Evolution, Medicine, and Public Health最新文献

Background and objectives: Circadian rhythms contribute to treatment efficacy in several non-communicable diseases. However, chronotherapy (administering drugs at a particular time-of-day) against infectious diseases has been overlooked. Yet, the daily rhythms of both hosts and disease-causing agents can impact the efficacy of drug treatment. We use the rodent malaria parasite Plasmodium chabaudi, to test whether the daily rhythms of hosts, parasites and their interactions affect sensitivity to the key antimalarial, artemisinin.

Methodology: Asexual malaria parasites develop rhythmically in the host's blood, in a manner timed to coordinate with host daily rhythms. Our experiments coupled or decoupled the timing of parasite and host rhythms, and we administered artemisinin at different times of day to coincide with when parasites were either at an early (ring) or later (trophozoite) developmental stage. We quantified the impacts of parasite developmental stage, and alignment of parasite and host rhythms, on drug sensitivity.

Results: We find that rings were less sensitive to artemisinin than trophozoites, and this difference was exacerbated when parasite and host rhythms were misaligned, with little direct contribution of host time-of-day on its own. Furthermore, the blood concentration of haem at the point of treatment correlated positively with artemisinin efficacy but only when parasite and host rhythms were aligned.

Conclusions and implications: Parasite rhythms influence drug sensitivity in vivo. The hitherto unknown modulation by alignment between parasite and host daily rhythms suggests that disrupting the timing of parasite development could be a novel chronotherapeutic approach.

Lay summary: We reveal that chronotherapy (providing medicines at a particular time-of-day) could improve treatment for malaria infections. Specifically, parasites' developmental stage at the time of treatment and the coordination of timing between parasite and host both affect how well antimalarial drug treatment works.

Background and objectives: Among placental mammals, females undergo immunological shifts during pregnancy to accommodate the fetus (i.e. fetal tolerance). Fetal tolerance has primarily been characterized within post-industrial populations experiencing evolutionarily novel conditions (e.g. reduced pathogen exposure), which may shape maternal response to fetal antigens. This study investigates how ecological conditions affect maternal immune status during pregnancy by comparing the direction and magnitude of immunological changes associated with each trimester among the Tsimane (a subsistence population subjected to high pathogen load) and women in the USA.

Methodology: Data from the Tsimane Health and Life History Project (N = 935) and the National Health and Nutrition Examination Survey (N = 1395) were used to estimate population-specific effects of trimester on differential leukocyte count and C-reactive protein (CRP), a marker of systemic inflammation.

Results: In both populations, pregnancy was associated with increased neutrophil prevalence, reduced lymphocyte and eosinophil count and elevated CRP. Compared to their US counterparts, pregnant Tsimane women exhibited elevated lymphocyte and eosinophil counts, fewer neutrophils and monocytes and lower CRP. Total leukocyte count remained high and unchanged among pregnant Tsimane women while pregnant US women exhibited substantially elevated counts, resulting in overlapping leukocyte prevalence among all third-trimester individuals.

Conclusions and implications: Our findings indicate that ecological conditions shape non-pregnant immune baselines and the magnitude of immunological shifts during pregnancy via developmental constraints and current trade-offs. Future research should investigate how such flexibility impacts maternal health and disease susceptibility, particularly the degree to which chronic pathogen exposure might dampen inflammatory response to fetal antigens.

Lay summary: This study compares immunological changes associated with pregnancy between the Tsimane (an Amazonian subsistence population) and individuals in the USA. Results suggest that while pregnancy enhances non-specific defenses and dampens both antigen-specific immunity and parasite/allergy response, ecological conditions strongly influence immune baselines and the magnitude of shifts during gestation.

