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The paper explores three periods in the UK electricity consumption-production system since World War II. The first two involved the development of an increasingly centralized, integrated system that provided electricity to meet growing post-war demand. It saw two major changes in governance, first to nationalization, then to privatization and liberalization. The third period started at the turn of the Century, driven by increasing evidence of the impact of fossil fuels on the Earth's climate. The paper focuses on the drivers of change, within the UK and externally, and how they affected governance, technology deployment, and industry structure. It draws on the multilevel perspective and the concepts of governance and technological branching points to inform the analysis of each period. It shows that there is a considerable distance to travel toward a truly sustainable electricity system. [ABSTRACT FROM AUTHOR]

In one of the first papers on the impact of early-life conditions on individuals' health in older age, Barker and Osmond [Lancet, 327, 1077-1081 (1986)] show a strong positive relationship between infant mortality rates in the 1920s and ischemic heart disease in the 1970s. We merge historical data on infant mortality rates to 370,000 individual records in the UK Biobank using information on local area and year of birth. We replicate the association between the early-life infant mortality rate and laterlife ischemic heart disease in our sample. We then go "beyond Barker," by showing considerable genetic heterogeneity in this association that is robust to within-area as well as within-family analyses. We find no association between the polygenic index and heart disease in areas with the lowest infant mortality rates, but a strong positive relationship in areas characterized by high infant mortality. These findings suggest that advantageous environments can cushion one's genetic disease risk. [ABSTRACT FROM AUTHOR]

Childhood maltreatment (CM) leads to a lifelong susceptibility to mental ill-health which might be reflected by its effects on adult brain structure, perhaps indirectly mediated by its effects on adult metabolic, immune, and psychosocial systems. Indexing these systemic factors via body mass index (BMI), C-reactive protein (CRP), and rates of adult trauma (AT), respectively, we tested three hypotheses: (H1) CM has direct or indirect effects on adult trauma, BMI, and CRP; (H2) adult trauma, BMI, and CRP are all independently related to adult brain structure; and (H3) childhood maltreatment has indirect effects on adult brain structure mediated in parallel by BMI, CRP, and AT. Using path analysis and data from N = 116,887 participants in UK Biobank, we find that CM is related to greater BMI and AT levels, and that these two variables mediate CM's effects on CRP [H1]. Regression analyses on the UKB MRI subsample (N = 21,738) revealed that greater CRP and BMI were both independently related to a spatially convergent pattern of cortical effects (Spearman's ρ = 0.87) characterized by fronto-occipital increases and temporo-parietal reductions in thickness. Subcortically, BMI was associated with greater volume, AT with lower volume and CPR with effects in both directions [H2]. Finally, path models indicated that CM has indirect effects in a subset of brain regions mediated through its direct effects on BMI and AT and indirect effects on CRP [H3]. Results provide evidence that childhood maltreatment can influence brain structure decades after exposure by increasing individual risk toward adult trauma, obesity, and inflammation. [ABSTRACT FROM AUTHOR]

This paper examines some of the science communication challenges involved when designing and conducting public deliberation processes on issues of national importance. We take as our illustrative case study a recent research project investigating public values and attitudes toward future energy system change for the United Kingdom. National-level issues such as this are often particularly difficult to engage the public with because of their inherent complexity, derived from multiple interconnected elements and policy frames, extended scales of analysis, and different manifestations of uncertainty. With reference to the energy system project, we discuss ways of meeting a series of science communication challenges arising when engaging the public with national topics, including the need to articulate systems thinking and problem scale, to provide balanced information and policy framings in ways that open up spaces for reflection and deliberation, and the need for varied methods of facilitation and data synthesis that permit access to participants' broader values. Although resource intensive, national-level deliberation is possible and can produce useful insights both for participants and for science policy. [ABSTRACT FROM AUTHOR]

Electricity system decarbonization is key for environmental sustainability. From a consumption-production perspective, much attention has been paid to changes in how electricity is generated and used, but electricity systems also rely on a grid infrastructure that connects and integrates production and consumption, and which will also need to transform. At the same time, new technologies in the electricity system, including the grid, offer the potential for more socially sustainable ways of producing and consuming energy. However, in practice, change has been slow, uneven, and often dysfunctional. A socio-technical transitions approach offers insights into why this is so, seeing electricity system change not simply in technical and economic terms, but also as the outcomes of interactions between technology and social and political processes. The approach draws attention to the particular challenges of achieving rapid transitions in complex critical infrastructures like electricity with strong institutional logics of security. This article applies this approach to the case of Great Britain, where despite strong commitments to sustainability in the form of high-level climate policy, the electricity grid has often been a constraint on the pace of change. The nature of the British transition is explained partly by weak links between these high-level goals on the one hand and the detailed rules and practices in the electricity system on the other. It is also explained by patterns of ownership and grid regulation in the British case that protect incumbents and make it difficult for new actors to develop the system in more socially sustainable directions. [ABSTRACT FROM AUTHOR]

While the negative environmental, social and health impacts of the current food system have been acknowledged and evidenced for several decades, the recent and current transformations in food systems at diverse scales are not yet addressing the many inter-related stakes at play. Due to the much wider set of interactions in this consumptionproduction system, new conceptual tools are required for understanding and assessing sustainability transitions and what prevents them. The article will draw on the cases of France and the UK to examine these countries' national food systems' historical trajectories and suggest a periodization of these in order to reveal common characteristics and differences. This will show that despite common major trends and common transition or inertia mechanisms, pathways differ, especially from the 1990s, due to different configurations of power relationships between the state, economic actors and civil society in a context of an increasing competition between sustainability narratives that leads to an increasing fragmentation in food systems. It will lead us to join the recent progress in the sustainability transitions' community towards a shift in the analysis from a focus on niches' trajectories and effects to a deeper focus on power configurations and competing narratives, as well as to suggest a larger inclusion of socioecological and spatial dimensions. [ABSTRACT FROM AUTHOR]

Experimental and interventional studies show that light can regulate sleep timing and sleepiness while awake by setting the phase of circadian rhythms and supporting alertness. The extent to which differences in light exposure explain variations in sleep and sleepiness within and between individuals in everyday life remains less clear. Here, we establish a method to address this deficit, incorporating an open-source wearable wrist-worn light logger (SpectraWear) and smartphone-based online data collection. We use it to simultaneously record longitudinal light exposure (in melanopic equivalent daylight illuminance), sleep timing, and subjective alertness over seven days in a convenience sample of 59 UK adults without externally imposed circadian challenge (e.g., shift work or jetlag). Participants reliably had strong daily rhythms in light exposure but frequently were exposed to less light during the daytime and more light in pre-bedtime and sleep episodes than recommended [T. M. Brown et al., PLoS Biol. 20, e3001571 (2022)]. Prior light exposure over several hours was associated with lower subjective sleepiness with, in particular, brighter light in the late sleep episode and after wake linked to reduced early morning sleepiness (sleep inertia). Higher pre-bedtime light exposure was associated with longer sleep onset latency. Early sleep timing was correlated with more reproducible and robust daily patterns of light exposure and higher daytime/lower night-time light exposure. Our study establishes a method for collecting longitudinal sleep and health/performance data in everyday life and provides evidence of associations between light exposure and important determinants of sleep health and performance. [ABSTRACT FROM AUTHOR]

