Microbial life in slow and stopped lanes.

Microbes in nature often lack nutrients and face extreme or widely fluctuating temperatures, unlike microbes in growth-optimized settings in laboratories that much of the literature examines. Slowed or suspended lives are the norm for microbes. Studying them is important for understanding the consequences of climate change and for addressing fundamental questions about life: are there limits to how slowly a cell's life can progress, and how long cells can remain viable without self-replicating? Recent studies began addressing these questions with single-cell-level measurements and mathematical models. Emerging principles that govern slowed or suspended lives of cells - including lives of dormant spores and microbes at extreme temperatures - are re-defining discrete cellular states as continuums and revealing intracellular dynamics at new timescales. Nearly inactive, lifeless-appearing microbes are transforming our understanding of life.

A predictive model to analyze the factors affecting the presence of serious chest injury in the occupants on motor vehicle crashes: Logistic regression approach.

OBJECTIVE: Chest injuries that occur in motor vehicle crashes (MVCs) include rib fractures, pneumothorax, hemothorax, and hemothorax depending on the injury mechanism. Many risk factors are associated with serious chest injuries from MVCs. The Korean In-Depth Accident Study database was analyzed to identify risk factors associated with motor vehicle occupants' serious chest injury. METHODS: Among 3,697 patients who visited the emergency room in regional emergency medical centers after MVCs between 2011 and 2018, we analyzed data from 1,226 patients with chest injuries. Vehicle damage was assessed using the Collision Deformation Classification (CDC) code and images of the damaged vehicle, and trauma scores were used to determine injury severity. Serious chest injury was defined as an Abbreviated Injury Scale (AIS) score for the chest code was more than 3. The patients were divided into two groups: serious chest injury patients with MAIS ≥ 3 and those with non-serious chest injury with MAIS < 3. A predictive model to analyze the factors affecting the presence of serious chest injury in the occupants on MVCs was constructed by a logistic regression analysis. RESULTS: Among the 1,226 patients with chest injuries, 484 (39.5%) had serious chest injuries. Patients in the serious group were older than those in the non-serious group (p=.001). In analyses based on vehicle type, the proportion of light truck occupants was higher in the serious group than in the non-serious group (p=.026). The rate of seatbelt use was lower in the serious group than in the non-serious group (p=.008). The median crush extent (seventh column of the CDC code) was higher in the serious group than in the non-serious group (p<.001). Emergency room data showed that the rates of intensive care unit (ICU) admission and death were higher among patients with serious injuries (p<.001). Similarly, the general ward/ICU admission data showed that the transfer and death rates were higher in patients with serious injuries (p<.001). The median ISS was higher in the serious group than in the non-serious group (p<.001). A predictive model was derived based on sex, age, vehicle type, seating row, belt status, collision type, and crush extent. This predictive model had an explanatory power of 67.2% for serious chest injuries. The model was estimated for external validation using the confusion matrix by applying the predictive model to the 2019 and 2020 data of the same structure as the data at the time of model development in the KIDAS database. CONCLUSIONS: Although this study had a major limitation in that the explanatory power of the predictive model was weak due to the small number of samples and many exclusion conditions, it was meaningful in that it suggested a model that could predict serious chest injuries in motor vehicle occupants (MVOs) based on actual accident investigation data in Korea. Future studies should yield more meaningful results, for example, if the chest compression depth value is derived through the reconstruction of MVCs using accurate collision speed values, and better models can be developed to predict the relationship between these values and the occurrence of serious chest injury.

Internet of medical things-based real-time digital health service for precision medicine: Empirical studies using MEDBIZ platform.

The aim of this study was to introduce the implemented MEDBIZ platform based on the internet of medical things (IoMT) supporting real-time digital health services for precision medicine. In addition, we demonstrated four empirical studies of the digital health ecosystem that could provide real-time healthcare services based on IoMT using real-world data from in-hospital and out-hospital patients. Implemented MEDBIZ platform based on the IoMT devices and big data to provide digital healthcare services to the enterprise and users. The big data platform is consisting of four main components: IoMT, core, analytics, and services. Among the implemented MEDBIZ platform, we performed four clinical trials that designed monitoring services related to chronic obstructive pulmonary disease, metabolic syndrome, arrhythmia, and diabetes mellitus. Of the four empirical studies on monitoring services, two had been completed and the rest were still in progress. In the metabolic syndrome monitoring service, two studies were reported. One was reported that intervention components, especially wearable devices and mobile apps, made systolic blood pressure, diastolic blood pressure, waist circumference, and glycosylated hemoglobin decrease after 6 months. Another one was presented that increasing high-density lipoprotein cholesterol and triglyceride levels were prevented in participants with the pre-metabolic syndrome. Also, self-care using healthcare devices might help prevent and manage metabolic syndrome. In the arrhythmia monitoring service, during the real-time monitoring of vital signs remotely at the monitoring center, 318 (15.9%) general hikers found abnormal signals, and 296 (93.1%) people were recommended for treatment. We demonstrated the implemented MEDBIZ platform based on IoMT supporting digital healthcare services by acquiring real-world data for getting real-world evidence. And then through this platform, we were developing software as a medical device, digital therapeutics, and digital healthcare services, and contributing to the development of the digital health ecosystem.

