Kareenhalli Viswanath Venkatesh

Iron deficiency (ID) in children caused by dietary deprivation can be alleviated in ∼40% cases with iron-fortified nutritional solutions. Devising more effective nutritional solutions requires a quantitative understanding of iron homeostasis, which is lacking. Here, we developed a physiologically-based mathematical model of paediatric iron homeostasis that recapitulates ID due to dietary deprivation and its alleviation using nutritional solutions. The model integrates key cellular and systemic iron regulatory processes, associated anatomical sites, the gut microbiota, and nutritional solutions, and shows how their complex interplay governs iron homeostasis. The model quantitatively described the alleviation of ID with nutritional solutions in a large clinical trial in Bangladesh. In virtual Indian populations, the model predicts that over-the-counter iron-fortified nutritional solutions can restore haemoglobin level to normalcy in >85% mildly anaemic infants and young children. Our study thus elucidates individual- and population-level underpinnings of ID, describes clinical observations, and informs efforts to improve intervention strategies.

Nuclear morphology, which is closely linked to various cell functions and disease states, is known to be modulated by mechanical stimuli and chromatin modifications. In many pathological contexts such as cancer, fibrosis, and aging, changes in tissue stiffness coincide with extensive epigenetic remodeling, yet these two regulatory mechanisms have always been studied in isolation. Since cells in vivo are simultaneously subjected to both mechanical and chromatin driven perturbations, it is important to understand how these two signals work together to shape nuclear mechanics and architecture. In this study, we investigated the interplay between substrate rigidity and histone acetylation, mediated by the histone deacetylase inhibitor (HDACi) valproic acid (VA), in modulating nuclear morphology in human mesenchymal stem cells (hMSCs) cultured on substrates of varying rigidities. We found that VA-induced chromatin decondensation diminished the effects of soft substrates on nuclear morphological parameters, a change not observed on stiff substrates. Furthermore, we showed that the reduction in nuclear stiffness with VA treatment on both substrates was independent of lamin expression, highlighting chromatin decondensation as a key determinant of the observed change in nuclear stiffness. Moreover, we observed that nuclear wrinkling was pronounced in cells cultured on soft substrates but was markedly reduced following VA treatment, whereas cells on stiff substrates exhibited only minimal wrinkling that remained unaltered in the presence of VA. Together, our findings suggest that chromatin remodeling via HDACi can override substrate-dependent nuclear mechanotransduction on soft substrates. This study underscores the importance of mechano-epigenetic interactions and offers new insights into the epigenetic regulation of nuclear mechanics with potential implications for pathologies associated with nuclear morphology.

Nuclear morphology which is closely linked to various cell functions and disease states, is known to be modulated by mechanical stimuli and chromatin modifications. However, the combined effects of substrate rigidity and chromatin modifications remain largely unexplored. In this study, we investigated the interplay between substrate rigidity and histone acetylation, mediated by the histone deacetylase inhibitor (HDACi) valproic acid (VA), in modulating nuclear morphology in human mesenchymal stem cells (hMSCs) cultured on substrates with varying rigidities. We found that VA-induced chromatin decondensation diminished the effects of soft substrates on nuclear morphological parameters, a change not observed on stiff substrates. Furthermore, we showed that the reduction in nuclear stiffness with VA treatment on both substrates was independent of lamin expression, highlighting chromatin decondensation as a key determinant of the observed change in nuclear stiffness. In addition, we demonstrated that soft substrates induced significant nuclear wrinkling, which was alleviated by HDACi treatment, while no such effect of VA was observed on stiff substrates. Together, our findings suggest that chromatin remodeling via HDACi can override substrate-dependent nuclear mechanotransduction on soft substrates, offering new insights into the epigenetic regulation of nuclear mechanics with potential implications for pathologies associated with nuclear morphology.

