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Summary: The utilisation of in vitro digestive simulation models holds significant importance in the development, quality control, and safety evaluation of functional foods. This review presents an overview of the classification, design, and construction methods of in vitro digestive models while summarising the emerging trends towards miniaturisation and intelligence. Miniaturisation technology enhances the ability of these models to simulate physiological processes within the human digestive system more accurately, thereby improving experiment repeatability and controllability. Intelligent technology further facilitates optimal design, data collection, and analysis for in vitro digestive models. [ABSTRACT FROM AUTHOR]

The mechanism behind hemodialysis arteriovenous fistula (AVF) failure remains poorly understood, despite previous efforts to correlate altered hemodynamics with vascular remodeling. We have recently demonstrated that transitional flow induces high-frequency vibrations in the AVF wall, albeit with a simplified model. This study addresses the key limitations of our original fluid–structure interaction (FSI) approach, aiming to evaluate the vibration response using a more realistic model. A 3D AVF geometry was generated from contrast-free MRI and high-fidelity FSI simulations were performed. Patient-specific inflow and pressure were incorporated, and a three-term Mooney–Rivlin model was fitted using experimental data. The viscoelastic effect of perivascular tissue was modeled with Robin boundary conditions. Prescribing pulsatile inflow and pressure resulted in a substantial increase in vein displacement ( + 400 %) and strain ( + 317 %), with a higher maximum spectral frequency becoming visible above -42 dB (from 200 to 500 Hz). Transitioning from Saint Venant–Kirchhoff to Mooney–Rivlin model led to displacement amplitudes exceeding 10 micrometers and had a substantial impact on strain ( + 116 %). Robin boundary conditions significantly damped high-frequency displacement ( - 60 %). Incorporating venous tissue properties increased vibrations by 91%, extending up to 700 Hz, with a maximum strain of 0.158. Notably, our results show localized, high levels of vibration at the inner curvature of the vein, a site known for experiencing pronounced remodeling. Our findings, consistent with experimental and clinical reports of bruits and thrills, underscore the significance of incorporating physiologically plausible modeling approaches to investigate the role of wall vibrations in AVF remodeling and failure. [ABSTRACT FROM AUTHOR]

Background: We used two 3D ultrasound volumes of fetal heads at 13 weeks to create live-size 3D-printed phantoms with a view to training or assessment of diagnostic abilities for normal and abnormal nuchal translucency measurements. The phantoms are suitable for use in a water bath, imitating a real-life exam. They were then used to study measurement accuracy and reproducibility in examiners of different skill levels. Methods: Ultrasound scans of a 13 + 0-week fetus were processed using 3D Slicer software, producing a stereolithography file for 3D printing. The model, crafted in Autodesk Fusion360™, adhered to FMF guidelines for NT dimensions (NT 2.3 mm). Additionally, a model with pathologic NT was designed (NT 4.2 mm). Printing was performed via Formlabs Form 3® printer using High Temp Resin V2. The externally identical looking 3D models were embedded in water-filled condoms for ultrasound examination. Eight specialists of varying expertise levels conducted five NT measurements for each model, classifying them in physiological and abnormal models. Results: Classification of the models in physiological or abnormal NT resulted in a detection rate of 100%. Average measurements for the normal NT model and the increased NT model were 2.27 mm (SD ± 0.38) and 4.165 mm (SD ± 0.51), respectively. The interrater reliability was calculated via the intraclass correlation coefficient (ICC) which yielded a result of 0.883, indicating robust agreement between the raters. Cost-effectiveness analysis demonstrated the economical nature of the 3D printing process. Discussion: This study underscores the potential of 3D printed fetal models for enhancing ultrasound training through high inter-rater reliability, consistency across different expert levels, and cost-effectiveness. Limitations, including population variability and direct translation to clinical outcomes, warrant further exploration. The study contributes to ongoing discussions on integrating innovative technologies into medical education, offering a practical and economical method to acquire, refine and revise diagnostic skills in prenatal ultrasound. Future research should explore broader applications and long-term economic implications, paving the way for transformative advancements in medical training and practice. [ABSTRACT FROM AUTHOR]

This work was conducted mainly to provide a healthy and safe monitoring system for the elderly living in the home environment. In this paper, two different target fall detection schemes are proposed based on whether the target is visible or not. When the target is visible, a vision-based fall detection algorithm is proposed, where an image of the target captured by a camera is transmitted to the improved You Only Look Once version 5s (YOLOv5s) model for posture detection. In contrast, when the target is invisible, a WiFi-based fall detection algorithm is proposed, where channel state information (CSI) signals are used to estimate the target's posture with an improved long short-term memory (LSTM) model. In the improved YOLOv5s model, adaptive picture scaling technology named Letterbox is used to maintain consistency in the aspect ratio of images in the dataset, and the weighted bidirectional feature pyramid (BiFPN) and the attention mechanisms of squeeze-and-excitation (SE) and coordinate attention (CA) modules are added to the Backbone network and Neck network, respectively. In the improved LSTM model, the Hampel filter is used to eliminate the noise from CSI signals and the convolutional neural network (CNN) model is combined with the LSTM to process the image made from CSI signals, and thus the object of the improved LSTM model at a point in time is the analysis of the amplitude of 90 CSI signals. The final monitoring result of the health status of the target is the result of combining the fall detection of the improved YOLOv5s and LSTM models with the physiological information of the target. Experimental results show the following: (1) the detection precision, recall rate, and average precision of the improved YOLOv5s model are increased by 7.2%, 9%, and 7.6%, respectively, compared with the original model, and there is almost no missed detection of the target; (2) the detection accuracy of the improved LSTM model is improved by 15.61%, 29.36%, and 52.39% compared with the original LSTM, CNN, and neural network (NN) models, respectively, while the convergence speed is improved by 90% compared with the original LSTM model; and (3) the proposed algorithm can meet the requirements of accurate, real-time, and stable applications of health monitoring. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady‐state systemic exposure on co‐administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5–12.5 mg/kg and fluconazole at 3–12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co‐administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0−t) was increased by approximately sevenfold and five to threefold by strong and high‐moderate and low‐moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies. [ABSTRACT FROM AUTHOR]

The authors discusses the wide availability of analytical procedures for determining exercise physiology thresholds that has led to uncertainty about the method that may offer the highest precision or accuracy for regular testing. They explain the need for a consensus about exercise threshold determination to validate the pioneering physiological models proposed by the research groups of Wildor Hollman and Karlman Wasserman.

Forests are critical to water resources, but high evapotranspiration (ET) can reduce water yield. Thinning and prescribed fire reduce forest density and often reduce ET, promoting higher water yield. However, results from such treatments have been inconsistent, possibly because of unknown interactions among individual ET components. We compare water budget components of longleaf pine (Pinus palustris Mill.) woodlands with frequent prescribed fire to the water budget components of fire‐excluded stands. We hypothesized that fire exclusion would result in higher ET due to increased midstory transpiration (Et) and interception (Ei), and higher evaporation from litter (Ilitter). Reference plots were burned every two years while treatment plots had fire excluded for 15–20 years. Fire treatments were repeated in two sites representing a soil moisture gradient, noted as mesic and xeric. We measured woody Et using sap flux, and we modeled groundcover Et using physiological models. We measured Ei of canopy and groundcover layers, modeled Es litter biomass, and constructed a total component‐based water budget for each site and treatment. Compared with reference plots, midstory Et was 300%–800% higher in fire exclusion plots. Groundcover Et was ~80% less than reference treatments, countering the effects of midstory growth on total ET. Stand Ei followed similar trends, with groundcover Ei in reference plots countering the effects of midstory and litter Ei in fire exclusion plots. As expected, total ET in the xeric site was 18% higher in fire exclusion plots. However, ET in the mesic site was 16% lower in the fire exclusion plots due to high groundcover Et and Ei in reference plots. Thus, our results show that fire exclusion changes total forest ET, but the size and direction of the effect vary depending on the balance between midstory and groundcover transpiration and interception. These results highlight the importance of groundcover in ecosystem function in low‐density forests and may help explain inconsistent results from studies of water yields following thinning and fire. While prescribed fire is a valuable tool in forest management, we suggest that the effects of fire on ET are complex and require careful accounting of all water fluxes within a forest ecosystem. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is a bacterium of great global importance, responsible for more than one million deaths per year. This bacterium is commonly acquired in the first years of life and colonizes the upper respiratory tract asymptomatically by forming biofilms that persist for extended times in the nasopharynx. However, under conditions that alter the bacterial environment, such as viral infections, pneumococci can escape from the biofilm and invade other niches, causing local and systemic disease of varying severity. The polyamine transporter PotABCD is required for optimal survival of the organism in the host. Immunization of mice with recombinant PotD can reduce subsequent bacterial colonization. PotD has also been suggested to be involved in pneumococcal biofilm development. Therefore, in this study we aimed to elucidate the role of PotABCD and polyamines in pneumococcal biofilm formation. First, the formation of biofilms was evaluated in the presence of exogenous polyamines–the substrate transported by PotABCD–added to culture medium. Next, a potABCD-negative strain was used to determine biofilm formation in different model systems using diverse levels of complexity from abiotic surface to cell substrate to in vivo animal models and was compared with its wild-type strain. The results showed that adding more polyamines to the medium stimulated biofilm formation, suggesting a direct correlation between polyamines and biofilm formation. Also, deletion of potABCD operon impaired biofilm formation in all models tested. Interestingly, more differences between wild-type and mutant strains were observed in the more complex model, which emphasizes the significance of employing more physiological models in studying biofilm formation. [ABSTRACT FROM AUTHOR]

