Physiological State Research Articles

An analytic method to investigate hemodynamics of the cardiovascular system: Biventricular system.

Previously, we found analytic solutions for single ventricular system based on the lumped parameter model (LPM). In this study, we generalized the method to biventricular system and derived its analytic solutions. LPM is just a set of differential equations, but it is difficult to solve due to time-varying ventricular elastance and high order. Mathematically, there exist no elementary solutions for time-varying equations. It turns out that instead of differential equations, according to volume conservation, a set of algebraic equations can be carried out. The solutions of the set of equations are just physiological states at end of systolic and diastolic phases such as end systolic/diastolic pressure/volume of left ventricle. As a preliminary application, the method is utilized to deduce the hemodynamic effects of VA ECMO. Left ventricular (LV) distension, a serious complication of VA ECMO, is usually attributed to factors such as increased afterload, inadequate LV unloading, reduced myocardial contractility or aortic valve regurgitation (AR), bronchial and Thebesian return in the absence of aortic valve (AoV) opening. Among these, reduced contractility and AR are strongly associated with LV distension. However, in the absence of reduced contractility or AR, it is less clear whether increased afterload or inadequate LV unloading alone can cause LV distension. This leads to the critical question: under what conditions does LV distension occur in the absence of reduced contractility or AR? The analytic formulas derived in this study give conditions for LV distension. Furthermore, the results show that the analytic hemodynamics are coincident with simulated results.

Phytoplankton cell-states: multiparameter fluorescence lifetime flow-based monitoring reveals cellular heterogeneity.

Phytoplankton are a major source of primary productivity. Their photosynthetic fluorescence are unique measures of their type, physiological state, and response to environmental conditions. Changes in phytoplankton photophysiology are commonly monitored by bulk fluorescence spectroscopy, where gradual changes are reported in response to different perturbations, such as light intensity changes. What is the meaning of such trends in bulk parameters if their values report ensemble averages of multiple unsynchronized cells? To answer this, we developed an experimental scheme that enables tracking fluorescence intensities, brightnesses, and their ratios, as well as mean photon nanotimes equivalent to mean fluorescence lifetimes, one cell at a time. We monitored three different phytoplankton species during diurnal cycles and in response to an abrupt increase in light intensity. Our results show that we can define specific subpopulations of cells by their fluorescence parameters for each of the phytoplankton species, and in response to varying light conditions. Importantly, we identify the cells undergo well-defined transitions between these subpopulations. The approach shown in this work will be useful in the exact characterization of phytoplankton cell states and parameter signatures in response to different changes these cells experience in marine environments, which will be applicable for monitoring marine-related environmental effects.

The Respiratory Compensation Point: Mechanisms and Relation to the Maximal Metabolic Steady State.

At a point during the latter third of an incremental exercise protocol, ventilation begins to exceed the rate of clearance of carbon dioxide (CO2) at the lungs ( CO2). The onset of this hyperventilation, which is confirmed by a fall from a period of stability in end-tidal and arterial CO2 tensions (PCO2), is referred to as the respiratory compensation point (RCP). The mechanisms that contribute to the RCP remain debated as does its surrogacy for the maximal metabolic steady state of constant-power exercise (i.e., the highest work rate associated with maintenance of physiological steady state). The objective of this current opinion is to summarize the original research contributions that support and refute the hypotheses that: (i) the RCP represents a rapid, peripheral chemoreceptor-mediated reflex response engaged when the metabolic rate at which the buffering systems can no longer constrain the rise in hydrogen ions ([H+]) associated with rising lactate concentration and metabolic CO2 production is surpassed; and (ii) the metabolic rate at which this occurs is equivalent to the maximal metabolic steady state of constant power exercise. In doing so, we will shed light on potential mechanisms contributing to the RCP, attempt to reconcile disparate findings, make a case for its adoption for exercise intensity stratification and propose strategies for the use of RCP in aerobic exercise prescription.

CombiningNitellopsis obtusaautofluorescence intensity and F680/F750 ratio to discriminate responses to environmental stressors.