Because human same-sex sexual behavior (SSB) is heritable and leads to fewer offspring, it is puzzling why SSB-associated alleles have not been selectively purged. Current evidence supports the antagonistic pleiotropy hypothesis that SSB-associated alleles benefit individuals exclusively performing opposite-sex sexual behavior by increasing their number of sexual partners and consequently their number of offspring. However, by analyzing the UK Biobank, here, we show that having more sexual partners no longer predicts more offspring since the availability of oral contraceptives in the 1960s and that SSB is now genetically negatively correlated with the number of offspring, suggesting a loss of SSB's genetic maintenance in modern societies. [ABSTRACT FROM AUTHOR]

There is growing need to distinguish between sex and gender. While sex is assigned at birth, gender is socially constructed and may not correspond to one's assigned sex. However, in most research studies, sex or gender is assessed in isolation or the terms are used interchangeably, which has implications for research accuracy and inclusivity. We used data from the UK Biobank to quantify the prevalence of disagreement between chromosomal and self-reported sex and identify potential reasons for discordance. Among approximately 200 individuals with sex discordance, 71% of discordances were potentially explained by the presence of intersex traits or transgender identity. The findings indicate that when describing sex-and/or gender-specific differences in health, researchers may be limited in their ability to draw conclusions regarding specific sex and/or gender health information. [ABSTRACT FROM AUTHOR]

Natural hybridization can have a profound evolutionary impact, with consequences ranging from the extinction of rare taxa to the origin of new species. Natural hybridization is particularly common in plants; however, our understanding of the general factors that promote or prevent hybridization is hampered by the highly variable outcomes in different lineages. Here, we quantify the influence of different predictors on hybrid formation across species from an entire flora. We combine estimates of hybridization with ecological attributes and a new species-level phylogeny for over 1,100 UK flowering plant species. Our results show that genetic factors, particularly parental genetic distance, as well as phylogenetic position and ploidy, are key determinants of hybrid formation, whereas many other factors such as range overlap and genus size explain much less variation in hybrid formation. Overall, intrinsic genetic factors shape the evolutionary and ecological consequences of natural hybridization across species in a flora. [ABSTRACT FROM AUTHOR]

Numerous studies have investigated the impacts of common types of chronic pain (CP) on patients’ cognitive function and observed that CP was associated with later dementia. More recently, there is a growing recognition that CP conditions frequently coexist at multiple body sites and may bring more burdens on patients’ overall health. However, whether and how multisite CP (MCP) contributes to an increased risk of dementia, compared to single-site CP (SCP) and pain-free (PF), is largely unclear. In the current study, utilizing the UK Biobank cohort, we first investigated dementia risk in individuals (n = 354,943) with different numbers of coexisting CP sites using Cox proportional hazards regression models. We then applied generalized additive models to investigate whether MCP leads to excessive deterioration of participants’ (n = 19,116) cognition and brain structure. We found that individuals with MCP were associated with significantly higher dementia risk, broader and faster cognitive impairment, and greater hippocampal atrophy than both PF individuals and those with SCP. Moreover, the detrimental effects of MCP on dementia risk and hippocampal volume aggravated along with the number of coexisting CP sites. Mediation analyses further revealed that the decline of fluid intelligence in MCP individuals was partially mediated by hippocampal atrophy. Our results suggested that cognitive decline and hippocampal atrophy interact biologically and may underlie the increased risk of dementia associated with MCP. [ABSTRACT FROM AUTHOR]

Alterations in brain size and organization represent some of the most distinctive changes in the emergence of our species. Yet, there is limited understanding of how genetic factors contributed to altered neuroanatomy during human evolution. Here, we analyze neuroimaging and genetic data from up to 30,000 people in the UK Biobank and integrate with genomic annotations for different aspects of human evolution, including those based on ancient DNA and comparative genomics. We show that previously reported signals of recent polygenic selection for cortical anatomy are not replicable in a more ancestrally homogeneous sample. We then investigate relationships between evolutionary annotations and common genetic variants shaping cortical surface area and white-matter connectivity for each hemisphere. Our analyses identify single-nucleotide polymorphism heritability enrichment in human-gained regulatory elements that are active in early brain development, affecting surface areas of several parts of the cortex, including left-hemispheric speech-associated regions. We also detect heritability depletion in genomic regions with Neanderthal ancestry for connectivity of the uncinate fasciculus; this is a white-matter tract involved in memory, language, and socioemotional processing with relevance to neuropsychiatric disorders. Finally, we show that common genetic loci associated with left-hemispheric pars triangularis surface area overlap with a human-gained enhancer and affect regulation of ZIC4, a gene implicated in neurogenesis. This work demonstrates how genomic investigations of present-day neuroanatomical variation can help shed light on the complexities of our evolutionary past. [ABSTRACT FROM AUTHOR]

Sedentary behavior (SB) is associated with cardiometabolic disease and mortality, but its association with dementia is currently unclear. This study investigates whether SB is associated with incident dementia regardless of engagement in physical activity (PA). A total of 146,651 participants from the UK Biobank who were 60 years or older and did not have a diagnosis of dementia (mean [SD] age: 64.59 [2.84] years) were included. Selfreported leisure-time SBs were divided into two domains: time spent watching television (TV) or time spent using a computer. A total of 3,507 individuals were diagnosed with all-cause dementia over a mean follow-up of 11.87 (±1.17) years. In models adjusted for a wide range of covariates, including time spent in PA, time spent watching TV was associated with increased risk of incident dementia (HR [95% CI] = 1.24 [1.15 to 1.32]) and time spent using a computer was associated with decreased risk of incident dementia (HR [95% CI] = 0.85 [0.81 to 0.90]). In joint associations with PA, TV time and computer time remained significantly associated with dementia risk at all PA levels. Reducing time spent in cognitively passive SB (i.e., TV time) and increasing time spent in cognitively active SB (i.e., computer time) may be effective behavioral modification targets for reducing risk of dementia regardless of engagement in PA. [ABSTRACT FROM AUTHOR]