In order to improve the prediction accuracy of the sound quality of vehicle interior noise, a novel sound quality prediction model was proposed based on the physiological response predicted metrics, i.e., loudness, sharpness, and roughness. First, a human-ear sound transmission model was constructed by combining the outer and middle ear finite element model with the cochlear transmission line model. This model converted external input noise into cochlear basilar membrane response. Second, the physiological perception models of loudness, sharpness, and roughness were constructed by transforming the basilar membrane response into sound perception related to neuronal firing. Finally, taking the calculated loudness, sharpness, and roughness of the physiological model and the subjective evaluation values of vehicle interior noise as the parameters, a sound quality prediction model was constructed by TabNet model. The results demonstrate that the loudness, sharpness, and roughness computed by the human-ear physiological model exhibit a stronger correlation with the subjective evaluation of sound quality annoyance compared to traditional psychoacoustic parameters. Furthermore, the average error percentage of sound quality prediction based on the physiological model is only 3.81%, which is lower than that based on traditional psychoacoustic parameters. [ABSTRACT FROM AUTHOR]

Abstract The purpose of this study was to investigate the effectiveness of two non‐invasive mechanical ventilation (NIV) modalities to treat sleep apnea: (1) Average Volume Assured Pressure Support (AVAPS) NIV, and (2) Pressure Support (PS) NIV with Continuously Calculated Average Required Ventilation (CCARV). Two detailed (previously developed and tested) simulation models were used to assess the effectiveness of the NIV modalities. One simulated subjects without chronic obstructive pulmonary disease (COPD), and the other simulated patients with COPD. Sleep apnea was simulated in each model (COPD and Non‐COPD), and the ability of each NIV modality to normalize breathing was measured. In both NIV modalities, a low level continuous positive airway pressure was used and a backup respiratory rate was added to the algorithm in order to minimize the respiratory work rate. Both modalities could help normalize breathing in response to an episode of sleep apnea within about 5 min (during which time blood gases were within safe limits). AVAPS NIV and PS NIV with CCARV have potential value to be used for treatment of sleep apnea. Clinical evaluations are needed to fully assess the effectiveness of these NIV modalities.

Introduction: Type 1 Diabetes (T1D) affects over 9 million worldwide and necessitates meticulous self-management for blood glucose (BG) control. Utilizing BG prediction technology allows for increased BG control and a reduction in the diabetes burden caused by self-management requirements. This paper reviews BG prediction models in T1D, which include nutritional components. Method: A systematic search, utilizing the PRISMA guidelines, identified articles focusing on BG prediction algorithms for T1D that incorporate nutritional variables. Eligible studies were screened and analyzed for model type, inclusion of additional aspects in the model, prediction horizon, patient population, inputs, and accuracy. Results: The study categorizes 138 blood glucose prediction models into data-driven (54%), physiological (14%), and hybrid (33%) types. Prediction horizons of ≤30 min are used in 36% of models, 31–60 min in 34%, 61–90 min in 11%, 91–120 min in 10%, and >120 min in 9%. Neural networks are the most used data-driven technique (47%), and simple carbohydrate intake is commonly included in models (data-driven: 72%, physiological: 52%, hybrid: 67%). Real or free-living data are predominantly used (83%). Conclusion: The primary goal of blood glucose prediction in T1D is to enable informed decisions and maintain safe BG levels, considering the impact of all nutrients for meal planning and clinical relevance. [ABSTRACT FROM AUTHOR]

Damaged articular cartilage has limited self-healing potential and often leads to osteoarthritis (OA), pain, and dysfunction of the affected joint. Autologous and allogenic transplants cannot fully meet the needs of clinical treatment. Two dimensional (2D) and three-dimensional (3D) cell cultures can help to study growth modeling and physiological characteristics of the human body. Among the problems that 2D and single-layer cultures have the lack of proper and accurate tissue modeling and the lack of tissue complications similar is to the original tissue. With organoid models, cellular and tissue structural studies and functional and physiological studies of tissues have been revolutionized and more accurate. Organoids are useful for studying repair and drug efficacy. Physiological and pathological investigations by combining in vitro and in vivo methods have become more effective today. The purpose of this study is to investigate the factors involved in the formation of cartilage organoids so that we can introduce the best method of organoid production for the healing of cartilage damage by using cell types and organoid model. [ABSTRACT FROM AUTHOR]

Vulnerability curves (VCs) have been measured extensively to describe the differences in plant vulnerability to cavitation. Although the roles of hydraulic conductivity (K s,max) and hydraulic safety (P50, embolism resistance), both of which are parameters of VCs ('sigmoidal' type), in tree demography have been evaluated across different forests, the direct linkages between VCs and tree demography are rarely explored. In this study, we combined measured VCs and plot data of 16 tree species in Panamanian seasonal tropical forests to investigate the connections between VCs and tree mortality, recruitment and growth. We found that the mortality and recruitment rates of evergreen species were most significantly positively correlated with P50. However, the mortality and recruitment rates of deciduous species only exhibited significant positive correlations with parameter a , which describes the steepness of VCs and indicates the sensitivity of conductivity loss with water potential decline, but is often neglected. These differences among evergreen and deciduous species may contribute to the poor performance of existing quantitative relationships (such as the fitting relationships for all 16 species) in capturing tree mortality and recruitment dynamics. Additionally, evergreen species presented a significant positive relationship between relative growth rate (RGR) and K s,max, while deciduous species did not display such relationship. The RGR of both evergreen and deciduous species also displayed no significant correlations with P50 and a. Further analysis demonstrated that species with steeper VCs tended to have high mortality and recruitment rates, while species with flatter VCs were usually those with low mortality and recruitment rates. Our results highlight the important role of parameter a in tree demography, especially for deciduous species. Given that VC is a key component of plant hydraulic models, integrating measured VC rather than optimizing its parameters will help improve the ability to simulate and predict forest response to water availability. [ABSTRACT FROM AUTHOR]

Over the course of multiple divisions, cells accumulate diverse nongenetic, somatic damage including misfolded and aggregated proteins and cell wall defects. If the rate of damage accumulation exceeds the rate of dilution through cell growth, a dedicated mitigation strategy is required to prevent eventual population collapse. Strategies for somatic damage control can be divided into two categories, asymmetric allocation and repair, which are not, in principle, mutually exclusive. We explore a mathematical model to identify the optimal strategy, maximizing the total cell number, over a wide range of environmental and physiological conditions. The optimal strategy is primarily determined by extrinsic, damage-independent mortality and the physiological model for damage accumulation that can be either independent (linear) or increasing (exponential) with respect to the prior accumulated damage. Under the linear regime, the optimal strategy is either exclusively repair or asymmetric allocation, whereas under the exponential regime, the optimal strategy is a combination of asymmetry and repair. Repair is preferred when extrinsic mortality is low, whereas at high extrinsic mortality, asymmetric damage allocation becomes the strategy of choice. We hypothesize that at an early stage of life evolution, optimization over repair and asymmetric allocation of somatic damage gave rise to r and K selection strategists. [ABSTRACT FROM AUTHOR]

