Renal hemodynamics, renal transporter expression levels, and urine excretion exhibit circadian variations. Disruption of these diurnal patterns is associated with the pathophysiology of hypertension ...and chronic kidney disease. Renal hemodynamics determines oxygen delivery, whereas renal transport and metabolism determines oxygen consumption; the balance between them yields renal oxygenation which also demonstrates 24-h periodicity. Another notable modulator of kidney function is sex, which has impacts on renal hemodynamics and transport function that are regulated by as well as independent of the circadian clock. The goal of this study was to investigate the diurnal and sexual variations in renal oxygen consumption and oxygenation. For this purpose, we developed computational models of rat kidney function that represent sexual dimorphism and circadian variation in renal hemodynamics and transporter activities. Model simulations predicted substantial differences in tubular Na.sup.+ transport and oxygen consumption among different nephron segments. We also simulated the effect of loop diuretics, which are used in the treatment of renal hypoxia, on medullary oxygen tension. Our model predicted a significantly higher effect of loop diuretics on medullary oxygenation in female rats compared to male rats and when administered during the active phase.
Calcium (Ca2+) and magnesium (Mg2+) are essential for cellular function. The kidneys play an important role in maintaining the homeostasis of these cations. Their reabsorption along the nephron is ...dependent on distinct trans- and paracellular pathways and is coupled to the transport of other electrolytes. Notably, sodium (Na+) transport establishes an electrochemical gradient to drive Ca2+ and Mg2+ reabsorption. Consequently, alterations in renal Na+ handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+ and Mg2+ transport. One such condition is the administration of diuretics, which are used to treat a large range of clinical conditions, but most commonly for the management of blood pressure and fluid balance. While the pharmacological targets of diuretics typically directly mediate Na+ transport, they also indirectly affect renal Ca2+ and Mg2+ handling through alterations in the electrochemical gradient. To investigate renal Ca2+ and Mg2 handling and how those processes are affected by diuretic treatment, we have developed computational models of electrolyte transport along the nephrons. Model simulations indicate that along the proximal tubule and thick ascending limb, the transport of Ca2+ and Mg2+ occurs in parallel with Na+, but those processes are dissociated along the distal convoluted tubule. We also simulated the effects of acute administration of loop, thiazide, and K-sparing diuretics. The model predicted significantly increased Ca2+ and Mg2+ excretions and significantly decreased Ca2+ and Mg2+ excretions on treatment with loop and K-sparing diuretics, respectively. Treatment with thiazide diuretics significantly decreased Ca2+ excretion, but there was no significant alteration in Mg2+ excretion. The present models can be used to conduct in silico studies on how the kidney adapts to alterations in Ca2+ and Mg2+ homeostasis during various physiological and pathophysiological conditions, such as pregnancy, diabetes, and chronic kidney disease.
The kidneys are crucial for maintaining Mg
homeostasis. Along the proximal tubule and thick ascending limb, Mg
is reabsorbed paracellularly, while along the distal convoluted tubule (DCT), Mg
is ...reabsorbed transcellularly via transient receptor potential melastatin 6 (TRPM6). TRPM6 and other renal transporter expressions are regulated by sex hormones. To investigate renal Mg
handling, we have developed sex-specific computational models of electrolyte transport along rat superficial nephron. Model simulations indicated that along the proximal tubule and thick ascending limb, Mg
and Na
transport occur parallelly, but they are dissociated along the DCT. In addition, our models predicted higher paracellular Mg
permeability in females to attain similar cortical thick ascending limb fractional Mg
reabsorption in both sexes. Furthermore, DCT fractional Mg
reabsorption is higher in females than in males, allowing females to better fine-tune Mg
excretion. We validated our models by simulating the administration of three classes of diuretics. The model predicted significantly increased, marginally increased and significantly decreased Mg
excretions for loop, thiazide and K-sparing diuretics, respectively, aligning with experimental findings. The models can be used to conduct
studies on kidney adaptations to Mg
homeostasis alterations during conditions such as pregnancy, diabetes and chronic kidney disease.
