Paradoxes in magnesium transport in type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis.

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman's syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.NEW & NOTEWORTHY Although changes in Ca2+ excretion in type 1 Bartter's syndrome and Gitelman's syndrome are well understood, Mg2+ excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca2+ and Mg2+ transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg2+ preservation over Ca2+ in Bartter's syndrome and Ca2+ preservation over Mg2+ in Gitelman's syndrome and are stronger in females than in males.

Renal calcium and magnesium handling during pregnancy: modeling and analysis.

Pregnancy is associated with elevated demand of most nutrients, with many trace elements and minerals critical for the development of fetus. In particular, calcium (Ca2+) and magnesium (Mg2+) are essential for cellular function, and their deficiency can lead to impaired fetal growth. A key contributor to the homeostasis of these ions is the kidney, which in a pregnant rat undergoes major changes in morphology, hemodynamics, and molecular structure. The goal of this study is to unravel the functional implications of these pregnancy-induced changes in renal handling of Ca2+ and Mg2+, two cations that are essential in a healthy pregnancy. To achieve that goal, we developed computational models of electrolyte and water transport along the nephrons of a rat in mid and late pregnancy. Model simulations reveal a substantial increase in the reabsorption of Mg2+ along the proximal tubules and thick ascending limbs. In contrast, the reabsorption of Ca2+ is increased in the proximal tubules but decreased in the thick ascending limbs, due to the lower transepithelial concentration gradient of Ca2+ along the latter. Despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of Ca2+ and Mg2+ in pregnancy. Furthermore, we conducted simulations of hypocalcemia and hypomagnesemia. We found that hypocalcemia lowers Ca2+ excretion substantially more than Mg2+ excretion, with this effect being more pronounced in virgin rats than in pregnant ones. Conversely, hypomagnesemia reduces the excretion of Mg2+ and Ca2+ to more similar degrees. These differences can be explained by the greater sensitivity of the calcium-sensing receptor (CaSR) to Ca2+ compared with Mg2+.NEW & NOTEWORTHY A growing fetus' demands of minerals, notably calcium and magnesium, necessitate adaptations in pregnancy. In particular, the kidney undergoes major changes in morphology, hemodynamics, and molecular structure. This computational modeling study provides insights into how these pregnancy-induced renal adaptation impact calcium and magnesium transport along different nephron segments. Model simulations indicate that, despite the enhanced transport capacity, the marked increase in glomerular filtration rate results in elevated urinary excretions of calcium and magnesium in pregnancy.

Coupling of renal sodium and calcium transport: a modeling analysis of transporter inhibition and sex differences.

Ca2+ 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 Ca2+ reabsorption. Hence, alterations in renal Na+ handling, under pathophysiological conditions or pharmacological manipulations, can have major effects on Ca2+ 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 Ca2+ 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 Ca2+ handling are represented. Model simulations predicted in the female rat nephron lower Ca2+ 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 Ca2+ excretion than the female model, consistent with animal experiments. Model results indicated that along the proximal tubule and thick ascending limb, Ca2+ 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 Ca2+ transport. Simulation results revealed alterations in transepithelial Ca2+ 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 Ca2+ balance by regulating Ca2+ reabsorption and excretion. This computational modeling study provides insights into how Ca2+ transport along the nephron is coupled to Na+. Model results indicated that along the proximal tubule and thick ascending limb, Ca2+ 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.

Influence of administration time and sex on natriuretic, diuretic, and kaliuretic effects of diuretics.

Sex differences in renal function and blood pressure have been widely described across many species. Blood pressure dips during sleep and peaks in the early morning. Similarly, glomerular filtration rate, filtered electrolyte loads, urine volume, and urinary excretion all exhibit notable diurnal rhythms, which reflect, in part, the regulation of renal transporter proteins by circadian clock genes. That regulation is sexually dimorphic; as such, sex and time of day are not two independent regulators of kidney function and blood pressure. The objective of the present study was to assess the effect of sex and administration time on the natriuretic and diuretic effects of loop, thiazide, and K+-sparing diuretics, which are common treatments for hypertension. Loop diuretics inhibit Na+-K+-2Cl- cotransporters on the apical membrane of the thick ascending limb, thiazide diuretics inhibit Na+-Cl- cotransporters on the distal convoluted tubule, and K+-sparing diuretics inhibit epithelial Na+ channels on the connecting tubule and collecting duct. We simulated Na+ transporter inhibition using sex- and time-of-day-specific computational models of mouse kidney function. The simulation results highlighted significant sex and time-of-day differences in the drug response. Loop diuretics induced larger natriuretic and diuretic effects during the active phase. The natriuretic and diuretic effects of thiazide diuretics exhibited sex and time-of-day differences, whereas these effects of K+-sparing diuretics exhibited a significant time-of-day difference in females only. The kaliuretic effect depended on the type of diuretics and time of administration. The present computational models can be a useful tool in chronotherapy, to tailor drug administration time to match the body's diurnal rhythms to optimize the drug effect.NEW & NOTEWORTHY Sex influences cardiovascular disease, and the timing of onset of acute cardiovascular events exhibits circadian rhythms. Kidney function also exhibits sex differences and circadian rhythms. How do the natriuretic and diuretic effects of diuretics, a common treatment for hypertension that targets the kidneys, differ between the sexes? And how do these effects vary during the day? To answer these questions, we conducted computer simulations to assess the effects of loop, thiazide, and K+-sparing diuretics.

