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While senescence is a common occurrence in wild populations, not all traits decline with age simultaneously and some do not show any senescence. A lack of senescence in secondary sexual traits is thought to be due to their importance for reproductive success. However, if reproductive success senesces, why would secondary sexual traits apparently not senesce? Here, we explored this question in a wild population of red deer (Cervus elaphus) using antler form (number of points), a secondary sexual trait which shows little senescence, despite the occurrence of reproductive senescence. In line with expectations for traits that senesce, genetic variance in antler form increased with age and selection weakened with age. Therefore, there was no indication that a stronger selection on individuals that survived to older ages was countering the dilution of selection due to fewer individuals being alive. Furthermore, the effect of selective disappearance masking a slight decline in antler form in the oldest years was small. Interestingly, although genetic variance and positive selection of antler form were found, there was no evidence of a response to selection, supporting a genetic decoupling of antler senescence and reproductive senescence. Finally, a positive genetic covariance in antler form among age classes provides a possible explanation for the lack of senescence. These findings suggest that the antler form is under a genetic constraint that prevents it from senescing, providing an interesting evolutionary explanation for negligible senescence in a secondary sexual trait, and consequently, the existence of asynchrony in senescence among traits within populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Evolutionary Biology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Environmental characteristics including water quality and sediment properties alter the hazard that metals pose to aquatic systems by governing the speciation and partitioning of metals between water, sediment, and biotic ligands; however, alternate ligands are being introduced into aquatic systems through anthropogenic activity. Microplastics are a ligand on which metals interact through adsorption to the plastic surface. It remains unknown what factors determine the amount of metal bound to microplastic. Using a combination of laboratory experiments and machine learning, we tested a suite of eighteen environmental parameters (inclusive of both water and sediment) to understand how they influence association of cadmium to a representative microplastic, polyethylene. From this, we developed and tested a predictive model that outlines the characteristics that favour the association of cadmium to microplastic. Alkalinity, humification index of dissolved organic matter, and pH (all of which are water quality characteristics) were the three factors determining the proportion of cadmium adsorbed to plastics. These results align with other predictive models, such as the Biotic Ligand Model in demonstrating the governance of metal behaviour by water quality characteristics. To assess the relationship of the amount of cadmium bound to microplastic and cadmium uptake, an exposure was completed in which fathead minnows (Pimephales promelas) were acclimated to environments representing each of the potential outcomes of the model. The uptake of cadmium was not significantly different between groups, indicating that the stress of alterations to water quality may be a confounding factor in determining the exposure risk of microplastics and cadmium., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Meiotic recombination through chromosomal crossing-over is a fundamental feature of sex and an important driver of genomic diversity. It ensures proper disjunction, allows increased selection responses, and prevents mutation accumulation; however, it is also mutagenic and can break up favorable haplotypes. This cost-benefit dynamic is likely to vary depending on mechanistic and evolutionary contexts, and indeed, recombination rates show huge variation in nature. Identifying the genetic architecture of this variation is key to understanding its causes and consequences. Here, we investigate individual recombination rate variation in wild house sparrows (Passer domesticus). We integrate genomic and pedigree data to identify autosomal crossover counts (ACCs) and intrachromosomal allelic shuffling (r¯intra) in 13,056 gametes transmitted from 2,653 individuals to their offspring. Females had 1.37 times higher ACC, and 1.55 times higher r¯intra than males. ACC and r¯intra were heritable in females and males (ACC h2 = 0.23 and 0.11; r¯intra  h2 = 0.12 and 0.14), but cross-sex additive genetic correlations were low (rA = 0.29 and 0.32 for ACC and r¯intra). Conditional bivariate analyses showed that all measures remained heritable after accounting for genetic values in the opposite sex, indicating that sex-specific ACC and r¯intra can evolve somewhat independently. Genome-wide models showed that ACC and r¯intra are polygenic and driven by many small-effect loci, many of which are likely to act in trans as global recombination modifiers. Our findings show that recombination rates of females and males can have different evolutionary potential in wild birds, providing a compelling mechanism for the evolution of sexual dimorphism in recombination., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Through emission processes, palladium (Pd) particulates from industrial sources are introduced into a range of ecosystems including freshwater environments. Despite this, research on Pd-induced bioaccumulation, uptake, and toxicity is limited for freshwater fishes. Unlike other metals, there are currently no regulations or protective guidelines to limit Pd release into aquatic