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We run stochastic simulations of the spatial version of the rock-paper-scissors game, considering that individuals use sensory abilities to scan the environment to detect the presence of enemies. If the local dangerousness level is above a tolerable threshold, individuals aggregate instead of moving randomly on the lattice. We study the impact of the locally adaptive aggregation on the organisms' spatial organisation by measuring the characteristic length scale of the spatial domains occupied by organisms of a single species. Our results reveal that aggregation is beneficial if triggered when the local density of opponents does not exceed 30%; otherwise, the behavioural strategy may harm individuals by increasing the average death risk. We show that if organisms can perceive further distances, they can accurately scan and interpret the signals from the neighbourhood, maximising the effects of the locally adaptive aggregation on the death risk. Finally, we show that the locally adaptive aggregation behaviour promotes biodiversity independently of the organism's mobility. The coexistence probability rises if organisms join conspecifics, even in the presence of a small number of enemies. We verify that our conclusions hold for more complex systems by simulating the generalised rock-paper-scissors models with five and seven species. Our discoveries may be helpful to ecologists in understanding systems where organisms' self-defence behaviour adapts to local environmental cues., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Antipredator behavior is a self-preservation strategy present in many biological systems, where individuals join the effort in a collective reaction to avoid being caught by an approaching predator. We study a nonhierarchical tritrophic system, whose predator-prey interactions are described by the rock-paper-scissors game rules. We perform a set of spatial stochastic simulations where organisms of one out of the species can resist predation in a collective strategy. The drop in predation capacity is local, which means that each predator faces a particular opposition depending on the prey group size surrounding it. Considering that the interference in a predator action depends on the prey's physical and cognitive ability, we explore the role of a conditioning factor that indicates the fraction of the species apt to perform the antipredator strategy. Because of the local unbalancing of the cyclic predator-prey interactions, departed spatial domains mainly occupied by a single species emerge. Unlike the rock-paper-scissors model with a weak species because of a nonlocal reason, our findings show that if the predation probability of one species is reduced because individuals face local antipredator response, the species does not predominate. Instead, the local unbalancing of the rock-paper-scissors model results in the prevalence of the weak species' prey. Finally, the outcomes show that local unevenness may jeopardize biodiversity, with the coexistence being more threatened for high mobility.

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

We study a three-species cyclic game system where organisms face a contagious disease whose virulence may change by a pathogen mutation. As a responsive defence strategy, organisms' mobility is restricted to reduce disease dissemination in the system. The impact of the collective self-preservation strategy on the disease infection risk is investigated by performing stochastic simulations of the spatial version of the rock-paper-scissors game. Our outcomes show that the mobility control strategy induces plasticity in the spatial patterns with groups of organisms of the same species inhabiting spatial domains whose characteristic length scales depend on the level of dispersal restrictions. The spatial organisation plasticity allows the ecosystems to adapt to minimise the individuals' disease contamination risk if an eventual pathogen alters the disease virulence. We discover that if a pathogen mutation makes the disease more transmissible or less lethal, the organisms benefit more if the mobility is not strongly restricted, thus forming large spatial domains. Conversely, the benefits of protecting against a pathogen causing a less contagious or deadlier disease are maximised if the average size of groups of individuals of the same species is significantly limited, reducing the dimensions of groups of organisms significantly. Our findings may help biologists understand the effects of dispersal control as a conservation strategy in ecosystems affected by epidemic outbreaks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The Covid-19 coronavirus, SARS-CoV-2, is inactivated much faster on paper (3 h) than on plastic (7 d). By classifying materials according to virus stability on their surface, the following list is obtained (from long to short stability): polypropylene (mask), plastic, glass, stainless steel, pig skin, cardboard, banknote, cotton, wood, paper, tissue, copper. These observations and other studies suggest that SARS-CoV-2 may be inactivated by dryness on water absorbent porous materials but sheltered by long-persisting micro-droplets of water on waterproof surfaces. If such physical phenomenons were confirmed by direct evidence, the persistence of the virus on any surface could be predicted, and new porous objects could be designed to eliminate the virus faster., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases., (© 2024. Springer Nature Limited.)