Understanding and communicating the environmental impacts of food products is key to enabling transitions to environmentally sustainable food systems [El Bilali and Allahyari, Inf. Process. Agric. 5, 456-464 (2018)]. While previous analyses compared the impacts of food commodities such as fruits, wheat, and beef [Poore and Nemecek, Science 360, 987-992 (2018)], most food products contain numerous ingredients. However, because the amount of each ingredient in a product is often known only by the manufacturer, it has been difficult to assess their environmental impacts. Here, we develop an approach to overcome this limitation. It uses prior knowledge from ingredient lists to infer the composition of each ingredient, and then pairs this with environmental databases [Poore and Nemecek Science 360, 987-992 (2018); Gephart et al., Nature 597, 360-365 (2021)] to derive estimates of a food product's environmental impact across four indicators: greenhouse gas emissions, land use, water stress, and eutrophication potential. Using the approach on 57,000 products in the United Kingdom and Ireland shows food types have low (e.g., sugary beverages, fruits, breads), to intermediate (e.g., many desserts, pastries), to high environmental impacts (e.g., meat, fish, cheese). Incorporating NutriScore reveals more nutritious products are often more environmentally sustainable but there are exceptions to this trend, and foods consumers may view as substitutable can have markedly different impacts. Sensitivity analyses indicate the approach is robust to uncertainty in ingredient composition and in most cases sourcing. This approach provides a step toward enabling consumers, retailers, and policy makers to make informed decisions on the environmental impacts of food products. [ABSTRACT FROM AUTHOR]

The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants in UMOD cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact variants strongly associate with kidney function and the risk of chronic kidney disease (CKD) in the general population. It is unknown whether intermediate-effect variants in UMOD contribute to CKD. Here, candidate intermediate-effect UMOD variants were identified using large-population and ADTKD cohorts. Biological and phenotypical effects were investigated using cell models, in silico simulations, patient samples, and international databases and biobanks. Eight UMOD missense variants reported in ADTKD are present in the Genome Aggregation Database (gnomAD), with minor allele frequency (MAF) ranging from 10-5 to 10-3. Among them, the missense variant p.Thr62Pro is detected in ~1/1,000 individuals of European ancestry, shows incomplete penetrance but a high genetic load in familial clusters of CKD, and is associated with kidney failure in the 100,000 Genomes Project (odds ratio [OR] = 3.99 [1.84 to 8.98]) and the UK Biobank (OR = 4.12 [1.32 to 12.85). Compared with canonical ADTKD mutations, the p. Thr62Pro carriers displayed reduced disease severity, with slower progression of CKD and an intermediate reduction of urinary uromodulin levels, in line with an intermediate trafficking defect in vitro and modest induction of endoplasmic reticulum (ER) stress. Identification of an intermediate-effect UMOD variant completes the spectrum of UMOD-associated kidney diseases and provides insights into the mechanisms of ADTKD and the genetic architecture of CKD. [ABSTRACT FROM AUTHOR]

Haplotype-based analyses have recently been leveraged to interrogate the fine-scale structure in specific geographic regions, notably in Europe, although an equivalent haplotype-based understanding across the whole of Europe with these tools is lacking. Furthermore, study of identity-by-descent (IBD) sharing in a large sample of haplotypes across Europe would allow a direct comparison between different demographic histories of different regions. The UK Biobank (UKBB) is a population-scale dataset of genotype and phenotype data collected from the United Kingdom, with established sampling of worldwide ancestries. The exact content of these non-UK ancestries is largely uncharacterized, where study could highlight valuable intracontinental ancestry references with deep phenotyping within the UKBB. In this context, we sought to investigate the sample of European ancestry captured in the UKBB. We studied the haplotypes of 5,500 UKBB individuals with a European birthplace; investigated the population structure and demographic history in Europe, showing in parallel the variety of footprints of demographic history in different genetic regions around Europe; and expand knowledge of the genetic landscape of the east and southeast of Europe. Providing an updated map of European genetics, we leverage IBD-segment sharing to explore the extent of population isolation and size across the continent. In addition to building and expanding upon previous knowledge in Europe, our results show the UKBB as a source of diverse ancestries beyond Britain. These worldwide ancestries sampled in the UKBB may complement and inform researchers interested in specific communities or regions not limited to Britain. [ABSTRACT FROM AUTHOR]

The extent of shared and distinct neural mechanisms underlying major depressive disorder (MDD), anxiety, and stress-related disorders is still unclear. We compared the neural signatures of these disorders in 5,405 UK Biobank patients and 21,727 healthy controls. We found the greatest case--control differences in resting-state functional connectivity and cortical thickness in MDD, followed by anxiety and stress-related disorders. Neural signatures for MDD and anxiety disorders were highly concordant, whereas stress-related disorders showed a distinct pattern. Controlling for crossdisorder genetic risk somewhat decreased the similarity between functional neural signatures of stress-related disorders and both MDD and anxiety disorders. Among cases and healthy controls, reduced within-network and increased between-network frontoparietal and default mode connectivity were associated with poorer cognitive performance (processing speed, attention, associative learning, and fluid intelligence). These results provide evidence for distinct neural circuit function impairments in MDD and anxiety disorders compared to stress disorders, yet cognitive impairment appears unrelated to diagnosis and varies with circuit function. [ABSTRACT FROM AUTHOR]

Infectious disease transmission models require assumptions about how the pathogen spreads between individuals. These assumptions may be somewhat arbitrary, particularly when it comes to describing how transmission varies between individuals of different types or in different locations, and may in turn lead to incorrect conclusions or policy decisions. We develop a general Bayesian nonparametric framework for transmission modeling that removes the need to make such specific assumptions with regard to the infection process. We use multioutput Gaussian process prior distributions to model different infection rates in populations containing multiple types of individuals. Further challenges arise because the transmission process itself is unobserved, and large outbreaks can be computationally demanding to analyze. We address these issues by data augmentation and a suitable efficient approximation method. Simulation studies using synthetic data demonstrate that our framework gives accurate results. We analyze an outbreak of foot and mouth disease in the United Kingdom, quantifying the spatial transmission mechanism between farms with different combinations of livestock. [ABSTRACT FROM AUTHOR]

Spatial heterogeneities and spatial separation of hosts are often seen as key factors when developing accurate predictive models of the spread of pathogens. The question we address in this paper is how coarse the resolution of the spatial data can be for a model to be a useful tool for informing control policies. We examine this problem using the specific case of foot-and-mouth disease spreading between farms using the formulation developed during the 2001 epidemic in the United Kingdom. We show that, if our model is carefully parameterized to match epidemic behavior, then using aggregate county-scale data from the United States is sufficient to closely determine optimal control measures (specifically ring culling). This result also holds when the approach is extended to theoretical distributions of farms where the spatial clustering can be manipulated to extremes. We have therefore shown that, although spatial structure can be critically important in allowing us to predict the emergent population-scale behavior from a knowledge of the individual-level dynamics, for this specific applied question, such structure is mostly subsumed in the parameterization allowing us to make policy predictions in the absence of high-quality spatial information. We believe that this approach will be of considerable benefit across a range of disciplines where data are only available at intermediate spatial scales. [ABSTRACT FROM AUTHOR]