Modulation of the cervix by steroid hormones and commensal microbiome play a central role in the health of the female reproductive tract. Here we describe organ-on-a-chip (Organ Chip) models that recreate the human cervical epithelial-stromal interface with a functional epithelial barrier and production of mucus with biochemical and hormone-responsive properties similar to living cervix. When Cervix Chips are populated with optimal healthy versus dysbiotic microbial communities (dominated by Lactobacillus crispatus and Gardnerella vaginalis, respectively), significant differences in tissue innate immune responses, barrier function, cell viability, proteome, and mucus composition are observed that are similar to those seen in vivo. Thus, human Cervix Organ Chips represent physiologically relevant in vitro models to study cervix physiology and host-microbiome interactions, and hence may be used as a preclinical testbed for development of therapeutic interventions to enhance women's health. Human cervical mucosa and its interactions with the microbiome play a central role in female reproductive tract health and disease. Here, the authors develop physiological models of the human cervix using Organ-on-a-Chip technology that produce mucus, and respond to hormonal, environmental, and microbial cues similar to the living cervix. [ABSTRACT FROM AUTHOR]

Widespread species experience a variety of climates across their distribution, which can structure their thermal tolerance, and ultimately, responses to climate change. For ectotherms, activity is highly dependent on temperature, its variability and availability of favourable microclimates. Thermal exposure and tolerance may be structured by the availability and heterogeneity of microclimates for species living along temperature and/or precipitation gradients – but patterns and mechanisms underlying such gradients are poorly understood. We measured critical thermal limits (CTmax and CTmin) for five populations of two sympatric lizard species, a nocturnal gecko (Chondrodactylus bibronii) and a diurnal skink (Trachylepis variegata) and recorded hourly thermal variation for a year in three types of microclimate relevant to the activity of lizards (crevice, full sun and partial shade) for six sites across a precipitation gradient. Using a combination of physiological and modelling approaches, we derived warming tolerance for the present and the end of the century. In the present climate, we found an overall wider thermal tolerance for the nocturnal species relative to the diurnal species, and no variation in CTmax but variable CTmin along the precipitation gradient for both species. However, warming tolerances varied significantly over the course of the day, across months and microhabitats. The diurnal skink was most restricted in its daily activity in the three driest sites with up to six daily hours of restricted activity in the open (i.e. outside refugia) during the summer months, while the impacts for the nocturnal gecko were less severe, due to its higher CTmax and night activity. With climate change, lizards will experience more months where activity is restricted and increased exposure to high temperatures even within the more sheltered microhabitats. Together our results highlight the importance of considering the relevant spatiotemporal scale and habitat for understanding the thermal exposure of diurnal and nocturnal species. [ABSTRACT FROM AUTHOR]

Intracellular delivery of nano‐drug‐carriers (NDC) to specific cells, diseased regions, or solid tumors has entered the era of precision medicine that requires systematic knowledge of nano‐biological interactions from multidisciplinary perspectives. To this end, this review first provides an overview of membrane‐disruption methods such as electroporation, sonoporation, photoporation, microfluidic delivery, and microinjection with the merits of high‐throughput and enhanced efficiency for in vitro NDC delivery. The impact of NDC characteristics including particle size, shape, charge, hydrophobicity, and elasticity on cellular uptake are elaborated and several types of NDC systems aiming for hierarchical targeting and delivery in vivo are reviewed. Emerging in vitro or ex vivo human/animal‐derived pathophysiological models are further explored and highly recommended for use in NDC studies since they might mimic in vivo delivery features and fill the translational gaps from animals to humans. The exploration of modern microscopy techniques for precise nanoparticle (NP) tracking at the cellular, organ, and organismal levels informs the tailored development of NDCs for in vivo application and clinical translation. Overall, the review integrates the latest insights into smart nanosystem engineering, physiological models, imaging‐based validation tools, all directed towards enhancing the precise and efficient intracellular delivery of NDCs. [ABSTRACT FROM AUTHOR]

Using mathematical models of physiological systems in medicine has allowed for the development of diagnostic, treatment, and medical educational tools. However, their complexity restricts, in most cases, their application for predictive, preventive, and personalized purposes. Although there are strategies that reduce the complexity of applying models based on fitting techniques, most of them are focused on a single instant of time, neglecting the effect of the system's temporal evolution. The objective of this research was to introduce a dynamic fitting strategy for physiological models with an extensive array of parameters and a constrained amount of experimental data. The proposed strategy focused on obtaining better predictions based on the temporal trends in the system's parameters and being capable of predicting future states. The study utilized a cardiorespiratory model as a case study. Experimental data from a longitudinal study of healthy adult subjects undergoing aerobic exercise were used for fitting and validation. The model predictions obtained in a steady state using the proposed strategy and the traditional single-fit approach were compared. The most successful outcomes were primarily linked to the proposed strategy, exhibiting better overall results regarding accuracy and behavior than the traditional population fitting approach at a single instant in time. The results evidenced the usefulness of the dynamic fitting strategy, highlighting its use for predictive, preventive, and personalized applications. [ABSTRACT FROM AUTHOR]

Objective: Emotions play an important role in consumers' perception of a sensory experience. The objective of this work was to investigate the ability of basic skin care formulas (i.e. without interference of odour, colour and packaging) and pillar ingredients (i.e. emollients and rheology modifiers) to elicit emotions. Another objective was to track, as claimed by neurocosmetics, the possible effect of formulas to trigger emotions from their direct biochemical effects on the skin. Methods: Standard methodologies were mobilized, combining subjective and behavioural parameters (i.e. verbatim, prosody and gesture). Sense and Story methodology based on a collection of metaphoric verbatim was conducted after an induction phase. In addition, an experimental electrophysiological real‐time visualization method was tried as a first experience in cosmetics. Finally, the ability of formulations with emotional benefits to modulate the release of neuropeptides by sensory neurons was evaluated on a 3D human model (epidermis co‐cultured with sensory neurons). Results: Skin care formulas were shown to play a role in emotional potential and the types of emotion generated, while changing one ingredient mostly acted on the intensity of the emotions. Verbatim provided contrasted answers depending on the protocol, highlighting the interest of non‐verbal approaches to detect subtle effects. The in vitro model substantiated physiological effects of skin care formulas with emotional potential on human skin sensory neuron activity. Conclusion: Emotions were impacted by the change in ingredients and were better captured through non‐verbal methods. [ABSTRACT FROM AUTHOR]

Background and Purpose: Drug‐induced reduction of the rapid delayed rectifier potassium current carried by the human Ether‐à‐go‐go‐Related Gene (hERG) channel is associated with increased risk of arrhythmias. Recent updates to drug safety regulatory guidelines attempt to capture each drug's hERG binding mechanism by combining in vitro assays with in silico simulations. In this study, we investigate the impact on in silico proarrhythmic risk predictions due to uncertainty in the hERG binding mechanism and physiological hERG current model. Experimental Approach: Possible pharmacological binding models were designed for the hERG channel to account for known and postulated small molecule binding mechanisms. After selecting a subset of plausible binding models for each compound through calibration to available voltage‐clamp electrophysiology data, we assessed their effects, and the effects of different physiological models, on proarrhythmic risk predictions. Key Results: For some compounds, multiple binding mechanisms can explain the same data produced under the safety testing guidelines, which results in different inferred binding rates. This can result in substantial uncertainty in the predicted torsade risk, which often spans more than one risk category. By comparison, we found that the effect of a different hERG physiological current model on risk classification was subtle. Conclusion and Implications: The approach developed in this study assesses the impact of uncertainty in hERG binding mechanisms on predictions of drug‐induced proarrhythmic risk. For some compounds, these results imply the need for additional binding data to decrease uncertainty in safety‐critical applications. [ABSTRACT FROM AUTHOR]

