Modeling Studies Research Articles

Mechanism of protective actions of sparsentan in the kidney: lessons from studies in models of chronic kidney disease.

Simultaneous inhibition of angiotensin II AT1 and endothelin ETA receptors has emerged as a promising approach for treatment of chronic progressive kidney disease. This therapeutic approach has been advanced by the introduction of sparsentan, the first dual AT1 and ETA receptor antagonist. Sparsentan is a single molecule with high affinity for both receptors. It is US Food and Drug Administration approved for immunoglobulin A nephropathy (IgAN) and is currently being developed as a treatment for rare kidney diseases, such as focal segmental glomerulosclerosis. Clinical studies have demonstrated the efficacy and safety of sparsentan in these conditions. In parallel with clinical development, studies have been conducted to elucidate the mechanisms of action of sparsentan and its position in the context of published evidence characterizing the nephroprotective effects of dual ETA and AT1 receptor inhibition. This review summarizes this evidence, documenting beneficial anti-inflammatory, antifibrotic, and hemodynamic actions of sparsentan in the kidney and protective actions in glomerular endothelial cells, mesangial cells, the tubulointerstitium, and podocytes, thus providing the rationale for the use of sparsentan as therapy for focal segmental glomerulosclerosis and IgAN and suggesting potential benefits in other renal diseases, such as Alport syndrome.

A modeling study with 4th graders

<span lang="EN-US">People need effective writing skills to successfully maintain their personal development and academic life. This research studies, the correlations among primary school 4th graders’ writing anxiety, writing attitude, and writing self-efficacy. The research has been designed in the correlational survey model; and a total of 255 primary school 4th-grade students, 95 male and 160 female, participated voluntarily in the research. Three psychometric tools have been used for data collection. Due to small number of participants, the data have been analyzed using the partial least squares structural equation modeling. According to the results, primary school 4th-grade students’ writing attitude does not significantly affect writing anxiety (H1). Moreover, writing self-efficacy does not have a significant effect on writing anxiety (H2) as well. However, writing self-efficacy significantly affects writing attitude (H3). The success of writing depends on the students’ writing self-efficacy, attitude towards writing, and writing anxiety. In order for successful writing, the level of self-efficacy should be high, the attitude towards writing should be positive and there should be no anxiety about writing.</span>

Measuring the Replicability of our own Research

In the study of transgenic mouse models of neurodevelopmental and neurodegenerative disorders, we use batteries of tests to measure deficits in behaviour and from the results of these tests, we make inferences about the mental states of the mice that we interpret as deficits in "learning", "memory", "anxiety", "depression", etc. This paper discusses the problems of determining whether a particular transgenic mouse is a valid mouse model of disease X, the problem of background strains, and the question of whether our behavioural tests are measuring what we say they are. The problem of the reliability of results is then discussed: are they replicable between labs and can we replicate our results in our own lab? This involves the study of intra- and inter- experimenter reliability. The variables that influence replicability and the importance of conducting a complete behavioural phenotype: sensory, motor, cognitive and social emotional behaviour are discussed. Then the thorny question of failure to replicate is examined: Is it a curse or a blessing? Finally, the role of failure in research and what it tells us about our research paradigms is examined.

Membraneless and membrane-bound organelles in an anhydrobiotic cell line are protected from desiccation-induced damage.

Anhydrobiotic species can survive virtually complete water loss by entering a reversible ametabolic glassy state that may persist for years in ambient conditions. The Pv11 cell line was derived from the egg mass of the anhydrobiotic midge, Polypedilum vanderplanki, and is currently the only available anhydrobiotic cell line. Our results demonstrate that the necessary preconditioning for Pv11 cells to enter anhydrobiosis causes autophagy and reduces mitochondrial respiration by over 70%. We speculate that reorganizing cellular bioenergetics to create and conserve energy stores may be valuable to successfully recover after rehydration. Furthermore, mitochondria in preconditioned cells lose their membrane potential during desiccation but rapidly restore it within 30min upon rehydration, demonstrating that the inner mitochondrial membrane integrity is well-preserved. Strikingly, the nucleolus remains visible immediately upon rehydration in preconditioned cells while absent in control cells. In contrast, a preconditioning-induced membraneless organelle reformed after rehydration, demonstrating that membraneless organelles in Pv11 cells can be either stabilized or recovered. Staining the endoplasmic reticulum and the Golgi apparatus revealed that these organelles fragment during preconditioning. We hypothesize that this process reduces sheering stress caused by rapid changes in cellular volume during desiccation and rehydration. Additionally, preconditioning was found to cause the filamentous-actin (F-actin) network to disassemble significantly and reduce the fusion of adjacent plasma membranes. This study offers several exciting avenues for future studies in the animal model and Pv11 cell line that will further our understanding of anhydrobiosis and may lead to advancements in storing sensitive biologics at ambient temperatures for months or years.