Myasthenia gravis is a chronic autoimmune disease characterized by autoantibody-mediated interference of signal transmission across the neuromuscular junction. We performed a genome-wide association study (GWAS) involving 1,873 patients diagnosed with acetylcholine receptor antibody-positive myasthenia gravis and 36,370 healthy individuals to identify disease-associated genetic risk loci. Replication of the discovered loci was attempted in an independent cohort from the UK Biobank. We also performed a transcriptome-wide association study (TWAS) using expression data from skeletal muscle, whole blood, and tibial nerve to test the effects of disease-associated polymorphisms on gene expression. We discovered two signals in the genes encoding acetylcholine receptor subunits that are the most common antigenic target of the autoantibodies: a GWAS signal within the cholinergic receptor nicotinic alpha 1 subunit (CHRNA1) gene and a TWAS association with the cholinergic receptor nicotinic beta 1 subunit (CHRNB1) gene in normal skeletal muscle. Two other loci were discovered on 10p14 and 11q21, and the previous association signals at PTPN22, HLA-DQA1/HLA-B, and TNFRSF11A were confirmed. Subgroup analyses demonstrate that early- and late-onset cases have different genetic risk factors. Genetic correlation analysis confirmed a genetic link between myasthenia gravis and other autoimmune diseases, such as hypothyroidism, rheumatoid arthritis, multiple sclerosis, and type 1 diabetes. Finally, we applied Priority Index analysis to identify potentially druggable genes/proteins and pathways. This study provides insight into the genetic architecture underlying myasthenia gravis and demonstrates that genetic factors within the loci encoding acetylcholine receptor subunits contribute to its pathogenesis. [ABSTRACT FROM AUTHOR]

The goals of the Earth Biogenome Project--to sequence the genomes of all eukaryotic life on earth--are as daunting as they are ambitious. The Darwin Tree of Life Project was founded to demonstrate the credibility of these goals and to deliver at-scale genome sequences of unprecedented quality for a biogeographic region: the archipelago of islands that constitute Britain and Ireland. The Darwin Tree of Life Project is a collaboration between biodiversity organizations (museums, botanical gardens, and biodiversity institutes) and genomics institutes. Together, we have built a workflow that collects specimens from the field, robustly identifies them, performs sequencing, generates high-quality, curated assemblies, and releases these openly for the global community to use to build future science and conservation efforts. [ABSTRACT FROM AUTHOR]

Roughly 10% of the human population is left-handed, and this rate is increased in some brain-related disorders. The neuroanatomical correlates of hand preference have remained equivocal. We resampled structural brain image data from 28,802 right-handers and 3,062 left-handers (UK Biobank population dataset) to a symmetrical surface template, and mapped asymmetries for each of 8,681 vertices across the cerebral cortex in each individual. Lefthanders compared to right-handers showed average differences of surface area asymmetry within the fusiform cortex, the anterior insula, the anterior middle cingulate cortex, and the precentral cortex. Meta-analyzed functional imaging data implicated these regions in executive functions and language. Polygenic disposition to left-handedness was associated with two of these regional asymmetries, and 18 loci previously linked with left-handedness by genome-wide screening showed associations with one or more of these asymmetries. Implicated genes included six encoding microtubule-related proteins: TUBB, TUBA1B, TUBB3, TUBB4A, MAP2, and NME7--mutations in the latter can cause left to right reversal of the visceral organs. There were also two cortical regions where average thickness asymmetry was altered in lefthandedness: on the postcentral gyrus and the inferior occipital cortex, functionally annotated with hand sensorimotor and visual roles. These cortical thickness asymmetries were not heritable. Heritable surface area asymmetries of language-related regions may link the etiologies of hand preference and language, whereas nonheritable asymmetries of sensorimotor cortex may manifest as consequences of hand preference. [ABSTRACT FROM AUTHOR]

Gene-based tests are valuable techniques for identifying genetic factors in complex traits. Here, we propose a gene-based testing framework that incorporates data on long-range chromatin interactions, several recent technical advances for region-based tests, and leverages the knockoff framework for synthetic genotype generation for improved gene discovery. Through simulations and applications to genome-wide association studies (GWAS) and whole-genome sequencing data for multiple diseases and traits, we show that the proposed test increases the power over stateof- the-art gene-based tests in the literature, identifies genes that replicate in larger studies, and can provide a more narrowfocus on the possible causal genes at a locus by reducing the confounding effect of linkage disequilibrium. Furthermore, our results show that incorporating genetic variation in distal regulatory elements tends to improve power over conventional tests. Results for UK Biobank and BioBank Japan traits are also available in a publicly accessible database that allows researchers to query gene-based results in an easy fashion. [ABSTRACT FROM AUTHOR]

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) involves the attachment of the receptor-binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down-to-up conformational change in the spike protein, the change that presents the RBD to the receptor. To date, computational and experimental studies that search for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and is therefore a hotspot for drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. This allows for a deeper understanding of the underlying molecular recognition events and prediction of the highest-effect key mutations in distant, allosteric sites, with implications for therapeutics. Also, these sites can appear in emerging mutants with possibly higher transmissibility and virulence, and preidentifying them can give clues for designing pan-coronavirus vaccines against future outbreaks. Our model, based on time-lagged independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Residues involved in the most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab initio from our model. Conversely, broad-spectrum therapeutics like drugs and monoclonal antibodies can target these key distant-but-conserved regions of the spike protein. [ABSTRACT FROM AUTHOR]

We present a comprehensive statistical framework to analyze data from genome-wide association studies of polygenic traits, producing interpretable findings while controlling the false discovery rate. In contrast with standard approaches, our method can leverage sophisticated multivariate algorithms but makes no parametric assumptions about the unknown relation between genotypes and phenotype. Instead, we recognize that genotypes can be considered as a random sample from an appropriate model, encapsulating our knowledge of genetic inheritance and human populations. This allows the generation of imperfect copies (knockoffs) of these variables that serve as ideal negative controls, correcting for linkage disequilibrium and accounting for unknown population structure, which may be due to diverse ancestries or familial relatedness. The validity and effectiveness of our method are demonstrated by extensive simulations and by applications to the UK Biobank data. These analyses confirm our method is powerful relative to state-of-the-art alternatives, while comparisons with other studies validate most of our discoveries. Finally, fast software is made available for researchers to analyze Biobank-scale datasets. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic led to lockdowns in countries across the world, changing the lives of billions of people. The United Kingdom’s first national lockdown, for example, restricted people’s ability to socialize and work. The current study examined how changes to socializing and working during this lockdown impacted ongoing thought patterns in daily life. We compared the prevalence of thought patterns between two independent real-world, experience-sampling cohorts, collected before and during lockdown. In both samples, young (18 to 35 y) and older (55+ y) participants completed experience-sampling measures five times daily for 7 d. Dimension reduction was applied to these data to identify common “patterns of thought.” Linear mixed modeling compared the prevalence of each thought pattern 1) before and during lockdown, 2) in different age groups, and 3) across different social and activity contexts. During lockdown, when people were alone, social thinking was reduced, but on the rare occasions when social interactions were possible, we observed a greater increase in social thinking than prelockdown. Furthermore, lockdown was associated with a reduction in future-directed problem solving, but this thought pattern was reinstated when individuals engaged in work. Therefore, our study suggests that the lockdown led to significant changes in ongoing thought patterns in daily life and that these changes were associated with changes to our daily routine that occurred during lockdown. [ABSTRACT FROM AUTHOR]