Detection of autofluorescence parameters is a useful approach to gain insight into the physiological state of plants and algae, but the effect of reabsorption hinders unambiguous interpretation of in vivo data. The exceptional morphological features ofNitellopsis obtusamade it possible to measure autofluorescence spectra along single internodal cells and estimate relative changes in autofluorescence intensity in selected spectral regions at room temperatures, avoiding the problems associated with thick or optically dense samples. The response of algal cells to controlled white light and DCMU herbicide was analyzed by monitoring changes in peak FL intensity at 680 nm and in F680/F750 ratio. Determining the association between the selected spectral FL parameters revealed an exponential relationship, which provides a quantitative description of photoinduced changes. The ability to discern the effect of DCMU not only in the autofluorescence spectra of dark-adapted cells, but also in the case of light-adapted cells, and even after certain doses of excess light, suggests that the proposed autofluorescence analysis ofN. obtusamay be useful for detecting external stressors in the field.

Moderate Drought Stress Interferes with the Physiological State and Promotes the Accumulation of Isoflavone in Reproductive Iris domestica Rhizomes

Drought stress is one of the main factors affecting the growth and secondary metabolism of plants. Iris domestica, rich in isoflavones, is a common herbal medicine in China. In this study, the effects of drought stress and rehydration on resistance physiological characteristics and the secondary metabolism of two-year-old I. domestica during the vegetative and reproductive growth period were investigated. The results showed that the dry weight and fresh weight of rhizomes and roots under severe drought stress were significantly decreased, while those under moderate drought stress were not significantly changed. Meanwhile, the SOD activities, POD activities, MDA content and Pro content increased to resist drought at D1 and D2. In the vegetative growth period, the changes in isoflavone concentration and the expression levels of genes in isoflavone synthesis were more dramatic. Isoflavone accumulation was promoted, to some extent, in the reproductive growth period under the D1 drought treatment. In the actual production process, different measures, namely short-term stress regulation in the vegetative growth period and moderate drought stress (13.44% < soil water content ≤ 16.8%) in the reproductive growth period, need to be adopted to regulate isoflavone biosynthesis.

Quantitative non-contrast perfusion MRI in the body using arterial spin labeling.

Arterial spin labeling (ASL) is a non-invasive magnetic resonance imaging (MRI) method that enables the assessment and the quantification of perfusion without the need for an exogenous contrast agent. ASL was originally developed in the early 1990s to measure cerebral blood flow. The utility of ASL has since then broadened to encompass various organ systems, offering insights into physiological and pathological states. In this review article, we present a synopsis of ASL for quantitative non-contrast perfusion MRI, as a contribution to the special issue titled "Quantitative MRI-how to make it work in the body?" The article begins with an introduction to ASL principles, followed by different labeling strategies, such as pulsed, continuous, pseudo-continuous, and velocity-selective approaches, and their role in perfusion quantification. We proceed to address the technical challenges associated with ASL in the body and outline some of the innovative approaches devised to surmount these issues. Subsequently, we summarize potential clinical applications, challenges, and state-of-the-art ASL methods to quantify perfusion in some of the highly perfused organs in the thorax (lungs), abdomen (kidneys, liver, pancreas), and pelvis (placenta) of the human body. The article concludes by discussing future directions for successful translation of quantitative ASL in body imaging.

Enhancing Row-column array (RCA)-based 3D ultrasound vascular imaging with spatial-temporal similarity weighting.