Advancing hydrogen storage predictions in metal-organic frameworks: A comparative study of LightGBM and random forest models with data enhancement

The escalating consumption of fossil fuels has given rise to a substantial upsurge in greenhouse gas concentrations and global temperatures, which, in turn, has triggered severe climate-related consequences. The critical imperative to reduce CO2 emissions and combat global warming has spurred extensive investigations into clean energy alternatives, with hydrogen emerging as a compelling zero-emission energy source. As a pivotal component of clean energy strategies, hydrogen requires designing compact, lightweight, and efficient storage systems. This study focuses on the development and evaluation of machine learning models for predicting the efficiency of Metal-Organic Frameworks (MOFs) in hydrogen storage, a key aspect of advancing clean energy technologies. MOFs, a class of nanoporous materials, show remarkable potential for hydrogen storage due to their high surface area and porosity. However, selecting the most suitable MOF for this application from a vast array of possible structures is a daunting task. In this context, machine learning algorithms offer an efficient alternative for predicting MOF suitability by considering their structural and chemical properties. We used ensemble learning methods, specifically Light Gradient Boosting Machine (LightGBM) and Random Forest (RF), to predict hydrogen uptake of MOFs based on a dataset of 219 experimentally tested samples. Two modeling scenarios were considered: one using the entire dataset, and the other involving strategic data pre-processing, including outlier removal and feature engineering. The results demonstrate that the measures taken to refine the dataset significantly enhance the predictive performance of the developed models, reducing prediction errors and improving overall goodness of fit. Specifically, the Mean Absolute Error (MAE) values for both the LightGBM and random forest models were reduced from 0.48 and 0.94, respectively, to 0.16 for both models, and the coefficients of determination (R2) increased substantially from 0.84 and 0.72 to 0.95, in both cases. Moreover, feature importance analysis unveiled that pressure-related features make the most significant contributions to the formation of tree ensembles during the model training process. A parametric sensitivity analysis was conducted revealing that H2 uptake in MOFs is most sensitive to changes in adsorption enthalpy, followed by surface area and temperature, while showing lower sensitivity to variations in pressure, consistent with established literature. These results underscore the pivotal role of data enhancement methods in refining machine learning models and can be instrumental in accelerating the development and optimization of MOF materials for clean energy applications.

Study of a mechano-electrochemical model: a numerical and experimental approach

The mechanochemical effects of elasticity and plasticity are introduced into a peridynamic (PD) corrosion model. A PD equation that couples the mechanics and kinetics of electrochemistry is proposed for the first time. This clarifies the influence of the mechanical load in governing the occurrence of diffusion during corrosion. The phase changes experienced by a material are used to characterize the movement of the corrosion boundary, and the concentration of material points is used to characterize the degree and extent of damage caused to the chosen metal. Immersion tests and in situ electrochemical tests are carried out, and the results are used to explore the effects of stress and/or load on the kinetics of environment-induced damage to an aluminum alloy. The model predictions are in good agreement with the experimental observations. The results of this study demonstrate that a coupled mechano-electrochemical PD corrosion model can capture corrosion-induced damage and can be used to study damage propagation upon exposure to an aggressive environment.

