain proteostasis. iCrMNs better prevent mislocalization of TDP43 from the nucleus, a hallmark of ALS progression. iSpMNs contain more splicing defects than iCrMNs in response to ALS-related stress with genes involved in splicing and proteostasis maintenance. Therefore, iCrMNs resist ALS at two levels, preventing protein accumulation and reducing splicing defects in response to TDP43 nuclear depletion. Thus, ALS-sensitive iSpMNs appear to enter a downward spiral compromising their ability to maintain proteostasis and splicing.

neuroscience↗

bioRxiv2022

Vascular mimicry by VE-cadherin enables trophoblast endovascular invasion and spiral artery remodeling during placental development

During formation of the mammalian placenta trophoblasts invade the maternal decidua and remodel spiral arteries to bring maternal blood into the placenta. This process, known as endovascular invasion, is thought to involve the adoption of functional characteristics of vascular endothelial cells (ECs) by trophoblasts through a process termed vascular mimicry. The genetic and molecular basis of vascular mimicry remains poorly defined, however, and whether trophoblasts utilize specialized endothelial proteins in an analogous manner to create vascular channels remains untested. Vascular endothelial (VE-)cadherin is a homotypic adhesion protein that is expressed selectively by ECs in which it enables formation of tight vessels and regulation of EC junctions. VE-cadherin is also expressed in invasive trophoblasts and is a prime candidate for a molecular mechanism of vascular mimicry by those cells. Here, we show that the VE-cadherin is required for trophoblast migration and endovascular invasion into the maternal decidua in the mouse. VE-cadherin deficiency results in loss of spiral artery remodeling that leads to decreased flow of maternal blood into the placenta, fetal growth restriction, and death. These studies identify a non-endothelial role for VE-cadherin in trophoblasts during placental development and suggest that endothelial proteins may play functionally unique roles in trophoblasts that do not simply mimic those in ECs.

developmental biology↗

bioRxiv2021

Circadian regulation of lung repair and regeneration

Optimal lung repair and regeneration is essential for recovery from viral infections such as that induced by influenza A virus (IAV). We have previously demonstrated that lung inflammation induced by IAV is under circadian control. However, it is not known if the circadian clock exerts its influence on lung repair and regenerative processes independent of acute inflammation from IAV. Here, we demonstrate for the first time that lung organoids have a functional clock as they mature and that the absence of an intact circadian clock impairs regenerative capacity. Using several models of circadian disruption, we show that with the absence of an intact clock lung proliferation is disrupted. Further, we find that the circadian clock acts through direct control of the Wnt/{beta}-catenin pathway. We speculate, that adding the circadian dimension to the critical process of lung repair and regeneration will lead to novel therapies and improve outcomes. Finally, we use data from UK Biobank to demonstrate at the population level, the role of poor circadian rhythms in mediating negative outcomes following lung infection.

cell biology↗

bioRxiv2020

GSK3 inhibition rescues growth and telomere dysfunction in dyskeratosis congenita iPSC-derived type II alveolar epithelial cells

Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human iPSC-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC related pathologies.

cell biology↗

bioRxiv2020

Antioxidant, Anti-inflammatory and Anticancer activities of Methanolic Extract of Thottea siliquosa: An In Vitro study

Background and AimOxidative stress and inflammation are the predominant cause of chronic diseases including cancers, thereby making it as an essential target for preventing these disorders. Various natural products and plants have been shown to prevent the process of free radical induced damages. The present study evaluated the biological properties of Thottea siliquosa, belonging to the family Aristolochiaceae, which is a traditionally used Ayurvedic plant. Experimental ProcedureAntioxidant assays carried out were DPPH, FRAP, hydrogen peroxide scavenging and hemolysis inhibition assay; nitric oxide and lipoxygenase inhibition assays were used for anti-inflammatory studies. Anticancer activity was done using human endometrial and breast cancer cells by MTT assay. Results and ConclusionThe results of the present study showed antioxidant properties for the methanolic crude extract of T. siliquosa as DPPH radical scavenging (110.40{+/-} 4.5g/mL), FRAP capacity (41.1{+/-} 6.2), peroxide scavenging (233.4{+/-} 14.2 g/mL) etc. In addition, anti-inflammatory properties are also evident in terms of nitric oxide radical scavenging (28.76{+/-} 3.9 g/mL) and lipoxygenase inhibition (39.2{+/-} 3.2 g/mL) assays. Further, the anticancer activity of these extract has been identified against human endometrial and breast cancer cells. Further studies together with a bioassay guided fractionation may identify possible bioactive compounds. HighlightsO_LIThottea siliquosa is a traditional Ayurvedic medicine C_LIO_LIT. siliquosa exhibits significant anti-inflammatory and anticancer properties C_LIO_LIPolyphenolic compounds may be responsible for the bioactivities of T. siliquosa C_LIO_LIT. siliquosa may be a source for novel bioactive components C_LI

pharmacology and toxicology↗