The Prolonged Terminal Phase of Human Life Induces Survival Response in the Skin Transcriptome.

Human death marks the end of organismal life under conditions such that the components of the human body continue to be alive. Such postmortem cellular survival depends on the nature (Hardy scale of slow-fast death) of human death. Slow and expected death typically results from terminal illnesses and includes a prolonged terminal phase of life. As such organismal death process unfolds, do cells of the human body adapt for postmortem cellular survival? Organs with low energy cost-of-living, such as the skin, are better suited for postmortem cellular survival. In this work, the effect of different durations of terminal phase of human life on postmortem changes in cellular gene expression was investigated using RNA sequencing data of 701 human skin samples from the Genotype-Tissue Expression (GTEx) database. Longer terminal phase (slow-death) was associated with a more robust induction of survival pathways (PI3K-Akt signaling) in postmortem skin. Such cellular survival response was associated with the upregulation of embryonic developmental transcription factors such as FOXO1 , FOXO3 , ATF4 and CEBPD . Upregulation of PI3K-Akt signaling was independent of sex or duration of death-related tissue ischemia. Analysis of single nucleus RNA-seq of post-mortem skin tissue specifically identified the dermal fibroblast compartment to be most resilient as marked by adaptive induction of PI3K-Akt signaling. In addition, slow death also induced angiogenic pathways in the dermal endothelial cell compartment of postmortem human skin. In contrast, specific pathways supporting functional properties of the skin as an organ were downregulated following slow death. Such pathways included melanogenesis and those representing the skin extracellular matrix (collagen expression and metabolism). Efforts to understand the significance of death as a biological variable (DABV) in influencing the transcriptomic composition of surviving component tissues has far-reaching implications including rigorous interpretation of experimental data collected from the dead and mechanisms involved in transplant-tissue obtained from dead donors.

The effect of endurance training on non-alcoholic fatty liver disease in mice.

Chronic endurance exercise is a therapeutic strategy in the treatment of non-alcoholic fatty liver disease (NAFLD). Metabolic, cardiorespiratory, and endocrine pathways targeted by chronic endurance exercise have been identified; however, the specific cellular and molecular pathways modified by exercise in the steatotic liver remain unresolved. In this study, we show hepatic gene expression, and the structure, characteristics, and clinical differences between sedentary and exercised mice, by an endurance exercise model with wheels with a controlled velocity that allows for the quantification of a human-relevant endurance "dosage," after exposure to regular and high-fat diet. Chronic exercise modified the transcription of hepatic genes related to liver nuclear receptors, cell growth, fibrosis, inflammation, and oxidative stress, and decreased the amount of lipid accumulation in the liver. Moreover, the combination of endurance training with the change in diet differentially modified the genetic expression of the biomarkers relative to the separate interventions. Even though exercise by itself showed counteract NAFLD development, the combined intervention was sufficient to convert the structure and clinical aspects of the liver from steatotic to healthy. Given our findings, the combination of endurance exercise and change in diet should be considered a therapeutic option for NASH.

Advancing therapies for viral infections using mechanistic computational models of the dynamic interplay between the virus and host immune response.

The COVID-19 pandemic has highlighted a need for improved frameworks for drug discovery, repurposing, clinical trial design and therapy optimization and personalization. Mechanistic computational models can play an important role in developing these frameworks. We discuss how mechanistic models, which consider viral entry, replication in target cells, viral spread in the body, immune response, and the complex factors involved in tissue and organ damage and recovery, can clarify the mechanisms of humoral and cellular immune responses to the virus, viral distribution and replication in tissues, the origins of pathogenesis and patient-to-patient heterogeneity in responses. These models are already improving our understanding of the mechanisms of action of antivirals and immune modulators. We discuss how closer collaboration between the experimentalists, clinicians and modelers could result in more predictive models which may guide therapies for viral infections, improving survival and leading to faster and more complete recovery.

Run for your life: an integrated virtual tissue platform for incorporating exercise oncology into immunotherapy.

The purpose of this paper is to introduce a novel in silico platform for simulating early-stage solid tumor growth and anti-tumor immune response. We present the model, test the sensitivity and robustness of its parameters, and calibrate it with clinical data from exercise oncology experiments which offer a natural biological backdrop for modulation of anti-tumor immune response. We then perform two virtual experiments with the model that demonstrate its usefulness in guiding pre-clinical and clinical studies of immunotherapy. The first virtual experiment describes the intricate dynamics in the tumor microenvironment between the tumor and the infiltrating immune cells. Such dynamics is difficult to probe during a pre-clinical study as it requires significant redundancy in lab animals and is prohibitively time-consuming and labor-intensive. The result is a series of spatiotemporal snapshots of the tumor and its microenvironment that can serve as a platform to test mechanistic hypotheses on the role and dynamics of different immune cells in anti-tumor immune response. The second virtual experiment shows how dosage and/or frequency of immunotherapy drugs can be optimized based on the aerobic fitness of the patient, so that possible adverse side effects of the treatment can be minimized.

Effect of endurance exercise training on liver gene expression in male and female mice.