Ultrasound vascular imaging (UVI) is a valuable tool for monitoring the physiological states and evaluating the pathological diseases. Advancing from conventional two-dimensional (2D) to three-dimensional (3D) UVI would enhance the vasculature visualization, thereby improving its reliability. Row-column array (RCA) has emerged as a promising approach for cost-effective ultrafast 3D imaging with a low channel count. However, ultrafast RCA imaging is often hampered by high-level sidelobe artifacts and low signal-to-noise ratio (SNR), which makes RCA-based UVI challenging. In this study, we propose a spatial-temporal similarity weighting (St-SW) method to overcome these challenges by exploiting the incoherence of sidelobe artifacts and noise between datasets acquired using orthogonal transmissions. Simulation, in vitro blood flow phantom, and in vivo experiments were conducted to compare the proposed method with existing orthogonal plane wave imaging (OPW), row-column-specific frame-multiply-and-sum beamforming (RC-FMAS), and XDoppler techniques. Qualitative and quantitative results demonstrate the superior performance of the proposed method. In simulations, the proposed method reduced the sidelobe level by 31.3 dB, 20.8 dB, and 14.0 dB, compared to OPW, XDoppler, and RC-FMAS, respectively. In the blood flow phantom experiment, the proposed method significantly improved the contrast-to-noise ratio (CNR) of the tube by 26.8 dB, 25.5 dB, and 19.7 dB, compared to OPW, XDoppler, and RC-FMAS methods, respectively. In the human submandibular gland experiment, it not only reconstructed a more complete vasculature but also improved the CNR by more than 15 dB, compared to OPW, XDoppler, and RC-FMAS methods. In summary, the proposed method effectively suppresses the side-lobe artifacts and noise in images collected using an RCA under low SNR conditions, leading to improved visualization of 3D vasculatures.

Segmenting hydrogen‐induced cracking defects in steel through scanning acoustic microscopy and deep neural networks

AbstractHydrogen‐induced cracking (HIC) presents a significant concern in industries, such as oil and gas, petrochemicals, and aerospace, where high‐strength steel is prevalently used. This phenomenon compromises the structural integrity of steel pipelines and equipment. Accurate detection and monitoring of HIC are crucial for the safety and reliability of these assets. While traditional defect detection methods are usually costly and easily affected by human physiological state, deep learning approaches offer both time and financial benefits along with high accuracy. This study focuses on employing deep learning to segment HIC in steel, utilizing the robust and state‐of‐the‐art YOLOv8‐seg architecture for defect identification and segmentation. The process involves acquiring two‐dimensional B‐scan images through a scanning acoustic microscopy (SAM) system, followed by employing the YOLOv8‐seg architecture to address the segmentation task within these images. The experimental results demonstrate the effectiveness of the YOLOv8‐seg model, achieving a mean average precision (mAP) score greater than ˜0.95. Notably, this research pioneers the development of a framework for reconstructing HIC within steel based on B‐scan image segmentation results, offering researchers and professionals a comprehensive understanding of internal defects in steel blocks. This work underscores the potential of YOLOv8‐seg architecture for accurate detection and segmentation of HIC in steel, providing a valuable tool for inspection and maintenance activities.

Exploring the Potential of a Smart Ring to Predict Postoperative Pain Outcomes in Orthopedic Surgery Patients

Poor pain alleviation remains a problem following orthopedic surgery, leading to prolonged recovery time, increased morbidity, and prolonged opioid use after hospitalization. Wearable device data, collected during postsurgical recovery, may help ameliorate poor pain alleviation because a patient’s physiological state during the recovery process may be inferred from sensor data. In this study, we collected smart ring data from 37 inpatients following orthopedic surgery and developed machine learning models to predict if a patient had postsurgical poor pain alleviation. Machine learning models based on the smart ring data were able to predict if a patient had poor pain alleviation during their hospital stay with an accuracy of 70.0%, an F1-score of 0.769, and an area under the receiver operating characteristics curve of 0.762 on an independent test dataset. These values were similar to performance metrics from existing models that rely on static, preoperative patient factors. Our results provide preliminary evidence that wearable device data may help control pain after orthopedic surgery by incorporating real-time, objective estimates of a patient’s pain during recovery.