Several studies have been devoted to establishing the effects of the COVID-19 pandemic on mental health across gender, age, and ethnicity. However, much less attention has been paid to the differential effect of COVID-19 according to different personalities. We do this using the UK Household Longitudinal Study (UKHLS), a large-scale panel survey representative of the UK population. The UKHLS allows us to assess the mental health of the same respondent before and during the COVID-19 period based on their "Big Five" personality traits and cognitive skills. We find that during the COVID-19 period, individuals who have more extravert and open personality traits report a higher mental health deterioration, while those scoring higher in agreeableness are less affected. The effect of openness is particularly strong: One more SD predicts up to 0.23 more symptoms of mental health deterioration in the 12-item General Health Questionnaire (GHQ-12) test during the COVID-19 period. In particular, for females, cognitive skills and openness are strong predictors of mental health deterioration, while for non-British White respondents, these predictors are extraversion and openness. Neuroticism strongly predicts worse mental health cross-sectionally, but it does not lead to significantly stronger deterioration during the pandemic. The study's results are robust to the inclusion of potential confounding variables such as changes in physical health, household income, and job status (like unemployed or furloughed). [ABSTRACT FROM AUTHOR]

How did people change their behavior over the different phases of the UK COVID-19 restrictions, and how did these changes affect their risk of being exposed to infection? Time-use diary surveys are unique in providing a complete chronicle of daily behavior: 24-h continuous records of the populations' activities, their social context, and their location. We present results from four such surveys, collected in real time from representative UK samples, both before and at three points over the course of the current pandemic. Comparing across the four waves, we find evidence of substantial changes in the UK population's behavior relating to activities, locations, and social context. We assign different levels of risk to combinations of activities, locations, and copresence to compare riskrelated behavior across successive "lockdowns." We find evidence that during the second lockdown (November 2020), there was an increase in high-risk behaviors relative to the first (starting March 2020). This increase is shown to be associated with more paid work time in theworkplace. At a timewhen capacity is still limited both in respect of immunization and track-trace technology, governments must continue to rely on changes in people's daily behaviors to contain the spread of COVID-19 and similar viruses. Time-use diary information of this type, collected in real time across the course of the COVID-19 pandemic, can provide policy makers with information to assess and quantify changes in daily behaviors and the impact they are likely to have on overall behavioral-associated risks. [ABSTRACT FROM AUTHOR]

TheMesozoic Dipole Low (MDL) is a period, covering at least ~80 My, of low dipole moment that ended at the start of the Cretaceous Normal Superchron. Recent studies of Devonian age Siberian localities identified similarly low field values a few tens of million years prior to the Permo-Carboniferous Reverse Superchron (PCRS). To constrain the length and timing of this potential dipole low, this study presents paleointensity estimates from Strathmore (~411 to 416Ma) and Kinghorn (~332 Ma) lava flows, United Kingdom. Both localities have been studied for paleomagnetic poles (Q values of 6 to 7), and the sites were assessed for their suitability for paleointensity from paleodirections, rock magnetic analysis, and microscopy. Thermal and microwave experiments were used to determine site mean paleointensity estimates of ~3 to 51 µT (6 to 98 ZAm²) and 4 to 11 µT (9 to 27 ZAm²) fromthe Strathmore and Kinghorn localities, respectively. These, and all the sites from 200 to 500 Ma from the (updated) Paleointensity database (PINT15), were assessed using the Qualitative Paleointensity criteria (QPI). The procurement of reliable (QPI = 5) weak paleointensity estimates from this and other studies indicates a period of low dipole moment (median field strength of 17 ZAm²) from 332 to 416 Ma. This "Mid-Paleozoic Dipole Low (MPDL)" bears a number of similarities to the MDL, including the substantial increase in field strength near the onset of the PCRS. The MPDL also adds support to the inverse relationship between reversal frequency and field strength and a possible ~200-My cycle in paleomagnetic behavior relating to mantle convection. [ABSTRACT FROM AUTHOR]

Interactions between genetic variants--epistasis--is pervasive in model systems and can profoundly impact evolutionary adaption, population disease dynamics, genetic mapping, and precision medicine efforts. In this work, we develop a model for structured polygenic epistasis, called coordinated epistasis (CE), and prove that several recent theories of genetic architecture fall under the formal umbrella of CE. Unlike standard epistasis models that assume epistasis and main effects are independent, CE captures systematic correlations between epistasis and main effects that result from pathway-level epistasis, on balance skewing the penetrance of genetic effects. To test for the existence of CE, we propose the even-odd (EO) test and prove it is calibrated in a range of realistic biological models. Applying the EO test in the UK Biobank, we find evidence of CE in 18 of 26 traits spanning disease, anthropometric, and blood categories. Finally, we extend the EO test to tissue-specific enrichment and identify several plausible tissue-trait pairs. Overall, CE is a dimension of genetic architecture that can capture structured, systemic forms of epistasis in complex human traits. [ABSTRACT FROM AUTHOR]

Skin pigmentation is a classic example of a polygenic trait that has experienced directional selection in humans. Genome-wide association studies have identified well over a hundred pigmentationassociated loci, and genomic scans in present-day and ancient populations have identified selective sweeps for a small number of light pigmentation-associated alleles in Europeans. It is unclear whether selection has operated on all of the genetic variation associated with skin pigmentation as opposed to just a small number of large-effect variants. Here, we address this question using ancient DNA from 1,158 individuals from West Eurasia covering a period of 40,000 y combined with genome-wide association summary statistics from the UK Biobank. We find a robust signal of directional selection in ancient West Eurasians on 170 skin pigmentation-associated variants ascertained in the UK Biobank. However, we also show that this signal is driven by a limited number of large-effect variants. Consistent with this observation, we find that a polygenic selection test in present-day populations fails to detect selection with the full set of variants. Our data allow us to disentangle the effects of admixture and selection. Most notably, a large-effect variant at SLC24A5 was introduced to Western Europe by migrations of Neolithic farming populations but continued to be under selection post-admixture. This study shows that the response to selection for light skin pigmentation in West Eurasia was driven by a relatively small proportion of the variants that are associated with present-day phenotypic variation. [ABSTRACT FROM AUTHOR]

