Biology subjects

Choudhary, G.

Publications and source records attributed to Choudhary, G..

8 recordsLinked to original sources

bioRxiv2026

Physics-informed neural network for predicting myocardial mechanics from in vivo physiological measurements

Structural heart diseases (SHDs) are characterized by progressive myocardial remodeling, yet the tissue-level mechanical properties underlying this process cannot be measured directly in vivo. This limitation restricts the ability of conventional physiological measurements to fully characterize myocardial remodeling and disease progression. Here, we present a physics-informed neural network (PINN) framework that integrates constitutive biomechanics with organ-level physiological measurements to simultaneously infer myocardial biomechanical descriptors and predict physically consistent stress responses. By embedding a hyperelastic constitutive model within the learning process, the framework links physiological measurements with tissue-level mechanics while preserving biomechanical consistency. Using right ventricular remodeling in pulmonary hypertension (PH) as a representative model of SHDs, the proposed framework accurately reproduced nonlinear stress-stretch behavior and outperformed conventional data-driven machine learning approaches for stress prediction. Furthermore, incorporation of PINN-derived tissue-level descriptors with organ-level physiological measurements improved disease stratification and enhanced separation between control, mild, and severe PH remodeling states. These findings support physics-informed constitutive learning as an interpretable framework for integrating organ-level physiology with tissue-level biomechanics and establish a foundation for future biomechanics-informed characterization of myocardial remodeling across SHDs.

bioengineering↗

bioRxiv2026

Proteomics Defines Shared and Divergent Alterations in the Right Atrium and Right Ventricle in Porcine Right Heart Failure

Right heart failure is due to both right atrial and right ventricular dysfunction. While the two chambers are distinct, the proteomic response to pressure overload is undefined. Here, we used quantitative proteomics to evaluate changes in both chambers in pulmonary artery banded pigs. We found common alterations in oxidative phosphorylation, ribosome regulation, integrin-mediated adhesion, and glycolysis enzymes. However, the right atrium had more pronounced deficits in the TCA cycle and branched chain amino acid metabolism. Thus, these data highlight metabolic pathways that could be evaluated to selectively enhance right atrial function.

biochemistry↗

bioRxiv2025

Multi-omic Evaluations Nominate an ER-Mitochondrial Axis and Inflammatory Macrophage as Drivers of Right Atrial Dysfunction

BackgroundRight atrial (RA) dysfunction is an emerging risk factor for poor outcomes in pulmonary arterial hypertension, however the mechanisms underlying compromised RA function are understudied. ObjectivesMulti-omic analyses defined the cellular and molecular mediators associated with RA dysfunction in pulmonary artery banded (PAB) swine. Methods4-week-old castrated male Yorkshire pigs were subjected to PAB and aged six weeks to induce right heart failure. Cardiac MRI evaluated RA size and function. snRNAseq defined the cell-specific alterations in RA tissue. Mitochondrial proteomics and metabolomics analyses examined the metabolic alterations in RA samples. Inducible pluripotent stem cell-derived atrial cardiomyocytes (iPSC-ACM) were treated with tunicamycin to induce endoplasmic reticulum (ER) stress and mitochondrial structure and function were probed. ResultsPAB induced RA dilation/dysfunction and atrial cardiomyocyte hypertrophy. snRNAseq demonstrated PAB altered the cellular composition of the RA defined by increased inflammatory macrophages and an alteration of cardiomyocyte subpopulations. RA cardiomyocytes exhibited ER stress and mitochondrial metabolic enzyme dysregulation. PAB RAs, but not PAB right ventricles, had downregulation of branched chain amino acid degrading enzymes. Metabolomics profiling revealed BCAA and fatty acid metabolism were impaired in the dysfunctional RA. Tunicamycin-induced ER stress disrupted mitochondrial structure/function in iPSC-ACMs. ConclusionsMulti-omic evaluations demonstrate RA dysfunction is characterized by cardiomyocyte metabolic derangements due to ER dysregulation and an accumulation of pro-inflammatory macrophages.