In vitro models for screening new cancer chemotherapeutics often rely on two-dimensional cultures to predict therapeutic potential. Unfortunately, the predictive power of these models is limited, as they fail to recapitulate the complex three-dimensional environments in tumors that promote a chemoresistant phenotype. In this study, we describe the preparation and characterization of paper-based cultures (PBCs) engineered to assess chemotherapeutic effectiveness in three dimensional, diffusion-limited environments. Similar environments are found in poorly vascularized tumors. Monotonic gradients develop across these cultures, which are assembled by stacking cell-laden paper scaffolds to yield thick tissue-like structures, and provide distinct chemical environments for each scaffold. After prolonged incubation, the scaffolds can simply be peeled apart and analyzed. Through fluorescence imaging, we determined that viable and proliferative cell populations were most abundant in scaffolds close to the nutrient-rich medium. By adjusting the cell density, we modulated the spatiotemporal evolution of oxygen gradients across the cultures and correlated these environmental changes with cellular sensitivity to SN-38 exposure. From these results, we showed that differences in the oxygen gradients produced cellular populations with significantly different chemosensitivities. Through this work, we highlight PBCs ability to serve as an analytical model capable of determining chemotherapeutic effectiveness under a range of chemical environments.

This work investigates the spreading dynamics of three candidate sol-gel solutions, of ranging viscosities, surface tensions and densities, and compares them with water and two commercial blood substitute products. Droplets were created with different sizes (10 to75μL) and impact velocities (1.4 to 6.0m/s) to strike 176gsm cardstock. Over 2200 droplets were created using the six different fluids and their final dried stain diameter was measured. Droplet spread was plotted using the Scheller and Bousfield correlation and uses effective viscosity as a parameter for non-Newtonian fluids. Comparing the results to an expected whole human blood range validated the spread of the candidate FBS sol-gel material in passive drip bloodstain pattern simulation. These findings complement the practical application of the material as a safe substitute for demonstrating droplet spread under controlled conditions on hard paper surfaces., (Copyright © 2017 Elsevier B.V. All rights reserved.)

DNA methylation is a biochemical process that modifies gene expression without changing the underlying DNA sequence, and this represents the molecular basis for imprinting and epigenetics. Recent reports have revealed alterations in DNA methylation profiles in the placenta of babies born from assisted reproductive technologies (ART). This supports several previous observations that suggested an increase in the prevalence of imprinting diseases following ART treatment, and also fits our observations regarding the metabolism and requirements of early human embryos. Human embryo culture media (HECM) are currently formulated according to requirements based on the mouse embryo model, and in fact need to pass the Mouse Embryo Assay test in order to be accepted by the relevant authorities, despite the fact that physiological (especially the time necessary to reach genomic activation) and biochemical requirements of mouse and human embryos are quite different. This commentary aims to explain some of the discrepancies, and emphasize why human embryo metabolism tells us that the composition of HECM, as well as the role of the MEA as a unique model, should be re-evaluated.

Maribavir, an orally available antiviral agent, has been approved in multiple countries for the treatment of patients with refractory post-transplant cytomegalovirus (CMV) infection and/or disease. Maribavir is primarily metabolized by CYP3A4; coadministration with CYP3A4 inducers and inhibitors may significantly alter maribavir exposure, thereby affecting its efficacy and safety. The effect of CYP3A4 inducers and inhibitors on maribavir exposure was evaluated based on a drug-drug interaction (DDI) study and physiologically-based pharmacokinetic (PBPK) modeling. The effect of rifampin (a strong inducer of CYP3A4 and moderate inducer of CYP1A2), administered at a 600 mg dose once daily, on maribavir pharmacokinetics was assessed in a clinical phase 1 DDI study in healthy participants. A full PBPK model for maribavir was developed and verified using in vitro and clinical pharmacokinetic data from phase 1 studies. The verified PBPK model was then used to simulate maribavir DDI interactions with various CYP3A4 inducers and inhibitors. The DDI study results showed that coadministration with rifampin decreased the maribavir maximum plasma concentration (C max ), area under the plasma concentration-time curve (AUC), and trough concentration (C trough ) by 39%, 60%, and 82%, respectively. Based on the results from the clinical DDI study, the coadministration of maribavir with rifampin is not recommended. The PBPK model did not predict a clinically significant effect of CYP3A4 inhibitors on maribavir exposure; however, it predicted that strong or moderate CYP3A4 inducers, including carbamazepine, efavirenz, phenobarbital, and phenytoin, may reduce maribavir exposure to a clinically significant extent, and may prompt the consideration of a maribavir dosing increase, in accordance with local approved labels and/or regulations., (© 2023 American College of Clinical Pharmacology.)

