Biology subjects

Krishnamurthy, P.

Publications and source records attributed to Krishnamurthy, P..

6 recordsLinked to original sources

bioRxiv2025

Targeted αGalCer/CD1d Therapy Engages Invariant Natural Killer T Cells to Facilitate Cardiac Healing in Chronic Doxorubicin-Induced Cardiomyopathy

Invariant natural killer T (iNKT) cells are a unique subset of innate immune cells activated by T cell receptor (TCR) signaling through CD1d molecules presenting lipid antigens. By localizing to specific tissues, iNKT cells play critical roles in maintaining homeostasis and regulating pathophysiology, making them attractive therapeutic targets for inflammatory diseases. However, their frequency in the heart and potential roles in mitigating inflammation-induced cardiac damage remain poorly understood. In this study, we examined the distribution of cardiac iNKT subsets and their response to TCR-directed alpha Galactosyl ceramide/cluster of differentiation 1d (GalCer/CD1d) complexes in a mouse model of Doxorubicin (Dox)-induced cardiotoxicity. In healthy mice, the heart harbored distinct iNKT subsets, dominated by pro-inflammatory iNKT1 cells, followed by iNKT2 subsets. Treatment with GalCer/CD1d complexes preferentially expanded the iNKT1 subset. In Dox-induced cardiotoxicity, this treatment unexpectedly increased both IFN-{gamma}, a hallmark cytokine of iNKT1 cells, and IL-10, a key anti-inflammatory mediator typically associated with regulatory iNKT subsets. Despite the expansion of iNKT1 cells and elevated IFN-{gamma} levels, GalCer/CD1d treatment did not exacerbate cardiac damage and showed modest clinical improvements compared to controls. These findings highlight the complexity of iNKT-mediated immune regulation in the heart and emphasize the need for modified TCR-directed immunotherapeutics to skew immune responses toward a regulatory phenotype. Such approaches could hold promise for treating inflammatory cardiac diseases, including Dox-induced myocarditis, myocardial infarction, and autoimmune myocarditis.

immunology↗

bioRxiv2024

Age-dependent Changes in a Chaperone Complex in the Mouse Heart

The exquisitely organized sarcomere, the unit of contraction of striated muscle, is a stable structure with slow turnover of its components. The myosin chaperone UNC-45 and its binding partners, Hsp90 and Hsp70, are required for the initial folding of the myosin head domain and the assembly of myosin into thick filaments. There is increasing evidence that the UNC-45 system has an important role during aging to preserve sarcomere organization. Its decline may be a key factor in sarcopenia. Unlike skeletal muscle, the UNC-45 system in cardiac muscle in aging heart has not been examined extensively. Here we show that Unc45b and Hsp70 are localized to sarcomeric Z-discs in the mouse heart. We further show that during aging, there is a decline in the levels of myosin heavy chain, Unc-45b and Hsp70, but not Hsp90. While the decrease in Unc45b appears to be at the mRNA level, the decrease in the levels of myosin and Hsp70 were not at the mRNA but at the protein level. We have reported that in skeletal muscle, there is a decline in both Unc45b and Hsp90, and here we show that there is no such decline of Hsp70 in skeletal muscle. Hsp70 levels also did not decline with age in the brain or the liver. This heart-specific decrease of Hsp70 through its function as an Unc45b/Hsp70 complex might account for the age-dependent worsening of cardiomyopathies, and through Hsp70s multiple Unc-45b-independent functions, affect the folding and assembly of many other proteins in the aging heart.

cell biology↗

bioRxiv2024

Obg-like ATPase 1 Genetic Deletion Leads to Dilated Cardiomyopathy in Mice and Structural Changes in Drosophila Heart

Cardiomyopathy, disease of the heart muscle, is a significant contributor to heart failure. The pathogenesis of cardiomyopathy is multifactorial and involves genetic, environmental, and lifestyle factors. Identifying and characterizing novel genes that contribute to cardiac pathophysiology are crucial for understanding cardiomyopathy and effective therapies. In this study, we investigated the role of a novel gene, Obg-like ATPase 1 (Ola1), in cardiac pathophysiology using a cardiac-specific knockout mouse model as well as a Drosophila model. Our previous work demonstrated that OLA1 modulates the hypertrophic response of cardiomyocytes through the GSK-beta/beta-catenin signaling pathway. Furthermore, recent studies have suggested that OLA1 plays a critical role in organismal growth and development. For example, Ola1 null mice exhibit increased heart size and growth retardation. It is not known, however, if loss of function for Ola1 leads to dilated cardiomyopathy. We generated cardiac-specific Ola1 knockout mice (OLA1-cKO) to evaluate the role of OLA1 in cardiac pathophysiology. We found that Ola1-cKO in mice leads to dilated cardiomyopathy (DCM) and left ventricular (LV) dysfunction. These mice developed severe LV dilatation, thinning of the LV wall, reduced LV function, and, in some cases, ventricular wall rupture and death. In Drosophila, RNAi-mediated knock-down specifically in developing heart cells led to the change in the structure of pericardial cells from round to elongated, and abnormal heart function. This also caused significant growth reduction and pupal lethality. Thus, our findings suggest that OLA1 is critical for cardiac homeostasis and that its deficiency leads to dilated cardiomyopathy and dysfunction. Furthermore, our study highlights the potential of the Ola1 gene as a therapeutic target for dilated cardiomyopathy and heart failure.

