Evolution, Medicine, and Public Health最新文献

Background and objectives: Several studies have linked longer legs with favorable adult metabolic health outcomes and greater offspring birth weight. A recent Mendelian randomization study suggested a causal link between height and cardiometabolic risk; however, the underlying reasons remain poorly understood.

Methodology: Using a cross-sectional design, we tested in a convenience sample of 70 healthy young women whether birth weight and tibia length as markers of early-life conditions associated more strongly with metabolically beneficial traits like organ size and skeletal muscle mass (SMM) than a statistically derived height-residual variable indexing later, more canalized growth.

Results: Consistent with the 'developmental origins of health and disease' hypothesis, we found relatively strong associations of tibia length-but not birth weight-with adult organ size, brain size, SMM and resting energy expenditure measured by magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry and indirect calorimetry, respectively.

Conclusions and implications: Building on prior work, these results suggest that leg length is a sensitive marker of traits directly impacting metabolic and reproductive health. Alongside findings in the same sample relating tibia length and height-residual to MRI-measured pelvic dimensions, we suggest there may exist a degree of coordination in the development of long bone, lean mass and pelvic traits, possibly centered on early, pre-pubertal growth periods. Such phenotypic coordination has important implications for fitness, serving to benefit both adult health and the health of offspring in subsequent generations.

Background and objectives: A key strategy for resolving the antibiotic resistance crisis is the development of new drugs with antimicrobial properties. The engineered cationic antimicrobial peptide WLBU2 (also known as PLG0206) is a promising broad-spectrum antimicrobial compound that has completed Phase I clinical studies. It has activity against Gram-negative and Gram-positive bacteria including infections associated with biofilm. No definitive mechanisms of resistance to WLBU2 have been identified.

Methodology: Here, we used experimental evolution under different levels of mutation supply and whole genome sequencing (WGS) to detect the genetic pathways and probable mechanisms of resistance to this peptide. We propagated populations of wild-type and hypermutator Pseudomonas aeruginosa in the presence of WLBU2 and performed WGS of evolved populations and clones.

Results: Populations that survived WLBU2 treatment acquired a minimum of two mutations, making the acquisition of resistance more difficult than for most antibiotics, which can be tolerated by mutation of a single target. Major targets of resistance to WLBU2 included the orfN and pmrB genes, previously described to confer resistance to other cationic peptides. More surprisingly, mutations that increase aggregation such as the wsp pathway were also selected despite the ability of WLBU2 to kill cells growing in a biofilm.

Conclusions and implications: The results show how experimental evolution and WGS can identify genetic targets and actions of new antimicrobial compounds and predict pathways to resistance of new antibiotics in clinical practice.

Background and objectives: Theory suggests that some types of vaccines against infectious pathogens may lead to the evolution of variants that cause increased harm, particularly when they infect unvaccinated individuals. This theory was supported by the observation that the use of an imperfect vaccine to control Marek's disease virus in chickens resulted in the virus evolving to be more lethal to unvaccinated birds. This raises the concern that the use of some other vaccines may lead to similar pernicious outcomes. We examine that theory with a focus on considering the regimes in which such outcomes are expected.

Methodology: We evaluate the plausibility of assumptions in the original theory. The previous theory rested heavily on a particular form of transmission-mortality-recovery trade-off and invoked other assumptions about the pathways of evolution. We review alternatives to mortality in limiting transmission and consider evolutionary pathways that were omitted in the original theory.

Results: The regime where the pernicious evolutionary outcome occurs is narrowed by our analysis but remains possible in various scenarios. We propose a more nuanced consideration of alternative models for the within-host dynamics of infections and for factors that limit virulence. Our analysis suggests imperfect vaccines against many pathogens will not lead to the evolution of pathogens with increased virulence in unvaccinated individuals.

Conclusions and implications: Evolution of greater pathogen mortality driven by vaccination remains difficult to predict, but the scope for such outcomes appears limited. Incorporation of mechanistic details into the framework, especially regarding immunity, may be requisite for prediction accuracy.