Organoids have emerged as a powerful platform for studying complex biological processes and diseases in vitro. However, most studies have focused on individual organoids, overlooking the inter‐organ interactions in vivo and limiting the physiological relevance of the models. To address this limitation, the development of a multi‐organoid system has gained considerable attention. This system aims to recapitulate inter‐organ communication and enable the study of complex physiological processes. This review provides a comprehensive overview of the recent advancements in organoid engineering and the emerging strategies for constructing a multi‐organoid system. First, we highlight the critical mechanical, structural, and biochemical factors involved in designing suitable materials for the growth of different organoids. Additionally, we discuss the incorporation of dynamic culture environments to enhance organoid culture and enable inter‐organoid communication. Furthermore, we explore techniques for manipulating organoid morphogenesis and spatial positioning of organoids to establish effective inter‐organoid communication networks. We summarize the achievements in utilizing organoids to recapitulate inter‐organ communication in vitro, including assembloids and microfluidic multi‐organoid platforms. Lastly, we discuss the existing challenges and opportunities in developing a multi‐organoid system from its technical bottlenecks in scalability to its applications toward complex human diseases. [ABSTRACT FROM AUTHOR]

Most in vitro models of oviduct epithelial cells (OEC) used thus far to gain insights into embryo–maternal communication induce cell dedifferentiation or are technically challenging. Moreover, although the presence of developing embryos has been shown to alter gene expression in OEC, the effect of embryos on OEC physiology remains largely unknown. Here, we propose a model based on bovine oviduct epithelial spheroids (OES) with specific shape and diameter (100–200 μm) criteria. The aims of this study were to i) determine the appropriate culture conditions of bovine OES cultured in suspension by evaluating their morphology, total cell number, viability, and activity of ciliated cells; ii) monitor gene expression in OES at the time of their formation (day 0) and over the 10 days of culture; and iii) test whether the vicinity of developing embryos affects OES quality criteria. On day 10, the proportions of vesicle-shaped OES (V-OES) were higher in M199/500 (500 μl of HEPES-buffered TCM-199) and synthetic oviduct fluid (SOF)/25 (25-μL droplet of SOF medium under mineral oil) than in M199/25 (25-μL droplet of M199 under mineral oil). The proportion of viable cells in V-OES was not affected by culture conditions and remained high (>80%) through day 10. The total number of cells per V-OES decreased over time except in SOF/25, while the proportions of ciliated cells increased over time in M199/500 but decreased in M199/25 and SOF/25. The movement amplitude of OES in suspension decreased over time under all culture conditions. Moreover, the gene expression of ANXA1 , ESR1 , HSPA8 , and HSPA1A in OES remained stable during culture, while that of PGR and OVGP1 decreased from day 0 to day 10. Last, the co-culture of developing embryos with OES in SOF/25 increased the rates of blastocysts on days 7 and 8 compared to embryos cultured alone, and increased the proportion of V-OES compared to OES cultured alone. In conclusion, M199/500 and SOF/25 provided the optimal conditions for the long-time culture of OES. The supporting effect of OES on embryo development and of developing embryos on OES morphology was evidenced for the first time. Altogether, these results point OES as an easy-to-use, standardizable, and physiological model to study embryo–maternal interactions in cattle. • Oviduct epithelial spheroids (OES) were obtained from isthmic mucosa fragments. • Large volume of M199 and droplets of SOF offered good culture conditions for OES. • OES expressed oviduct epithelial cell markers during 10 days in culture. • OES supported embryo development in SOF medium. • Embryo supported OES morphology in SOF medium. [ABSTRACT FROM AUTHOR]

Objective: Irritability, typically defined as a proneness to anger, particularly in response to frustration, falls at the intersection of emotion and disruptive behavior. Despite well-defined translational models, there are few convergent findings regarding the pathophysiology of irritability. Most studies utilize computer-based tasks to examine neural responses to frustration, with little work examining stress-related responding to frustration in social contexts. The present study is the first to utilize the novel Frustration Social Stressor for Adolescents (FSS-A) to examine associations between adolescent irritability and psychological and physiological responses to frustration. Method: The FSS-A was completed by a predominantly male, racially, ethnically, and socioeconomically diverse sample of 64 12- to 17-year-olds, who were originally recruited as children with varying levels of irritability. Current irritability was assessed using the Multidimensional Assessment Profiles-Temper Loss scale (MAP-TL-Youth). Adolescents rated state anger and anxiety before and after the FSS-A, and usable salivary cortisol data were collected from 43 participants. Results: Higher MAP-TL-Youth scores were associated with greater increases in anger during the FSS-A, but not increases in anxiety, or alterations in cortisol. Pre-task state anger negatively predicted the slope of the rise in cortisol observed in anticipation of the FSS-A. Conclusions: Results provide support for unique associations between adolescent irritability and anger during, and in anticipation of, frustrating social interactions. Such findings lay a foundation for future work aimed at informing physiological models and intervention targets. [ABSTRACT FROM AUTHOR]

Most plant thermal tolerance studies focus on single critical thresholds, which limit the capacity to generalise across studies and predict heat stress under natural conditions. In animals and microbes, thermal tolerance landscapes describe the more realistic, cumulative effects of temperature. We tested this in plants by measuring the decline in leaf photosynthetic efficiency (FV/FM) following a combination of temperatures and exposure times and then modelled these physiological indices alongside recorded environmental temperatures. We demonstrate that a general relationship between stressful temperatures and exposure durations can be effectively employed to quantify and compare heat tolerance within and across plant species and over time. Importantly, we show how FV/FM curves translate to plants under natural conditions, suggesting that environmental temperatures often impair photosynthetic function. Our findings provide more robust descriptors of heat tolerance in plants and suggest that heat tolerance in disparate groups of organisms can be studied with a single predictive framework. [ABSTRACT FROM AUTHOR]

Human trophoblast organoids (TOs) are a three-dimensional ex vivo culture model that can be used to study various aspects of placental development, physiology and pathology. However, standard culturing of TOs does not recapitulate the cellular orientation of chorionic villi in vivo given that the multi-nucleated syncytiotrophoblast (STB) develops largely within the inner facing surfaces of these organoids (STBin). Here, we developed amethod to culture TOs under conditions that recapitulate the cellular orientation of chorionic villi in vivo. We show that culturing STBin TOs in suspension with gentle agitation leads to the development of TOs containing the STB on the outer surface (STBout). Using membrane capacitance measurements, we determined that the outermost surface of STBout organoids contain large syncytia comprising >50 nuclei, whereas STBin organoids contain small syncytia (<10 nuclei) and mononuclear cells. The growth of TOs under conditions that mimic the cellular orientation of chorionic villi in vivo thus allows for the study of a variety of aspects of placental biology under physiological conditions. [ABSTRACT FROM AUTHOR]

The intricate nature of native cartilage, characterized by zonal variations in oxygen levels and ECM composition, poses a challenge for existing hydrogelbased tissue models. Consequently, these 3D models often present simplified renditions of the native tissue, failing to fully capture its heterogenous nature. The combined effects of hydrogel components, network properties, and structural designs on cellular responses are often overlooked. In this work, we aim to establish more physiological cartilage models through biofabrication of photopolymerizable allylated-gelatin (GelAGE) and Thiolated Heparin (HepSH) constructs with tailorable matrix stiffness and customized architectures. This involves systematically studying how the native glycosaminoglycan Heparin together with hydrogel stiffness, and oxygen availability within 3D structures influence chondrogenic differentiation and regional heterogeneity. A comprehensive library of 3D hydrogel constructs was successfully developed, encompassing GelAGE-HepSH hydrogels with three distinct stiffness levels: 12, 55 and 121 kPa, and three unique geometries: spheres, discs, and square lattices. In soft GelAGE-HepSH hydrogels, the localization of differentiating cells was observed to be irregular, while stiff hydrogels restricted the overall secretion of ECM components. The medium-stiff hydrogels were found to be most applicable, supporting both uniform tissue formation and maintained shape fidelity. Three different 3D architectures were explored, where biofabrication of smaller GelAGE-HepSH spheres without oxygen gradients induced homogenous, hyaline cartilage tissue formation. Conversely, fabrication of larger constructs (discs and lattices) with oxygen gradients could be utilized to design heterogenous cartilage tissue models. Similarly, temporal oxygen gradients were observed to drive interconnected deposition of glycosaminoglycans (GAGs). Control samples of GelAGE without HepSH did not exhibit any notable changes in chondrogenesis as a function of stiffness, architectures, or oxygen concentrations. Overall, the incorporation of HepSH within GelAGE hydrogels was observed to serve as an amplifier for the biological effects from both stiffness and oxygen cues. In conclusion, fabrication of GelAGE-HepSH constructs designed to impose limitations on oxygen availability induce more zone-specific cartilage tissue alignment. This systematic study of matrix components, network stiffness, and oxygen levels in 3D biofabricated structures contributes to the development of more physiologically relevant cartilage models while further enhancing our overall understanding of cartilage tissue engineering. [ABSTRACT FROM AUTHOR]