During anaerobic batch fermentation of substrates by Escherichia coli, there is a decline in cell proliferation rates and a huge demand is placed on cellular proteome to cater to its catabolic and anabolic needs under anoxic growth. Considering cell growth rates as a physiological parameter, previous studies have established a direct relationship between E. coli growth rate and cellular ribosomal content for fast-proliferating cells. In this study, we integrated experimental findings with a systemic coarse-grained proteome allocation model, to characterize the physiological outcomes at slow growth rate during anaerobic fermentative catabolism of different glycolytic and non-glycolytic substrates. The anaerobic catabolism of substrates favored high ribosomal abundances at lower growth rates. Interestingly, a modification of the previously discussed “growth law”, the ratio of active to inactive ribosomal proteome was found to be linearly related to the growth rate for cells proliferating at slow to moderate regime (growth rate < 0.8 h− 1). Also, under nutrient- and oxygen-limiting growth conditions, the proteome proportion allocated for ribosomal activity was reduced, and the resources were channelized towards metabolic activities to overcome the limitations imposed during uptake and metabolizing substrate. The energy-intensive uptake mechanism or lower substrate affinity, expended more catabolic proteome, which reduced its availability to other cellular functions. Thus, the nature of catabolic substrates imposed either uptake limitation or metabolic limitation coupled with ribosomal limitation (arising due to anoxic and nutritional stress), which resulted in higher proteome expenditure leading to sub-optimal growth phenotype. This study can form the basis for analyzing E. coli’s ability to optimize metabolic efficiency under different environmental conditions- including stress responses. It can be further extended to optimizing the industrial anaerobic conversions for improving productivity and yield.

Normal epithelial cells receive proper signals for growth and survival from attachment to the underlying extracellular matrix (ECM). They perceive detachment from the ECM as a stress and die — a phenomenon termed as ‘anoikis’. However, metastatic cancer cells acquire anoikis-resistance and circulate through the blood and lymphatics to seed metastasis. Under normal (adherent) growth conditions, the serine-threonine protein kinase Akt stimulates protein synthesis and cell growth, maintaining an anabolic state in the cancer cell. In contrast, previously we showed that the stress due to matrix deprivation is sensed by yet another serine-threonine kinase, AMP-activated protein kinase (AMPK), that inhibits anabolic pathways while promoting catabolic processes. We illustrated a switch from Akt^high/AMPK^low in adherent condition to AMPK^high/Akt^low in matrix-detached condition, with consequent metabolic switching from an anabolic to a catabolic state, which aids cancer cell stress-survival. In this study, we utilized these experimental data and developed a deterministic ordinary differential equation (ODE)-based mechanistic mathematical model to mimic attachment-detachment signaling network. To do so, we used the framework of insulin-glucagon signaling with consequent metabolic shifts to capture the pathophysiology of matrix-deprived state in breast cancer cells. Using the developed metastatic breast cancer signaling (MBCS) model, we identified perturbation of several signaling proteins such as IRS, PI3K, PKC, GLUT1, IP3, DAG, PKA, cAMP, and PDE3 upon matrix deprivation. Further, in silico molecular perturbations revealed that several feedback/crosstalks like DAG to PKC, PKC to IRS, S6K1 to IRS, cAMP to PKA, and AMPK to Akt are essential for the metabolic switching in matrix-deprived cancer cells. AMPK knockdown simulations identified a crucial role for AMPK in maintaining these adaptive changes. Thus, this mathematical framework provides insights on attachment-detachment signaling with metabolic adaptations that promote cancer metastasis.

During anaerobic batch fermentation by Escherichia coli , there is a decline in cell proliferation rates and a huge demand is placed on cellular proteome to cater its catabolic and anabolic needs under anoxic growth. Previous studies have established a direct relationship between E. coli growth rate and cellular ribosomal content for fast proliferating cells. In this study, we integrated experimental findings with a systemic coarse-grained model of proteome allocation, to characterize the physiological outcomes at slow growth rate during anaerobic fermentative catabolism of different glycolytic and non-glycolytic substrates. The anaerobic catabolism of substrates favored high ribosomal abundances at lower growth rates. Interestingly, a modification of previously discussed “growth law”, the ratio of active to inactive ribosomal proteome was found to be linearly related to growth rate for cells proliferating in slow to moderate regime (growth rate < 0.8 h ^-1 ). Also, under nutrient- and oxygen-limited growth conditions, the proteome proportion allocated for ribosomal activity was reduced, and resources were channelized towards catabolic and metabolic activities to overcome the limitations imposed while uptake and metabolizing substrate. The energy intensive uptake mechanism or lower substrate affinity, expended more catabolic proteome, which reduced its availability to other cellular functions. Conclusively, the nature of catabolic substrates imposed either uptake limitation or metabolic limitation coupled with ribosomal limitation (arising due to anoxic and nutritional stress), which resulted in higher proteome expenditure leading to sub-optimal phenotype.