Flow Characteristics of Cylinders with Asymmetric Grooves: A Modeling and Experimental Study

Flow Characteristics of Cylinders with Asymmetric Grooves: A Modeling and Experimental Study

Adsorption of antiretroviral drugs, abacavir, nevirapine, and efavirenz from river water and wastewater using exfoliated graphite: isotherm and kinetic studies

In this work, exfoliated graphite was used to adsorb antiretroviral drugs from river water and wastewater. The exfoliated graphite was prepared from natural graphite by intercalating it with the acids and exfoliating it at 800˚C. It was characterized using Fourier Transform Infrared Spectroscopy which showed phenolic, alcoholic, and carboxylic functional groups between 1000 cm-1 and 1700 cm-1. Energy-dispersive X-ray spectroscopy results showed carbon as the main element with splashes of oxygen. The Scanning Electron Microscopy images showed increased c-axis distance between graphene layers after intercalation, which further increased after the exfoliation. The exfoliation resulted in elongated distorted cylinders, which were confirmed by the lower density (0.0068 g/mL) of exfoliated graphite material compared to the natural graphite (0.54 g/mL). The X-ray diffraction pattern showed the characteristics of hexagonal phase graphitic structure by the diffraction plane (002) at 26.74°. Raman spectroscopy results showed the natural graphite, graphite intercalated, and exfoliated graphite contained the D, G, D', and G' peaks at about 1350 cm-1, 1570 cm-1, 2440 cm-1, and 2720 cm-1, respectively indicating that the material’s crystallinity was not affected by the modification. The highest antiretroviral drugs removal (95-99%), from the water was achieved with a solution pH of 7, an adsorbent mass of 30 mg, and an adsorption time of 30 minutes. The kinetic model and adsorption isotherm studies showed that the experimental data fit well in pseudo-second-order kinetics and is well explained by Freundlich’s adsorption isotherm. The maximum adsorption capacity of the exfoliated graphite for antiretroviral drugs ranges between 1.660-197.0, 1.660-232.5, and 1.650-237.7 mg/g for abacavir, nevirapine, and efavirenz, respectively. The obtained removal percentages were 100% in river water, 63-100% in influent and 70-100% in effluent wastewater unspiked samples.

Multi-cancer risk stratification based on national health data: a retrospective modelling and validation study

Multi-cancer risk stratification based on national health data: a retrospective modelling and validation study

Comparative assessment of chondral defect repair using migratory chondroprogenitors suspended in either gelled or freeze-dried platelet-rich plasma: An in vitro and ex vivo human osteochondral unit model study

BackgroundChondroprogenitors, with enhanced chondrogenic potential, have emerged to be a promising alternative for cell-based therapy in cartilage repair. Platelet-rich plasma (PRP), widely used for intra-articular treatment, has a short half-life. Freeze-dried PRP (FD-PRP), with an extended half-life and retained growth factors, is gaining attention. This study compares the efficacy of Migratory Chondroprogenitors (MCPs) in gelled PRP and FD-PRP using in-vitro and ex-vivo models, assessing FD-PRP as a potential off-the-shelf option for effective cartilage repair. MethodologyMCPs were isolated from osteoarthritic cartilage samples (n = 3), characterized through FACS and RT-PCR. For in-vitro analysis, cells were loaded into gelled PRP and FD-PRP scaffolds at a density of 1x106 cells per scaffold. Trilineage differentiation studies and live-dead assays were conducted on MCPs using Calcein AM/Propidium Homodimer-1. In ex-vivo analysis, MCPs of the same density were added to Osteochondral Units (OCU) with chondral defects containing PRP gel and FD-PRP scaffolds, harvested on the 15th and 35th days for histological examination. Controls included cell-free scaffolds. ResultsOur in-vitro analysis demonstrates the robust viability of MCPs in both scaffolds, with no discernible impact on their differentiation capacity. Ex-vivo analysis of the OCU for cartilage repair showed that the chondrogenic potential characterized by the accumulation of extracellular matrix containing glycosaminoglycans and collagen type II production (with no alteration in collagen type X), was observed to be better with the gel PRP and the gel PRP containing MCP groups. ConclusionsThese findings support the preference for gel PRP as a superior synergistic scaffold for chondroprogenitor delivery.