Sex and circadian regulation of metabolic demands in the rat kidney: A modeling analysis.

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+ 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.

How the kidney regulates magnesium: a modelling study.

The kidneys are crucial for maintaining Mg2+ homeostasis. Along the proximal tubule and thick ascending limb, Mg2+ is reabsorbed paracellularly, while along the distal convoluted tubule (DCT), Mg2+ is reabsorbed transcellularly via transient receptor potential melastatin 6 (TRPM6). TRPM6 and other renal transporter expressions are regulated by sex hormones. To investigate renal Mg2 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, Mg2+ and Na+ transport occur parallelly, but they are dissociated along the DCT. In addition, our models predicted higher paracellular Mg2+ permeability in females to attain similar cortical thick ascending limb fractional Mg2+ reabsorption in both sexes. Furthermore, DCT fractional Mg2+ reabsorption is higher in females than in males, allowing females to better fine-tune Mg2+ excretion. We validated our models by simulating the administration of three classes of diuretics. The model predicted significantly increased, marginally increased and significantly decreased Mg2+ excretions for loop, thiazide and K-sparing diuretics, respectively, aligning with experimental findings. The models can be used to conduct in silico studies on kidney adaptations to Mg2+ homeostasis alterations during conditions such as pregnancy, diabetes and chronic kidney disease.

Electrochromic and Energy Storage Performance Enhancement by Introducing Jahn-Teller Distortion: Experimental and Theoretical Study.

Aqueous electrochromic batteries (ECBs) have recently garnered significant attention within the realm of renewable rechargeable technology due to their potential applicability in diverse multifunctional devices featuring visible-level indicator batteries. However, there exists an imperative to comprehend the underlying structural factors that contribute to achieving an elevated electrochemical performance. In this context, we have synthesized and compared WO3·H2O (HWO) specifically for heightened ECB application as against the performance of a standard anhydrous WO3 (AWO). To unravel the underlying cause, a density functional theory (DFT) investigation is carried out, disclosing a structural deformation of HWO, unlike AWO, due to Jahn-Teller distortion induced by the presence of interlayer water. It results in a fully compatible HWO ion host to devise a zinc-ion aqueous electrolyte electrochromic battery, exhibiting superior redox reactivity, optical modulation (50%), capacity (200 mAh/m2), and cyclic stability. To glean insights into the dynamic structural alterations during the intercalation and deintercalation processes of Zn2+, ex situ X-ray diffraction and Raman spectroscopic studies are carried out. These investigations culminate in the determination that HWO films are better suited for the application than their AWO counterparts. This finding holds promise for advancing the applications of ECBs and represents a significant step forward in this field.

Dual-Functional Electrochromic Smart Window Using WO3·H2O-rGO Nanocomposite Ink Spray-Coated on a Low-Cost Hybrid Electrode.

Electrochromic windows have gained growing interest for their ability to change their optical state in the visible and NIR ranges with minimal input power, making them energy-efficient. However, material processing costs, fabrication complexity, and poor electrochromic properties can be barriers to the widespread adoption of this technology. To address these issues, electrochromic material and fabrication processes are designed to realize their potential as a cost-effective and energy-efficient technology. In this work, an electrochromic composite material-based ink is synthesized consisting of WO3·H2O nanoplates supported on rGO (reduced graphene oxide) nanosheets (WH-rGO), wherein an optimized amount of rGO (0.05 to 0.5 wt %) is introduced for providing a higher conduction pathway for efficient charge transport without sacrificing the electrochromic performance of WO3·H2O nanoplates. The stable ink dispersion prepared in the study is deposited by spray coating on transparent conducting electrodes over large areas (25 cm2). The WH-rGO nanocomposite (0.4 wt %) results in 43% optical modulation at 700 nm, with bleaching and coloration times of 6 and 8 s, respectively. Interestingly, the device also possesses an electrochemical energy storage capability with an areal capacitance of 16.3 mF/cm2. The electrochromic composite material is successfully translated on tin doped indium oxide (ITO)-coated Al metal mesh hybrid electrodes (T = 80%, Rs = 40 Ω/□) to replace ITO. Finally, an electrochromic device of 5 × 5 cm2 is fabricated by spray-coating the ink on cost-effective ITO/Al-mesh hybrid electrodes. The device displays blue to colorless modulation with an excellent bleaching time of 0.43 s and a coloration time of 2.16 s, making it one among the fast-operating devices fabricated by complete solution processing. This work showcases the economical production of a dual-function electrochromic device, which can be a feasible option as an alternative to existing ITO-based devices in both automotive and infrastructure applications.