Proximity labeling reveals dynamic changes in the SQSTM1 protein network

Sequestosome1 (SQSTM1) is an autophagy receptor that mediates degradation of intracellular cargo, including protein aggregates, through multiple protein interactions. These interactions form the SQSTM1 protein network, and these interactions are mediated by SQSTM1 functional interaction domains, which include LIR, PB1, UBA and KIR. Technological advances in cell biology continue to expand our knowledge of the SQSTM1 protein network and of the relationship of the actions of the SQSTM1 protein network in cellular physiology and disease states. Here we apply proximity profile labeling to investigate the SQSTM1 protein interaction network by fusing TurboID with the human protein SQSTM1 (TurboID::SQSTM1). This chimeric protein displayed well-established SQSTM1 features including production of SQSTM1 intracellular bodies, binding to known SQSTM1 interacting partners, and capture of novel SQSTM1 protein interactors. Strikingly, aggregated tau protein altered the protein interaction network of SQSTM1 to include many stress-associated proteins. We demonstrate the importance of the PB1 and/or UBA domains for binding network members, including the K18 domain of tau. Overall, our work reveals the dynamic landscape of the SQSTM1 protein network and offers a resource to study SQSTM1 function in cellular physiology and disease state.

Practical Advice on Measuring and Applying Light for Laboratory Mammals.

Light is recognized as an important component of the environment for laboratory animals. It supports vision, sets the phase of circadian clocks, and drives wide-ranging adjustments in physiological and behavioral state. Manipulating light is meanwhile a key experimental approach in the fields of vision science and chronobiology. Nevertheless, until recently, there has been no consensus on methods for quantifying light as experienced by laboratory animals. Widely adopted practices employ metrics such as illuminance (units = lux) that are designed to quantify light as experienced by human observers. These weight energy across the spectrum according to a spectral sensitivity profile for human vision that is not widely replicated for non-human species. Recently, a Consensus View was published that proposes methods of light measurement and standardization that take account of these species-specific differences in wavelength sensitivity. Here, we draw upon the contents of that consensus to provide simplified advice on light measurement in laboratory mammal experimentation and husbandry and quantitative guidance on what constitutes appropriate lighting for both visual and circadian function.

Optimization of oral isavuconazole dose for population in special physiological or pathological state: a physiologically based pharmacokinetics model-informed precision dosing.

To recommend precision dosing and improve therapeutic efficacy against invasive fungal disease, a physiologically based pharmacokinetic model (PBPK) of oral isavuconazole (ISA) was established and used to explore its disposition across populations in different physiological and pathological states. Twenty-five pharmacokinetic (PK) studies of oral ISA were identified through a systematic search of PubMed. Concentration-time data were extracted using WebPlotDigitizer. Physiochemical parameters were obtained from published literature and DrugBank. Model development and simulation used the Simcyp population-based simulator, and visual predictive check and predictive error were used for the model evaluation. Probability of target attainment and the cumulative fraction of response analyses were performed for dose optimization. The developed PBPK model was successfully validated in different populations. Most predicted concentration-time points aligned with the observed data, with acceptable predictive errors for the critical parameters. We predicted the PK profiles and parameters of ISA in a population with severe hepatic impairment (HI), a population with obesity and paediatric patients aged 1 to less than 6 years old. The probability of target attainment and cumulative fraction of response analyses indicated that the population with severe HI should have half the maintenance dose. The population with obesity and population with severe HI should have a loading dose of 300 mg every 8 h for 2 days. For paediatric patients aged 1 to less than 6 years old, a weight-based dosing regimen (5.38 mg/kg) of ISA was suggested. The predicted value aligns with observations, suggesting ISA's potential predictability in PK profiles for other populations. The recommended dosing regimens increase our understanding of the use of ISA in special populations.

An overview of benefits and risks of chronic melanocortin-1 receptor activation.