Introduction: Chronic Obstructive Pulmonary Disease (COPD) is a common and treatable disease characterised by progressive airflow limitation and tissue destruction. Smoking is a common risk factor ...but non smokers can also develop COPD. There may be change in serum level of inflammatory marker, oxidative stress markers, bio-markers among these patients. In this study smoker and non smoker group in COPD patients studied and may helpful for comparing levels and to corelate with severity of disease and also for group specific management. Aim: To evaluate the level of Serum C-Reactive Protein (CRP), total cholesterol, Magnesium (Mg++), and uric acid in COPD patients and also, to compare these parameters in smoker and non smoker patients with COPD. Materials and Methods: This cross-sectional study was conducted in Department of Biochemistry and Department of Pulmonary Medicine at People’s College of Medical Sciences and Research Centre, Bhopal, Madhya Pradesh, India, from October 2021 to December 2022. A total of 100 COPD patients, aged between 40 to 60 years were included and divided into two groups: 50 smokers and 50 non smokers. Parameters such as CRP, Mg++, total cholesterol and uric acid, were estimated by autoanalyser. Data were statistically analysed using unpaired t-test. Results: In smokers, mean age was 53.08±5.89 years, whereas in non smokers, mean age was 53.9±4.84 years. Out of the 100 subjects, 50 were smokers (F=6 and M=44) and 50 were non smokers (F=6 and M=44). In the present study, observed increased CRP levels and cholesterol levels, low serum magnesium, and normal uric acid in smoker compared to non smokers COPD. There was significant difference in cholesterol (p-value=0.044), serum magnesium (p-value=0.001) and CRP levels (p-value=0.0001) but there was no significant difference in uric acid (p-value=0.989). Conclusion: Smokers with COPD had increased level of CRP, Cholesterol and low level of Magnesium as compared to non smoker COPD patients. This may attribute that smokers COPD patients are in risk of developing recurrent exacerbations and more disease severity
Abstract
Identification of potential virus–host interactions is useful and vital to control the highly infectious virus-caused diseases. This may contribute toward development of new drugs to treat ...the viral infections. Recently, database records of clinically and experimentally validated interactions between a small set of human proteins and Ebola virus (EBOV) have been published. Using the information of the known human interaction partners of EBOV, our main objective is to identify a set of proteins that may interact with EBOV proteins. Here, we first review the state-of-the-art, computational methods used for prediction of novel virus–host interactions for infectious diseases followed by a case study on EBOV–human interactions. The assessment result shows that the predicted human host proteins are highly similar with known human interaction partners of EBOV in the context of structure and semantics and are responsible for similar biochemical activities, pathways and host–pathogen relationships.
•A game theory model for donations to blood service organizations is constructed.•The blood service organizations seek to maximize their transaction utilities and compete on the quality of ...service.•Alternative formulations of the governing Nash Equilibrium are provided.•Theoretical results are provided along with an effective computational scheme.•Numerical examples of increasing complexity illustrate the applicability of the framework.
In this paper, we focus on the blood services industry in the US, which is undergoing major changes, including a rise in competition, and we develop a novel game theory model for blood donations among blood service organizations in which the organizations seek to maximize their transaction utilities and compete on the quality of service that they provide at the blood collection sites in different regions. The governing equilibrium concept is that of Nash Equilibrium. We formulate the equilibrium as a variational inequality problem and prove the existence of the equilibrium quality level service pattern. We also provide conditions for uniqueness and present a Lagrange analysis and interpretation associated with the lower and upper bounds on the quality service levels. An algorithm with nice features for computations is proposed and then applied to numerical examples of increasing complexity. The results demonstrate that enhanced competition can improve the quality service level and that blood service organizations can also benefit from having collection sites in multiple regions.
In this paper we present a Generalized Nash Equilibrium model of supply chain network competition among blood service organizations which compete not only for blood donors but also for business from ...hospitals and medical centers. The model incorporates not only link capacities and associated arc multipliers to capture perishability, but also bounds on the number of donors in regions as well as lower and upper bounds on the demands at the demand points in order to ensure needed amounts for surgeries, treatments, etc., while reducing wastage. The concept of a variational equilibrium is utilized to transform the problem into a variational inequality problem, and alternative formulations are given. A Lagrange analysis yields economic insights. The proposed algorithmic procedure is then applied to a series of numerical examples in order to illustrate the impacts of disruptions in the form of a reduction on the number of donors as well as that of decreases in capacities of critical links such as testing and processing on RBC prices, demands, net revenues of the blood service organizations, and their overall utilities.
