Fundamental Biological Features of Spaceflight: Advancing the Field to Enable Deep-Space Exploration.

Research on astronaut health and model organisms have revealed six features of spaceflight biology that guide our current understanding of fundamental molecular changes that occur during space travel. The features include oxidative stress, DNA damage, mitochondrial dysregulation, epigenetic changes (including gene regulation), telomere length alterations, and microbiome shifts. Here we review the known hazards of human spaceflight, how spaceflight affects living systems through these six fundamental features, and the associated health risks of space exploration. We also discuss the essential issues related to the health and safety of astronauts involved in future missions, especially planned long-duration and Martian missions.

A second space age spanning omics, platforms and medicine across orbits.

The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a 'second space age'. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons.

Haplotype diversity and sequence heterogeneity of human telomeres.

Telomeres are regions of repetitive nucleotide sequences capping the ends of eukaryotic chromosomes that protect against deterioration, and whose lengths can be correlated with age and adverse health risk factors. Yet, given their length and repetitive nature, telomeric regions are not easily reconstructed from short-read sequencing, thus making telomere sequencing, mapping, and variant resolution challenging problems. Recently, long-read sequencing, with read lengths measuring in hundreds of kilobase pairs, has made it possible to routinely read into telomeric regions and inspect their sequence structure. Here, we describe a framework for extracting telomeric reads from whole-genome single-molecule sequencing experiments, including de novo identification of telomere repeat motifs and repeat types, and also describe their sequence variation. We find that long, complex telomeric stretches and repeats can be accurately captured with long-read sequencing, observe extensive sequence heterogeneity of human telomeres, discover and localize noncanonical telomere sequence motifs (both previously reported, as well as novel), and validate them in short-read sequence data. These data reveal extensive intra- and inter-population diversity of repeats in telomeric haplotypes, reveal higher paternal inheritance of telomeric variants, and represent the first motif composition maps of multi-kilobase-pair human telomeric haplotypes across three distinct ancestries (Ashkenazi, Chinese, and Utah), which can aid in future studies of genetic variation, aging, and genome biology.

Telomeres and aging: on and off the planet!

Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective "caps" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the "end-replication problem" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.

Medical education: Accommodating students with ADHD.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that affects a significant number of medical students worldwide. It is poorly recognised by educators, and therefore inadequately accommodated for in educational strategies. In order to investigate this further, a literature review and pilot survey were conducted. Health educators employed by The University of Newcastle, Australia, completed a short online survey, which focused on their understanding of, and ability to recognise and adapt teaching strategies for students with ADHD. The results of the survey informed the development of a resource that provided evidence-based strategies for supporting the learning of tertiary students with ADHD. In addition, the results of this pilot study may form the basis for further research in this domain. Given the prevalence and potential impact of ADHD on higher education, it is important to gain deeper insight into how medical educators can best engage and support students with ADHD. This knowledge may potentially reduce the negative impacts of this neurodiversity on students and support their learning and well-being throughout their medical career. Ultimately this may help doctors to achieve their full potential, especially in clinical decision-making.

Destabilizing Effects of Ionizing Radiation on Chromosomes: Sizing up the Damage.

For long-term survival and evolution, all organisms have depended on a delicate balance between processes involved in maintaining stability of their genomes and opposing processes that lead toward destabilization. At the level of mammalian somatic cells in renewal tissues, events or conditions that can tip this balance toward instability have attracted special interest in connection with carcinogenesis. Mutations affecting DNA (and its subsequent repair) would, of course, be a major consideration here. These may occur spontaneously through endogenous cellular processes or as a result of exposure to mutagenic environmental agents. It is in this context that we discuss the rather unique destabilizing effects of ionizing radiation (IR) in terms of its ability to cause large-scale structural rearrangements to the genome. We present arguments supporting the conclusion that these and other important effects of IR originate largely from microscopically visible chromosome aberrations.

Climate change, activism, and supporting the mental health of children and young people: Perspectives from Western Australia.