Macroscopic quorum sensing sustains differentiating embryonic stem cells.

Cells can secrete molecules that help each other's replication. In cell cultures, chemical signals might diffuse only within a cell colony or between colonies. A chemical signal's interaction length-how far apart interacting cells are-is often assumed to be some value without rigorous justifications because molecules' invisible paths and complex multicellular geometries pose challenges. Here we present an approach, combining mathematical models and experiments, for determining a chemical signal's interaction length. With murine embryonic stem (ES) cells as a testbed, we found that differentiating ES cells secrete FGF4, among others, to communicate over many millimeters in cell culture dishes and, thereby, form a spatially extended, macroscopic entity that grows only if its centimeter-scale population density is above a threshold value. With this 'macroscopic quorum sensing', an isolated macroscopic, but not isolated microscopic, colony can survive differentiation. Our integrated approach can determine chemical signals' interaction lengths in generic multicellular communities.

Slowest possible replicative life at frigid temperatures for yeast.

Determining whether life can progress arbitrarily slowly may reveal fundamental barriers to staying out of thermal equilibrium for living systems. By monitoring budding yeast's slowed-down life at frigid temperatures and with modeling, we establish that Reactive Oxygen Species (ROS) and a global gene-expression speed quantitatively determine yeast's pace of life and impose temperature-dependent speed limits - shortest and longest possible cell-doubling times. Increasing cells' ROS concentration increases their doubling time by elongating the cell-growth (G1-phase) duration that precedes the cell-replication (S-G2-M) phase. Gene-expression speed constrains cells' ROS-reducing rate and sets the shortest possible doubling-time. To replicate, cells require below-threshold concentrations of ROS. Thus, cells with sufficiently abundant ROS remain in G1, become unsustainably large and, consequently, burst. Therefore, at a given temperature, yeast's replicative life cannot progress arbitrarily slowly and cells with the lowest ROS-levels replicate most rapidly. Fundamental barriers may constrain the thermal slowing of other organisms' lives.

Effective Prevention and Management Tools for Metabolic Syndrome Based on Digital Health-Based Lifestyle Interventions Using Healthcare Devices.

Digital health-based lifestyle interventions (e.g., mobile applications, short messaging service, wearable devices, social media, and interactive websites) are widely used to manage metabolic syndrome (MetS). This study aimed to confirm the utility of self-care for prevention or management of MetS. We recruited 106 participants with one or more MetS risk factors from December 2019 to September 2020. Participants were provided five healthcare devices and applications. Characteristics were compared at baseline and follow-up to examine changes in risk factors, engagement, persistence, and physical activity (analyzed through device use frequency and lifestyle interventions performed). Participants with 1-2 MetS risk factors showed statistically significant reductions in waist circumference (WC) and blood pressure (BP). Participants with ≥3 MetS risk factors showed statistically significant reductions in risk factors including weight, body mass index, WC, BP, and fasting blood sugar (FBS). The prevention and improvement groups used more healthcare devices than the other groups. Smartwatch was the most frequently used device (5 times/week), and physical activity logged more than 7000 steps/week. WC, BP, and FBS of the improvement group were reduced by more than 40%. Based on engagement, persistence, and physical activity, digital health-based lifestyle interventions could be helpful for MetS prevention and management.

Noninvasive Screening Tool for Hyperkalemia Using a Single-Lead Electrocardiogram and Deep Learning: Development and Usability Study.