While natural communities can contain hundreds of species, modern coexistence theory focuses primarily on species pairs. Alternatively, the structural stability approach considers the feasibility of equilibria, gaining scalability to larger communities but sacrificing information about dynamic stability. Three-species competitive communities are a bridge to more-diverse communities. They display novel phenomena while remaining amenable to mathematical analysis, but remain incompletely understood. Here, we combine these approaches to identify the key quantities that determine three-species competition outcomes. We show that pairwise niche overlap and fitness differences are insufficient to completely characterize competitive outcomes, which requires a strictly triplet-wise quantity: cyclic asymmetry, which underlies intransitivity. Low pairwise niche overlap stabilizes the triplet, while high fitness differences promote competitive exclusion. The effect of cyclic asymmetry on stability is complex and depends on pairwise niche overlap. In summary, we elucidate how pairwise niche overlap, fitness differences and cyclic asymmetry determine three-species competition outcomes., (© 2024 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)

This work deals with the effects of an apex predator on the cyclic competition among three distinct species that follow the rules of the rock-paper-scissors game. The investigation develops standard stochastic simulations but is motivated by a procedure which is explained in the work. We add the apex predator as the fourth species in a system that contains three species that evolve following the standard rules of migration, reproduction, and predation, and study how the system evolves in this new environment, in comparison with the case in the absence of the apex predator. The results show that the apex predator engenders the tendency to spread uniformly in the lattice, contributing to destroy the spiral patterns, keeping biodiversity but diminishing the average size of the clusters of the species that compete cyclically.

Islet transplantation is currently in clinical use as a treatment for type I diabetes, but donor shortages and long-term immunosuppression limit broad application. Alginate microcapsules coated with poly-l-ornithine can be used to encapsulate islets in an environment that allows diffusion of glucose, insulin, nutrients, and waste products while inhibiting cells and antibodies. While clinical trials are ongoing using islets encapsulated in alginate microbeads, there are concerns in regards to long-term stability. Evaluation of the local tissue response following implantation provides insight into the underlying mechanisms contributing to biomaterial failure, which can be used to the design of new material strategies. Macrophages play an important role in driving the response. In this study, the stability of alginate microbeads coated with PLO containing islets transplanted in the omentum pouch model was investigated. Biomaterial structure and the inflammatory response were characterized by X-ray phase contrast (XPC) μCT imaging, histology, and immunostaining. XPC allowed evaluation of microbead 3D structure and identification of failed and stable microbeads. A robust inflammatory response characterized by high cell density and the presence of pro-inflammatory macrophages was found around the failed grafts. The results obtained provide insight into the local tissue response and possible failure mechanisms for alginate microbeads. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1581-1590, 2016., (© 2016 Wiley Periodicals, Inc.)

The rock-paper-scissors game is a paradigmatic model for biodiversity, with applications ranging from microbial populations to human societies. Research has shown, however, that mobility jeopardizes biodiversity by promoting the formation of spiral waves, especially if there is no conservation law in place for the total number of competing players. First, we show that even if such a conservation law applies, mobility still jeopardizes biodiversity in the spatial rock-paper-scissors game if only a small fraction of links of the square lattice is randomly rewired. Secondly, we show that zealots are very effective in taming the amplitude of oscillations that emerge due to mobility and/or interaction randomness, and this regardless of whether the later is quenched or annealed. While even a tiny fraction of zealots brings significant benefits, at 5% occupancy zealots practically destroy all oscillations regardless of the intensity of mobility, and regardless of the type and strength of randomness in the interaction structure. Interestingly, by annealed randomness the impact of zealots is qualitatively the same as by mobility, which highlights that fast diffusion does not necessarily destroy the coexistence of species, and that zealotry thus helps to recover the stable mean-field solution. Our results strengthen the important role of zealots in models of cyclic dominance, and they reveal fascinating evolutionary outcomes in structured populations that are a unique consequence of such uncompromising behavior.

This paper discusses the wing inertial effects and the important role of the mean stroke angle on the pitch dynamics of hovering insects. The paper also presents a dynamic model appropriate for averaging and discusses the pitch stability results derived from the model. The model is used to predict the body angle of five insect species during hover, which are in good agreement with the available experimental results from different literature. The results suggest that the wing inertial forces have a considerable effect on pitch dynamics of insect flight and should not be ignored in dynamic analysis of hovering insects. The results also suggest that the body of hovering insects can not be vibrationally stabilized in a non-vertical orientation. Instead, the pitch angle of a hovering insect's body is mainly due to a balance of the moment of the insect's weight and the aerodynamic moment due to flapping kinematics with a nonzero mean stroke angle. Experiments with a flapping wing device confirm this results. To clearly explain the used model and clarify the difference between vibrational and non-vibrational stabilization, first this paper discusses the vibrational control of a three-degree-of-freedom force-input pendulum with its pivot moving in a vertical plane., (© 2024. The Author(s).)