The melanocortin-1 receptor (MC1R) is a G protein-coupled receptor that plays a pivotal role in human skin pigmentation, melanin synthesis, redox homeostasis and inflammation. Loss-of-function MC1R variants suppress G protein-coupled receptor coupling or cell surface expression leading to a decrease in adenyl cyclase activation and intracellular levels of cyclic adenosine monophosphate. Chronic activation of MC1R can occur in certain medical conditions such as Addison's disease and physiologic states such as pregnancy melasma. MC1R activation is more commonly caused by environmental exposure to ultraviolet (UV) radiation. Approved pharmacologic melanocortin agonists that activate MC1R signalling in a targeted manner or as a bystander effect have recently become available for erythropoietic protoporphyria, sexual desire disorders, monogenic obesity and syndromic obesity. Further, small peptide analogues of α-melanocortin-stimulating hormone, human MC1R selective agonists, are photoprotective, decreasing the adverse impact of UV radiation (a primary risk factor for skin cancer) and are being investigated as potential chemoprevention strategies. MC1R activation through induction of UV-protective skin pigmentation increased DNA repair, and control of aberrant cell growth may reduce the risk of melanoma but importantly does not prevent melanoma particularly in individuals with risk factors and regular skin examination remains critical in high-risk individuals.

Morphological and physiological investigations reveal the regulatory effect of exogenous paclobutrazol on flowering promotion by winter warming in Chaenomeles speciosa ‘Changshouguan’

The application of exogenous paclobutrazol (PP333) can improve the ability of winter warming to promote flowering in Chaenomeles speciosa, but the underlying mechanism is unclear. In this study, the cultivar ‘Changshouguan’ was sprayed with different concentrations of PP333 during flower bud differentiation, and the changes in the anatomical structures and physiological characteristics of the flower buds during the differentiation process, as well as the growth state of the flower buds and the effect on flowering promotion after winter warming treatment, were comprehensively investigated. The results showed that different concentrations of PP333 could advance the flowering time of ‘Changshouguan’ by 15–24 d under the warming treatment and increase the flowering duration to 17 d compared with those under the warming treatment alone (CK), and 1000 mg/L was the best treatment. Compared with the CK treatment, the PP333 treatment decreased the contents of indole acetic acid (IAA) and gibberellic acid (GAs) and increased the contents of zeatin ribosides (ZRs) and abscisic acid (ABA), thus changing the balance of hormones during flower bud differentiation. The inflection point (low point) of the curve shapes of the ZRs/GAs and ZRs/IAA ratios appeared significantly earlier, which showed a pattern consistent with soluble sugar and protein content and antioxidant activity. Interestingly, the above changes also corresponded to earlier flowering times during the warming process. Taken together, these results indicate that spraying an appropriate concentration of PP333 in the early stage of ‘Changshouguan’ flower bud differentiation promotes the early differentiation of flower buds and early flowering under winter warming treatment by altering their endogenous hormone content and homeostasis and changing their physiological state. The key to maintaining a relatively long flowering period in plants in the PP333 treatment group after flowering promotion was the increased accumulation of sugars and proteins.

Физиологическое состояние стерляди в условиях садковых и бассейновых хозяйств

The growing conditions of sturgeon fish affect the growth and physiological state, their morphological characteristics. The study of changes in physiological processes under the influence of a complex of factors in the conditions of cage complexes and closed water supply systems will allow for timely adjustment of technology and reduce risks when growing commercial products. The repair and breeding herds of fish breeding enterprises contain sterlet individuals of different ages, which annually, upon reaching puberty, enter the fish breeding process as producers. In this regard, we have studied the main morphophysiological indicators of two-year-olds kept in cages and in closed water supply installations (CWSI). The influence of environmental factors was noted not only on growth indicators, but also on the size of the internal organs of fish and their condition. The unstable temperature regime in the cages, dependence on unpredictable changes in the hydrochemical parameters of the aquatic environment contributes to deep physiological transformations of an adaptive nature, which slows down the growth rate and accumulation of reserve substances. Changes in morphometric parameters were also evident. In sturgeon, there is an increase in the relative weight of the heart, spleen and gonads, a decrease in the weight of the kidneys and liver. The influence of optimal temperature and trophic conditions on the index of the gastrointestinal tract was noted, which was slightly lower in fish from the CWSI than in individuals exposed to negative factors in cages. Sterlet blood counts, regardless of the conditions of detention, corresponded to physiologically healthy individuals. The creation of optimal hydrological and trophic conditions in CWSI contribute to the accumulation of phospholipids and linolenic fatty acids in tissues, which play an important role in the adaptation of the body to negative environmental factors.