Homologous recombination (HR) is a template-based DNA double-strand break repair pathway that functions to maintain genomic integrity. A vital component of the HR reaction is the identification of template DNA to be used during repair. This occurs through a mechanism known as the homology search. The homology search occurs in two steps: a collision step in which two pieces of DNA are forced to collide and a selection step that results in homologous pairing between matching DNA sequences. Selection of a homologous template is facilitated by recombinases of the RecA/Rad51 family of proteins in cooperation with helicases, translocases, and topoisomerases that determine the overall fidelity of the match. This menagerie of molecular machines acts to regulate critical intermediates during the homology search. These intermediates include recombinase filaments that probe for short stretches of homology and early strand invasion intermediates in the form of displacement loops (D-loops) that stabilize paired DNA. Here, we will discuss recent advances in understanding how these specific intermediates are regulated on the molecular level during the HR reaction. We will also discuss how the stability of these intermediates influences the ultimate outcomes of the HR reaction. Finally, we will discuss recent physiological models developed to explain how the homology search protects the genome. [ABSTRACT FROM AUTHOR]

Harmful algal blooms of Microcystis have become a global problem. Turbulence, a determining factor affecting blooms, not only disperses surface scum but also controls the growth of Microcystis. Numerous studies have analyzed the effects of turbulence on the growth and colony size of Microcystis in laboratories, but the turbulence thresholds for Microcystis growth and colony disaggregation in the field are difficult to determine due to the complex environment. In addition, the quantitative contribution of turbulence‐driven blooms and the intrinsic mechanisms of the spatial distribution responding to turbulence are unclear. In this study, a fully integrated filed scale computational model focusing on turbulence‐driven blooms was developed, which incorporates physical processes (turbulence‐induced vertical mixing, VMT) and physiological processes such as buoyancy‐controlling transport (BCT), turbulence‐induced colony size variation (CSV), and growth rate variation (GRV). We performed model sensitivity analysis and evaluated the effects of turbulence intensity and duration on the biomass and vertical distribution of Microcystis. The results show that the optimal turbulence dissipation rate for Microcystis growth in the field is 1.0 × 10−5 m2/s3 and the critical turbulence dissipation rate for aggregation distribution is 3.81 × 10−6 m2/s3 in shallow lakes. A quantitative comparison of the effects of physical/physiological processes on blooms shows that physiological processes (CSV, GRV, and BCT) are critical for biomass enrichment, and the accumulation of Microcystis at the water surface is dominated by physical processes (VMT). This study reveals the mechanisms of turbulence‐driven Microcystis blooms and provides new insights for algal bloom prediction and control. Plain Language Summary: Harmful algal blooms of Microcystis can lead to a decrease in water clarity, disruption of aquatic ecosystem balance, and health risks to animals and humans from algal toxins. Turbulence, a determining factor affecting blooms, not only controls the growth of Microcystis biomass but also determines whether Microcystis can migrate to the water surface, which are prerequisites for blooms. To determine the turbulence thresholds for Microcystis growth and colony disaggregation in the field and clarify the mechanisms of turbulence‐driven blooms, we constructed a model and found that turbulence affects the Microcystis biomass by changing the colony size and growth rate, and biomass enrichment increases the possibility of Microcystis aggregation. The time lag between the turbulence enhancement and the occurrence or disappearance of blooms may lead to misjudgment of bloom risk. This study provides new insights for bloom algal prediction and control. Key Points: Critical turbulence intensity of disaggregating Microcystis colonies increases with biomass abundanceTurbulence‐induced colony size variation and growth rate variation are critical for the enrichment of Microcystis biomassA hysteresis phenomenon exists between the occurrence or disappearance of blooms and the turbulence enhancement [ABSTRACT FROM AUTHOR]

Music and speech are encountered daily and are unique to human beings. Both are transformed by the auditory pathway from an initial acoustical encoding to higher level cognition. Studies of cortex have revealed distinct brain responses to music and speech, but differences may emerge in the cortex or may be inherited from different subcortical encoding. In the first part of this study, we derived the human auditory brainstem response (ABR), a measure of subcortical encoding, to recorded music and speech using two analysis methods. The first method, described previously and acoustically based, yielded very different ABRs between the two sound classes. The second method, however, developed here and based on a physiological model of the auditory periphery, gave highly correlated responses to music and speech. We determined the superiority of the second method through several metrics, suggesting there is no appreciable impact of stimulus class (i.e., music vs speech) on the way stimulus acoustics are encoded subcortically. In this study's second part, we considered the cortex. Our new analysis method resulted in cortical music and speech responses becoming more similar but with remaining differences. The subcortical and cortical results taken together suggest that there is evidence for stimulus-class dependent processing of music and speech at the cortical but not subcortical level. [ABSTRACT FROM AUTHOR]

Frost resistance is the major factor affecting the distribution of plant species at high latitude and elevation. The main effects of freeze–thaw cycles are damage to living cells and formation of gas embolism in tree xylem vessels. Lethal intracellular freezing can be prevented in living cells by two mechanisms, such as dehydration and deep supercooling. We developed a multiphysics numerical model coupling water flow, heat transfer and phase change, considering different cell types in plant tissues, to study the dynamics and extent of cell dehydration, xylem pressure changes and stem diameter changes in response to freezing and thawing. Results were validated using experimental data for stem diameter changes of walnut trees (Juglans regia). The effect of cell mechanical properties was found to be negligible as long as the intracellular tension developed during dehydration was sufficiently low compared with the ice-induced cryostatic suction. The model was finally used to explore the coupled effects of relevant physiological parameters (initial water and sugar content) and environmental conditions (air temperature variations) on the dynamics and extent of dehydration. It revealed configurations where cell dehydration could be sufficient to protect cells from intracellular freezing, and situations where supercooling was necessary. This model, freely available with this paper, could easily be extended to explore different anatomical structures, different species and more complex physical processes. [ABSTRACT FROM AUTHOR]

Cardiovascular rhythms representing functional states of the autonomic nervous system (ANS) are insufficiently reflected by the current physiological model based on low and high frequency bands (LF, HF, resp.). An intermediate (IM) frequency band generated by a brainstem pacemaker was included in systemic physiological ANS analyses of forehead skin perfusion (SP), ECG, and respiration. Data of 38 healthy participants at T0 and T1 (+1 week) before, during, and following osteopathic cranial vault hold (CVH) stimulation were analyzed including momentary frequencies of highest amplitude, amplitudes in low (0.05–0.12 Hz), IM (0.12–0.18 Hz), and high (0.18–0.4 Hz) frequency bands, and established heart rate variability (HRV) metrics. During CVH, LF interval durations increased, whereas IM/HF band durations decreased significantly. Amplitudes increased significantly in all frequency bands. A cluster analysis found one response pattern dominated by IM activity (47% of participants) with highly stable 0.08 Hz oscillation to CVH, and one dominated by LF activity (0.10 Hz) at T0, increasing to IM activity at T1. Showing frequency ratios at ≈3:1, respiration was not responsible for oscillations in PPG during CVH. HRV revealed no significant responses. Rhythmic patterns in SP and respiration matched previous findings on a reticular "0.15 Hz rhythm". Involvement of baroreflex pathways is discussed as alternative explanation. [ABSTRACT FROM AUTHOR]

