Somatic evolution of cancer involves a series of mutations, and attendant changes, in one or more clones of cells. A "bad luck" type model assumes chance accumulation of mutations. The clonal ...expansion model assumes, on the other hand, that any mutation leading to partial loss of regulation of cell proliferation will give a selective advantage to the mutant. However, a number of experiments show that an intermediate pre-cancer mutant has only a conditional selective advantage. Given that tissue microenvironmental conditions differ across individuals, this selective advantage to a mutant could be widely distributed over the population. We evaluate three models, namely "bad luck", context-independent, and context-dependent selection, in a comparative framework, on their ability to predict patterns in total incidence, age-specific incidence, stem cell number-incidence relationship and other known phenomena associated with cancers. Results show that among the factors considered in the model, context dependence is necessary and sufficient to explain observed epidemiological patterns, and that cancer evolution is largely selection-limited, rather than mutation-limited. A wide range of physiological, genetic and behavioural factors influence the tissue micro-environment, and could therefore be the source of this context dependence in somatic evolution of cancer. The identification and targeting of these micro-environmental factors that influence the dynamics of selection offer new possibilities for cancer prevention.
Behavioural environment and behavioural responses of an individual are known to affect multiple aspects of physiology including neuroendocrine and growth factor signalling, angiogenesis, stem cell ...dynamics, tissue homeostasis, and maintenance. Despite substantial evidence, the role of behaviour-physiology interface in human health and disease remains underappreciated. The hypothesis proposed here suggests that deficiencies of certain behaviours that have evolved to become essential or “vitactions” can potentially trigger multiple health problems. Altered growth factor expression because of vitaction deficiencies affects angiogenesis and vascular function, neuronal maintenance, transport of glucose and other nutrients to the brain, mitochondrial function, oxidative stress, inflammation, and protein aggregation dynamics all implicated in Alzheimer’s disease (AD). Exercise is already known to be effective in prevention of AD. The hypothesis suggests that it is the behavioural component of exercise over mechanical activity and calorie burning that has crucial effects on brain health through multiple signalling pathways. Similar to vitamin deficiencies, where supplying the deficient vitamin is the only effective solution, for vitaction deficiencies supplying the deficient behavioural stimuli through behaviourally enriched exercise can be the most effective remedy.
Proxy failure in academia has progressed much ahead of what John et al. describe. We see advanced phenomena such as proxy complimentarity in which different players push each others' proxy failures; ...proxy exploitation in which external agents exploit players' proxies and predatory proxies that devour the goal itself. Academics need to avoid proxy failures by designing behaviorally sound systems.
Streptomyces is the largest antibiotic-producing genus in the microbial world discovered so far. The number of antimicrobial compounds reported from the species of this genus per year increased ...almost exponentially for about two decades, followed by a steady rise to reach a peak in the 1970s, and with a substantial decline in the late 1980s and 1990s. The cumulative number shows a sigmoid curve that is much flatter than what a logistic equation would predict. We attempted to fit a mathematical model to this curve in order to estimate the number of undiscovered antimicrobials from this genus as well as to predict the trends in the near future. A model assuming that the screening efforts are encouraged by a previous year's success and that the probability of finding a new antibiotic is a function of the fraction of antibiotics undiscovered so far offered a good fit after optimizing parameters. The model estimated the total number of antimicrobial compounds that this genus is capable of producing to be of the order of a 100,000 - a tiny fraction of which has been unearthed so far. The decline in the slope appeared to be due to a decline in screening efforts rather than an exhaustion of compounds. Left to itself, the slope will become zero in the next one or two decades, but if the screening efforts are maintained constant, the rate of discovery of new compounds will not decline for several decades to come.
Type 2 diabetes mellitus (T2DM) is believed to be irreversible although no component of the pathophysiology is irreversible. We show here with a network model that the apparent irreversibility is ...contributed by the structure of the network of inter-organ signalling. A network model comprising all known inter-organ signals in T2DM showed bi-stability with one insulin sensitive and one insulin resistant attractor. The bi-stability was made robust by multiple positive feedback loops suggesting an evolved allostatic system rather than a homeostatic system. In the absence of the complete network, impaired insulin signalling alone failed to give a stable insulin resistant or hyperglycemic state. The model made a number of correlational predictions many of which were validated by empirical data. The current treatment practice targeting obesity, insulin resistance, beta cell function and normalization of plasma glucose failed to reverse T2DM in the model. However certain behavioural and neuro-endocrine interventions ensured a reversal. These results suggest novel prevention and treatment approaches which need to be tested empirically.