Cross-sectional studies are widely prevalent since they are more feasible to conduct compared with longitudinal studies. However, cross-sectional data lack the temporal information required to study ...the evolution of the underlying dynamics. This temporal information is essential to develop predictive computational models, which is the first step towards causal modelling. We propose a method for inferring computational models from cross-sectional data using Langevin dynamics. This method can be applied to any system where the data-points are influenced by equal forces and are in (local) equilibrium. The inferred model will be valid for the time span during which this set of forces remains unchanged. The result is a set of stochastic differential equations that capture the temporal dynamics, by assuming that groups of data-points are subject to the same free energy landscape and amount of noise. This is a 'baseline' method that initiates the development of computational models and can be iteratively enhanced through the inclusion of domain expert knowledge as demonstrated in our results. Our method shows significant predictive power when compared against two population-based longitudinal datasets. The proposed method can facilitate the use of cross-sectional datasets to obtain an initial estimate of the underlying dynamics of the respective systems.
•We develop an integrated multitiered competitive agricultural supply chain network model where agricultural firms and processing firms compete to sell their differentiated products.•The focus here ...is on fresh produce and minimally processed agricultural products in which we capture the quality decay of agricultural products through kinetic functions based on time and temperature at every stage of the supply chain.•The competition among agricultural firms and processing firms is studied through game theory, where the governing Cournot-Nash equilibrium conditions correspond to a variational inequality problem.•A numerical study consisting of several supply chain disruption scenarios demonstrates the applicability of our modeling framework.•The numerical study results suggest that a gricultural firms increase their profit by selling their agricultural products at the demand markets, and to the processing firms.
In this paper, we develop an integrated multitiered competitive agricultural supply chain network model in which agricultural firms and processing firms compete to sell their differentiated products. The focus here is on fresh produce and minimally processed such agricultural products, with quality also captured. The competition among agricultural firms and processing firms is studied through game theory, where the governing Cournot–Nash equilibrium conditions correspond to a variational inequality problem. The algorithm, at each iteration, yields explicit closed form expressions for the agricultural product path flows, the agricultural product shipments from agricultural firms to the processing firms, and the Lagrange multipliers. A numerical study consisting of several supply chain disruption scenarios demonstrates the applicability of our modeling framework.
The kidney plays an important role in the maintenance of whole body Ca
2+
balance by regulating Ca
2+
reabsorption and excretion. This computational modeling study provides insights into how Ca
2+
...transport along the nephron is coupled to Na
+
. Model results indicated that along the proximal tubule and thick ascending limb, Ca
2+
and Na
+
transport occur in parallel, but those processes were dissociated in the distal convoluted tubule. Simulations also revealed sex-specific responses to different pharmacological manipulations.
Ca
2+
transport along the nephron occurs via specific transcellular and paracellular pathways and is coupled to the transport of other electrolytes. Notably, Na
+
transport establishes an electrochemical gradient to drive Ca
2+
reabsorption. Hence, alterations in renal Na
+
handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca
2+
transport. An important class of pharmacological agent is diuretics, which are commonly prescribed for the management of blood pressure and fluid balance. The pharmacological targets of diuretics generally directly facilitate Na
+
transport but also indirectly affect renal Ca
2+
handling. To better understand the underlying mechanisms, we developed a computational model of electrolyte transport along the superficial nephron in the kidney of a male and female rat. Sex differences in renal Ca
2+
handling are represented. Model simulations predicted in the female rat nephron lower Ca
2+
reabsorption in the proximal tubule and thick ascending limb, but higher reabsorption in the late distal convoluted tubule and connecting tubule, compared with the male nephron. The male rat kidney model yielded a higher urinary Ca
2+
excretion than the female model, consistent with animal experiments. Model results indicated that along the proximal tubule and thick ascending limb, Ca
2+
and Na
+
transport occurred in parallel, but those processes were dissociated in the distal convoluted tubule. Additionally, we conducted simulations of inhibition of channels and transporters that play a major role in Na
+
and Ca
2+
transport. Simulation results revealed alterations in transepithelial Ca
2+
transport, with differential effects among nephron segments and between the sexes.
NEW & NOTEWORTHY The kidney plays an important role in the maintenance of whole body Ca
2+
balance by regulating Ca
2+
reabsorption and excretion. This computational modeling study provides insights into how Ca
2+
transport along the nephron is coupled to Na
+
. Model results indicated that along the proximal tubule and thick ascending limb, Ca
2+
and Na
+
transport occur in parallel, but those processes were dissociated in the distal convoluted tubule. Simulations also revealed sex-specific responses to different pharmacological manipulations.
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