Biology subjects

Kulkarni, C.

Publications and source records attributed to Kulkarni, C..

4 recordsLinked to original sources

bioRxiv2021

Temporal Progression: A case study in Porcine Survivability through Hemostatic Nanoparticles

This paper focuses on the analysis of time series representation of blood loss and cytokines in animals experiencing trauma to understand the temporal progression of factors affecting survivability of the animal. Trauma related grave injuries cause exsanguination and lead to death. 50% of deaths especially in the armed forces are due to trauma injuries. Restricting blood loss usually requires the presence of first responders, which is not feasible in certain cases. Hemostatic nanoparticles have been developed to tackle these kinds of situations to help achieve efficient blood coagulation. Hemostatic nanoparticles were administered into trauma induced porcine animals (pigs) to observe impact on the cytokine and blood loss experienced by them. In this paper we present temporal models to study the impact of the hemostatic nanoparticles and provide snapshots about the trend in cytokines and blood loss in the porcine data to study their progression over time. We utilized Piecewise Aggregate Approximation, Similarity based Merging and clustering to evaluate the impact of the different hemostatic nanoparticles administered. In some cases the fluctuations in the cytokines may be too small. So in addition we highlight situations where temporal modelling that produces a smoothed time series may not be useful as it may remove out the noise and miss the overall fluctuations resulting from the nanoparticles. Our results indicate certain nanoparticles stand out and lead to novel hypothesis formation.

bioengineering↗

bioRxiv2021

Computational Design Map for Heterogeneous Experimental Studies

This paper focuses on the discovery of a computational design map of disparate heterogeneous outcomes from bioinformatics experiments in pig (porcine) studies to help identify key variables impacting the experiment outcomes. Specifically we aim to connect discoveries from disparate laboratory experimentation in the area of trauma, blood loss and blood clotting using data science methods in a collaborative ensemble setting. Trauma related grave injuries cause exsanguination and death, constituting up to 50% of deaths especially in the armed forces. Restricting blood loss in such scenarios usually requires the presence of first responders, which is not feasible in certain cases. Moreover, a traumatic event may lead to a cytokine storm, reflected in the cytokine variables. Hemostatic nanoparticles have been developed to tackle these kinds of situations of trauma and blood loss. This paper highlights a collaborative effort of using data science methods in evaluating the outcomes from a lab study to further understand the efficacy of the nanoparticles. An intravenous administration of hemostatic nanoparticles was executed in pigs that had to undergo hemorrhagic shock and blood loss and other immune response variables, cytokine response variables are measured. Thus, through various hemostatic nanoparticles used in the intervention, multiple data outcomes are produced and it becomes critical to understand which nanoparticles are critical and what variables are key to study further variations in the lab. We propose a collaborative data mining framework which combines the results from multiple data mining methods to discover impactful features. We used frequent patterns observed in the data from these experiments. We further validate the connections between these frequent rules by comparing the results with decision trees and feature ranking. Both the frequent patterns and the decision trees help us identify the critical variables that stand out in the lab studies and need further validation and follow up in future studies. The outcomes from the data mining methods help produce a computational design map of the experimental results. Our preliminary results from such a computational design map provided insights in determining which features can help in designing the most effective hemostatic nanoparticles.

bioengineering↗

bioRxiv2020

Complex effects of pH on ROS from mitochondrial complex II driven complex I reverse electron transport challenge its role in tissue reperfusion injury

Generation of mitochondrial reactive oxygen species (ROS) is an important process in triggering cellular necrosis and tissue infarction during ischemia-reperfusion (IR) injury. Ischemia results in accumulation of the metabolite succinate. Rapid oxidation of this succinate by mitochondrial complex II (Cx-II) during reperfusion reduces the co-enzyme Q (Co-Q) pool, thereby driving electrons backward into complex-I (Cx-I), a process known as reverse electron transport (RET), which is thought to be a major source of ROS. During ischemia, enhanced glycolysis results in an acidic cellular pH at the onset of reperfusion. While the process of RET within Cx-I is known to be enhanced by a high mitochondrial trans-membrane {Delta}pH, the impact of pH itself on the integrated process of Cx-II to Cx-I RET has not been fully studied. Using isolated mitochondria under conditions which mimic the onset of reperfusion (i.e., high [ADP]). We show that mitochondrial respiration (state 2 and state 3) as well as isolated Cx-II activity are impaired at acidic pH, whereas the overall generation of ROS by Cx-II to Cx-I RET was insensitive to pH. Together these data indicate that the acceleration of Cx-I RET ROS by {Delta}pH appears to be cancelled out by the impact of pH on the source of electrons, i.e. Cx-II. Implications for the role of Cx-II to Cx-I RET derived ROS in IR injury are discussed.

biochemistry↗

bioRxiv2020

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

Alkb homolog 7 (ALKBH7) is a mitochondrial -ketoglutarate dioxygenase required for necrotic cell death in response to DNA alkylating agents, but its physiologic role within tissues remains unclear. Herein, we show that ALKBH7 plays a key role in the regulation of dialdehyde metabolism, which impacts cardiac survival in response to ischemia-reperfusion (IR) injury. Using a multi-omics approach, we do not find evidence that ALKBH7 functions as a prolyl-hydroxylase. However, we do find that mice lacking ALKBH7 exhibit a significant increase in glyoxalase I (GLO-1), a dialdehyde detoxifying enzyme. Consistent with increased dialdehyde production, metabolomics analysis reveals rewiring of metabolic pathways related to the toxic glycolytic by-product methylglyoxal (MGO), as well as accelerated glycolysis and elevated levels of MGO protein adducts, in mice lacking ALKBH7. Consistent with roles for both necrosis and glycative stress in cardiac IR injury, hearts from male but not female Alkbh7-/- mice are protected against IR, although somewhat unexpectedly this protection does not appear to involve modulation of the mitochondrial permeability transition pore. Highlighting the importance of MGO metabolism for the observed protection, removal of glucose as a metabolic substrate or pharmacologic inhibition of GLO-1 both abrogate cardioprotection in ALKBH7 deficient mice. Integrating these observations, we propose that ALKBH7 plays a role in the regulation of glyoxal metabolism, and that protection against necrosis and IR injury bought on by ALKBH7 deficiency originates from hormetic signaling in response to elevated MGO stress.

cell biology↗