Inferring temporal dynamics from cross-sectional data using Langevin dynamics.

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.

Social norms and obesity prevalence: From cohort to system dynamics models.

Group-level obesity can be seen as an emergent property of a complex system, consisting of feedback loops between individual body weight perception, individual weight-related behaviour and group-level social norms (a product of group-level 'normal' body mass index (BMI) and sociocultural 'ideal' BMI). As overweight becomes normal, the norm might be counteracting health awareness in shaping individual weight-related behaviour. System dynamics modelling facilitates understanding and simulating this system's emergent behaviour. We constructed six system dynamics models (SDMs) based on an expert-informed causal loop diagram and data from six sociocultural groups (Dutch, Moroccan and South-Asian Surinamese men and women). The SDMs served to explore the effect of three scenarios on group-level BMI: 'what if' weight-related behaviour were driven by (1) health awareness, (2) norms or (3) a combination of the two. Median BMI decreased approximately 50% and 30% less in scenarios 2 and 3, respectively, than in 1. In men, the drop in BMI was approximately two times larger in scenario 1 versus 3, whereas in women, the drop was approximately equal in these scenarios. This study indicates that the overweight norm in men holds group-level BMI close to overweight despite health awareness. Since norms are counteracting health awareness less strongly in women, other drivers of obesity must be more relevant.

Boolean network modeling of ß-cell apoptosis and insulin resistance in type 2 diabetes mellitus.

BACKGROUND: Major alteration in lifestyle of human population has promoted Type 2 diabetes mellitus (T2DM) to the level of an epidemic. This metabolic disorder is characterized by insulin resistance and pancreatic ß-cell dysfunction and apoptosis, triggered by endoplasmic reticulum (ER) stress, oxidative stress and cytokines. Computational modeling is necessary to consolidate information from various sources in order to obtain a comprehensive understanding of the pathogenesis of T2DM and to investigate possible interventions by performing in silico simulations. RESULTS: In this paper, we propose a Boolean network model integrating the insulin resistance pathway with pancreatic ß-cell apoptosis pathway which are responsible for T2DM. The model has five input signals, i.e. ER stress, oxidative stress, tumor necrosis factor α (TNF α), Fas ligand (FasL), and interleukin-6 (IL-6). We performed dynamical simulations using random order asynchronous update and with different combinations of the input signals. From the results, we observed that the proposed model made predictions that closely resemble the expression levels of genes in T2DM as reported in the literature. CONCLUSION: The proposed model can make predictions about expression levels of genes in T2DM that are in concordance with literature. Although experimental validation of the model is beyond the scope of this study, the model can be useful for understanding the aetiology of T2DM and discovery of therapeutic intervention for this prevalent complex disease. The files of our model and results are available at https://github.com/JieZheng-ShanghaiTech/boolean-t2dm .

Assessment of Semantic Similarity between Proteins Using Information Content and Topological Properties of the Gene Ontology Graph.

The semantic similarity between two interacting proteins can be estimated by combining the similarity scores of the GO terms associated with the proteins. Greater number of similar GO annotations between two proteins indicates greater interaction affinity. Existing semantic similarity measures make use of the GO graph structure, the information content of GO terms, or a combination of both. In this paper, we present a hybrid approach which utilizes both the topological features of the GO graph and information contents of the GO terms. More specifically, we 1) consider a fuzzy clustering of the GO graph based on the level of association of the GO terms, 2) estimate the GO term memberships to each cluster center based on the respective shortest path lengths, and 3) assign weightage to GO term pairs on the basis of their dissimilarity with respect to the cluster centers. We test the performance of our semantic similarity measure against seven other previously published similarity measures using benchmark protein-protein interaction datasets of Homo sapiens and Saccharomyces cerevisiae based on sequence similarity, Pfam similarity, area under ROC curve, and measure.

A survey on Ebola genome and current trends in computational research on the Ebola virus.

A detailed understanding of the Ebola virus (EBOV) pathogenesis has not been possible because of safety concerns, which arise while handling the live EBOV. Understanding the mechanisms involved in EBOV entry, replication and inhibition of the antiviral response in the host cell are crucial for the development of effective therapeutic measures. In this article, we provide a description of the EBOV genome and the role of each EBOV protein in spreading infection in the host cell. We also discuss some of the major computational works done on EBOV for the purpose of developing effective vaccines and drugs. In addition, we list the known host proteins with which EBOV proteins interact to enter and spread infection in the host and also estimate their semantic similarity (SS) scores to test the efficiency of SS metric for the prediction of novel EBOV-human protein interactions.

Review of computational methods for virus-host protein interaction prediction: a case study on novel Ebola-human interactions.

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.