The negative organic carbon isotope excursion (CIE) associated with the end-Triassic mass extinction (ETE) is conventionally interpreted as the result of a massive flux of isotopically light carbon from exogenous sources into the atmosphere (e.g., thermogenic methane and/or methane clathrate dissociation linked to the Central Atlantic Magmatic Province [CAMP]). Instead, we demonstrate that at its type locality in the Bristol Channel Basin (UK), the CIE was caused by a marine to nonmarine transition resulting from an abrupt relative sea level drop. Our biomarker and compoundspecific carbon isotopic data show that the emergence of microbial mats, influenced by an influx of fresh to brackish water, provided isotopically light carbon to both organic and inorganic carbon pools in centimeter-scale water depths, leading to the negative CIE. Thus, the iconic CIE and the disappearance of marine biota at the type locality are the result of local environmental change and do not mark either the global extinction event or input of exogenous light carbon into the atmosphere. Instead, the main extinction phase occurs slightly later in marine strata, where it is coeval with terrestrial extinctions and ocean acidification driven by CAMP-induced increases in PCO2; these effects should not be conflated with the CIE. An abrupt sea-level fall observed in the Central European basins reflects the tectonic consequences of the initial CAMP emplacement, with broad implications for all extinction events related to large igneous provinces. [ABSTRACT FROM AUTHOR]

The rapid growth rate of COVID-19 continues to threaten to overwhelm healthcare systems in multiple countries. In response, severely affected countries have had to impose a range of public health strategies achieved via nonpharmaceutical interventions. Broadly, these strategies have fallen into two categories: 1) "mitigation," which aims to achieve herd immunity by allowing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus to spread through the population while mitigating disease burden, and 2) "suppression," aiming to drastically reduce SARS-CoV-2 transmission rates and halt endogenous transmission in the target population. Using an age-structured transmission model, parameterized to simulate SARS-CoV-2 transmission in the United Kingdom, we assessed the long-term prospects of success using both of these approaches. We simulated a range of different nonpharmaceutical intervention scenarios incorporating social distancing applied to differing age groups. Our modeling confirmed that suppression of SARS-CoV-2 transmission is possible with plausible levels of social distancing over a period of months, consistent with observed trends. Notably, our modeling did not support achieving herd immunity as a practical objective, requiring an unlikely balancing of multiple poorly defined forces. Specifically, we found that 1) social distancing must initially reduce the transmission rate to within a narrow range, 2) to compensate for susceptible depletion, the extent of social distancing must be adaptive over time in a precise yet unfeasible way, and 3) social distancing must be maintained for an extended period to ensure the healthcare system is not overwhelmed. [ABSTRACT FROM AUTHOR]

Major depressive disorder emerges from the complex interactions of biological systems that span genes and molecules through cells, networks, and behavior. Establishing how neurobiological processes coalesce to contribute to depression requires a multiscale approach, encompassing measures of brain structure and function as well as genetic and cell-specific transcriptional data. Here, we examine anatomical (cortical thickness) and functional (functional variability, global brain connectivity) correlates of depression and negative affect across three population-imaging datasets: UK Biobank, Brain Genomics Superstruct Project, and Enhancing Neuro- Imaging through Meta Analysis (ENIGMA; combined n = 23,723). Integrative analyses incorporate measures of cortical gene expression, postmortem patient transcriptional data, depression genome-wide association study (GWAS), and single-cell gene transcription. Neuroimaging correlates of depression and negative affect were consistent across three independent datasets. Linking ex vivo gene down-regulation with in vivo neuroimaging, we find that transcriptional correlates of depression imaging phenotypes track gene down-regulation in postmortem cortical samples of patients with depression. Integrated analysis of single-cell and Allen Human Brain Atlas expression data reveal somatostatin interneurons and astrocytes to be consistent cell associates of depression, through both in vivo imaging and ex vivo cortical gene dysregulation. Providing converging evidence for these observations, GWAS-derived polygenic risk for depression was enriched for genes expressed in interneurons, but not glia. Underscoring the translational potential of multiscale approaches, the transcriptional correlates of depression-linked brain function and structure were enriched for disorder-relevant molecular pathways. These findings bridge levels to connect specific genes, cell classes, and biological pathways to in vivo imaging correlates of depression. [ABSTRACT FROM AUTHOR]

Sustainable development aims for a viable interaction between human and physical nature. However, how do we perceive the social and natural world, rationalize our behavior, and modify our ways of life? Here, we apply the idea of worldviews to cognition and rationality in transport since a transition to sustainable mobility is crucial in dealing with global climate change. We utilize Cultural Theory and the British Social Attitudes survey (N = 1,120) to study how three worldviews--egalitarianism, hierarchy, and individualism--relate to people's attitudes to sustainable mobility. First, we use factor analysis to extract the three worldviews or ways of life in Great Britain. Second, we construct hypotheses concerning the correlations between the worldviews and social attitudes to sustainable mobility. Our statistical analysis of 11 mobility issues in the survey confirms our hypotheses, elucidating the cultural cognition or rationality that underlies people's transport decision-making. Egalitarianism favors demand control, environmental friendliness, and action driven by inner conviction; hierarchy privileges conformity, order, and security; and individualism embraces freedom, speed, and external incentives. The findings show that the worldviews have a systematic and comprehensive impact on how people assess sustainable mobility debates. Moreover, we perform regression analysis to investigate how these cultural styles are associated with British people's sociodemographics and political party identification, which can help identify the characteristics of stakeholders in sustainability planning and engagement. We conclude that the worldviews form the bedrock of individual decisions on sustainable mobility and have a wider significance for holistic sustainability governance. [ABSTRACT FROM AUTHOR]

Global perturbations to the Early Jurassic environment (~201 to ~174 Ma), notably during the Triassic-Jurassic transition and Toarcian Oceanic Anoxic Event, are well studied and largely associated with volcanogenic greenhouse gas emissions released by large igneous provinces. The long-term secular evolution, timing, and pacing of changes in the Early Jurassic carbon cycle that provide context for these events are thus far poorly understood due to a lack of continuous high-resolution δ13C data. Here we present a δ13CTOC record for the uppermost Rhaetian (Triassic) to Pliensbachian (Lower Jurassic), derived from a calcareous mudstone succession of the exceptionally expanded Llanbedr (Mochras Farm) borehole, Cardigan Bay Basin, Wales, United Kingdom. Combined with existing δ13CTOC data from the Toarcian, the compilation covers the entire Lower Jurassic. The dataset reproduces large-amplitude δ13CTOC excursions (>3‰) recognized elsewhere, at the Sinemurian-Pliensbachian transition and in the lower Toarcian serpentinum zone, as well as several previously identified medium-amplitude (~0.5 to 2‰) shifts in the Hettangian to Pliensbachian interval. In addition, multiple hitherto undiscovered isotope shifts of comparable amplitude and stratigraphic extent are recorded, demonstrating that those similar features described earlier from stratigraphically more limited sections are nonunique in a long-term context. These shifts are identified as long-eccentricity (~405-ky) orbital cycles. Orbital tuning of the δ13CTOC record provides the basis for an astrochronological duration estimate for the Pliensbachian and Sinemurian, giving implications for the duration of the Hettangian Stage. Overall the chemostratigraphy illustrates particular sensitivity of the marine carbon cycle to long-eccentricity orbital forcing. [ABSTRACT FROM AUTHOR]