Prediction of diagnosis and diastolic filling pressure by AI-enhanced cardiac MRI: a modelling study of hospital data

Prediction of diagnosis and diastolic filling pressure by AI-enhanced cardiac MRI: a modelling study of hospital data

A novel algorithm to the shell model study of heavy deformed nuclei using the variation after projection approach

We introduce an extension to the conventional variation after projection (VAP) method, in which wave functions of different spin states projected from a shared intrinsic wave function are first varied simultaneously. Then a second variation is carried out for each individual state starting from the obtained intrinsic wave function. This novel algorithm enables the efficient extraction of a rotational band from chaotic non-rotational states by adopting only one Slater determinant, which can not be reached by the conventional VAP method. Some examples including the heavy deformed nuclei in the jj56 model space have been calculated. The calculated results show that this new method could be a useful tool to systematically study the collective rotational states in heavy deformed nuclei. Furthermore, the present method holds potential for probing significant correlations, such as octupole correlations, within nuclear structures.

Design, Synthesis, Evaluation and Toxicity Studies of Novel Acridine Derivatives in Zebra Fish Larvae

Background: Alzheimer’s disease (AD) is a complex neurodegenerative condition for which a single protein-targeting medication is not enough to provide a cure. All the medications now available for AD are palliative. FDA has approved five medications for the treatment of AD, i.e., tacrine, donepezil, galantamine, rivastigmine, and memantine. Due to hepatotoxicity, tacrine is no longer utilized in clinical practice. Due to the lack of therapeutic efficiency of single-target medications and the multifaceted etiology of AD, multitarget-directed ligands have been developed. Objectives: The present research focused on incorporating a flavone nucleus into the amino group of 9-amino acridine nucleus to make it an acetylcholinesterase (AChE) and butyryl cholinesterase inhibitor (BuChE) with less toxicity Methods: We designed and synthesized ten flavone-substituted acridine derivatives and evaluated them for in vitro AChE and BuChE inhibitory activity. Molecular modeling studies were conducted using AutoDock Vina with hAChE (PDB ID: 4EY7) and hBuChE (PDB ID: 4TPK). The toxicity profile of the most active novel compound tested on zebrafish larvae for determining the liver and cardiac toxicity and LD50 value of the compound were determined. Results: In vitro AChE and BuChE inhibitory study by Ellman assay showed acceptable results. The compound AF2 showed the highest activity with an IC50 value of 0.99 ± 0.1 µM for AChE and 1.78 ± 0.19 for BuChE. The in vivo acute toxicity studies conducted on zebra fish larvae did not show cardiac and hepatotoxicity, and the LD50 value was found to be 1000 µL Conclusion: The results highlighted the AChE and BuChE inhibitory effects of the novel acridine-flavone hybrids, and they can be promising multitarget-directed ligands for AD.

Experimental Study of Model on Soil Slope Failure Subjected to Artificial Rainfall

Abstract: The paper's purpose is to introduce a miniature form of slope for the study of infiltration process under various rainfall conditions. To mimic the infiltration process on a slope, we utilize artificial precipitation by using a sprinkler to model it. system at a rainfall intensity, ie, 100,110,120mm/h. Pore-water pressure (PWP) and displacements are measured by scale, is put in the model at different spots to track alterations. The purpose is to investigate the effects of slope movements on soil water content, pore-water pressures and. movement in both conditions, with and without geonet placement. The research attempts to forecast slop failure initiated by excessive precipitation by continuously observing these measures. From the outcomes, time to first failure can be assessed.

Oxytocin: A key regulator of mitochondrial metabolism and energy homeostasis

Oxytocin, traditionally recognized for its roles in social bonding and reproductive behaviors, is emerging as a crucial regulator of mitochondrial metabolism and energy homeostasis. This review synthesizes current research illustrating how oxytocin influences cellular energy processes, particularly within the context of metabolic disorders. By interacting with oxytocin receptors in key metabolic organs, oxytocin modulates mitochondrial biogenesis, enhances glucose uptake, and optimizes energy utilization, thereby contributing to overall metabolic stability. Recent studies in rodent models highlight the potential of oxytocin analogs in ameliorating symptoms of metabolic syndromes, such as obesity and diabetes, by improving mitochondrial function and energy expenditure. This review aims to consolidate these findings, propose mechanisms of action, and discuss the therapeutic prospects of oxytocin in managing metabolic diseases. The implications of oxytocin’s metabolic effects extend beyond traditional reproductive and social domains, suggesting a multifaceted hormone with significant potential for addressing public health challenges related to metabolic disorders.