UNSTRUCTURED Natural sources such as herbs, nutraceuticals, and medicinal mushrooms are increasingly used to manage diseases and promote wellness by balancing metabolic, immune, and oxidative stress. Type 2 diabetes (T2D), characterized by metabolic dysregulation, is a key area where these natural interventions show significant promise. In this study, a predictive algorithm was developed and applied to assess the therapeutic potential of three specific mushrooms—Pleurotus citrinopileatus, Pleurotus sajor-caju, and Pleurotus ostreatus—in managing T2D biomarkers. The algorithm was first validated against existing literature, accurately predicting the effects of these mushroom combinations on key biomarkers, including fasting glucose, HbA1c, insulin, HOMA-IR, triglycerides, LDL/HDL ratio, and total cholesterol, with a maximum fold change difference of 0.5 between expected and predicted values.The algorithm also identified an optimal dosage that maximized biomarker improvement while considering cost efficiency. Simulated outcomes for the optimal combination (C19), comprising 50% P. ostreatus, 25% P. sajor-caju, and 25% P. citrinopileatus by net weight , indicated a 40% reduction in glucose levels, a 17% decrease in insulin levels, a 45% drop in triglyceride levels, and a 13% reduction in cholesterol levels within one month in a diabetic population. The formulation consistently normalized biomarker levels within three months. A case study using the C19 combination as an intervention further validated the algorithm, highlighting its accuracy and reliability through a close correlation with actual outcomes. By integrating literature data, case study validation, and cost analysis, this approach offers a robust framework for designing effective and economical interventions for T2D.

Understanding the pleiotropic effects of global TFs on gene expression and their relevance underlying a specific response in a particular environment has been challenging. Here, we distinguish the TF-driven direct effects and growth rate-mediated indirect effects on gene expression using single- and double-deletion mutants of FNR, ArcA, and IHF regulators under anaerobic glucose fermentation.

Background: Nutritional deficiencies have many immediate and long-term effects on physical and cognitive development outcomes, with the children not achieving their full potential. A milk-based health drink fortified with micronutrients as a part of a daily balanced diet can promote physical and cognitive growth in children by increasing macronutrients and micronutrients availability in the body. The systematic analysis aims to quantify the effect of a formulated health drink on children’s physical, clinical, and cognitive development outcomes. Methods: The dataset used in the analysis was obtained from literature and consisted of 900 children between 7 to 12 years of age. These children were distributed equally into the Control group (no micronutrient-fortified health drink is given), Group I (micronutrient-fortified health drink in water), and Group II (micronutrient-fortified health drink in the toned milk). Results: The analysis shows that micronutrient-fortified health drinks in water (by 2.1-fold) and toned milk (by 2.5-fold) improve the height gain velocities and anthropometric and body composition parameters. It helped children achieve healthy IAP growth percentiles compared to the control group. The analysis also shows a 1.6- and 2-fold change in the cognitive tests grades in groups I & II, respectively, compared to the control group. Conclusions: The analysis indicates that two servings of 33g micronutrient-fortified health drink in water and toned milk for a year significantly improved the gain velocities of anthropometric and body composition parameters, reduced time taken to complete the physical activity task, reduced the number of anaemia and morbidity cases among groups, and improved the scoring grades in cognitive assessment test in studied children population. The IAP data benchmarking clearly indicated that a micronutrient fortified milk-protein-based powder significantly improved children’s overall growth with better health.