Past research suggests that use of psychedelic substances such as LSD or psilocybin may have positive effects on mood and feelings of social connectedness. These psychological effects are thought to be highly sensitive to context, but robust and direct evidence for them in a naturalistic setting is scarce. In a series of field studies involving over 1,200 participants across six multiday mass gatherings in the United States and the United Kingdom, we investigated the effects of psychedelic substance use on transformative experience, social connectedness, and positive mood. This approach allowed us to test preregistered hypotheses with high ecological validity and statistical precision. Controlling for a host of demographic variables and the use of other psychoactive substances, we found that psychedelic substance use was significantly associated with positive mood--an effect sequentially mediated by self-reported transformative experience and increased social connectedness. These effects were particularly pronounced for those who had taken psychedelic substances within the last 24 h (compared to the last week). Overall, this research provides robust evidence for positive affective and social consequences of psychedelic substance use in naturalistic settings. [ABSTRACT FROM AUTHOR]

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBa in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBa in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBa revealed regulation of the little-understood transcription factor TBPL1. Both REVERBa and TBPL1 altered integrinß1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBa expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBa inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBa could be a viable therapeutic approach. [ABSTRACT FROM AUTHOR]

Early childhood deprivation is associated with higher rates of neurodevelopmental and mental disorders in adulthood. The impact of childhood deprivation on the adult brain and the extent to which structural changes underpin these effects are currently unknown. To investigate these questions, we utilized MRI data collected from young adults who were exposed to severe deprivation in early childhood in the Romanian orphanages of the Ceaușescu era and then, subsequently adopted by UK families; 67 Romanian adoptees (with between 3 and 41 mo of deprivation) were compared with 21 nondeprived UK adoptees. Romanian adoptees had substantially smaller total brain volumes (TBVs) than nondeprived adoptees (8.6% reduction), and TBV was strongly negatively associated with deprivation duration. This effect persisted after covarying for potential environmental and genetic confounds. In whole-brain analyses, deprived adoptees showed lower right inferior frontal surface area and volume but greater right inferior temporal lobe thickness, surface area, and volume than the nondeprived adoptees. Right medial prefrontal volume and surface area were positively associated with deprivation duration. No deprivation-related effects were observed in limbic regions. Global reductions in TBV statistically mediated the observed relationship between institutionalization and both lower intelligence quotient (IQ) and higher levels of attention deficit/hyperactivity disorder symptoms. The deprivation-related increase in right inferior temporal volume seemed to be compensatory, as it was associated with lower levels of attention deficit/hyperactivity disorder symptoms. We provide compelling evidence that time-limited severe deprivation in the first years of life is related to alterations in adult brain structure, despite extended enrichment in adoptive homes in the intervening years. [ABSTRACT FROM AUTHOR]

Maternal brain adaptations have been found across pregnancy and postpartum, but little is known about the long-term effects of parity on the maternal brain. Using neuroimaging and machine learning, we investigated structural brain characteristics in 12,021 middle-aged women from the UK Biobank, demonstrating that parous women showed less evidence of brain aging compared to their nulliparous peers. The relationship between childbirths and a "younger-looking" brain could not be explained by common genetic variation or relevant confounders. Although prospective longitudinal studies are needed, the results suggest that parity may involve neural changes that could influence women's brain aging later in life. [ABSTRACT FROM AUTHOR]

Research reveals that a "finite pool of worry" constrains concern about and action on climate change. Nevertheless, a longitudinal panel survey of 1,858 UK residents, surveyed in April 2019 and June 2020, reveals little evidence for diminishing climate change concern during the COVID-19 pandemic. Further, the sample identifies climate change as a bigger threat than COVID-19. The findings suggest climate change has become an intransigent concern within UK public consciousness. [ABSTRACT FROM AUTHOR]

The role of obesity and overweight in occurrence of COVID-19 is unknown. We conducted a large-scale general population study using data from a community-dwelling sample in England (n = 334,329; 56.4 ±8.1 y; 54.5% women) with prospective linkage to national registry on hospitalization for COVID-19. Body mass index (BMI, from measured height and weight) was used as an indicator of overall obesity, and waist-hip ratio for central obesity. Main outcome was cases of COVID-19 serious enough to warrant a hospital admission from 16 March 2020 to 26 April 2020. Around 0.2% (n = 640) of the sample were hospitalized for COVID-19. There was an upward linear trend in the likelihood of COVID-19 hospitalization with increasing BMI, that was evident in the overweight (odds ratio, 1.39; 95% CI 1.13 to 1.71; crude incidence 19.1 per 10,000) and obese stage I (1.70;1.34 to 2.16; 23.3 per 10,000) and stage II (3.38; 2.60 to 4.40; 42.7 per 10,000) compared to normal weight (12.5 per 10,000). This gradient was little affected after adjustment for a wide range of covariates; however, controlling for biomarkers, particularly high-density lipoprotein cholesterol and glycated hemoglobin, led to a greater degree of attenuation. A similar pattern of association emerged for waist-hip ratio. In summary, overall and central obesity are risk factors for COVID-19 hospital admission. Elevated risk was apparent even at modest weight gain. The mechanisms may involve impaired glucose and lipid metabolism. [ABSTRACT FROM AUTHOR]

The article focuses on science communication. Topics discussed include internal collaboration which can be observed in the European Center for Nuclear Research, the Intergovernmental Panel on Climate Change, and European Union projects, importance of better communication in the public and policy makers, and energy policy in Great Britain.