physiology↗

bioRxiv2024

IL-1β-driven NF-κB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2

Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected by SARS-CoV-2. We sought to identify mechanisms regulating macrophage expression of ACE2, the primary receptor for SARS-CoV-2, and to determine if macrophages are susceptible to productive infection. We developed a humanized ACE2 (hACE2) mouse whereby hACE2 cDNA was cloned into the mouse ACE2 locus under control of the native promoter. We validated the susceptibility of hACE2 mice to SARS-CoV-2 infection relative to wild-type mice and an established K18-hACE2 model of acute fulminating disease. Intranasal exposure to SARS-CoV-2 led to pulmonary consolidations with cellular infiltrate, edema, and hemorrhage, consistent with pneumonia, yet unlike the K18-hACE2 model, hACE2 mice survived and maintained stable weight. Infected hACE2 mice also exhibited a unique plasma chemokine, cytokine, and growth factor inflammatory signature relative to K18-hACE2 mice. Infected hACE2 mice demonstrated evidence of viral replication in infiltrating lung macrophages, and infection of macrophages in vitro revealed a transcriptional profile indicative of altered RNA and ribosomal processing machinery as well as activated cellular antiviral defense. Macrophage IL-1{beta}-driven NF-{kappa}B transcription of ACE2 was an important mechanism of dynamic ACE2 upregulation, promoting macrophage susceptibility to infection. Experimental models of COVID-19 that make use of native hACE2 expression will allow for mechanistic insight into factors that can either promote host resilience or increase susceptibility to worsening severity of infection.

immunology↗

bioRxiv2024

Dissecting contributions of pulmonary arterial remodeling to right ventricular afterload in pulmonary hypertension

Pulmonary hypertension (PH) is defined as an elevation in the right ventricle (RV) afterload, characterized by increased hemodynamic pressure in the main pulmonary artery (PA). Elevations in RV afterload increase RV wall stress, resulting in RV remodeling and potentially RV failure. From a biomechanical standpoint, the primary drivers for RV afterload elevations include increases in pulmonary vascular resistance (PVR) in the distal vasculature and decreases in vessel compliance in the proximal PA. However, the individual contributions of the various vascular remodeling events toward the progression of PA pressure elevations and altered vascular hemodynamics remain elusive. In this study, we used a subject-specific one-dimensional (1D) fluid-structure interaction (FSI) model to investigate the alteration of pulmonary hemodynamics in PH and to quantify the contributions of vascular stiffening and increased resistance towards increased main pulmonary artery (MPA) pressure. We used a combination of subject-specific hemodynamic measurements, ex-vivo mechanical testing of arterial tissue specimens, and ex-vivo X-ray micro-tomography imaging to develop the 1D-FSI model and dissect the contribution of PA remodeling events towards alterations in the MPA pressure waveform. Both the amplitude and pulsatility of the MPA pressure waveform were analyzed. Our results indicated that increased distal resistance has the greatest effect on the increase in maximum MPA pressure, while increased stiffness caused significant elevations in the characteristic impedance. The method presented in this study will serve as an essential step toward understanding the complex interplay between PA remodeling events that leads to the most severe adverse effect on RV dysfunction.

bioengineering↗

bioRxiv2024

Right ventricular stiffening and anisotropy alterations in pulmonary hypertension: Mechanisms and relations to function

