The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

Increasing prevalence of hot drought across western North America since the 16th century.

Across western North America (WNA), 20th-21st century anthropogenic warming has increased the prevalence and severity of concurrent drought and heat events, also termed hot droughts. However, the lack of independent spatial reconstructions of both soil moisture and temperature limits the potential to identify these events in the past and to place them in a long-term context. We develop the Western North American Temperature Atlas (WNATA), a data-independent 0.5° gridded reconstruction of summer maximum temperatures back to the 16th century. Our evaluation of the WNATA with existing hydroclimate reconstructions reveals an increasing association between maximum temperature and drought severity in recent decades, relative to the past five centuries. The synthesis of these paleo-reconstructions indicates that the amplification of the modern WNA megadrought by increased temperatures and the frequency and spatial extent of compound hot and dry conditions in the 21st century are likely unprecedented since at least the 16th century.

Genetic background and thermal regime influence adaptation to novel environment in the seed beetle, Callosobruchus maculatus.

Climate change is associated with the increase in both the mean and variability of thermal conditions. Therefore, the use of more realistic fluctuating thermal regimes is the most appropriate laboratory method for predicting population responses to thermal heterogeneity. However, the long- and short-term implications of evolving under such conditions are not well understood. Here, we examined differences in key life-history traits among populations of seed beetles (Callosobruchus maculatus) that evolved under either constant control conditions or in an environment with fluctuating daily temperatures. Specifically, individuals from two distinct genetic backgrounds were kept for 19 generations at one of two temperatures, a constant temperature (T = 29 °C) or a fluctuating daily cycle (Tmean = 33 °C, Tmax = 40 °C, and Tmin = 26 °C), and were assayed either in their evolved environment or in the other environment. We found that beetles that evolved in fluctuating environments but were then switched to constant 29 °C conditions had far greater lifetime reproductive success compared with beetles that were kept in their evolved environments. This increase in reproductive success suggests that beetles raised in fluctuating environments may have evolved greater thermal breadth than control condition beetles. In addition, the degree of sexual dimorphism in body size and development varied as a function of genetic background, evolved thermal environment, and current temperature conditions. These results not only highlight the value of incorporating diel fluctuations into climate research but also suggest that populations that experience variability in temperature may be better able to respond to both short- and long-term changes in environmental conditions.

Implementing code review in the scientific workflow: Insights from ecology and evolutionary biology.

Code review increases reliability and improves reproducibility of research. As such, code review is an inevitable step in software development and is common in fields such as computer science. However, despite its importance, code review is noticeably lacking in ecology and evolutionary biology. This is problematic as it facilitates the propagation of coding errors and a reduction in reproducibility and reliability of published results. To address this, we provide a detailed commentary on how to effectively review code, how to set up your project to enable this form of review and detail its possible implementation at several stages throughout the research process. This guide serves as a primer for code review, and adoption of the principles and advice here will go a long way in promoting more open, reliable, and transparent ecology and evolutionary biology.

A multifault earthquake threat for the Seattle metropolitan region revealed by mass tree mortality.

Compound earthquakes involving simultaneous ruptures along multiple faults often define a region's upper threshold of maximum magnitude. Yet, the potential for linked faulting remains poorly understood given the infrequency of these events in the historic era. Geological records provide longer perspectives, although temporal uncertainties are too broad to clearly pinpoint single multifault events. Here, we use dendrochronological dating and a cosmogenic radiation pulse to constrain the death dates of earthquake-killed trees along two adjacent fault zones near Seattle, Washington to within a 6-month period between the 923 and 924 CE growing seasons. Our narrow constraints conclusively show linked rupturing that occurred either as a single composite earthquake of estimated magnitude 7.8 or as a closely spaced double earthquake sequence with estimated magnitudes of 7.5 and 7.3. These scenarios, which are not recognized in current hazard models, increase the maximum earthquake size needed for seismic preparedness and engineering design within the Puget Sound region of >4 million residents.

Advice for improving the reproducibility of data extraction in meta-analysis.