The yeast vacuole membrane can phase separate into ordered and disordered domains, a phenomenon that is required for micro-lipophagy under nutrient limitation. Despite its importance as a biophysical model and physiological significance, it is not yet resolved if specific lipidome changes drive vacuole phase separation. Here we report that the metabolism of sphingolipids (SLs) and their sorting into the vacuole membrane can control this process. We first developed a vacuole isolation method to identify lipidome changes during the onset of phase separation in early stationary stage cells. We found that early stationary stage vacuoles are defined by an increased abundance of putative raft components, including 40% higher ergosterol content and a nearly 3-fold enrichment in complex SLs (CSLs). These changes were not found in the corresponding whole cell lipidomes, indicating that lipid sorting is associated with domain formation. Several facets of SL composition--headgroup stoichiometry, longer chain lengths, and increased hydroxylations--were also markers of phaseseparated vacuole lipidomes. To test SL function in vacuole phase separation, we carried out a systematic genetic dissection of their biosynthetic pathway. The abundance of CSLs controlled the extent of domain formation and associated micro-lipophagy processes, while their headgroup composition altered domain morphology. These results suggest that lipid trafficking can drive membrane phase separation in vivo and identify SLs as key mediators of this process in yeast. [ABSTRACT FROM AUTHOR]

The study analyzed the variation of some morphological parameters and physiological indices in the annual vine shoots, the 'Cabernet Sauvignon' and 'Feteasca Neagra' grape cultivars, as well as the functionality of the leaf area in relation to grapes and sugars production. In the BBCH 71-73 stage, were determined the length of the internodes (Int L, cm), the length of the leaf petiole (Pet L, cm), the length of the leaf (LL, cm), the width of the leaf (Lw, cm), leaf area (LA, cm²), chlorophyll content (Chl, SPAD), and carotenoid content (Car). The leaf area was calculated in relation to the unitary production of grapes (LA/1 kg berry - LAGup) and the leaf surface to the unitary production of sugars (LA/1 kg sugar - LASup). The comparative analysis between the mean values of the parameters in the two cultivars highlighted differences in statistical safety conditions for Car (p<0.05), for Lw and LASug (p<0.01) and for IL, LL, LA, and LAGup (p<0.01). The LA functionality for grape unitary production (Gup) and sugar unitary production (Sup) was described by mathematical and graphical models under statistical safety conditions (p<0.001). [ABSTRACT FROM AUTHOR]

When designing and optimizing the hull of vehicles, their sound quality needs to be considered, which greatly depends on the psychoacoustic parameters. However, the traditional psychoacoustic calculation method does not consider the influence of the real human ear anatomic structure, even the loudness which is most related to the auditory periphery. In order to introduce the real physiological structure of the human ear into the evaluation of vehicle sound quality, this paper first carried out the vehicle internal noise test to obtain the experimental samples. Then, the physiological loudness was predicted based on an established human ear physiological model, and the noise evaluation vector was constructed by combining the remaining four psychoacoustic parameters. Finally, the evaluation vector was fitted into the subjective evaluation results of vehicle interior noise by a deep neural network. The results show that our proposed method can estimate the human subjective perception of vehicle interior noise well. [ABSTRACT FROM AUTHOR]

In this work extensive misconceptions of university students' —from nutrition area— about the metabolism of carbohydrates (CHM) in the human organism have been documented. The results lead to consider their difficulties concerning the learning of a complex set of imbricated biochemical models involved. Pursuant to these considerations, three physiological models are proposed as conceptual axes around which CHM in the human organism could be taught, in order to avoid fragmentation in students' knowledge and to give simple physiological contexts where to integrate those biochemical models. These contexts are: (a) a physiological model of the carbon cycle, (b) a physiological model of blood glucose uptake and homeostasis, and (c) a physiological model of the availability of small metabolites. [ABSTRACT FROM AUTHOR]

Climate change is affecting global viticulture, increasing heatwaves and drought. Precision irrigation, supported by robust water status indicators (WSIs), is inevitable in most of the Mediterranean basin. One of the most reliable WSIs is the leaf water potential ( Ψ l e a f ), which is determined via an intrusive and time-consuming method. The aim of this work is to discern the most effective variables that are correlated with plants' water status and identify the variables that better predict Ψ l e a f . Five grapevine varieties grown in the Alentejo region (Portugal) were selected and subjected to three irrigation treatments, starting in 2018: full irrigation (FI), deficit irrigation (DI), and no irrigation (NI). Plant monitoring was performed in 2023. Measurements included stomatal conductance ( g s ), predawn water potential Ψ p d , stem water potential ( Ψ s t e m ), thermal imaging, and meteorological data. The WSIs, namely Ψ p d and g s , responded differently according to the irrigation treatment. Ψ s t e m measured at mid-morning (MM) and mid-day (MD) proved unable to discern between treatments. MM measurements presented the best correlations between WSIs. g s showed the best correlations between the other WSIs, and consequently the best predictive capability to estimate Ψ p d . Machine learning regression models were trained on meteorological, thermal, and g s data to predict Ψ p d , with ensemble models showing a great performance (ExtraTrees: R 2 = 0.833 , M A E = 0.072 ; Gradient Boosting: R 2 = 0.830 ; M A E = 0.073 ). [ABSTRACT FROM AUTHOR]

The computational simulation of human voluntary muscle contraction is possible with EMG-driven Hill-type models of whole muscles. Despite impactful applications in numerous fields, the neuromechanical information and the physiological accuracy such models provide remain limited because of multiscale simplifications that limit comprehensive description of muscle internal dynamics during contraction. We addressed this limitation by developing a novel motoneuron-driven neuromuscular model, that describes the force-generating dynamics of a population of individual motor units, each of which was described with a Hill-type actuator and controlled by a dedicated experimentally derived motoneuronal control. In forward simulation of human voluntary muscle contraction, the model transforms a vector of motoneuron spike trains decoded from high-density EMG signals into a vector of motor unit forces that sum into the predicted whole muscle force. The motoneuronal control provides comprehensive and separate descriptions of the dynamics of motor unit recruitment and discharge and decodes the subject's intention. The neuromuscular model is subject-specific, muscle-specific, includes an advanced and physiological description of motor unit activation dynamics, and is validated against an experimental muscle force. Accurate force predictions were obtained when the vector of experimental neural controls was representative of the discharge activity of the complete motor unit pool. This was achieved with large and dense grids of EMG electrodes during medium-force contractions or with computational methods that physiologically estimate the discharge activity of the motor units that were not identified experimentally. This neuromuscular model advances the state-of-the-art of neuromuscular modelling, bringing together the fields of motor control and musculoskeletal modelling, and finding applications in neuromuscular control and human-machine interfacing research. Author summary: Neuromuscular computational simulations of human muscle contractions are typically obtained with a mathematical model that transforms an electromyographic signal recorded from the muscle into force. This single-input single-output approach, however, limits the comprehensive description of muscle internal dynamics during contraction because of necessary multiscale simplifications. Here, we advance the state-of-the-art in neuromuscular modelling by proposing a novel mathematical model that describes the force-generating dynamics of the individual motor units that constitute the muscle. For the first time, the control to the population of modelled motor units was inferred from decomposed high-density electromyographic signals. The model was experimentally validated, and the sensitivity of its predictions to different experimental neural controls was assessed. The neuromuscular model, coupled with an image-based musculoskeletal model, includes a novel and advanced neuromechanical model of the motor unit excitation-contraction properties, and is suited for subject-specific simulations of human voluntary contraction, with applications in neurorehabilitation and the control of neuroprosthetics. [ABSTRACT FROM AUTHOR]

Displacing the physiological model that had held sway in 19th-century medical thinking, early 20th-century medical scientists working on hormones promoted a new understanding of the body, psychological reactions, and the sexual instinct, arguing that each were fundamentally malleable. Hormones came to be understood as the chemical messengers that regulated an individual's growth and sexual development, and sexologists interested in this area focused primarily on children and adolescents. Hormone research also promoted a view of the body in which 'hermaphroditism', homosexuality, and 'sexual perversions' such as masochism and sadism were attributed to anomalies in the internal secretions produced by the testes or the ovaries. This article focuses on Spanish, Italian, Argentinian, and Brazilian sexology shaped by endocrinological research in the interwar period. First, it shows the key role hormone treatments played in the historical development of sexology in Southern Europe and Latin America. Second, it looks at how sexologists employed hormone research to study human sexual development in the early stages of life, and how they set about 'correcting' what they viewed as 'sexual anomalies'. [ABSTRACT FROM AUTHOR]