BACKGROUND: Hyperkalemia monitoring is very important in patients with chronic kidney disease (CKD) in emergency medicine. Currently, blood testing is regarded as the standard way to diagnose hyperkalemia (ie, using serum potassium levels). Therefore, an alternative and noninvasive method is required for real-time monitoring of hyperkalemia in the emergency medicine department. OBJECTIVE: This study aimed to propose a novel method for noninvasive screening of hyperkalemia using a single-lead electrocardiogram (ECG) based on a deep learning model. METHODS: For this study, 2958 patients with hyperkalemia events from July 2009 to June 2019 were enrolled at 1 regional emergency center, of which 1790 were diagnosed with chronic renal failure before hyperkalemic events. Patients who did not have biochemical electrolyte tests corresponding to the original 12-lead ECG signal were excluded. We used data from 855 patients (555 patients with CKD, and 300 patients without CKD). The 12-lead ECG signal was collected at the time of the hyperkalemic event, prior to the event, and after the event for each patient. All 12-lead ECG signals were matched with an electrolyte test within 2 hours of each ECG to form a data set. We then analyzed the ECG signals with a duration of 2 seconds and a segment composed of 1400 samples. The data set was randomly divided into the training set, validation set, and test set according to the ratio of 6:2:2 percent. The proposed noninvasive screening tool used a deep learning model that can express the complex and cyclic rhythm of cardiac activity. The deep learning model consists of convolutional and pooling layers for noninvasive screening of the serum potassium level from an ECG signal. To extract an optimal single-lead ECG, we evaluated the performances of the proposed deep learning model for each lead including lead I, II, and V1-V6. RESULTS: The proposed noninvasive screening tool using a single-lead ECG shows high performances with F1 scores of 100%, 96%, and 95% for the training set, validation set, and test set, respectively. The lead II signal was shown to have the highest performance among the ECG leads. CONCLUSIONS: We developed a novel method for noninvasive screening of hyperkalemia using a single-lead ECG signal, and it can be used as a helpful tool in emergency medicine.

Diffusion of a Lifelog-Based Digital Healthcare Platform for Future Precision Medicine: Data Provision and Verification Study.

We propose a method for data provision, validation, and service expansion for the spread of a lifelog-based digital healthcare platform. The platform is an operational cloud-based platform, implemented in 2020, that has launched a tool that can validate and de-identify personal information in a data acquisition system dedicated to a center. The data acquired by the platform can be processed into products of statistical analysis and artificial intelligence (AI)-based deep learning modules. Application programming interfaces (APIs) have been developed to open data and can be linked in a programmatic manner. As a standardized policy, a series of procedures were performed from data collection to external sharing. The proposed platform collected 321.42 GB of data for 146 types of data. The reliability and consistency of the data were evaluated by an information system audit institution, with a defects ratio of approximately 0.03%. We presented definitions and examples of APIs developed in 17 functional units for data opening. In addition, the suitability of the de-identification tool was confirmed by evaluating the reduced risk of re-identification using quasi-identifiers. We presented specific methods for data verification, personal information de-identification, and service provision to ensure the sustainability of future digital healthcare platforms for precision medicine. The platform can contribute to the diffusion of the platform by linking data with external organizations and research environments in safe zones based on data reliability.

The Effect of a Mobile and Wearable Device Intervention on Increased Physical Activity to Prevent Metabolic Syndrome: Observational Study.