The climate crisis has detrimental impacts on the mental health and wellbeing of children and young people. Psychological effects include feelings of fear, overwhelm, worry, distress, hopelessness and anger; PTSD; depression; anxiety; phobias; panic disorder; sleep disturbances; attachment disorders; learning difficulties; substance abuse; shock and trauma symptoms; adjustment problems; behavioural problems; and, suicidal thinking. First Nations' children and young people are particularly at risk due to loss of place, identity, culture, land and customs informed by kinship relationships with the Earth; while sustainable land use practices and connection to Country and community can enhance climate resilience. In Western Australia (WA), some young people engage in climate activism - including striking from school - to demand government action to address the causes of climate change, including colonisation and capitalism. Climate activism can promote resilience, particularly when children and young people can emotionally engage in the climate crisis; when mental health is systemically supported; when climate communication is transparent and comprehensive; and, when activism is informed by the knowledges and wisdoms of First Nations peoples and grounded on Country. This article is co-authored by WA young people, Aboriginal and non-Aboriginal academics, activists and practitioners engaged in youth, mental health and climate justice spaces. We argue for structural change to address the causes of the climate crisis, alongside enhanced evidence and approaches to appropriately support the mental health of children and young people. Furthermore, we support the call of Aboriginal peoples to ensure culturally appropriate, place-based responses based in caring for Country.

A remark on "Biological control through provision of additional food to predators: A theoretical study" [Theor. Popul. Biol. 72 (2007) 111-120].

Biological control, the use of predators and pathogens to control target pests, is a promising alternative to chemical control. It is hypothesized that the introduced predators efficacy can be boosted by providing them with an additional food source. The current literature (Srinivasu, 2007; 2010; 2011) claims that if the additional food is of sufficiently large quantity and quality then pest eradication is possible in finite time. The purpose of the current manuscript is to show that to the contrary, pest eradication is not possible in finite time, for any quantity and quality of additional food. We show that pest eradication will occur only in infinite time, and derive decay rates to the extinction state. We posit a new modeling framework to yield finite time pest extinction. Our results have large scale implications for the effective design of biological control methods involving additional food.

Maternal Grief: A Qualitative Investigation of Mothers' Responses to the Death of a Child From Cancer.

This study explored bereaved mothers' responses to the death of a child from cancer, with a focus on identifying adaptive and complicated grief reactions. To understand the unique meaning of their loss, in-depth interviews were conducted with 13 mothers at two time points. Interpretative phenomenological analysis-guided by meaning-making theories of loss-revealed five master categories: the perceptions of the child's life with cancer and death from the disease, changed self-identity, coping style, developing an ongoing relationship to the deceased child, and the postdeath social environment. Each of these master categories and associated subthemes provided insights into the characteristics of the bereaved mothers' adaptive and complicated grief responses to their loss. Given all the mothers evidenced multiple forms or types of these responses over time, they could not be categorized as adaptive or complicated grievers. However, the varying proportions of each of these responses highlighted differences in overall bereavement adaptation.

What drives parallel evolution?: How population size and mutational variation contribute to repeated evolution.

Parallel evolution is the repeated evolution of the same phenotype or genotype in evolutionarily independent populations. Here, we use evolve-and-resequence experiments with bacteria and yeast to dissect the drivers of parallel evolution at the gene level. A meta-analysis shows that parallel evolution is often rare, but there is a positive relationship between population size and the probability of parallelism. We present a modeling approach to estimate the contributions of mutational and selective heterogeneity across a genome to parallel evolution. We show that, for two experiments, mutation contributes between ∼10 and 45%, respectively, of the variation associated with selection. Parallel evolution cannot, therefore, be interpreted as a phenomenon driven by selection alone; it must also incorporate information on heterogeneity in mutation rates along the genome. More broadly, the work discussed here helps lay the groundwork for a more sophisticated, empirically grounded theory of parallel evolution.

Twelve tips for implementing effective service learning.

Service learning is an educational methodology that facilitates transformation of students' knowledge, attitudes and attitudes around holistic care through work with community organizations. To implement academically, defensible service learning requires faculty endorsement, consideration of course credit, an enthusiastic champion able to negotiate agreements with organizations, organizations' identification of their own projects so they are willing to both fund and supervise them, curricular underpinning that imparts the project skills necessary for success, embedding at a time when students' clinical identity is being formed, small packets of curriculum elements delivered "just in time" as students engage with their project, flexible online platform/s, assessment that is organically related to the project, providing cross cultural up-skilling, and focused on the students' responsibility for their own product. The result is a learning experience that is engaging for medical students, links the university to the community, and encourages altruism which is otherwise reported to decline through medical school.