Beyond abiotic conditions, do population dynamics mostly depend on a species' direct predators, preys and conspecifics? Or can indirect feedback that ripples across the whole community be equally important? Determining where ecological communities sit on the spectrum between these two characterizations requires a metric able to capture the difference between them. Here we show that the spectral radius of a community's interaction matrix provides such a metric, thus a measure of ecological collectivity, which is accessible from imperfect knowledge of biotic interactions and related to observable signatures. This measure of collectivity integrates existing approaches to complexity, interaction structure and indirect interactions. Our work thus provides an original perspective on the question of to what degree communities are more than loose collections of species or simple interaction motifs and explains when pragmatic reductionist approaches ought to suffice or fail when applied to ecological communities., (© 2024 John Wiley & Sons Ltd.)

An increasing number of publications include modeling. Often, such studies help us to gain a deeper insight into the phenomena studied and break down barriers between experimental and theoretical communities. However, combining experimental and theoretical work is challenging for authors, reviewers, and readers. To help maximize the usefulness and impact of combined theoretical and experimental research, this Primer describes the purpose, usefulness, and different types of models and addresses the practical aspect of integrated publications by outlining characteristics of good modeling, presentation, and fruitful collaborations., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Extensive degradation of coral reefs makes it imperative to create functional models that demonstrate ecological processes which occur in alternative states that persist over time. These models provide important information that can help in decision making regarding management measures for both the prevention of further degradation and the recovery of these ecosystems. Development of these models requires identifying and testing the ecological processes that will impose the reduction of coral cover and, preferably, identifying the disturbance that triggers this phenomenon. For this reason, research programs are a useful tool which allows a focus on the production of information for modeling. It should start with survey investigations and tests of hypotheses concerning the cause of the reduction of coral cover. Subsequently, projects should be guided by the most probable hypotheses, focusing on one guild or functional group at a time until the "trigger" process which unleashed the disturbance is identified. Even if incomplete, these models already provide information for focusing management steps., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: To improve predictive formulae for estimating body surface area (BSA) in healthy men and women using a modern three-dimensional scanner technology., Methods: Body surface areas were obtained from a convenience sample of 1267 US Marines (464 women and 803 men) using a whole body surface scanner (Size Stream SS20). The reliability of SS20 measures of total and regional BSA within participants was compared across triplicate scans. We then derived a series of formulae to estimate SS20-measured BSA using various combinations of sex, height, and mass. We also assessed relationships between percent body fat measured by dual-energy x-ray absorptiometry and sex-specific formulae errors in Marines., Results: Body surface areas recorded by the SS20 were highly reliable whether measured for the total body or by region (ICC ≥ .962). Formulae estimates of BSA from sex, height, and mass were precise (root-mean-square deviation, 0.031 m 2 ). Errors from the Marine Corps formulae were positively associated with percent body fat for men (p = .001) but not women (p = .843)., Conclusions: Clinicians, military leaders, and researchers can use the newly developed BSA formulae for precise estimates in healthy physically active men and women. Users should be aware that height- and mass-based BSA estimates are less accurate for individuals with extremely low or high percent body fat., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. American Journal of Human Biology published by Wiley Periodicals LLC.)

May and Leonard (SIAM J Appl Math 29:243-253, 1975) introduced a three-species Lotka-Volterra type population model that exhibits heteroclinic cycling. Rather than producing a periodic limit cycle, the trajectory takes longer and longer to complete each "cycle", passing closer and closer to unstable fixed points in which one population dominates and the others approach zero. Aperiodic heteroclinic dynamics have subsequently been studied in ecological systems (side-blotched lizards; colicinogenic Escherichia coli), in the immune system, in neural information processing models ("winnerless competition"), and in models of neural central pattern generators. Yet as May and Leonard observed "Biologically, the behavior (produced by the model) is nonsense. Once it is conceded that the variables represent animals, and therefore cannot fall below unity, it is clear that the system will, after a few cycles, converge on some single population, extinguishing the other two." Here, we explore different ways of introducing discrete stochastic dynamics based on May and Leonard's ODE model, with application to ecological population dynamics, and to a neuromotor central pattern generator system. We study examples of several quantitatively distinct asymptotic behaviors, including total extinction of all species, extinction to a single species, and persistent cyclic dominance with finite mean cycle length., (© 2022. The Author(s).)