In October 2022, the Human Factors and Medicine (HFM) panel of the NATO Science and Technology Organization convened a review of progress in military biomedical research for cold weather operations. This paper represents a summary of the research presentations and future directions. The importance of realistic training was an overarching theme. Many reported studies took advantage of cold weather training exercises to monitor soldiers' health and performance; these are valuable data, using winter exercises as a platform to gain further knowledge regarding human performance in the cold and represent an excellent extension of controlled laboratory studies. Topics also included prevention of Cold Weather Injuries (CWI); effects of cold weather stressors on cognitive function; field treatment of freezing cold injuries (FCI); and new consideration to injury and trauma care in the cold. Future work programmes re-emphasise development of cold weather training and establishment of consensus diagnostic criteria and treatments for FCI and non-FCI. CWI prevention should take advantage of biomathematical models that predict risk of CWI and provide guidance regarding optimal clothing and equipment and move from group averages to personalised predictions. The publication of selected presentations from the symposium in this special issue increases attention to military cold weather research. [ABSTRACT FROM AUTHOR]

Biomathematical models quantitatively describe human physiological responses to environmental and operational stressors and have been used for planning and real-time prevention of cold injury. These same models can be applied from a military tactical perspective to gain valuable insights into the health status of opponent soldiers. This paper describes a use case for predicting physiological status of Russian soldiers invading Ukraine using open-source information. In March 2022, media outlets reported Russian soldiers in a stalled convoy invading Ukraine were at serious risk of hypothermia and predicted these soldiers would be "freezing to death" within days because of declining temperatures (down to −20°C). Using existing Army models, clothing data and open-source intelligence, modelling and analyses were conducted within hours to quantitatively assess the conditions and provide science-based predictions. These predictions projected a significant increase in risks of frostbite for exposed skin and toes and feet, with a very low (negligible) risk of hypothermia. Several days later, media outlets confirmed these predictions, reporting a steep rise in evacuations for foot frostbite injuries in these Russian forces. This demonstrated what can be done today with the existing mathematical physiology and how models traditionally focused on health risk can be used for tactical intelligence. [ABSTRACT FROM AUTHOR]

Background: The spaceflight environment is an extreme environment that affects the immune system of approximately 50% of astronauts. With planned long-duration missions, such as the deployment of the Lunar Gateway and possible interplanetary missions, it is mandatory to determine how all components of the immune system are affected, which will allow the establishment of countermeasures to preserve astronaut health. However, despite being an important component of the immune system, antibody-mediated humoral immunity has rarely been investigated in the context of the effects of the space environment. It has previously been demonstrated that 30 days aboard the BION-M1 satellite and 21 days of hindlimb unloading (HU), a model classically used to mimic the effects of microgravity, decrease murine B lymphopoiesis. Furthermore, modifications in B lymphopoiesis reported in young mice subjected to 21 days of HU were shown to be similar to those observed in aged mice (18–22 months). Since the primary antibody repertoire composed of IgM is created by V(D) J recombination during B lymphopoiesis, the objective of this study was to assess the degree of similarity between changes in the bone marrow IgM repertoire and in the V(D)J recombination process in 2.5-month-old mice subjected to 21 days of HU and aged (18 months) mice. Results: We found that in 21 days, HU induced changes in the IgM repertoire that were approximately 3-fold less than those in aged mice, which is a rapid effect. Bone remodeling and epigenetics likely mediate these changes. Indeed, we previously demonstrated a significant decrease in tibial morphometric parameters from day 6 of HU and a progressive reduction in these parameters until day 21 of HU, and it has been shown that age and microgravity induce epigenetic changes. Conclusion: These data reveal novel immune changes that are akin to advanced aging and underline the importance of studying the effects of spaceflight on antibody-mediated humoral immunity. [ABSTRACT FROM AUTHOR]

A novel method has been developed for analyzing connectivity between regions based on functional magnetic resonance imaging (fMRI) data. This method, termed structural and physiological modeling (SAPM), combines information about blood oxygenation-level dependent (BOLD) responses, anatomy, and physiology to model coordinated signaling across networks of regions, including input and output signaling from each region and whether signaling is predominantly inhibitory or excitatory. The present study builds on a prior proof-of-concept demonstration of the SAPM method by providing evidence for the choice of network model and anatomical sub-regions, demonstrating the reproducibility of the results and identifying statistical thresholds needed to infer significance. The method is further validated by applying it to investigate human nociceptive processing in the brainstem and spinal cord and comparing the results to the known neuroanatomy, including anatomical regions and inhibitory and excitatory signaling. The results of this analysis demonstrate that it is possible to obtain reliable information about input and output signaling from anatomical regions and to identify whether this signaling has predominantly inhibitory or excitatory effects. SAPM provides much more detailed information about neuroanatomy than was previously possible based on fMRI data. [ABSTRACT FROM AUTHOR]

Background: Adequate adaptation of the autonomic nervous system (ANS) is crucial in potentially life-threatening situations. The defence cascade provides a descriptive model of progressing dominant physiological reactions in such situations, including cardiovascular parameters and body mobility. The empirical evidence for this model is scarce, and the influence of physiological reactions in this model for predicting trauma-induced intrusions is unresolved. Objectives: Using a trauma-film paradigm, we aimed to test physiological reactions to a highly stressful film as an analogue to a traumatic event along the defence cascade model. We also aimed to examine the predictive power of physiological activity for subsequent intrusive symptoms. Method: Forty-seven healthy female participants watched a stressful and a neutral film in randomized order. Heart rate (HR), heart rate variability (HRV), and body sway were measured. Participants tracked frequency, distress, and quality of subsequent intrusions in a diary for 7 consecutive days. Results: For the stressful film, we observed an initial decrease in HR, followed by an increase, before the HR stabilized at a high level, which was not found during the neutral film. No differences in HRV were observed between the two films. Body sway and trembling frequency were heightened during the stressful film. Neither HR nor HRV predicted subsequent intrusions, whereas perceived distress during the stressful film did. Conclusions: Our results suggest that the physiological trauma-analogue response is characterized by an orientation response and subsequent hyperarousal, reaching a high physiological plateau. In contrast to the assumptions of the defence cascade model, the hyperarousal was not followed by downregulation. Potential explanations are discussed. For trauma-associated intrusions in the subsequent week, psychological distress during the film seems to be more important than physiological distress. Understanding the interaction between physiological and psychological responses during threat informs the study of ANS imbalances in mental disorders such as post-traumatic stress disorder. We used a trauma-film analogue to examine the defence cascade model and to investigate the influence of psychophysiological response on subsequent intrusions. While we found an orientation phase, upregulation phase, and coactivation indicated by heart rate, no downregulation phase was observed. None of the physiological parameters examined predicted subsequent intrusions, whereas subjective distress during the film did. [ABSTRACT FROM AUTHOR]

For several years, there has been a need in phenological modeling to better account for physiological processes during the winter dormancy of woody plants, which is here addressed to the sweet cherry cultivar 'Summit' (Prunus avium L.). This study compares three sequential phenology models (M1–M3) for the beginning of 'Summit' blossom in the experimental sweet cherry orchard in Berlin-Dahlem (Germany) between 2011/12–2019/20 (model development) and 2020/21–2022/23 (model validation). M1 represents an inverse modeling approach where the chilling and forcing requirements of 'Summit' were optimized solely from observed flowering data. In contrast, M2 and M3 are more physiologically based as they already incorporate biological knowledge, so that the model parameters were calculated directly within the specified developmental phases. Here, M2 is a two-phase model that considers experimental data for the date of endodormancy release (t1) of nine years (2011/12–2019/20) to calculate the chilling and forcing requirements. Finally, M3 is a newly developed three-phase model that additionally includes the onset of ontogenetic development (t1*) and the abscisic acid (ABA) content of 'Summit' flower buds during the ecodormancy phase (t1 − t1*). The results indicate that the inclusion of ABA-related heat weighting during ecodormancy significantly improves the performance of M3 compared to M1 and M2. While M1 gives satisfactory results in terms of fit and validation, it is considered physiologically unacceptable as it greatly overestimates the chilling requirement of 'Summit' by ignoring the ecodormancy phase. M2 accumulates too much heat during ecodormancy as it does not include control by the bud ABA content. The results highlight the need for parameters such as t1, t1*, and the bud ABA content for the physiological modeling of 'Summit' blossom. To the best of our knowledge, this is the first study to provide a pathway towards a physiologically based modeling approach. [ABSTRACT FROM AUTHOR]