Extracting data from studies is the norm in meta-analyses, enabling researchers to generate effect sizes when raw data are otherwise not available. While there has been a general push for increased reproducibility in meta-analysis, the transparency and reproducibility of the data extraction phase is still lagging behind. Unfortunately, there is little guidance of how to make this process more transparent and shareable. To address this, we provide several steps to help increase the reproducibility of data extraction in meta-analysis. We also provide suggestions of R software that can further help with reproducible data policies: the shinyDigitise and juicr packages. Adopting the guiding principles listed here and using the appropriate software will provide a more transparent form of data extraction in meta-analyses.

Expansion of clinical and variant spectrum of EEF2-related neurodevelopmental disorder: Report of two additional cases.

Eukaryotic translation elongation factor 2 (eEF2), encoded by the gene EEF2, is an essential factor involved in the elongation phase of protein translation. A specific heterozygous missense variant (p.P596H) in EEF2 was originally identified in association with autosomal dominant adult-onset spinocerebellar ataxia-26 (SCA26). More recently, additional heterozygous missense variants in this gene have been described to cause a novel, childhood-onset neurodevelopmental disorder with benign external hydrocephalus. Herein, we report two unrelated individuals with a similar gene-disease correlation to support this latter observation. Patient 1 is a 7-year-old male with a previously reported, de novo missense variant (p.V28M) who has motor and speech delay, autism spectrum disorder, failure to thrive with relative macrocephaly, unilateral microphthalmia with coloboma and eczema. Patient 2 is a 4-year-old female with a novel de novo nonsense variant (p.Q145X) with motor and speech delay, hypotonia, macrocephaly with benign ventricular enlargement, and keratosis pilaris. These additional cases help to further expand the genotypic and phenotypic spectrum of this newly described EEF2-related neurodevelopmental syndrome.

Technology-enhanced simulation for healthcare professionals: A meta-analysis.

Aim: There have been substantial changes in the simulation technology landscape, in particular virtual reality (VR), during the past decade, which have resulted in increased abundance and decreased cost. We therefore updated a previous meta-analysis conducted in 2011, aiming to quantify the impact of digital technology-enhanced simulation (T-ES) compared with traditional teaching in physicians, physicians-in-training, nurses, and nursing students. Design: We conducted a meta-analysis consisting of randomized controlled trials published in English between January 2011 and December 2021 in peer-reviewed journals indexed in seven databases. Moderators for study duration, instruction, type of healthcare worker, type of simulation, outcome measure, and study quality rated by Medical Education Research Study Quality Instrument (MERSQI) score were included in our model and used to calculate estimated marginal means (EMMs). Results: The overall effect of T-ES was positive across the 59 studies included in the analysis compared with traditional teaching [overall effect size 0.80 (95% CI 0.60, 1.00)]. This indicates that T-ES is effective in improving outcomes across a wide variety of settings and participants. The impact of T-ES was found to be greatest for expert-rated product metrics such as procedural success, and process metrics such as efficiency, compared with knowledge and procedure time metrics. Conclusions: The impacts of T-ES training on the outcome measures included in our study were greatest in nurses, nursing students and resident physicians. T-ES was strongest in studies featuring physical high-fidelity mannequins or centers, compared with VR sensory environment T-ES, though there was considerable uncertainty in all statistical analyses. Further high-quality studies are required to assess direct effects of simulation training on patient and public health outcomes.

Fasting increases investment in soma upon refeeding at the cost of gamete quality in zebrafish.

Fasting increases lifespan in invertebrates, improves biomarkers of health in vertebrates and is increasingly proposed as a promising route to improve human health. Nevertheless, little is known about how fasted animals use resources upon refeeding, and how such decisions affect putative trade-offs between somatic growth and repair, reproduction and gamete quality. Such fasting-induced trade-offs are based on strong theoretical foundations and have been recently discovered in invertebrates, but the data on vertebrates are lacking. Here, we report that fasted female zebrafish, Danio rerio, increase investment in soma upon refeeding, but it comes at a cost of egg quality. Specifically, an increase in fin regrowth was accompanied by a reduction in 24 h post-fertilization offspring survival. Refed males showed a reduction in sperm velocity and impaired 24 h post-fertilization offspring survival. These findings underscore the necessity of considering the impact on reproduction when assessing evolutionary and biomedical implications of lifespan-extending treatments in females and males and call for careful evaluation of the effects of intermittent fasting on fertilization.