Constructing dynamic mathematical models of biological systems requires estimating unknown parameters from available experimental data, usually using a statistical fitting procedure. This procedure is usually called parameter identification, parameter estimation, model fitting, or model calibration. In animal science, parameter identification is often performed without analytic considerations on the possibility of determining unique values of the model parameters. These analytical studies are related to the mathematical property of structural identifiability, which refers to the theoretical ability to recover unique values of the model parameters from the measures defined in an experimental setup and use the model structure as the sole basis. The structural identifiability analysis is a powerful tool for model construction because it informs whether the parameter identification problem is well-posed (i.e., the problem has a unique solution). Structural identifiability analysis is helpful to determine which actions (e.g., model reparameterization, choice of new data measurements, and change of the model structure) are needed to render the model parameters identifiable (when possible). The mathematical technicalities associated with structural identifiability analysis are very sophisticated. However, the development of dedicated, freely available software tools enables the application of identifiability analysis without needing to be an expert in mathematics and computer programming. We refer to such a non-expert user as a practitioner for hands-on purposes. However, a practitioner should be familiar with the model construction and software implementation process. In this paper, we propose to adopt a practitioner approach that takes advantage of available software tools to integrate identifiability analysis in the modeling practice in the animal science field. The application of structural identifiability implies switching our regard of the parameter identification problem as a downstream process (after data collection) to an upstream process (before data collection) where experiment design is applied to guarantee identifiability. This upstream approach will substantially improve the workflow of model construction toward robust and valuable models in animal science. Illustrative examples with different levels of complexity support our work. The source codes of the examples were provided for learning purposes and to promote open science practices., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Enzymatic versus chemical deinking is examined for MOW and photocopy prints. Several enzymatic preparations and two fibre/ink particle separation methods are tested. Deinking was monitored by image analysis and standard pulp and paper characterisation procedures. The effectiveness of the fibre/ink particle separation method depends on the ink particle's size: for smaller particles a washing step is recommended whereas for larger particles, the use of flotation is necessary. The enzymatic treatment is a competitive alternative for MOW and photocopy paper deinking. However, the process requires the selection of an adequate enzymatic preparation for each paper grade.

This note presents a brief commentary to a paper by Verbeni et al. concerning flux limited interpretation of morphogenetic actions. After a concise excursus on nonlinearity in diffusion phenomena, the commentary focuses on the derivation of macroscopic tissues equations from the underlying description at the cellular scale., (Copyright © 2013. Published by Elsevier B.V.)

This note presents a brief commentary to a paper by Verbeni et al. (2013) [8] concerning flux-limited interpretation of morphogenetic actions. After a concise excursus on the nonlinearity features in diffusion phenomena, three key questions are posed to Verbeni et al. (2013) [8]. The final comments looks ahead to research perspective concerning the interactions between biology and mathematics., (Copyright © 2013 Elsevier B.V. All rights reserved.)

"The viscosity of the blood in narrow capillary tubes" by Robin Fåhraeus and Torsten Lindqvist (Am J Physiol 96: 562-568, 1931) can be a valuable opportunity for teaching basic hemorheological principles in undergraduate cardiovascular physiology. This classic paper demonstrates that a progressive decline in apparent viscosity occurs when blood flows through glass capillary tubes of diminishing radius, which was later designated as the "Fåhraeus-Lindqvist effect." Subsequent studies have shown that apparent viscosity continues to decline at diameters that correspond to the arteriolar segments of the systemic vascular tree, where the majority of the total peripheral resistance resides and is actively regulated in vivo. The Fåhraeus-Lindqvist effect thus reduces microvascular resistance, thereby maintaining local tissue perfusion at a relatively lower blood pressure. The paper by Fåhraeus and Lindqvist can be used as a platform for a plenary discussion of these concepts as well as of the relationships among hematocrit, vessel diameter, red blood cell deformability, and resistance to blood flow and how these factors may affect the work of the heart.

Inspired by the morphology characteristics of the earthworms and the excellent deformability of origami structures, this research creates a novel earthworm-like locomotion robot through exploiting the origami techniques. In this innovation, appropriate actuation mechanisms are incorporated with origami ball structures into the earthworm-like robot 'body', and the earthworm's locomotion mechanism is mimicked to develop a gait generator as the robot 'centralized controller'. The origami ball, which is a periodic repetition of waterbomb units, could output significant bidirectional (axial and radial) deformations in an antagonistic way similar to the earthworm's body segment. Such bidirectional deformability can be strategically programmed by designing the number of constituent units. Experiments also indicate that the origami ball possesses two outstanding mechanical properties that are beneficial to robot development: one is the structural multistability in the axil direction that could contribute to the robot control implementation; and the other is the structural compliance in the radial direction that would increase the robot robustness and applicability. To validate the origami-based innovation, this research designs and constructs three robot segments based on different axial actuators: DC-motor, shape-memory-alloy springs, and pneumatic balloon. Performance evaluations reveal their merits and limitations, and to prove the concept, the DC-motor actuation is selected for building a six-segment robot prototype. Learning from earthworms' fundamental locomotion mechanism-retrograde peristalsis wave, seven gaits are automatically generated; controlled by which, the robot could achieve effective locomotion with qualitatively different modes and a wide range of average speeds. The outcomes of this research could lead to the development of origami locomotion robots with low fabrication costs, high customizability, light weight, good scalability, and excellent re-configurability.