Rising sea levels and increased storminess are expected to accelerate the erosion of soft-cliff coastlines, threatening coastal infrastructure and livelihoods. To develop predictive models of future coastal change we need fundamentally to know how rapidly coasts have been eroding in the past, and to understand the driving mechanisms of coastal change. Direct observations of cliff retreat rarely extend beyond 150 y, during which humans have significantly modified the coastal system. Cliff retreat rates are unknown in prior centuries and millennia. In this study, we derived retreat rates of chalk cliffs on the south coast of Great Britain over millennial time scales by coupling high-precision cosmogenic radionuclide geochronology and rigorous numerical modeling. Measured 10Be concentrations on rocky coastal platforms were compared with simulations of coastal evolution using a Monte Carlo approach to determine the most likely history of cliff retreat. The 10Be concentrations are consistent with retreat rates of chalk cliffs that were relatively slow (2-6 cm·y-1) until a few hundred years ago. Historical observations reveal that retreat rates have subsequently accelerated by an order of magnitude (22-32 cm·y-1). We suggest that acceleration is the result of thinning of cliff-front beaches, exacerbated by regional storminess and anthropogenic modification of the coast. [ABSTRACT FROM AUTHOR]

Research on the ecological impacts of environmental change has primarily focused at the species level, leaving the responses of ecosystem-level properties like energy flow poorly understood. This is especially so over millennial timescales inaccessible to direct observation. Here we examine how energy flow within a Great Basin small mammal community responded to climate-driven environmental change during the past 12,800 y, and use this baseline to evaluate responses observed during the past century. Our analyses reveal marked stability in energy flow during rapid climatic warming at the terminal Pleistocene despite dramatic turnover in the distribution of mammalian body sizes and habitat-associated functional groups. Functional group turnover was strongly correlated with climate-driven changes in regional vegetation, with climate and vegetation change preceding energetic shifts in the small mammal community. In contrast, the past century has witnessed a substantial reduction in energy flow caused by an increase in energetic dominance of smallbodied species with an affinity for closed grass habitats. This suggests that modern changes in land cover caused by anthropogenic activities—particularly the spread of nonnative annual grasslands—has led to a breakdown in the compensatory dynamics of energy flow. Human activities are thus modifying the small mammal community in ways that differ from climate-driven expectations, resulting in an energetically novel ecosystem. Our study illustrates the need to integrate across ecological and temporal scales to provide robust insights for long-term conservation and management. [ABSTRACT FROM AUTHOR]

Effective climate mitigation requires international cooperation, and these global efforts need broad public support to be sustainable over the long run. We provide estimates of public support for different types of climate agreements in France, Germany, the United Kingdom, and the United States. Using data from a large-scale experimental survey, we explore how three key dimensions of global climate cooperation—costs and distribution, participation, and enforcement—affect individuals' willingness to support these international efforts. We find that design features have significant effects on public support. Specifically, our results indicate that support is higher for global climate agreements that involve lower costs, distribute costs according to prominent fairness principles, encompass more countries, and include a small sanction if a country fails to meet its emissions reduction targets. In contrast to well-documented baseline differences in public support for climate mitigation efforts, opinion responds similarly to changes in climate policy design in all four countries. We also find that the effects of institutional design features can bring about decisive changes in the level of public support for a global climate agreement. Moreover, the results appear consistent with the view that the sensitivity of public support to design features reflects underlying norms of reciprocity and individuals' beliefs about the potential effectiveness of specific agreements. [ABSTRACT FROM AUTHOR]

Enhancements in sensitivity now allow DNA profiles to be obtained from only tens of picograms of DNA, corresponding to a few cells, even for samples subject to degradation from environmental exposure. However, low-template DNA (LTDNA) profiles are subject to stochastic effects, such as "dropout" and "dropin" of alleles, and highly variable stutter peak heights. Although the sensitivity of the newly developed methods is highly appealing to crime investigators, courts are concerned about the reliability of the underlying science. High-profile cases relying on LTDNA evidence have collapsed amid controversy, including the case of Hoey in the United Kingdom and the case of Knox and Sollecito in Italy. I argue that rather than the reliability of the science, courts and commentators should focus on the validity of the statistical methods of evaluation of the evidence. Even noisy DNA evidence can be more powerful than many traditional types of evidence, and it can be helpful to a court as long as its strength is not overstated. There have been serious shortcomings in statistical methods for the evaluation of LTDNA profile evidence, however. Here, I propose a method that allows for multiple replicates with different rates of dropout, sporadic dropins, different amounts of DNA from different contributors, relatedness of suspected and alternate contributors, "uncertain" allele designations, and degradation. R code implementing the method is open source, facilitating wide scrutiny. I illustrate its good performance using real cases and simulated crime scene profiles. [ABSTRACT FROM AUTHOR]

Phylogenetic trees can be used to infer the processes that generated them. Here, we introduce a model, the Bayesian birth-death skyline plot, which explicitly estimates the rate of transmission, recovery, and sampling and thus allows inference of the effective reproductive number directly from genetic data. Our method allows these parameters to vary through time in a piecewise fashion and is implemented within the BEAST2 software framework. The method is a powerful alternative to the existing coalescent skyline plot, providing insight into the differing roles of incidence and prevalence in an epidemic. We apply this method to data from the United Kingdom HIV-1 epidemic and Egyptian hepatitis C virus (HCV) epidemic. The analysis reveals temporal changes of the effective reproductive number that highlight the effect of past public health interventions. [ABSTRACT FROM AUTHOR]

Hospital-associated infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a global health burden dominated by a small number of bacterial clones. The pandemic EMRSA-16 clone (ST36-II) has been widespread in UK hospitals for 20 y, but its evolutionary origin and the molecular basis for its hospital association are unclear. We carried out a Bayesian phylogenetic reconstruction on the basis of the genome sequences of 87 S. aureus isolates including 60 EMRSA-16 and 27 additional clonal complex 30 (CC30) isolates, collected from patients in three continents over a 53-y period. The three major pandemic clones to originate from the CC30 lineage, including phage type 80/81, Southwest Pacific, and EMRSA-16, shared a most recent common ancestor that existed over 100 y ago, whereas the hospital-associated EMRSA-16 clone is estimated to have emerged about 35 y ago. Our CC30 genome-wide analysis revealed striking molecular correlates of hospital- or community-associated pandemics represented by mobile genetic elements and nonsynonymous mutations affecting antibiotic resistance and virulence. Importantly, phylogeographic analysis indicates that EMRSA-16 spread within the United Kingdom by transmission from hospitals in large population centers in London and Glasgow to regional health-care settings, implicating patient referrals as an important cause of nationwide transmission. Taken together, the high-resolution phylogenomic approach used resulted in a unique understanding of the emergence and transmission of a major MRSA clone and provided molecular correlates of its hospital adaptation. Similar approaches for hospitalassociated clones of other bacterial pathogens may inform appropriate measures for controlling their intra- and interhospital spread. [ABSTRACT FROM AUTHOR]

Drawing on over 4,000,000 individual and 2,000 agency observations across five countries, this paper examines the relationship between features of an employee's work environment and intrinsic motivation in public agencies. It finds that practices which foster employees' sense of autonomy, competence, and relatedness are associated with substantially higher levels of intrinsic motivation across a broad range of settings. This is true both at the individual and agency level and when examining changes within agency over time. These patterns appear to be at least partially a result of differential selection in and out of the agency, with lower levels of supportive practices associated with greater desire to exit for employees with higher levels of intrinsic motivation. Nonfinancial elements of job design are strongly associated with intrinsic motivation, as are potentially more difficult to alter features of an agency, such as satisfaction with compensation and managerial quality. There is also suggestive evidence that the relationship between agency practices and employee intrinsic motivation is stronger when tasks are more difficult to monitor., Competing Interests: The author declares no competing interest.