Chronic endurance exercise is a therapeutic strategy in the treatment of many chronic diseases in humans, including the prevention and treatment of metabolic diseases such as diabetes mellitus. Metabolic, cardiorespiratory, and endocrine pathways targeted by chronic endurance exercise have been identified. In the liver, however, the cellular and molecular pathways that are modified by exercise and have preventive or therapeutic relevance to metabolic disease need to be elucidated. The mouse model used in the current study allows for the quantification of a human-relevant exercise "dosage". In this study we show hepatic gene expression differences between sedentary female and sedentary male mice and that chronic exercise modifies the transcription of hepatic genes related to metabolic disease and steatosis in both male and female mice. Chronic exercise induces molecular pathways involved in glucose tolerance, glycolysis, and gluconeogenesis while producing a decrease in pathways related to insulin resistance, steatosis, fibrosis, and inflammation. Given these findings, this mouse exercise model has potential to dissect the cellular and molecular hepatic changes following chronic exercise with application to understanding the role that chronic exercise plays in preventing human diseases. Novelty: Exercise modifies the hepatic gene expression and hepatic pathways related to metabolic disease in male and female mice. Sex differences were seen in hepatic gene expression between sedentary and exercised mice. The mouse exercise model used in this study allows for application and evaluation of exercise effects in human disease.

A new aerobic fitness score based on lactate sensing during submaximal exercise.

Given the known clinical utility of cardiorespiratory fitness, measurement of physiological responses to submaximal exercise may be a feasible approach well suited for diagnostic and prognostic purposes in non-athletes and the chronically ill. Lactate levels and watt output during a short submaximal exercise and a subsequent relaxation period yield an aerobic score that is consistent with cardiorespiratory fitness grades in non-athletes and that may be used as a marker in such approaches. In this study, 28 females (23 ± 3 years) were submitted to a 15 min submaximal recumbent bike session, and their capillary and saliva lactate concentrations were recorded and plotted against time. An individual aerobic score was calculated from this curve, using watt output during equal relative percentiles of maximum heart-rate benchmarks. The scores were compared with respective results in a V̇O2max test and with a similar scoring system in 14 older (51 ± 9 years) females; they correlated with the 6 categories of the V̇O2max test results and classified into 3 categories of V̇O2max grades (very poor/poor; fair/good; excellent/superior) with a combined accuracy of 80.95%. More studies are required to validate the potential utility of this submaximal test as an additional risk factor for diagnostic purposes in non-athletes. Novelty points: A novel method for estimating cardiorespiratory fitness during submaximal exercise consistent with V̇O2max performance. The method yields an aerobic score that may be used as a marker for diagnostic and prognostic purposes.

How to train a mouse-methodological issues in pre-clinical exercise oncology.

We point at several challenges that current exercise oncology rodent models face, which call their human-relevance into question: the vast majority of pre-clinical studies in exercise oncology treat "physical exercise" as a primitive concept without further analysis or qualification, and their results are based on dosages that no human can endure. The lack of analysis and qualification together with the dosage mismatch conceal the fact that rodents do not run like humans. Consequently, while these pre-clinical studies may yield insights into potential biological mechanisms underlying the systemic effects of physical exercise on cancer, the applicability of this knowledge to preventive interventions in healthy humans and the ability to translate it to practical therapies in the critically ill remain limited. We propose an alternative exercise rodent model that has better chances of meeting these challenges.

Endurance training slows breast tumor growth in mice by suppressing Treg cells recruitment to tumors.

BACKGROUND: Aerobic exercise has been shown to slow tumor progression in rodents and humans, but the mechanisms behind this effect are still unclear. Here we show that aerobic exercise in the form of chronic endurance training suppresses tumor recruitment of FoxP3+ Treg cells thus enhancing antitumor immune efficiency. METHODS: Adult wild-type and athymic BALB/c female mice were endurance-trained for 8 weeks. Circulating leukocytes as well as muscle and liver mtDNA copy number were compared to aged-matched concurrent sedentary controls to establish systemic effects. 4 T1 murine mammary tumor cells were injected subcutaneously to the 4th mammary pad at the end of the training period. Tumor growth and survival rates were compared, together with antitumor immune response. RESULTS: Exercised wild-type had 17% slower growth rate, 24% longer survival, and 2-fold tumor-CD+ 8/FoxP3+ ratio than sedentary controls. Exercised athymic BALB/c females showed no difference in tumor growth or survival rates when compared to sedentary controls. CONCLUSIONS: Cytotoxic T cells are a significant factor in endurance exercise-induced suppression of tumor growth. Endurance exercise enhances antitumor immune efficacy by increasing intratumoral CD8+/FoxP3+ ratio.

TOWARDS A MULTI-SCALE AGENT-BASED PROGRAMMING LANGUAGE METHODOLOGY.

Living tissues are dynamic, heterogeneous compositions of objects, including molecules, cells and extra-cellular materials, which interact via chemical, mechanical and electrical process and reorganize via transformation, birth, death and migration processes. Current programming language have difficulty describing the dynamics of tissues because: 1: Dynamic sets of objects participate simultaneously in multiple processes, 2: Processes may be either continuous or discrete, and their activity may be conditional, 3: Objects and processes form complex, heterogeneous relationships and structures, 4: Objects and processes may be hierarchically composed, 5: Processes may create, destroy and transform objects and processes. Some modeling languages support these concepts, but most cannot translate models into executable simulations. We present a new hybrid executable modeling language paradigm, the Continuous Concurrent Object Process Methodology (CCOPM) which naturally expresses tissue models, enabling users to visually create agent-based models of tissues, and also allows computer simulation of these models.

Decoherence: the view from the history and philosophy of science.

We present a brief history of decoherence, from its roots in the foundations of classical statistical mechanics, to the current spin bath models in condensed matter physics. We then analyse the philosophical importance of decoherence in three different foundational problems, and find that its role in their solutions is less than that commonly believed. What makes decoherence more philosophically interesting, we argue, are the methodological issues it draws attention to, and the question of the universality of quantum mechanics.