The role of membrane transporters on pharmacokinetics (PKs), drug-drug interactions (DDIs), pharmacodynamics (PDs), and toxicity of drugs has been broadly recognized. However, our knowledge of modulation of transporter expression and/or function in the diseased patient population or specific populations, such as pediatrics or pregnancy, is still emerging. This white paper highlights recent advances in studying the changes in transporter expression and activity in various diseases (i.e., renal and hepatic impairment and cancer) and some specific populations (i.e., pediatrics and pregnancy) with the focus on clinical implications. Proposed alterations in transporter abundance and/or activity in diseased and specific populations are based on (i) quantitative transporter proteomic data and relative abundance in specific populations vs. healthy adults, (ii) clinical PKs, and emerging transporter biomarker and/or pharmacogenomic data, and (iii) physiologically-based pharmacokinetic modeling and simulation. The potential for altered PK, PD, and toxicity in these populations needs to be considered for drugs and their active metabolites in which transporter-mediated uptake/efflux is a major contributor to their absorption, distribution, and elimination pathways and/or associated DDI risk. In addition to best practices, this white paper discusses current challenges and knowledge gaps to study and quantitatively predict the effects of modulation in transporter activity in these populations, together with the perspectives from the International Transporter Consortium (ITC) on future directions., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics.)

Objective: Vancomycin is commonly used in the prevention and treatment of intracranial infections in postoperative neurosurgical patients with narrow therapeutic window and large pharmacokinetic variations. Several population pharmacokinetic (PPK) models of vancomycin have been established for neurosurgical patients. But comprehensive external evaluation has not been performed for almost all models. The objective of this study was to evaluate the predictive ability of published vancomycin PPK models in adult postoperative neurosurgical patients using an independent dataset., Method: PubMed, Embase and China National Knowledge Internet databases were searched to identify published vancomycin PPK models in adult postoperative neurosurgical patients. Prediction-based and simulation-based diagnostics were used to evaluate model predictability. Bayesian forecasting was used to assess the influence of prior concentration on model prediction performance., Result: A total of 763 vancomycin plasma concentrations from 493 postoperative neurosurgical patients were included in the external dataset. Eight population pharmacokinetic models of vancomycin in postoperative neurosurgical patients were included and evaluated. The model by Zhang et al. exhibited the best predictive performance in prediction-based diagnostics and prediction-corrected visual predictive checks, followed by the model by Shen et al. The predictive performance of other models was not satisfactory. The normalized predictive distribution error test shows that none of the models is suitable to describe our data. The predictive performance of vancomycin models was obviously improved by maximum a posteriori Bayesian forecasting., Conclusion: The published PPK models for adult postoperative neurosurgical patients show extensive variation in predictive performance in our patients. Although it is challenging to recommend initial doses of vancomycin from these predictive models, the combination of model-based prediction and therapeutic drug monitoring can be used for dose optimization., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

From the (patho)physiological point of view, diseases can be considered as emergent properties of living systems stemming from the complexity of these systems. Complex systems display some typical features, including the presence of emergent behavior and the organization in successive hierarchic levels. Drug treatments increase this complexity scenario, and from some years the use of network models has been introduced to describe drug-disease systems and to make predictions about them with regard to several aspects related to drug discovery. Here, we review some recent examples thereof with the aim to illustrate how network science tools can be very effective in addressing both tasks. We will examine the use of bipartite networks that lead to the important concept of "disease module", as well as the introduction of more articulated models, like multi-scale and multiplex networks, able to describe disease systems at increasing levels of organization. Examples of predictive models will then be discussed, considering both those that exploit approaches purely based on graph theory and those that integrate machine learning methods. A short account of both kinds of methodological applications will be provided. Finally, the point will be made on the present situation of modeling complex drug-disease systems highlighting some open issues. This article is categorized under: Neurological Diseases > Computational Models Infectious Diseases > Computational Models Cardiovascular Diseases > Computational Models., (© 2023 The Authors. WIREs Mechanisms of Disease published by Wiley Periodicals LLC.)