BACKGROUND: Research on whether wearable devices and app-based interventions can effectively prevent metabolic syndrome (MetS) by increasing physical activity (PA) among middle-aged people living in the rural areas of South Korea remains insufficient. OBJECTIVE: The aim of this study was to determine whether mobile and wearable device interventions can improve health indicators, including PA, in MetS risk groups in rural South Korea. METHODS: In this clinical trial, performed from December 2019 to June 2020, participants were asked to use a wearable device (GalaxyWatch Active1) alone (standard intervention) or the wearable device and mobile app (Yonsei Health Korea) (enhanced intervention). Clinical measures and International Physical Activity Questionnaire (IPAQ) scores were evaluated initially and after 6 months. The number of steps was monitored through the website. The primary outcome was the difference in PA and clinical measures between the enhanced intervention and standard intervention groups. The secondary outcome was the decrease in MetS factors related to the change in PA. RESULTS: A total of 267 participants were randomly selected, 221 of whom completed the 6-month study. Among the 221 participants, 113 were allocated to the enhanced intervention group and 108 were allocated to the standard intervention group. After 6 months, the body weight and BMI for the enhanced intervention group decreased by 0.6 (SD 1.87) and 0.21 (SD 0.76), respectively (P<.001). In both groups, systolic blood pressure, diastolic blood pressure, waist circumference, and glycated hemoglobin A1c (HbA1c) decreased (P<.001). The total PA was approximately 2.8 times lower in the standard intervention group (mean 44.47, SD 224.85) than in the enhanced intervention group (mean 124.36, SD 570.0). Moreover, the enhanced intervention group achieved the recommended level of moderate to vigorous physical activity (MVPA), whereas the standard intervention group did not (188 minutes/week vs 118 minutes/week). Additionally, the number of participants in the enhanced intervention group (n=113) that reached 10,000 daily steps or more after the intervention increased from 9 (8.0%) to 26 (23.1%) (P=.002), whereas this number did not increase significantly in the standard intervention group (n=108), from 8 (7.4%) to 16 (14.8%) (P=.72). The number of participants without any MetS factors increased by 12 (11%) and 8 (7%) in the enhanced and standard intervention group, respectively. CONCLUSIONS: PA monitoring and an intervention using wearable devices were effective in preventing MetS in a rural population in Korea. Blood pressure, waist circumference, and HbA1c were improved in both intervention groups, which were effective in reducing MetS factors. However, only the participants in the enhanced intervention group continuously increased their MVPA and step counts above the recommended level to prevent MetS. Body weight and BMI were further improved, and a higher number of participants with zero MetS factors was attained from the enhanced intervention. TRIAL REGISTRATION: Clinical Research Information Service KCT0005783; https://cris.nih.go.kr/cris/search/detailSearch.do/16123.

Concept and Proof of the Lifelog Bigdata Platform for Digital Healthcare and Precision Medicine on the Cloud.

PURPOSE: We propose the Lifelog Bigdata Platform as a sustainable digital healthcare system based on individual-centric lifelog datasets and describe the standardization of lifelog and clinical data in its full-cycle management system. MATERIALS AND METHODS: The Lifelog Bigdata Platform was developed by Yonsei Wonju Health System on the cloud to support digital healthcare and precision medicine. It consists of five core components: data acquisition system, de-identification of individual information, lifelog integration, analyzer, and service. We designed a gathering system into a dedicated virtual machine to save lifelog or clinical outcomes and established standard guidelines for maintaining the quality of gathering procedures. We used standard integration keys to integrate the lifelog and clinical data. Metadata were generated from the data warehouse after loading combined or fragmented data on it. We analyzed the de-identified lifelog and clinical data using the lifelog analyzer to prevent and manage acute and chronic diseases through providing results of statistics on analysis. RESULTS: The big data centers were built in four hospitals and seven companies for integrating lifelog and clinical data to develop the Lifelog Bigdata Platform. We integrated and loaded lifelog big data and clinical data for 3 years. In the first year, we uploaded 94 types of data on the platform with a total capacity of 221 GB. CONCLUSION: The Lifelog Bigdata Platform is the first to combine lifelog and clinical data. The proposed standardization guidelines can be used for future platforms to achieve a virtuous cycle structure of lifelogging big data and an industrial ecosystem.

Weight Change Is Associated with Osteoporosis: A Cross Sectional Study Using the Korean Community Health Survey.

The purpose of the present study was to analyze the associations between weight change and osteoporosis in Korean adults. METHODS: Data from the 2016 Korean Community Health Survey were analyzed. A total of 159,741 participants who were ≥40 years of age were included. The histories of osteoporosis were surveyed in two ways: 'osteoporosis for entire life' and 'current osteoporosis'. The participants were grouped into three categories for simplification as follows: 'Weight L&M' (Tried to lose weight or Tried to maintain weight), 'Weight gain' (Tried to gain weight), and 'Never tried'. Additionally, we analyzed their relationship with obesity using the BMI. RESULTS: The adjusted ORs for 'osteoporosis for entire life' were 1.20 (95% confidence interval [CI] 1.13-1.27) in the Weight L&M group and 1.83 (95% CI 1.64-2.05) in the Weight gain group. The adjusted ORs for 'current osteoporosis' were 1.16 (95% CI 1.08-1.25) in the Weight L&M group and 1.77 (95% CI 1.54-2.02) in the Weight gain group. CONCLUSIONS: Compared to the Never tried group, being in either the Weight L&M or Weight gain groups showed a significant impact on the possibility of osteoporosis.

Predictive landscapes hidden beneath biological cellular automata.