During exponential growth some cells of E. coli undergo senescence mediated by asymmetric segregation of damaged components, particularly protein aggregates. We showed previously that functional cell ...division asymmetry in E. coli was responsive to the nutritional environment. Short term exposure as well as long term selection in low calorie environments led to greater cell division symmetry and decreased frequency of senescent cells as compared to high calorie environments. We show here that long term selection in low nutrient environment decreased protein aggregation as revealed by fluorescence microscopy and proportion of insoluble proteins. Across selection lines protein aggregation was correlated significantly positively with the RNA content, presumably indicating metabolic rate. This suggests that the effects of caloric restriction on cell division symmetry and aging in E. coli may work via altered protein handling mechanisms. The demonstrable effects of long term selection on protein aggregation suggest that protein aggregation is an evolvable phenomenon rather than being a passive inevitable process. The aggregated proteins progressively disappeared on facing starvation indicating degradation and recycling demonstrating that protein aggregation is a reversible process in E. coli.
All genes critical for plasmid replication regulation are located on the plasmid rather than on the host chromosome. It is possible therefore that there can be copy-up "cheater" mutants. In spite of ...this possibility, low copy number plasmids appear to exist stably in host populations. We examined this paradox using a multilevel selection model. Simulations showed that, a slightly higher copy number mutant could out-compete the wild type. Consequently, another mutant with still higher copy number could invade the first invader. However, the realized benefit of increasing intra-host fitness was saturating whereas that of inter-host fitness was exponential. As a result, above a threshold, intra-host selection was overcompensated by inter-host selection and the low copy number wild type plasmid could back invade a very high copy number plasmid. This led to a rock-paper-scissor (RPS) like situation that allowed the coexistence of plasmids with varied copy numbers. Furthermore, another type of cheater that had lost the genes required for conjugation but could hitchhike on a conjugal plasmid, could further reduce the advantage of copy-up mutants. These sociobiological interactions may compliment molecular mechanisms of replication regulation in stabilizing the copy numbers.
Insulin resistance, which can lead to a number of diseases including type 2 diabetes and coronary heart disease, is believed to have evolved as an adaptation to periodic starvation. The "thrifty ...gene" and "thrifty phenotype" hypotheses constitute the dominant paradigm for over four decades. With an increasing understanding of the diverse effects of impairment of the insulin signaling pathway, the existing hypotheses are proving inadequate.
We propose a hypothesis that insulin resistance is a socio-ecological adaptation that mediates two phenotypic transitions, (i) a transition in reproductive strategy from "r" (large number of offspring with little investment in each) to "K" (smaller number of offspring with more investment in each) and (ii) a transition from "stronger to smarter" or "soldier to diplomat" i.e. from relatively more muscle dependent to brain dependent lifestyle. A common switch could have evolved for the two transitions since the appropriate environmental conditions for the two transitions are highly overlapping and interacting.
Gestational insulin resistance diverts more energy through the placenta, resulting in increased investment per offspring. On the other hand, insulin resistance is associated with reduced ovulation. The insulin signaling pathway is also related to longevity. Insulin resistance diverts more nutrients to the brain as compared to muscle. Also, hyperinsulinemia has direct positive effects on cognitive functions of the brain. The hypothesis gets support from known patterns in human clinical data and recent research on the molecular interactions in the insulin signaling pathway. Further we state many predictions of the hypothesis that can be tested experimentally or epidemiologically.
The hypothesis can bring about a significant change in the line of treatment as well as public health policies for the control of metabolic syndrome.
In host–parasite co-evolution, parasites are assumed to have an advantage owing to their shorter generation time. Evolution of pathogens within the lifetime of a host individual is implicated as a ...strong selective force in the evolution of sex and aging in the host. However, this assumption or its testable predictions have not been examined empirically. We classified infectious bacteria and viruses into those that can have continued long-term existence on the host body (group 1) versus those that have only a short-term interaction during an active infection (group 2). We surveyed the literature for age-specific incidence data about infections from both the groups. The age trends of the two groups show contrasting patterns. The incidence of infections by all group 1 pathogens showed a 2.28- to 28-fold increase in older ages. In group 2, 6 out of the 9 pathogens showed a significant declining trend in incidence with age. In both groups, there was greater mortality or morbidity among the infected in the old-age classes. These patterns are better explained by pathogen evolution than by age-related decline in immunity.
In the ongoing Covid-19 pandemic, in the global data on the case fatality ratio (CFR) and other indices reflecting death rate, there is a consistent downward trend from mid-April to mid-November. The ...downward trend can be an illusion caused by biases and limitations of data or it could faithfully reflect a declining death rate. A variety of explanations for this trend are possible, but a systematic analysis of the testable predictions of the alternative hypotheses has not yet been attempted.
We state six testable alternative hypotheses, analyze their testable predictions using public domain data and evaluate their relative contributions to the downward trend.
We show that a decline in the death rate is real; changing age structure of the infected population and evolution of the virus towards reduced virulence are the most supported hypotheses and together contribute to major part of the trend. The testable predictions from other explanations including altered testing efficiency, time lag, improved treatment protocols and herd immunity are not consistently supported, or do not appear to make a major contribution to this trend although they may influence some other patterns of the epidemic.
The fatality of the infection showed a robust declining time trend between mid April to mid November. Changing age class of the infected and decreasing virulence of the pathogen were found to be the strongest contributors to the trend.
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