Model informed drug development (MiDD) is useful to predict in vivo exposure of drugs during various stages of the drug development process. This approach employs a variety of quantitative tools to assess the risks during the drug development process. One important tool in the MiDD tool kit is the Physiologically Based Pharmacokinetic Modelling (PBPK). This tool is extensively used to reduce the development cost and to accelerate the access of medicines to the patients. In this work, we provide an overview of PBPK modelling approaches in the generic drug development process, with a special emphasis on the bio-waiver applications. We describe herein approaches and common pitfalls while submitting model based justifications as a response to the regulatory deficiencies during the generic drug development process. With some in-house case studies, we have attempted to provide a clear path for PBPK model based justifications for bio-waivers. With this review, the gap between theoretical knowledge and practical application of modelling and simulation tools for generic drug product development could be potentially reduced., (© 2023. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

The individual study of [Formula: see text] and [Formula: see text] dynamics respectively in a [Formula: see text]-cell has yielded limited information about the cell functions. But the systems biology approaches for such studies have received very little attention by the research workers in the past. In the present work, a system-dynamics model for the interdependent [Formula: see text] and [Formula: see text] signaling that controls insulin secretion in a [Formula: see text]-cell has been suggested. A two-way feedback system of [Formula: see text] and [Formula: see text] has been considered and one-way feedback between [Formula: see text] and insulin has been implemented in the model. The finite element method along with the Crank-Nicolson method have been applied for simulation. Numerical results have been used to analyze the impact of perturbations in [Formula: see text] and [Formula: see text] dynamics on insulin secretion for normal and Type-2 diabetic conditions. The results reveal that Type-2 diabetes comes from abnormalities in insulin secretion caused by the perturbation in buffers and pumps (SERCA and PMCA)., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We investigate the population dynamics in generalized rock-paper-scissors models with an arbitrary number of species N. We show that spiral patterns with N arms may develop both for odd and even N, in particular in models where a bidirectional predation interaction of equal strength between all species is modified to include one N-cyclic predator-prey rule. While the former case gives rise to an interface network with Y-type junctions obeying the scaling law L∝t1/2, where L is the characteristic length of the network and t is the time, the latter can lead to a population network with N-armed spiral patterns, having a roughly constant characteristic length scale. We explicitly demonstrate the connection between interface junctions and spiral patterns in these models and compute the corresponding scaling laws. This work significantly extends the results of previous studies of population dynamics and could have profound implications for the understanding of biological complexity in systems with a large number of species.

Disagreement over whether life is inevitable when the conditions can support life remains unresolved, but calculations show that self-organization can arise naturally from purely random effects. Closure to efficient causation, or the need for all specific catalysts used by an organism to be produced internally, implies that a true model of an organism cannot exist, though this does not exclude the possibility that some characteristics can be simulated. Such simulations indicate that there is a limit to how small a self-organizing system can be: much smaller than a bacterial cell, but around the size of a typical virus particle. All current theories of life incorporate, at least implicitly, the idea of catalysis, but they largely ignore the need for metabolic regulation., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Highly comminuted intra-articular fractures are complex and difficult injuries to treat. Once emergent care is rendered, the definitive treatment objective is to restore the original anatomy while minimizing surgically induced trauma. Operations that use limited or percutaneous approaches help preserve tissue vitality, but reduced visibility makes reconstruction more difficult. A pre-operative plan of how comminuted fragments would best be re-positioned to restore anatomy helps in executing a successful reduction., Methods: In this study, the methods for virtually reconstructing a tibial plafond fracture were developed and applied to clinical cases. Building upon previous benchtop work, novel image analysis techniques and puzzle solving algorithms were developed for clinical application. Specialty image analysis tools were used to segment the fracture fragment geometries from CT data. The original anatomy was then restored by matching fragment native (periosteal and subchondral) bone surfaces to an intact template, generated from the uninjured contralateral limb., Findings: Virtual reconstructions obtained for ten tibial plafond fracture cases had average alignment errors of 0.39 (0.5 standard deviation) mm. In addition to precise reduction planning, 3D puzzle solutions can help identify articular deformities and bone loss., Interpretation: The results from this study indicate that 3D puzzle solving provides a powerful new tool for planning the surgical reconstruction of comminuted articular fractures., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