Lay summary: A virus of chickens appears to have evolved high mortality in response to a vaccine that merely prevented disease symptoms. Theory has predicted this type of evolution in response to a variety of vaccines and other interventions such as drug treatment. Under what circumstances is this pernicious result likely to occur? Analysis of the theory in light of recent changes in our understanding of viral biology raises doubts that medicine-driven, pernicious evolution is likely to be common. But we are far from a mechanistic understanding of the interaction between pathogen and host that can predict when vaccines and other medical interventions will lead to the unwanted evolution of more virulent pathogens. So, while the regime where a pernicious result obtains may be limited, caution remains warranted in designing many types of interventions.

The COVID-19 pandemic has revealed an urgent need for a comprehensive, multidisciplinary understanding of how healthcare systems respond successfully to infectious pathogens-and how they fail. This study contributes a novel perspective that focuses on the selective pressures that shape healthcare systems over evolutionary time. We use a comparative approach to trace the evolution of care-giving and disease control behaviours across species and then map their integration into the contemporary human healthcare system. Self-care and pro-health environmental modification are ubiquitous across animals, while derived behaviours like care for kin, for strangers, and group-level organizational responses have evolved via different selection pressures. We then apply this framework to our behavioural responses to COVID-19 and demonstrate that three types of conflicts are occurring: (1) conflicting selection pressures on individuals, (2) evolutionary mismatches between the context in which our healthcare behaviours evolved and our globalized world of today and (3) evolutionary displacements in which older forms of care are currently dispensed through more derived forms. We discuss the significance of understanding how healthcare systems evolve and change for thinking about the role of healthcare systems in society during and after the time of COVID-19-and for us as a species as we continue to face selection from infectious diseases.

Background and objectives: Previously, we showed proof-of-concept in a mouse model that oral administration of cholestyramine prevented enrichment of daptomycin-resistant Enterococcus faecium in the gastrointestinal (GI) tract during daptomycin therapy. Cholestyramine binds daptomycin in the gut, which removes daptomycin selection pressure and so prevents the enrichment of resistant clones. Here, we investigated two open questions related to this approach: (i) can cholestyramine prevent the enrichment of diverse daptomycin mutations emerging de novo in the gut? and (ii) how does the timing of cholestyramine administration impact its ability to suppress resistance?

Methodology: Mice with GI E. faecium were treated with daptomycin with or without cholestyramine, and E. faecium was cultured from feces to measure changes in daptomycin susceptibility. A subset of clones was sequenced to investigate the genomic basis of daptomycin resistance.

Results: Cholestyramine prevented the enrichment of diverse resistance mutations that emerged de novo in daptomycin-treated mice. Whole-genome sequencing revealed that resistance emerged through multiple genetic pathways, with most candidate resistance mutations observed in the clsA gene. In addition, we observed that cholestyramine was most effective when administration started prior to the first dose of daptomycin. However, beginning cholestyramine after the first daptomycin dose reduced the frequency of resistant E. faecium compared to not using cholestyramine at all.

Conclusions and implications: Cholestyramine prevented the enrichment of diverse daptomycin-resistance mutations in intestinal E. faecium populations during daptomycin treatment, and it is a promising tool for managing the transmission of daptomycin-resistant E. faecium.

Background and objectives: Cesarean section may lead to suboptimal breastfeeding outcomes, though evidence has been mixed. Factors, such as premature birth, birth weight and maternal age may independently increase risk of cesarean and hinder breastfeeding initiation, while maternal preferences, support and sociostructural barriers may influence breastfeeding practices beyond the immediate postpartum period.

Methodology: We assessed impacts of cesarean section and gestational factors on breastfeeding duration among Indigenous Qom mothers in Argentina who have strong traditional breastfeeding support. We modeled transitions from exclusive breastfeeding to complementary feeding and from complementary feeding to full weaning in a Bayesian time-to-event framework with birth mode and gestational covariates (n = 89 infants).