Preoperative nutritional assessment by using subjective and objective criteria and its implication in the outcome of cancer patients undergoing abdomino-pelvic surgeries

The World Health Organization (WHO) defines “nutritional status” as the condition of the body resulting from the intake, absorption, and utilization of nutrients and the influence of particular physiological and pathological status.[1] Globally, malnutrition affects a significant proportion of individuals, with prevalence rates ranging from 30% to 85%, particularly prevalent among patients with gastric, pancreatic, lung, prostate, and colon cancers.[2] In cancer patients, malnutrition is associated with decreased treatment tolerance, increased postoperative morbidity and mortality, and diminished quality of life [3]The evaluation of nutritional status in cancer patients commonly relies on subjective methods such as the Patient-Generated Subjective Global Assessment (PG-SGA)[4] and objective measures like anthropometry and biochemical parameters[5]. Despite their widespread use, no single method is universally accepted as the "gold standard," each possessing its’ inherent limitations.

Water relations and photosystem II efficiency of the intertidal macroalga Fucus virsoides

Intertidal macroalgae are sessile poikilohydric organisms exposed to desiccation stress during emersion. Water relations parameters are useful tools to evaluate an organism's capacity to withstand water scarcity conditions, but such information on marine intertidal macroalgae is scarce. We assessed the water relations of the intertidal relict Fucus virsoides, the unique Fucus species endemic to the Mediterranean. We combined measurements of water potential (Ψ) parameters derived from pressure-volume curves and chlorophyll a fluorescence (Fv/Fm) in juvenile and adult thalli sampled in three different dates between March and April 2023. F. virsoides exhibited remarkable water stress tolerance, as evidenced by the low water potential at turgor loss point (Ψtlp, -7.0 MPa on average), and the maintenance of high Fv/Fm at low water potentials indicating a prolonged maintenance of healthy physiological status. While no differences were observed between growth stages, Ψtlp, capacitance (C) and the bulk modulus of elasticity (ε) varied significantly according to the sampling dates, whereas the osmotic potential at full turgor did not significantly change. Ψ measured on thalli collected after a typical prolonged emersion period was markedly lower (−12.3 MPa on average) than the estimated Ψtlp, suggesting that the population is frequently undergoing turgor loss. Further investigations are required to determine environmental tolerance ranges based on water status characteristics to enhance our understanding of F. virsoides responses and vulnerability to climate change, thus providing insight into the possible causes of its widespread decline.

Влияние кормовой пробиотической добавки «Ветоспорин-Ж» (Bacillus subtilis) и минеральной добавки «Цеолит» (опока) на проявление генотоксических эффектов в клетках крови молоди стерляди (Acipenser ruthenus) в условиях аквакультуры

In modern conditions of declining natural sturgeon populations in the Volga-Caspian basin, the role and importance of aquaculture is increasing. In the Astrakhan region, due to the presence of a large natural water fund, cage farming of fish, including sterlet, is widely developed. Cage farming of sturgeon in natural water bodies is associated with the impact of anthropogenic pollution, in this area it is associated with water pollution in the river delta Volga, and the deterioration of the hydrochemical regime, which directly affects fish farming. One of the factors of the negative impact of these changes in the aquatic environment is genotoxicity, the degree of manifestation of which can be assessed using accessible and modern methods, which include micronuclear and DNA comet tests. A serious consequence of the genotoxic effect of pollution is the formation of damage to the DNA of the fish body. The purpose of this work was to assess the frequency of appearance of micronuclei and the degree of DNA damage in the blood cells of juvenile sterlet, as well as the selection of functional additives in food that will reduce the effects of genotoxic pressure from a natural water source. In a scientific laboratory, a series of experiments was carried out on feeding juvenile sterlet delivered from a fish farm in the Volga delta. All juvenile sterlet, both at the beginning and at the end of the experiment, were characterized by a normal physiological state, low levels of DNA comets, and the number of erythrocytes with micronuclei was slightly higher than normal. As a result of experimental feeding, reliable data were obtained that food with the addition of the probiotic drug “Vetosporin-Zh” based on the bacteria Bacillus subtilis contributed to a significant increase in weight gain and body length. All analyzed indicators of DNA comets were significantly lower in the group that was fed with the introduction of a probiotic (the micronucleus test turned out to be less sensitive in this case). The mineral additive “Zeolite” did not show such effectiveness. Thus, the addition of Bacillus subtilis-based preparations when feeding juvenile sturgeon can be reasonably recommended to effectively reduce genotoxic stress for fish, mainly to reduce DNA damage.