We study the oscillatory dynamics in the generic three-species rock-paper-scissors games with mutations. In the mean-field limit, different behaviors are found: (a) for high mutation rate, there is a stable interior fixed point with coexistence of all species; (b) for low mutation rates, there is a region of the parameter space characterized by a limit cycle resulting from a Hopf bifurcation; (c) in the absence of mutations, there is a region where heteroclinic cycles yield oscillations of large amplitude (not robust against noise). After a discussion on the main properties of the mean-field dynamics, we investigate the stochastic version of the model within an individual-based formulation. Demographic fluctuations are therefore naturally accounted and their effects are studied using a diffusion theory complemented by numerical simulations. It is thus shown that persistent erratic oscillations (quasi-cycles) of large amplitude emerge from a noise-induced resonance phenomenon. We also analytically and numerically compute the average escape time necessary to reach a (quasi-)cycle on which the system oscillates at a given amplitude., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Cyclic dominance of species is a potential mechanism for maintaining biodiversity. The author investigates the generalised scenario when the cyclic dominance of three or more interacting species is described by a non-symmetric matrix game that has multiple Nash equilibria. Modified Lotka-Volterra equations are proposed to incorporate the effects of swarming, and the condition for biodiversity is derived. The species are modelled using replicator equations, where each member of the species is assigned a fitness value. The authors show, for the first time, that the 'swarming effect' has an important role to play in the maintenance of biodiversity. The authors have also discovered the existence of a critical value of the swarming parameter for a given mobility, above which there is a high probability of existence of biodiversity.

A fundamental question in nonlinear science and evolutionary biology is how epidemic spreading may affect coexistence. We address this question in the framework of mobile species under cyclic competitions by investigating the roles of both intra- and interspecies spreading. A surprising finding is that intraspecies infection can strongly promote coexistence while interspecies spreading cannot. These results are quantified and a theoretical paradigm based on nonlinear partial differential equations is derived to explain the numerical results.

Proof of concept (POC) may be defined as the earliest point in the drug development process at which the weight of evidence suggests that it is "reasonably likely" that the key attributes for success are present and the key causes of failure are absent. POC is multidimensional but is focused on attributes that, if not addressed, represent a threat to the success of the project in crucial areas such as safety, efficacy, pharmaceutics, and commercial and regulatory issues. The appropriate weight of evidence is assessed through the use of mathematical models and by evaluating the consequences of advancing a candidate drug that is not safe, effective, or commercially viable, vs. failing to advance a candidate that possesses these attributes. Tools for POC include biomarkers, targeted populations, pharmacokinetic (PK)/pharmacodynamic (PD) modeling, simulation, and adaptive study designs. Challenges to the success of POCs include a shortage of skilled personnel, failure to integrate multiple disciplines and information, and the demand made by organizations for certainty.

We study the collective dynamics of mobile species under cyclic competition by breaking the symmetry in the initial populations and examining the basins of the two distinct asymptotic states: extinction and coexistence, the latter maintaining biodiversity. We find a rich dependence of dynamical properties on initial conditions. In particular, for high mobility, only extinction basins exist and they are spirally entangled, but a basin of coexistence emerges when the mobility parameter is decreased through a critical value, whose area increases monotonically as the parameter is further decreased. The structure of extinction basins for high mobility can be predicted by a mean-field theory. These results provide a more comprehensive picture for the fundamental issue of species coexistence than previously achieved.

As the behavior of a system composed of cyclically competing species is strongly influenced by the presence of fluctuations, it is of interest to study cyclic dominance in low dimensions where these effects are the most prominent. We here discuss rock-paper-scissors games on a one-dimensional lattice where the interaction rates and the mobility can be species dependent. Allowing only single site occupation, we realize mobility by exchanging individuals of different species. When the interaction and swapping rates are symmetric, a strongly enhanced swapping rate yields an increased mixing of the species, leading to a mean-field-like coexistence even in one-dimensional systems. This coexistence is transient when the rates are asymmetric, and eventually only one species will survive. Interestingly, in our spatial games the dominating species can differ from the species that would dominate in the corresponding nonspatial model. We identify different regimes in the parameter space and construct the corresponding dynamical phase diagram.

We study the cyclic dominance of three species in two-dimensional constrained Newman-Watts networks with a four-state variant of the rock-paper-scissors game. By limiting the maximal connection distance Rmax in Newman-Watts networks with the long-range connection probability p , we depict more realistically the stochastic interactions among species within ecosystems. When we fix mobility and vary the value of p or Rmax, the Monte Carlo simulations show that the spiral waves grow in size, and the system becomes unstable and biodiversity is lost with increasing p or Rmax. These results are similar to recent results of Reichenbach et al. [Nature (London) 448, 1046 (2007)], in which they increase the mobility only without including long-range interactions. We compared extinctions with or without long-range connections and computed spatial correlation functions and correlation length. We conclude that long-range connections could improve the mobility of species, drastically changing their crossover to extinction and making the system more unstable.