Stress and telomere shortening among central Indian conservation refugees.

Research links psychosocial stress to premature telomere shortening and accelerated human aging; however, this association has only been demonstrated in so-called "WEIRD" societies (Western, educated, industrialized, rich, and democratic), where stress is typically lower and life expectancies longer. By contrast, we examine stress and telomere shortening in a non-Western setting among a highly stressed population with overall lower life expectancies: poor indigenous people--the Sahariya--who were displaced (between 1998 and 2002) from their ancestral homes in a central Indian wildlife sanctuary. In this setting, we examined adult populations in two representative villages, one relocated to accommodate the introduction of Asiatic lions into the sanctuary (n = 24 individuals), and the other newly isolated in the sanctuary buffer zone after their previous neighbors were moved (n = 22). Our research strategy combined physical stress measures via the salivary analytes cortisol and α-amylase with self-assessments of psychosomatic stress, ethnographic observations, and telomere length assessment [telomere-fluorescence in situ hybridization (TEL-FISH) coupled with 3D imaging of buccal cell nuclei], providing high-resolution data amenable to multilevel statistical analysis. Consistent with expectations, we found significant associations between each of our stress measures--the two salivary analytes and the psychosomatic symptom survey--and telomere length, after adjusting for relevant behavioral, health, and demographic traits. As the first study (to our knowledge) to link stress to telomere length in a non-WEIRD population, our research strengthens the case for stress-induced telomere shortening as a pancultural biomarker of compromised health and aging.

The effect of selection environment on the probability of parallel evolution.

Across the great diversity of life, there are many compelling examples of parallel and convergent evolution-similar evolutionary changes arising in independently evolving populations. Parallel evolution is often taken to be strong evidence of adaptation occurring in populations that are highly constrained in their genetic variation. Theoretical models suggest a few potential factors driving the probability of parallel evolution, but experimental tests are needed. In this study, we quantify the degree of parallel evolution in 15 replicate populations of Pseudomonas fluorescens evolved in five different environments that varied in resource type and arrangement. We identified repeat changes across multiple levels of biological organization from phenotype, to gene, to nucleotide, and tested the impact of 1) selection environment, 2) the degree of adaptation, and 3) the degree of heterogeneity in the environment on the degree of parallel evolution at the gene-level. We saw, as expected, that parallel evolution occurred more often between populations evolved in the same environment; however, the extent of parallel evolution varied widely. The degree of adaptation did not significantly explain variation in the extent of parallelism in our system but number of available beneficial mutations correlated negatively with parallel evolution. In addition, degree of parallel evolution was significantly higher in populations evolved in a spatially structured, multiresource environment, suggesting that environmental heterogeneity may be an important factor constraining adaptation. Overall, our results stress the importance of environment in driving parallel evolutionary changes and point to a number of avenues for future work for understanding when evolution is predictable.

Can the experimental evolution programme help us elucidate the genetic basis of adaptation in nature?

There have been a variety of approaches taken to try to characterize and identify the genetic basis of adaptation in nature, spanning theoretical models, experimental evolution studies and direct tests of natural populations. Theoretical models can provide formalized and detailed hypotheses regarding evolutionary processes and patterns, from which experimental evolution studies can then provide important proofs of concepts and characterize what is biologically reasonable. Genetic and genomic data from natural populations then allow for the identification of the particular factors that have and continue to play an important role in shaping adaptive evolution in the natural world. Further to this, experimental evolution studies allow for tests of theories that may be difficult or impossible to test in natural populations for logistical and methodological reasons and can even generate new insights, suggesting further refinement of existing theories. However, as experimental evolution studies often take place in a very particular set of controlled conditions--that is simple environments, a small range of usually asexual species, relatively short timescales--the question remains as to how applicable these experimental results are to natural populations. In this review, we discuss important insights coming from experimental evolution, focusing on four key topics tied to the evolutionary genetics of adaptation, and within those topics, we discuss the extent to which the experimental work compliments and informs natural population studies. We finish by making suggestions for future work in particular a need for natural population genomic time series data, as well as the necessity for studies that combine both experimental evolution and natural population approaches.