Multiple sclerosis and the intestine: Chasing the microbial offender.

Multiple sclerosis (MS) affects more than 2.8 million people worldwide but the distribution is not even. Although over 200 gene variants have been associated with susceptibility, studies of genetically identical monozygotic twin pairs suggest that the genetic make-up is responsible for only about 20%-30% of the risk to develop disease, while the rest is contributed by milieu factors. Recently, a new, unexpected player has entered the ranks of MS-triggering or facilitating elements: the human gut microbiota. In this review, we summarize the present knowledge of microbial effects on formation of a pathogenic autoreactive immune response targeting the distant central nervous system and delineate the approaches, both in people with MS and in MS animal models, which have led to this concept. Finally, we propose that a tight combination of investigations of human patients with studies of suitable animal models is the best strategy to functionally characterize disease-associated microbiota and thereby contribute to deciphering pathogenesis of a complex human disease.

The impact of early-life exercise on CREB-signaling pathway and hippocampus neuroplasticity in diabetic adult male rats; the study of developmental model.

Childhood exercise enhances brain structure, while diabetes detrimentally affects it. This study examines early-life exercise's influence on adult diabetic rats' memory and neuroplasticity. Male Wistar pups were divided into Control, Diabetes, Exercise Training, and Diabetes exercise groups. Diabetes was induced on day 23 with Alloxan (200 mg/kg). A 3-week regimen included aerobic and resistance training thrice weekly. The aerobic intensity was 70%, and resistance varied from 50% to 100% of the maximal carrying capacity (MCC). Following the last training sessions, spatial memory and retrieval tests were performed in infancy, childhood, and emerging adulthood using the Morris Water Maze test (MWM). The hippocampus was excised to measure protein and gene expression of brain-derived neurotrophic factor (BDNF), calmodulin-dependent protein kinase (CAMKII), N-methyl-D-aspartate receptors (NMDAR), and cAMP-response element-binding protein (CREB) by western blotting and reverse transcription-polymerase-chain reaction (RT-PCR) methods. Blood samples were collected during each developmental stage to measure glucose levels, at the study's conclusion, to assess Interleukin-1β levels using the ELISA method. The Nissel staining assessed dead hippocampal cells in CA1. Post-natal exercise improved spatial memory (p < 0.05) and glucose levels (p < 0.05) in diabetic rats during adolescence and emerging adulthood. Despite reduced mRNA expression (NMDAR 40%, BDNF 62%, CREB 43%, CAMKII 66%), diabetic rats, by study end, showed increased BDNF, NMDARR, CAMKII, CREB protein/gene expression (p < 0.05) in emerging adulthood for both training groups. Early-life exercise influenced hippocampal BDNF/NMDAR-CAMKII/CREB pathways in a diabetic rat model, highlighting post-natal exercise's role in neuroplasticity memory enhancement and improved glucose level.

Cost-effectiveness of drug consumption rooms in France: a modelling study

BackgroundPeople who inject drugs (PWID) experience many health problems which result in a heavy economic and public health burden. To tackle this issue, France opened two drug consumption rooms (DCRs) in Paris and Strasbourg in 2016. This study assessed their long-term health benefits, costs and cost-effectiveness.MethodsWe developed a model to simulate two fictive cohorts for each city (n=2,997 in Paris and n=2,971 in Strasbourg) i) PWID attending a DCR over the period 2016-2026, ii) PWID attending no DCR. The model accounted for HIV and HCV infections, skin abscesses and related infective endocarditis, drug overdoses and emergency department visits. We estimated the number of health events and associated costs over 2016-2026, the lifetime number of quality-adjusted life-years (QALYs) and costs, and the incremental cost-effectiveness ratio (ICER).ResultsThe numbers of abscesses and associated infective endocarditis, drug overdoses, and emergency department visits decreased significantly in PWID attending DCRs (-77%, -69%, and -65%, respectively) but the impact on HIV and HCV infections was modest (-11% and -6%, respectively). This resulted in savings of €6.6 (Paris) and €5.8 (Strasbourg) millions of medical costs. The ICER of DRCs was €30,600/QALY (Paris) and €9,200/QALY (Strasbourg). In scenario analysis where drug consumption spaces are implemented inside existing harm reduction structures, these ICERs decreased to €21,400/QALY and €2,500/QALY, respectively.ConclusionsOur findings show that DCRs are highly effective and efficient to prevent harms in PWID in France, and advocate extending this intervention to other cities by adding drug consumption spaces inside existing harm reduction centers.