The distribution of the Lansing Effect across animal species.

Maternal senescence is the reduction in individual performance associated with increased maternal age at conception. When manifested on adult lifespan, this phenomenon is known as the "Lansing Effect." Single-species studies report both maternal age-related increases and decreases in adult lifespan, but no comprehensive review of the literature has yet been undertaken to determine if the Lansing Effect is a widespread phenomenon. To address this knowledge gap, we performed a meta-analysis of maternal aging rates taken from all available published studies. We recovered 78 estimates from 22 studies representing 15 species. All studies taken together suggest a propensity for a Lansing Effect, with an estimated average effect of maternal age on offspring's adult lifespan of between -17% and -22%, depending upon our specific choice of model. We failed to find a significant effect of animal class or insect order but given the oversampling of insect species in the published literature and the paucity of vertebrate studies, we infer that only rotifers and insects yet demonstrate a tendency toward expressing the phenomenon.

Impacts of climate and tree morphology on tree-ring stable isotopes in central Mongolia.

Recent climate extremes in Mongolia have ignited a renewed interest in understanding past climate variability over centennial and longer time scales across north-central Asia. Tree-ring width records have been extensively studied in Mongolia as proxies for climate reconstruction, however, the climate and environmental signals of tree-ring stable isotopes from this region need to be further explored. Here, we evaluated a 182-year record of tree-ring δ13C and δ18O from Siberian Pine (Pinus sibirica Du Tour) from a xeric site in central Mongolia (Khorgo Lava) to elucidate the environmental factors modulating these parameters. First, we analyzed the climate sensitivity of tree-ring δ13C and δ18O at Khorgo Lava for comparison with ring-width records, which have been instrumental in reconstructing hydroclimate in central Mongolia over two millennia. We also compared stable isotope records of trees with partial cambial dieback ('strip-bark morphology'), a feature of long-lived conifers growing on resource-limited sites, and trees with a full cambium ('whole-bark morphology'), to assess the inferred leaf-level physiological behavior of these trees. We found that interannual variability in tree-ring δ13C and δ18O reflected summer hydroclimatic variability, and captured recent, extreme drought conditions, thereby complementing ring-width records. The tree-ring δ18O records also had a spring temperature signal and thus expanded the window of climate information recorded by these trees. Over longer time scales, strip-bark trees had an increasing trend in ring-widths, δ13C (and intrinsic water-use efficiency, iWUE) and δ18O, relative to whole-bark trees. Our results suggest that increases in iWUE at this site might be related to a combination of leaf-level physiological responses to increasing atmospheric CO2, recent drought, and stem morphological changes. Our study underscores the potential of stable isotopes for broadening our understanding of past climate in north-central Asia. However, further studies are needed to understand how stem morphological changes might impact stable isotopic trends.

Triparental ageing in a laboratory population of an insect with maternal care.

Parental age at reproduction influences offspring size and survival by affecting prenatal and postnatal conditions in a wide variety of species, including humans. However, most investigations into this manifestation of ageing focus upon maternal age effects; the effects of paternal age and interactions between maternal and paternal age are often neglected. Furthermore, even when maternal age effects are studied, pre- and post-natal effects are often confounded. Using a cross-fostered experimental design, we investigated the joint effects of pre-natal paternal and maternal and post-natal maternal ages on five traits related to offspring outcomes in a laboratory population of a species of burying beetle, Nicrophorus vespilloides. We found a significant positive effect of the age of the egg producer on larval survival to dispersal. We found more statistical evidence for interaction effects, which acted on larval survival and egg length. Both interaction effects were negative and involved the age of the egg-producer, indicating that age-related pre-natal maternal improvements were mitigated by increasing age in fathers and foster mothers. These results agree with an early study that found little evidence for maternal senescence, but it emphasizes that parental age interactions may be an important contributor to ageing patterns. We discuss how the peculiar life history of this species may promote selection to resist the evolution of parental age effects, and how this might have influenced our ability to detect senescence.

Global wood anatomical perspective on the onset of the Late Antique Little Ice Age (LALIA) in the mid-6th century CE.