An Investigation into the Effects of Correlated Color Temperature and Illuminance of Urban Motor Vehicle Road Lighting on Driver Alertness

Current international optical science research focuses on the non-visual effects of lighting on human cognition, mood, and biological rhythms to enhance overall well-being. Nocturnal roadway lighting, in particular, has a substantial impact on drivers’ physiological and psychological states, influencing behavior and safety. This study investigates the non-visual effects of correlated color temperature (CCT: 3000K vs. 4000K vs. 5000K) and illuminance levels (20 lx vs. 30 lx) of urban motor vehicle road lighting on driver alertness during various driving tasks. Conducted between 19:00 and 20:30, the experiments utilized a human-vehicle-light simulation platform. EEG (β waves), reaction time, and subjective evaluations using the Karolinska Sleepiness Scale (KSS) were measured. The results indicated that the interaction between CCT and illuminance, as well as between CCT and task type, significantly influenced driver alertness. However, no significant effect of CCT and illuminance on reaction time was observed. The findings suggest that higher illuminance (30 lx) combined with medium CCT (4000K) effectively reduces reaction time. This investigation enriches related research, provides valuable reference for future studies, and enhances understanding of the mechanisms of lighting’s influence on driver alertness. Moreover, the findings have significant implications for optimizing the design of urban road lighting.

A rule-based multiscale model of hepatic stellate cell plasticity: Critical role of the inactivation loop in fibrosis progression.

Hepatic stellate cells (HSC) are the source of extracellular matrix (ECM) whose overproduction leads to fibrosis, a condition that impairs liver functions in chronic liver diseases. Understanding the dynamics of HSCs will provide insights needed to develop new therapeutic approaches. Few models of hepatic fibrosis have been proposed, and none of them include the heterogeneity of HSC phenotypes recently highlighted by single-cell RNA sequencing analyses. Here, we developed rule-based models to study HSC dynamics during fibrosis progression and reversion. We used the Kappa graph rewriting language, for which we used tokens and counters to overcome temporal explosion. HSCs are modeled as agents that present seven physiological cellular states and that interact with (TGFβ1) molecules which regulate HSC activation and the secretion of type I collagen, the main component of the ECM. Simulation studies revealed the critical role of the HSC inactivation process during fibrosis progression and reversion. While inactivation allows elimination of activated HSCs during reversion steps, reactivation loops of inactivated HSCs (iHSCs) are required to sustain fibrosis. Furthermore, we demonstrated the model's sensitivity to (TGFβ1) parameters, suggesting its adaptability to a variety of pathophysiological conditions for which levels of (TGFβ1) production associated with the inflammatory response differ. Using new experimental data from a mouse model of CCl4-induced liver fibrosis, we validated the predicted ECM dynamics. Our model also predicts the accumulation of iHSCs during chronic liver disease. By analyzing RNA sequencing data from patients with non-alcoholic steatohepatitis (NASH) associated with liver fibrosis, we confirmed this accumulation, identifying iHSCs as novel markers of fibrosis progression. Overall, our study provides the first model of HSC dynamics in chronic liver disease that can be used to explore the regulatory role of iHSCs in liver homeostasis. Moreover, our model can also be generalized to fibroblasts during repair and fibrosis in other tissues.