To celebrate Hans Frauenfelder's achievements, we examine energy(-like) "landscapes" for complex living systems. Energy landscapes summarize all possible dynamics of some physical systems. Energy(-like) landscapes can explain some biomolecular processes, including gene expression and, as Frauenfelder showed, protein folding. But energy-like landscapes and existing frameworks like statistical mechanics seem impractical for describing many living systems. Difficulties stem from living systems being high dimensional, nonlinear, and governed by many, tightly coupled constituents that are noisy. The predominant modeling approach is devising differential equations that are tailored to each living system. This ad hoc approach faces the notorious "parameter problem": models have numerous nonlinear, mathematical functions with unknown parameter values, even for describing just a few intracellular processes. One cannot measure many intracellular parameters or can only measure them as snapshots in time. Another modeling approach uses cellular automata to represent living systems as discrete dynamical systems with binary variables. Quantitative (Hamiltonian-based) rules can dictate cellular automata (e.g., Cellular Potts Model). But numerous biological features, in current practice, are qualitatively described rather than quantitatively (e.g., gene is (highly) expressed or not (highly) expressed). Cellular automata governed by verbal rules are useful representations for living systems and can mitigate the parameter problem. However, they can yield complex dynamics that are difficult to understand because the automata-governing rules are not quantitative and much of the existing mathematical tools and theorems apply to continuous but not discrete dynamical systems. Recent studies found ways to overcome this challenge. These studies either discovered or suggest an existence of predictive "landscapes" whose shapes are described by Lyapunov functions and yield "equations of motion" for a "pseudo-particle." The pseudo-particle represents the entire cellular lattice and moves on the landscape, thereby giving a low-dimensional representation of the cellular automata dynamics. We outline this promising modeling strategy.

High Risk of Hip and Spinal Fractures after Distal Radius Fracture: A Longitudinal Follow-Up Study Using a National Sample Cohort.

The purpose of the present study was to estimate the risk of hip and spinal fracture after distal radius fracture. Data from the Korean National Health Insurance Service-National Sample Cohort were collected between 2002 and 2013. A total of 8013 distal radius fracture participants who were 50 years of age or older were selected. The distal radius fracture participants were matched for age, sex, income, region of residence, and past medical history in a 1:4 ratio with control participants. In the subgroup analysis, participants were stratified according to age group (50-59, 60-69, or ≥70 years) and sex (male or female). Distal radius fracture patients had a 1.51-fold and 1.40-fold higher incidence of hip fracture and spinal fracture in the adjusted models, respectively. Among males, patients of all ages had a significantly higher incidence of hip fracture, and those who were 50 to 69 years of age had a significantly higher incidence of spinal fracture. Among females, those older than 70 years had a significantly higher incidence of hip fracture, and patients of all ages had a significantly higher incidence of spinal fracture. Previous distal radius fracture has a significant impact on the risk of subsequent hip and spinal fractures.

A Predictive Model to Analyze the Factors Affecting the Presence of Traumatic Brain Injury in the Elderly Occupants of Motor Vehicle Crashes Based on Korean In-Depth Accident Study (KIDAS) Database.

Traumatic brain injury (TBI), also known as intracranial injury, occurs when an external force injures the brain. This study aimed to analyze the factors affecting the presence of TBI in the elderly occupants of motor vehicle crashes. We defined elderly occupants as those more than 55 years old. Damage to the vehicle was presented using the Collision Deformation Classification (CDC) code by evaluation of photos of the damaged vehicle, and a trauma score was used for evaluation of the severity of the patient's injury. A logistic regression model was used to identify factors affecting TBI in elderly occupants and a predictive model was constructed. We performed this study retrospectively and gathered all the data under the Korean In-Depth Accident Study (KIDAS) investigation system. Among 3697 patients who visited the emergency room in the regional emergency medical center due to motor vehicle crashes from 2011 to 2018, we analyzed the data of 822 elderly occupants, which were divided into two groups: the TBI patients (N = 357) and the non-TBI patients (N = 465). According to multiple logistic regression analysis, the probabilities of TBI in the elderly caused by rear-end (OR = 1.833) and multiple collisions (OR = 1.897) were higher than in frontal collision. Furthermore, the probability of TBI in the elderly was 1.677 times higher in those with unfastened seatbelts compared to those with fastened seatbelts (OR = 1.677). This study was meaningful in that it incorporated several indicators that affected the occurrence of the TBI in the elderly occupants. In addition, it was performed to determine the probability of TBI according to sex, vehicle type, seating position, seatbelt status, collision type, and crush extent using logistic regression analysis. In order to derive more precise predictive models, it would be needed to analyze more factors for vehicle damage, environment, and occupant injury in future studies.