The first treatments showing effectiveness for some psychiatric disorders, such as lithium for bipolar disorder and chlorpromazine for schizophrenia, were discovered by accident. Currently, psychiatric drug design is seen as a scientific enterprise, limited though it remains by the complexity of brain development and function. Relatively few novel and effective drugs have, however, been developed for many years. The purpose of this article is to demonstrate how evolutionary biology can provide a useful framework for psychiatric drug development. The framework is based on a diametrical nature of autism, compared with psychotic-affective disorders (mainly schizophrenia, bipolar disorder and depression). This paradigm follows from two inferences: (i) risks and phenotypes of human psychiatric disorders derive from phenotypes that have evolved along the human lineage and (ii) biological variation is bidirectional (e.g. higher vs lower, faster vs slower, etc.), such that dysregulation of psychological traits varies in two opposite ways. In this context, the author review the evidence salient to the hypothesis that autism and psychotic-affective disorders represent diametrical disorders in terms of current, proposed and potential psychopharmacological treatments. Studies of brain-derived neurotrophic factor, the PI3K pathway, the NMDA receptor, kynurenic acid metabolism, agmatine metabolism, levels of the endocannabinoid anandamide, antidepressants, anticonvulsants, antipsychotics, and other treatments, demonstrate evidence of diametric effects in autism spectrum disorders and phenotypes compared with psychotic-affective disorders and phenotypes. These findings yield insights into treatment mechanisms and the development of new pharmacological therapies, as well as providing an explanation for the longstanding puzzle of antagonism between epilepsy and psychosis. Lay Summary: Consideration of autism and schizophrenia as caused by opposite alterations to brain development and function leads to novel suggestions for pharmacological treatments.

Humans have evolved an elaborate system of self-consciousness, self-identity, self-agency, and self-embodiment that is grounded in specific neurological structures including an expanded insula. Instantiation of the bodily self has been most-extensively studied via the 'rubber hand illusion', whereby parallel stimulation of a hidden true hand, and a viewed false hand, leads to the felt belief that the false hand is one's own. Autism and schizophrenia have both long been regarded as conditions centrally involving altered development of the self, but they have yet to be compared directly with regard to the self and embodiment. Here, we synthesize the embodied cognition literature for these and related conditions, and describe evidence that these two sets of disorders exhibit opposite susceptibilities from typical individuals to the rubber hand illusion: reduced on the autism spectrum and increased in schizophrenia and other psychotic-affective conditions. Moreover, the opposite illusion effects are mediated by a consilient set of associated phenomena, including empathy, interoception, anorexia risk and phenotypes, and patterns of genetic correlation. Taken together, these findings: (i) support the diametric model of autism and psychotic-affective disorders, (ii) implicate the adaptive human system of self-embodiment, and its neural bases, in neurodevelopmental disorders, and suggest new therapies and (iii) experimentally ground Bayesian predictive coding models with regard to autism compared with psychosis. Lay summary: Humans have evolved a highly developed sense of self and perception of one's own body. The 'rubber hand illusion' can be used to test individual variation in sense of self, relative to connection with others. We show that this illusion is reduced in autism spectrum disorders, and increased in psychotic and mood disorders. These findings have important implications for understanding and treatment of mental disorders.

Extensive diversity (genetic, cytogenetic, epigenetic and phenotypic) exists within and between tumours, but reasons behind these variations, as well as their consistent hierarchical pattern between organs, are poorly understood at the moment. We argue that these phenomena are, at least partially, explainable by the evolutionary ecology of organs' theory, in the same way that environmental adversity shapes mutation rates and level of polymorphism in organisms. Organs in organisms can be considered as specialized ecosystems that are, for ecological and evolutionary reasons, more or less efficient at suppressing tumours. When a malignancy does arise in an organ applying strong selection pressure on tumours, its constituent cells are expected to display a large range of possible surviving strategies, from hyper mutator phenotypes relying on bet-hedging to persist (high mutation rates and high diversity), to few poorly variable variants that become invisible to natural defences. In contrast, when tumour suppression is weaker, selective pressure favouring extreme surviving strategies is relaxed, and tumours are moderately variable as a result. We provide a comprehensive overview of this hypothesis. Lay summary: Different levels of mutations and intra-tumour heterogeneity have been observed between cancer types and organs. Anti-cancer defences are unequal between our organs. We propose that mostly aggressive neoplasms (i.e. higher mutational and ITH levels), succeed in emerging and developing in organs with strong defences.

Background and objectives: The diversity of eutherian reproductive strategies has led to variation in many traits, such as number of offspring, age of reproductive maturity and gestation length. While reproductive trait variation has been extensively investigated and is well established in mammals, the genetic loci contributing to this variation remain largely unknown. The domestic dog, Canis lupus familiaris is a powerful model for studies of the genetics of inherited disease due to its unique history of domestication. To gain insight into the genetic basis of reproductive traits across domestic dog breeds, we collected phenotypic data for four traits, cesarean section rate, litter size, stillbirth rate and gestation length, from primary literature and breeders' handbooks.