physiology↗

bioRxiv2021

X-MyoNET: Biometric Identification using Deep Processing of Transient Surface Electromyography

The rapid development of the Internet and various applications such as the Internet of Medical Things (IoMT) has raised substantial concerns about personal information security. Conventional methods (e.g., passwords) and classic biological features (e.g., fingerprints) are security deficient because of potential information leakage and hacking. Biometrics that express behavioral features suggest a robust approach to achieving information security because of the corresponding uniqueness and complexity. In this paper, we consider identifying human subjects based on their transient neurophysiological signature captured using multichannel upper-limb surface electromyography (sEMG). An explainable artificial intelligence (XAI) approach is proposed to process the internal dynamics of temporal sEMG signals. We propose and prove the suitability of "transient sEMG" as a biomarker that can identify individuals. For this, we utilize the Gradient-weighted Class Activation Mapping (Grad-CAM) analysis to explain the networks attention. The outcome not only decodes and makes the unique neurophysiological pattern (i.e., motor unit recruitment during the transient phase of contraction) associated with each individual visualizable but also generates an optimizing two-dimensional (2D) spectrotemporal mask used to significantly reduce the size of the model and the trainable parameters. The resulting mask selectively and systematically samples the spectrotemporal characteristics of the users neurophysiological responses, discarding 40% of the input space while securing the accuracy of about 74% with much shallower neural network architecture. In the systematic comparative study, we find that our proposed model outperforms several state-of-the-art algorithms. For broader impacts, we anticipate our design of a compact, practical, interpretable, and robust identification system that requires only a minimal number of gestures and sensors (only 7% of the entire data set) to be a starting point for small and portable identification hardware.

bioengineering↗

bioRxiv2020

Regulation of CYP94B1 by WRKY33 controls apoplastic barrier formation in the roots leading to salt tolerance

Salinity is an environmental stress that causes decline in crop yield. Avicennia officinalis and other mangroves have adaptations such as ultrafiltration at the roots aided by apoplastic cell-wall barriers to thrive in saline conditions. We studied a Cytochrome P450 gene, AoCYP94B1 from A. officinalis and its Arabidopsis ortholog AtCYP94B1 that are involved in apoplastic barrier formation, and are induced by 30 minutes of salt treatment in the roots. Heterologous expression of AoCYP94B1 in atcyp94b1 Arabidopsis mutant and wild-type rice conferred increased NaCl tolerance to seedlings by enhancing root suberin deposition. Histochemical staining and GC-MS/MS quantification of suberin precursors confirmed the role of CYP94B1 in suberin biosynthesis. Using chromatin immunoprecipitation, yeast one-hybrid and luciferase assays, we identified AtWRKY33 as the upstream regulator of AtCYP94B1 in Arabidopsis. In addition, atwrky33 mutants exhibited reduced suberin and salt sensitive phenotypes, which were rescued by expressing 35S::AtCYP94B1 in atwrky33 mutant. This further confirms that the regulation of AtCYP94B1 by AtWRKY33 is part of the salt tolerance mechanism, and our findings can help in generating salt tolerant crops. One sentence summaryAtWRKY33 transcription factor regulates AtCYP94B1 to increase plant salt tolerance by enhanced suberin deposition in the endodermal cells of Arabidopsis roots

plant biology↗

bioRxiv2019

A novel technology for objective, accurate and non-invasive early diagnosis and monitoring of Alzheimer’s disease in clinics and clinical trials

We have developed a novel medical image processing technology for objective, accurate, and non-invasive diagnosis, prognosis, and monitoring of Alzheimers disease using standard clinical brain MRI (magnetic resonance imaging) and basic clinical cognitive assessment. The technology is a robust, highly accurate, fully automated, high-throughput, cloud-based platform, which operates in a fully integrated and controlled environment. In diagnosis mode, our technology performs with 91% balanced accuracy on blind testing to diagnose the current neurocognitive status, and in prognosis mode or early detection at mild cognitive impairment (MCI) stage with 88% balanced accuracy on blind testing to predict progression from MCI to Alzheimers dementia (AD) within 5 years. Such prognostic capability is currently non-existent, even in specialty clinics and hospitals, a major factor in Alzheimers clinical trial failures. The algorithms diagnostic certainty precisely mirrors the diagnostic confidence of an expert cognitive neurologist for both MCI (Spearmans Rho = 1) and AD (Rho = 1). In addition to widespread clinical applications, this novel technology can enable correct patient selection and therapeutic effect monitoring in clinical trials of Alzheimers disease, the crucial elements to finding a cure.

neuroscience↗