Dormancy-to-death transition in yeast spores occurs due to gradual loss of gene-expressing ability.

Dormancy is colloquially considered as extending lifespan by being still. Starved yeasts form dormant spores that wake-up (germinate) when nutrients reappear but cannot germinate (die) after some time. What sets their lifespans and how they age are open questions because what processes occur-and by how much-within each dormant spore remains unclear. With single-cell-level measurements, we discovered how dormant yeast spores age and die: spores have a quantifiable gene-expressing ability during dormancy that decreases over days to months until it vanishes, causing death. Specifically, each spore has a different probability of germinating that decreases because its ability to-without nutrients-express genes decreases, as revealed by a synthetic circuit that forces GFP expression during dormancy. Decreasing amounts of molecules required for gene expression-including RNA polymerases-decreases gene-expressing ability which then decreases chances of germinating. Spores gradually lose these molecules because they are produced too slowly compared with their degradations, causing gene-expressing ability to eventually vanish and, thus, death. Our work provides a systems-level view of dormancy-to-death transition.

Yeasts collectively extend the limits of habitable temperatures by secreting glutathione.

The conventional view is that high temperatures cause microorganisms to replicate slowly or die. In this view, microorganisms autonomously combat heat-induced damages. However, microorganisms co-exist with each other, which raises the underexplored and timely question of whether microorganisms can cooperatively combat heat-induced damages at high temperatures. Here, we use the budding yeast Saccharomyces cerevisiae to show that cells can help each other and their future generations to survive and replicate at high temperatures. As a consequence, even at the same temperature, a yeast population can exponentially grow, never grow or grow after unpredictable durations (hours to days) of stasis, depending on its population density. Through the same mechanism, yeasts collectively delay and can eventually stop their approach to extinction, with higher population densities stopping faster. These features arise from yeasts secreting and extracellularly accumulating glutathione-a ubiquitous heat-damage-preventing antioxidant. We show that the secretion of glutathione, which eliminates harmful extracellular chemicals, is both necessary and sufficient for yeasts to collectively survive at high temperatures. A mathematical model, which is generally applicable to any cells that cooperatively replicate by secreting molecules, recapitulates all of these features. Our study demonstrates how organisms can cooperatively define and extend the boundaries of life-permitting temperatures.

Cellular Dialogues: Cell-Cell Communication through Diffusible Molecules Yields Dynamic Spatial Patterns.

Cells form spatial patterns by coordinating their gene expressions. How a group of mesoscopic numbers (hundreds to thousands) of cells, without pre-existing morphogen gradients and spatial organization, self-organizes spatial patterns remains poorly understood. Of particular importance are dynamic spatial patterns such as spiral waves that perpetually move and transmit information. We developed an open-source software for simulating a field of cells that communicate by secreting any number of molecules. With this software and a theory, we identified all possible "cellular dialogues"-ways of communicating with two diffusing molecules-that yield diverse dynamic spatial patterns. These patterns emerge despite widely varying responses of cells to the molecules, gene-expression noise, spatial arrangements, and cell movements. A three-stage, "order-fluctuate-settle" process forms dynamic spatial patterns: cells form long-lived whirlpools of wavelets that, following erratic dynamics, settle into a dynamic spatial pattern. Our work helps in identifying gene-regulatory networks that underlie dynamic pattern formations.

Evaluation of Schink et al.: Having the Gem Shine through a Fog.

One snapshot of the peer review process for "Death Rate of E. coli during Starvation Is Set by Maintenance Cost and Biomass Recycling" (Schink et al., 2019).

Modeling cell-cell communication for immune systems across space and time.

Communicating is crucial for cells to coordinate their behaviors. Immunological processes, involving diverse cytokines and cell types, are ideal for developing frameworks for modeling coordinated behaviors of cells. Here, we review recent studies that combine modeling and experiments to reveal how immune systems use autocrine, paracrine, and juxtacrine signals to achieve behaviors such as controlling population densities and hair regenerations. We explain that models are useful because one can computationally vary numerous parameters, in experimentally infeasible ways, to evaluate alternate immunological responses. For each model, we focus on the length-scales and time-scales involved and explain why integrating multiple length-scales and time-scales in a model remain challenging. We suggest promising modeling strategies for meeting this challenge and their practical consequences.