Methodology: By matching our phenotypic data to genomic data from the Cornell Veterinary Biobank, we performed genome-wide association analyses for these four reproductive traits, using body mass and kinship among breeds as covariates.

Results: We identified 12 genome-wide significant associations between these traits and genetic loci, including variants near CACNA2D3 with gestation length, MSRB3 and MSANTD1 with litter size, SMOC2 with cesarean section rate and UFM1 with stillbirth rate. A few of these loci, such as CACNA2D3 and MSRB3, have been previously implicated in human reproductive pathologies, whereas others have been associated with domestication-related traits, including brachycephaly (SMOC2) and coat curl (KRT71).

Conclusions and implications: We hypothesize that the artificial selection that gave rise to dog breeds also influenced the observed variation in their reproductive traits. Overall, our work establishes the domestic dog as a system for studying the genetics of reproductive biology and disease.

Lay summary: The genetic contributors to variation in mammalian reproductive traits remain largely unknown. We took advantage of the domestic dog, a powerful model system, to test for associations between genome-wide variants and four reproductive traits (cesarean section rate, litter size, stillbirth rate and gestation length) that vary extensively across breeds. We identified associations at a dozen loci, including ones previously associated with domestication-related traits, suggesting that selection on dog breeds also influenced their reproductive traits.

Polycystic ovary syndrome (PCOS) is the most common female endocrine disorder and has important evolutionary implications for female reproduction and health. PCOS presents an interesting paradox, as it results in significant anovulation and potential sub-fecundity in industrialized populations, yet it has a surprisingly high prevalence and has a high heritability. In this review, we discuss an overview of PCOS, current diagnostic criteria, associated hormonal pathways and a review of proposed evolutionary hypotheses for the disorder. With a multifactorial etiology that includes ovarian function, metabolism, insulin signaling and multiple genetic risk alleles, PCOS is a complex disorder. We propose that PCOS is a mismatch between previously neutral genetic variants that evolved in physically active subsistence settings that have the potential to become harmful in sedentary industrialized environments. Sedentary obesogenic environments did not exist in ancestral times and exacerbate many of these pathways, resulting in the high prevalence and severity of PCOS today. Overall, the negative impacts of PCOS on reproductive success would likely have been minimal during most of human evolution and unlikely to generate strong selection. Future research and preventative measures should focus on these gene-environment interactions as a form of evolutionary mismatch, particularly in populations that are disproportionately affected by obesity and metabolic disorders.

Lay summary: The most severe form of polycystic ovary syndrome (PCOS) is likely a result of interactions between genetic predispositions for PCOS and modern obesogenic environments. PCOS would likely have been less severe ancestrally and the fitness reducing effects of PCOS seen today are likely a novel product of sedentary, urban environments.

Lay summary: Adaptive immune proteins in mothers' milk are more variable than innate immune proteins across populations and subsistence strategies. These results suggest that the immune defenses in milk are shaped by a mother's environment throughout her life.

Background and objectives: Mother's milk contains immune proteins that play critical roles in protecting the infant from infection and priming the infant's developing immune system during early life. The composition of these molecules in milk, particularly the acquired immune proteins, is thought to reflect a mother's immunological exposures throughout her life. In this study, we examine the composition of innate and acquired immune proteins in milk across seven populations with diverse disease and cultural ecologies.

Methodology: Milk samples (n = 164) were collected in Argentina, Bolivia, Nepal, Namibia, Philippines, Poland and the USA. Populations were classified as having one of four subsistence patterns: urban-industrialism, rural-shop, horticulturalist-forager or agro-pastoralism. Milk innate (lactalbumin, lactoferrin and lysozyme) and acquired (Secretory IgA, IgG and IgM) protein concentrations were determined using triple-quadrupole mass spectrometry.

Results: Both innate and acquired immune protein composition in milk varied among populations, though the acquired immune protein composition of milk differed more among populations. Populations living in closer geographic proximity or having similar subsistence strategies (e.g. agro-pastoralists from Nepal and Namibia) had more similar milk immune protein compositions. Agro-pastoralists had different milk innate immune protein composition from horticulturalist-foragers and urban-industrialists. Acquired immune protein composition differed among all subsistence strategies except horticulturist-foragers and rural-shop.

Conclusions and implications: Our results reveal fundamental variation in milk composition that has not been previously explored in human milk research. Further study is needed to understand what specific aspects of the local environment influence milk composition and the effects this variation may have on infant health outcomes.