Abstract Intracellular delivery of nano‐drug‐carriers (NDC) to specific cells, diseased regions, or solid tumors has entered the era of precision medicine that requires systematic knowledge of nano‐biological interactions from multidisciplinary perspectives. To this end, this review first provides an overview of membrane‐disruption methods such as electroporation, sonoporation, photoporation, microfluidic delivery, and microinjection with the merits of high‐throughput and enhanced efficiency for in vitro NDC delivery. The impact of NDC characteristics including particle size, shape, charge, hydrophobicity, and elasticity on cellular uptake are elaborated and several types of NDC systems aiming for hierarchical targeting and delivery in vivo are reviewed. Emerging in vitro or ex vivo human/animal‐derived pathophysiological models are further explored and highly recommended for use in NDC studies since they might mimic in vivo delivery features and fill the translational gaps from animals to humans. The exploration of modern microscopy techniques for precise nanoparticle (NP) tracking at the cellular, organ, and organismal levels informs the tailored development of NDCs for in vivo application and clinical translation. Overall, the review integrates the latest insights into smart nanosystem engineering, physiological models, imaging‐based validation tools, all directed towards enhancing the precise and efficient intracellular delivery of NDCs.

Abstract Chronic obstructive pulmonary disease (COPD) affects the lives of millions of patients worldwide. Patients with advanced COPD may require non‐invasive ventilation (NIV) to support the resultant deficiencies of the respiratory system. The purpose of this study was to evaluate the effects of varying the continuous positive airway pressure (CPAP) and oxygen supplementation components of NIV on simulated COPD patients by using an established and detailed model of the human respiratory system. The model used in the study simulates features of advanced COPD including the effects on the changes in ventilation control, increases in respiratory dead space and airway resistance, and the acid–base shifts in the blood seen in these patients over time. The results of the study have been compared with and found to be in general agreement with available clinical data. Our results demonstrate that under non‐emergency conditions, low levels of oxygen supplementation combined with low levels of CPAP therapy seem to improve hypoxemia and hypercapnia in the model, whereas prolonged high‐level CPAP and moderate‐to‐high levels of oxygen supplementation do not. The authors conclude that such modelling may be useful to help guide beneficial interventions for COPD patients using NIV.

Introduction: Type 1 Diabetes (T1D) affects over 9 million worldwide and necessitates meticulous self-management for blood glucose (BG) control. Utilizing BG prediction technology allows for increased BG control and a reduction in the diabetes burden caused by self-management requirements. This paper reviews BG prediction models in T1D, which include nutritional components. Method: A systematic search, utilizing the PRISMA guidelines, identified articles focusing on BG prediction algorithms for T1D that incorporate nutritional variables. Eligible studies were screened and analyzed for model type, inclusion of additional aspects in the model, prediction horizon, patient population, inputs, and accuracy. Results: The study categorizes 138 blood glucose prediction models into data-driven (54%), physiological (14%), and hybrid (33%) types. Prediction horizons of ≤30 min are used in 36% of models, 31–60 min in 34%, 61–90 min in 11%, 91–120 min in 10%, and >120 min in 9%. Neural networks are the most used data-driven technique (47%), and simple carbohydrate intake is commonly included in models (data-driven: 72%, physiological: 52%, hybrid: 67%). Real or free-living data are predominantly used (83%). Conclusion: The primary goal of blood glucose prediction in T1D is to enable informed decisions and maintain safe BG levels, considering the impact of all nutrients for meal planning and clinical relevance.

Aging elicits numerous effects that impact both musculoskeletal structure and walking function. Tendon stiffness (kT) and push-off propulsive force (FP) both impact the metabolic cost of walking and are diminished by age, yet their interaction has not been studied. We combined experimental and computational approaches to investigate whether age-related changes in function (adopting smaller FP) may be adopted to mitigate the metabolic consequences arising from changes in structure (reduced kT). We recruited 12 young adults and asked them to walk on a force-sensing treadmill while prompting them to change FP (±20% & ±40% of typical) using targeted biofeedback. In models driven by experimental data from each of those conditions, we altered the kT of personalized musculoskeletal models across a physiological range (2–8% strain) and simulated individual-muscle metabolic costs for each kT and FP combination. We found that kT and FP independently affect walking metabolic cost, increasing with higher kT or as participants deviated from their typical FP. Our results show no evidence for an interaction between kT and FP in younger adults walking at fixed speeds. We also reveal complex individual muscle responses to the kT and FP landscape. For example, although total metabolic cost increased by 5% on average with combined reductions in kT and FP, the triceps surae muscles experienced a 7% local cost reduction on average. Our simulations suggest that reducing FP during walking would not mitigate the metabolic consequences of lower kT. Wearable devices and rehabilitative strategies can focus on either kT or FP to reduce age-related increases in walking metabolic cost. [ABSTRACT FROM AUTHOR]

Clinical studies revealed detrimental skeletal and vascular effects of the insulin sensitizer rosiglitazone. We have shown earlier that rosiglitazone accelerates osteoblast differentiation from human mesenchymal stem cells (hMSC) at the expense of increased oxidative stress and cell death. In calcifying human vascular cells, rosiglitazone stimulates pathological mineralization, an effect diminished by the antioxidant resveratrol. Here, we aimed to elucidate transcriptional networks underlying the rosiglitazone-enhanced mineralization phenotype. We performed genome-wide transcriptional profiling of osteogenic hMSCs treated with rosiglitazone for short-term periods of 1 up to 48 h during the first two days of differentiation, a phase that we show is sufficient for rosiglitazone stimulation of mineralization. Microarray-based mRNA expression analysis revealed 190 probes that were differently expressed in at least one condition compared to vehicle-treated control. This rosiglitazone gene signature contained well-known primary PPAR targets and was also endogenously regulated during osteogenic hMSC differentiation and osteoblast-like differentiation of vascular smooth muscle cells (VSMCs) into calcifying vascular cells (CVCs). Comparative analysis revealed rosiglitazone targets that were commonly enriched in osteoblasts and CVCs or specifically enriched in either osteoblasts or CVCs. Finally, we compared expression patterns of CVC-specific genes with patient expression data from carotid plaque versus intact adjacent tissue, and identified five rosiglitazone targets to be differentially regulated in CVCs and carotid plaque but not osteoblasts when compared to their non-mineralizing counterparts. These targets, i.e., PDK4, SDC4, SPRY4, TCF4 and DACT1, may specifically control extracellular matrix mineralization in vascular cells, and hence provide target candidates for further investigations to improve vascular health. [ABSTRACT FROM AUTHOR]

The biogeography research of orchids through species distribution models (SDMs), a vital tool in the biogeography field, is critical to understanding the fundamental geographic distribution patterns and identifying conservation priorities. The correspondence between species occurrence and environmental information is crucial to the model's performance. However, ecological preferences unique to different orchid species, such as their life forms, are often overlooked during the modeling process. This oversight can introduce bias and increase model uncertainty. Additionally, human activities, as an important potential predictor, have not been quantified in any orchid SDMs. Taking the Hengduan Mountains as an example, we preprocessed all orchid species' occurrences based on physiological characteristics. Choosing five spatial factors related to human activities to quantify the interference and enter into models as HI factor. Using different modeling methods (GLM, MaxEnt, and RF) and evaluation indices (AUC, TSS, and Kappa), diverse modeling strategies have been constructed in the study. A double‐ranking method has been adopted to select the critical orchid distribution regions. The results showed that classification models based on physiological characteristics significantly improved the model's accuracy while adding the HI factor had the same effect but the absence of enough significance. Suitability maps indicated that highly heterogeneous mountainous areas were vital for the distribution of orchids in the Hengduan Mountains. Different distribution patterns and critical regions existed between various orchid life forms geographically – terrestrial orchids were dominant in the mountain, and mycoherterophical orchids were primarily located in the north, more influenced by vegetation and temperature. Critical regions of epiphytic orchids were in the south due to a greater dependence on precipitation and temperature. These studies are informative for understanding the orchids' geographic distribution patterns in the Hengduan Mountains, promoting conservation and providing references for similar research beyond orchids. [ABSTRACT FROM AUTHOR]