Results: Estimated median time to full weaning was 30 months. Cesarean-delivered babies were weaned an average of 5 months later adjusting for gestational age, maternal parity and infant sex. No factors were associated with time-to-complementary feeding, and time-to-complementary feeding was not associated with time-to-full weaning.

Conclusions and implications: Among Indigenous Qom mothers in Argentina, cesarean section was not associated with suboptimal breastfeeding outcomes. Although some Qom mothers do experience early breastfeeding problems, particularly following first birth, problems are not more frequent following cesarean delivery. Traditional postpartum kin and community support during prolonged postpartum periods may be instrumental in helping mothers to overcome early breastfeeding problems due to cesarean or other risk factors.

Background and objectives: To understand how organisms evolve, it is fundamental to study how mutations emerge and establish. Here, we estimated the rate of mutation accumulation of SARS-CoV-2 in vitro and investigated the repeatability of its evolution when facing a new cell type but no immune or drug pressures.

Methodology: We performed experimental evolution with two strains of SARS-CoV-2, one carrying the originally described spike protein (CoV-2-D) and another carrying the D614G mutation that has spread worldwide (CoV-2-G). After 15 passages in Vero cells and whole genome sequencing, we characterized the spectrum and rate of the emerging mutations and looked for evidences of selection across the genomes of both strains.

Results: From the frequencies of the mutations accumulated, and excluding the genes with signals of selection, we estimate a spontaneous mutation rate of 1.3 × 10 ^-6 ± 0.2 × 10^-6 per-base per-infection cycle (mean across both lineages of SARS-CoV-2 ± 2SEM). We further show that mutation accumulation is larger in the CoV-2-D lineage and heterogeneous along the genome, consistent with the action of positive selection on the spike protein, which accumulated five times more mutations than the corresponding genomic average. We also observe the emergence of mutators in the CoV-2-G background, likely linked to mutations in the RNA-dependent RNA polymerase and/or in the error-correcting exonuclease protein.

Conclusions and implications: These results provide valuable information on how spontaneous mutations emerge in SARS-CoV-2 and on how selection can shape its genome toward adaptation to new environments. Lay Summary: Each time a virus replicates inside a cell, errors (mutations) occur. Here, via laboratory propagation in cells originally isolated from the kidney epithelium of African green monkeys, we estimated the rate at which the SARS-CoV-2 virus mutates-an important parameter for understanding how it can evolve within and across humans. We also confirm the potential of its Spike protein to adapt to a new environment and report the emergence of mutators-viral populations where mutations occur at a significantly faster rate.

Background: In cooperatively breeding species, individuals may promote their inclusive fitness through allomothering. Humans exhibit some features of cooperative breeding, and previous studies have focused on allomothering by grandparents and juvenile siblings in the postnatal period. We hypothesize that a pregnant woman's relationships with her siblings (offspring's maternal aunts and uncles) are beneficial for maternal affect in ways that can enhance the siblings' inclusive fitness. Maternal affect during pregnancy is a salient target of allocare given the detrimental effects of antepartum mood disorders on birth and infant outcomes.

Methodology: We test our hypotheses in a cohort of pregnant Latina women in Southern California (N = 201). Predictor variables of interest include number of siblings a participant has, if she has sisters, frequency of seeing siblings, and frequency of communication with siblings. Outcome variables measuring maternal affect include depression, state anxiety, pregnancy-related anxiety and perceived stress.

Results: Having at least one sister and greater frequency of communication with siblings were associated with fewer depressive symptoms during pregnancy. No significant associations were found between sibling variables and other measures of affect.

Conclusion and implications: Results suggest that how frequently you communicate with, and not how often you see, siblings could be protective against risk of antepartum depression. Sibling allomothering could impart effects through social-emotional support rather than instrumental support, as a strategy to benefit the prenatal environment in which future nieces and nephews develop. Allomothering may be particularly important in cultural contexts that value family relationships. Future studies should investigate other communities.

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.