AimsPulmonary hypertension (PH) results in an increase in RV afterload, leading to RV dysfunction and failure. The mechanisms underlying maladaptive RV remodeling are poorly understood. In this study, we investigated the multiscale and mechanistic nature of RV free wall (RVFW) biomechanical remodeling and its correlations with RV function adaptations. Methods and ResultsMild and severe models of PH, consisting of hypoxia (Hx) model in Sprague-Dawley (SD) rats (n=6 each, Control and PH) and Sugen-hypoxia (SuHx) model in Fischer (CDF) rats (n=6 each, Control and PH), were used. Organ-level function and tissue-level stiffness and microstructure were quantified through in-vivo and ex-vivo measures, respectively. Multiscale analysis was used to determine the association between fiber-level remodeling, tissue-level stiffening, and organ-level dysfunction. Animal models with different PH severity provided a wide range of RVFW stiffening and anisotropy alterations in PH. Decreased RV-pulmonary artery (PA) coupling correlated strongly with stiffening but showed a weaker association with the loss of RVFW anisotropy. Machine learning classification identified the range of adaptive and maladaptive RVFW stiffening. Multiscale modeling revealed that increased collagen fiber tautness was a key remodeling mechanism that differentiated severe from mild stiffening. Myofiber orientation analysis indicated a shift away from the predominantly circumferential fibers observed in healthy RVFW specimens, leading to a significant loss of tissue anisotropy. ConclusionMultiscale biomechanical analysis indicated that although hypertrophy and fibrosis occur in both mild and severe PH, certain fiber-level remodeling events, including increased tautness in the newly deposited collagen fibers and significant reorientations of myofibers, contributed to excessive biomechanical maladaptation of the RVFW leading to severe RV-PA uncoupling. Collagen fiber remodeling and the loss of tissue anisotropy can provide an improved understanding of the transition from adaptive to maladaptive remodeling. Translational perspectiveRight ventricular (RV) failure is a leading cause of mortality in patients with pulmonary hypertension (PH). RV diastolic and systolic impairments are evident in PH patients. Stiffening of the RV wall tissue and changes in the wall anisotropy are expected to be major contributors to both impairments. Global assessments of the RV function remain inadequate in identifying patients with maladaptive RV wall remodeling primarily due to their confounded and weak representation of RV fiber and tissue remodeling events. This study provides novel insights into the underlying mechanisms of RV biomechanical remodeling and identifies the adaptive-to-maladaptive transition across the RV biomechanics-function spectrum. Our analysis dissecting the contribution of different RV wall remodeling events to RV dysfunction determines the most adverse fiber-level remodeling to RV dysfunction as new therapeutic targets to curtail RV maladaptation and, in turn, RV failure in PH.

bioengineering↗

bioRxiv2024

Reduction in activity and abundance of mitochondrial electron transport chain supercomplexes in pulmonary hypertension-induced right ventricular dysfunction

Pulmonary hypertension (PH) results in RV hypertrophy, fibrosis and dysfunction resulting in RV failure which is associated with impaired RV metabolism and mitochondrial respiration. Mitochondrial supercomplexes (mSC) are assemblies of multiple electron transport chain (ETC) complexes that consist of physically associated complex I, III and IV that may enhance respiration and lower ROS generation. The goal of this study was to determine if mSCs are reduced in RV dysfunction associated with PH. We induced PH in Sprague-Dawley rats by Sugen/Hypoxia (3 weeks) followed by normoxia (4 weeks). Control and PH rats were subjected to echocardiography, blue and clear native-PAGE to assess mSC abundance and activity, and cardiomyocyte isolation to assess mitochondrial reactive oxygen species (ROS). mSC formation was also assessed in explanted human hearts with and without RV dysfunction. RV activity of CI and CIV and abundance of CI, CIII and CIV in mitochondrial mSCs was severely reduced in PH rats compared to control. There were no differences in total CI or CIV activity or abundance in smaller ETC assemblies. There were no changes in both RV and LV of expression of representative ETC complex subunits. PAT, TAPSE and RV Wall thickness significantly correlated with CIV and CI activity in mSC, but not total CI and CIV activity in the RV. Consistent with reduced mSC activity, isolated PH RV myocytes had increased mitochondrial ROS generation compared to control. Reduced mSC activity was also demonstrated in explanted human RV tissue from patients undergoing cardiac transplant with RV dysfunction. The right atrial pressure/pulmonary capillary wedge pressure ratio (RAP/PCWP, an indicator of RV dysfunction) negatively correlated with RV mSC activity level. In conclusion, reduced assembly and activity of mitochondrial mSC is correlated with RV dysfunction in PH rats and humans with RV dysfunction.

pathology↗

bioRxiv2022

Activation of targetable inflammatory immune signaling is seen in Myelodysplastic Syndromes with SF3B1 mutations

BackgroundMutations in the SF3B1 splicing factor are commonly seen in Myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML), yet the specific oncogenic pathways activated by missplicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood. MethodsRNA-seq data from SF3B1 mutant samples was analyzed and functional roles of IRAK4 isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in pre-clinical models of MDS/AML ResultsRNA-seq splicing analysis of innate immune mediators in SF3B1 mutant MDS samples revealed retention of full-length exon 6 of interleukin-1 receptor-associated kinase 4 (IRAK4), a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-Long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteosomal degradation. Expression of IRAK4-Long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models. ConclusionsSF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.

cancer biology↗