Public health impact of herpes zoster vaccination on older adults in Singapore: a modeling study

ABSTRACT In Singapore, population aging and rising life expectancy are increasing herpes zoster (HZ) burden, which may be reduced by vaccination. The present study modeled the public health impact of HZ vaccination in Singapore using ZOster ecoNomic Analysis (ZONA) model adapted with Singapore-specific key model inputs, where available. Base case analysis was conducted in adults ≥ 50 years of age (YOA), exploring three vaccination strategies (no vaccination, recombinant zoster vaccine [RZV], zoster vaccine live [ZVL]) under mass vaccination setting (30% coverage). Scenario and sensitivity analyses were performed. Out of 1.51 million adults in 2021 (base case population), 406,513 (27.0%) cases of HZ, 68,264 (4.5%) cases of post-herpetic neuralgia (PHN), and 54,949 (3.6%) cases of other complications were projected without vaccination. RZV was estimated to avoid 73,129 cases of HZ, 11,094 cases of PHN, and 9,205 cases of other complications over the subjects’ remaining lifetime; ZVL would avoid 17,565 cases of HZ, 2,781 cases of PHN, and 1,834 cases of other complications. The number needed to vaccinate to prevent one case of HZ/PHN was lower for RZV (7/41) than ZVL (26/163). Among all five age-stratified cohorts (50–59/60–64/65–69/70–79/≥80 YOA), RZV (versus no vaccination/ZVL) avoided the largest number of cases in the youngest cohort, 50–59 YOA. Results were robust under scenario and sensitivity analyses. Mass vaccination with RZV is expected to greatly reduce the public health burden of HZ among Singapore individuals ≥ 50 YOA. Findings support value assessment and decision-making regarding public health vaccination strategies for HZ prevention in Singapore.

Development in the Study of Mechanical Prop-erties and Damage Constitutive Models of Rub-ber-Reclaimed Concrete

Advances in rubber-reinforced concrete technology and its applications in engineering are cru-cial for the thorough recycling and safe disposal of waste tire rubber and construction debris. Rubber-reinforced concrete (RAC) is a concrete material produced by substituting some fine and coarse aggregates with waste rubber particles and recycled aggregates. The incorporation of waste rubber particles endows RAC with distinctive mechanical properties and a distinct damage constitutive model. The mechanical properties of rubber recycled concrete mainly in-clude compressive strength, tensile strength, flexural strength, and elastic modulus. Compared to traditional concrete, RAC exhibits slightly lower compressive and flexural strengths but sig-nificantly enhanced tensile strength. This is due to the changes in mechanical properties caused by the softness and elastic properties of rubber particles. In addition, the addition of rubber particles can also improve the energy absorption capacity and impact resistance of concrete. On the other hand, in order to describe the damage behavior of rubber recycled con-crete, some constitutive models were studied. Common models include linear elastic model, plastic model, and damage model. The linear elastic model is suitable for describing the be-havior of rubber recycled concrete during the elastic stage; The plastic model is suitable for describing its deformation behavior during the plastic stage; The damage model can better describe the fracture and failure behavior of rubber recycled concrete, including shear damage, tensile damage, and compression damage. Tailored to the unique characteristics of RAC, these models consider the stiffness of rubber particles and the deformation characteristics of the binding materials, enabling accurate predictions of the stress-strain behavior of RAC. In conclusion, rubber-reinforced concrete possesses excellent mechanical and durability proper-ties, which can be accurately described and predicted using appropriate constitutive models. These findings are crucial for advancing the application and development of rubber-reinforced concrete.