Linked to major volcanic eruptions around 536 and 540 CE, the onset of the Late Antique Little Ice Age has been described as the coldest period of the past two millennia. The exact timing and spatial extent of this exceptional cold phase are, however, still under debate because of the limited resolution and geographical distribution of the available proxy archives. Here, we use 106 wood anatomical thin sections from 23 forest sites and 20 tree species in both hemispheres to search for cell-level fingerprints of ephemeral summer cooling between 530 and 550 CE. After cross-dating and double-staining, we identified 89 Blue Rings (lack of cell wall lignification), nine Frost Rings (cell deformation and collapse), and 93 Light Rings (reduced cell wall thickening) in the Northern Hemisphere. Our network reveals evidence for the strongest temperature depression between mid-July and early-August 536 CE across North America and Eurasia, whereas more localised cold spells occurred in the summers of 532, 540-43, and 548 CE. The lack of anatomical signatures in the austral trees suggests limited incursion of stratospheric volcanic aerosol into the Southern Hemisphere extra-tropics, that any forcing was mitigated by atmosphere-ocean dynamical responses and/or concentrated outside the growing season, or a combination of factors. Our findings demonstrate the advantage of wood anatomical investigations over traditional dendrochronological measurements, provide a benchmark for Earth system models, support cross-disciplinary studies into the entanglements of climate and history, and question the relevance of global climate averages.

Fitness benefits of dietary restriction.

Dietary restriction (DR) improves survival across a wide range of taxa yet remains poorly understood. The key unresolved question is whether this evolutionarily conserved response to temporary lack of food is adaptive. Recent work suggests that early-life DR reduces survival and reproduction when nutrients subsequently become plentiful, thereby challenging adaptive explanations. A new hypothesis maintains that increased survival under DR results from reduced costs of overfeeding. We tested the adaptive value of DR response in an outbred population of Drosophila melanogaster fruit flies. We found that DR females did not suffer from reduced survival upon subsequent re-feeding and had increased reproduction and mating success compared to their continuously fully fed (FF) counterparts. The increase in post-DR reproductive performance was of sufficient magnitude that females experiencing early-life DR had the same total fecundity as continuously FF individuals. Our results suggest that the DR response is adaptive and increases fitness when temporary food shortages cease.

Ageing as "early-life inertia": Disentangling life-history trade-offs along a lifetime of an individual.

The theory that ageing evolves because of competitive resource allocation between the soma and the germline has been challenged by studies showing that somatic maintenance can be improved without impairing reproduction. However, it has been suggested that cost-free improvement in somatic maintenance is possible only under a narrow range of benign conditions. Here, we show that experimental downregulation of insulin/IGF-1 signaling (IIS) in C. elegans nematodes, a robustly reproducible life span- and health span-extending treatment, reduces fitness in a complex variable environment when initiated during development but does not reduce fitness when initiated in adulthood. Thus, our results show that the costs and benefits of reduced IIS can be uncoupled when organisms inhabit variable environments, and, therefore, do not provide support for the resource allocation theory. Our findings support the theory that the force of natural selection on gene expression in evolutionarily conserved signaling pathways that shape life-history traits declines after the onset of reproduction resulting in organismal senescence.

Inbreeding reduces fitness of seed beetles under thermal stress.

Human-induced environmental change can influence populations both at the global level through climatic warming and at the local level through habitat fragmentation. As populations become more isolated, they can suffer from high levels of inbreeding, which contributes to a reduction in fitness, termed inbreeding depression. However, it is still unclear if this increase in homozygosity also results in a corresponding increase in sensitivity to stressful conditions, which could intensify the already detrimental effects of environmental warming. Here, in a fully factorial design, we assessed the life-long impact of increased inbreeding load and elevated temperature on key life history traits in the seed beetle, Callosobruchus maculatus. We found that beetles raised at higher temperatures had far reduced fitness and survival than beetles from control temperatures. Importantly, these negative effects were exacerbated in inbred beetles as a result of increased inbreeding load, with further detrimental effects manifesting on individual eclosion probability and lifetime reproductive success. These results reveal the harmful impact that increasing temperature and likelihood of habitat fragmentation due to anthropogenetic changes in environmental conditions could have on populations of organisms worldwide.