A Randomized Controlled Trial to Increase Navy Bean or Rice Bran Consumption in Colorectal Cancer Survivors.

Consumption of navy beans (NB) and rice bran (RB) have been shown to inhibit colon carcinogenesis. Given the overall poor diet quality in colorectal cancer (CRC) survivors and low reported intake of whole grains and legumes, practical strategies to increase consumption merit attention. This study determined feasibility of increasing NB or RB intake in CRC survivors to increase dietary fiber and examined serum inflammatory biomarkers and telomere lengths. Twenty-nine subjects completed a randomized controlled trial with foods that included cooked NB powder (35 g/day), heat-stabilized RB (30 g/day), or no additional ingredient. Fasting blood, food logs, and gastrointestinal health questionnaires were collected. The amount of NB or RB consumed equated to 4-9% of subjects' daily caloric intake and no major gastrointestinal issues were reported with increased consumption. Dietary fiber amounts increased in NB and RB groups at Weeks 2 and 4 compared to baseline and to control (P ≤ 0.01). Telomere length correlated with age and HDL cholesterol at baseline, and with improved serum amyloid A (SAA) levels at Week 4 (P ≤ 0.05). This study concludes feasibility of increased dietary NB and RB consumption to levels associated with CRC chemoprevention and warrants longer-term investigations with both foods in high-risk populations that include cancer prevention and control outcomes.

Evolution of Fitness Trade-Offs in Locally Adapted Populations of Pseudomonas fluorescens.

Local adaptation seems to be common in natural systems, but the genetic causes of its evolution remain poorly understood. Here we characterize the genetic causes of trade-offs generating local adaptation in populations of Pseudomonas fluorescens that had previously been evolved for specialization on three different carbon resources. We measured the fitness effects of mutations that arose during selection in that environment and in alternative environments to quantify the degree of specialization. We find that all mutations are beneficial in the environment of selection and that those arising later during adaptation are associated with increasingly antagonistic effects in alternative environments compared with those arising earlier, consistent with a multioptima version of Fisher's geometric model of adaptation. We also find that fitness of pairs of beneficial mutations are consistently less than additive in selection environments, producing a pattern of diminishing returns, but are more variable in alternative environments, being either positive or negative. Finally, we find that mutations in genes associated with loss of motility are beneficial across all environments, whereas mutations involving other functions, such as gene regulation, had more variable effects, being more environment specific. Taken together, these results provide a detailed account of the genetics of specialization and suggest that the evolution of trade-offs associated with local adaptation may often result from the antagonistic effects of beneficial mutations substituted later in adaptation.

SNMIB/Apollo protects leading-strand telomeres against NHEJ-mediated repair.

Progressive telomere attrition or deficiency of the protective shelterin complex elicits a DNA damage response as a result of a cell's inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. SNMIB/Apollo is a shelterin-associated protein and a member of the SMN1/PSO2 nuclease family that localizes to telomeres through its interaction with TRF2. Here, we generated SNMIB/Apollo knockout mouse embryo fibroblasts (MEFs) to probe the function of SNMIB/Apollo at mammalian telomeres. SNMIB/Apollo null MEFs exhibit an increased incidence of G2 chromatid-type fusions involving telomeres created by leading-strand DNA synthesis, reflective of a failure to protect these telomeres after DNA replication. Mutations within SNMIB/Apollo's conserved nuclease domain failed to suppress this phenotype, suggesting that its nuclease activity is required to protect leading-strand telomeres. SNMIB/Apollo(-/-)ATM(-/-) MEFs display robust telomere fusions when Trf2 is depleted, indicating that ATM is dispensable for repair of uncapped telomeres in this setting. Our data implicate the 5'-3' exonuclease function of SNM1B/Apollo in the generation of 3' single-stranded overhangs at newly replicated leading-strand telomeres to protect them from engaging the non-homologous end-joining pathway.