systems, indicating a global absence of measures addressing its environmental impact. To assess the olfactory toxicity potential of Pd, the present study aimed to explore Pd accumulation in olfactory tissues, olfactory disruption, and oxidative stress in rainbow trout (Oncorhynchus mykiss) following waterborne Pd exposure. Olfactory sensitivity, measured by electro-olfactography, demonstrated that Pd inhibits multiple pathways of the olfactory system following 96 h of Pd exposure. In this study, the concentrations of Pd for inhibition of olfactory function by 20% (2.5 μg/L; IC20) and 50% (19 μg/L; IC50) were established. Rainbow trout were then exposed to IC20 and IC50 Pd concentrations in combination with varying exposure conditions, as changes in water quality alter the toxicity of metals. Independent to Pd, increased water hardness resulted in decreased olfactory perception owing to ion competition at the olfactory epithelium. No other environmental parameter in this study significantly influenced Pd-induced olfactory toxicity. Membrane-associated Pd was measured at the olfactory rosette and gill following exposure; however, this accumulation did not translate to oxidative stress as measured by the production of malondialdehyde. Our data suggest that Pd is toxic to rainbow trout via waterborne contamination near field-measured levels. This study further demonstrated Pd bioavailability and uptake at water-adjacent tissues, adding to our collective understanding of the toxicological profile of Pd. Taken together, our results provide novel insights into the olfactory toxicity in fish following Pd exposure. Integr Environ Assess Manag 2024;20:1407-1419. © 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)., (© 2024 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).)

The death of a child is a complex and hugely significant time for a family and community. Sophisticated but sensitive management by clinicians can have both short-term and long-term impacts on how families process the death. There is a paucity of guidance for optimal child bereavement care. A description of the child death review process including key legalities is provided here, and other essential aspects such as memory making, cultural aspects and sibling involvement are explored. Useful agencies and resources are also detailed. We, as both clinicians and bereaved parents, can uniquely provide an overview of the logistics of managing such a challenging event and highlight important subtleties in communication. We attempt, using our own experiences, to provide a framework and best inform future practice., Competing Interests: Competing interests: SEJ has a sessional role with the Oxford School of GP VTS training to teach GP trainees on paediatric topics; this has included one session on child bereavement care. She is also a qualified coach, and coaches healthcare professionals on a freelance basis. LB is a Trustee for Forever Stars, a baby loss charity in Nottingham, UK. All other authors have no conflicts of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The death of a child is a devastating event. Families experience profound grief and loss immediately following the death, and this remains and evolves as time progresses. In this, the second in a series, we discuss the importance of longer term bereavement care and how continuing contact with healthcare can be navigated. As bereaved parents who are also doctors, we again share our experiences. The complex nature of parenting, supporting siblings or managing a pregnancy after loss are explored, and we look at the involvement of bereaved parents in developing bereavement services., Competing Interests: Competing interests: SEJ has a sessional role with the Oxford School of GP VTS training to teach GP trainees on paediatric topics—this has included one session on child bereavement care. She is also a qualified coach, and coaches healthcare professionals on a freelance basis. LB is a trustee for Forever Stars, a baby loss charity in Nottingham, UK., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Meiotic recombination is a fundamental feature of sexually reproducing species. It is often required for proper chromosome segregation and plays important role in adaptation and the maintenance of genetic diversity. The molecular mechanisms of recombination are remarkably conserved across eukaryotes, yet meiotic genes and proteins show substantial variation in their sequence and function, even between closely related species. Furthermore, the rate and distribution of recombination shows a huge diversity within and between chromosomes, individuals, sexes, populations, and species. This variation has implications for many molecular and evolutionary processes, yet how and why this diversity has evolved is not well understood. A key step in understanding trait evolution is to determine its genetic basis-that is, the number, effect sizes, and distribution of loci underpinning variation. In this perspective, I discuss past and current knowledge on the genetic basis of variation in recombination rate and distribution, explore its evolutionary implications, and present open questions for future research., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Inbreeding depression is of major concern in declining populations, but relatively little is known about its genetic architecture in wild populations, such as the degree to which it is composed of large or small effect loci and their distribution throughout the genome. Here, we combine fitness and genomic data from a wild population of red deer to investigate the genomic distribution of inbreeding effects. Based on the runs of homozygosity (ROH)-based inbreeding coefficient, F ROH , we use chromosome-specific inbreeding coefficients (F ROHChr ) to explore whether the effect of inbreeding varies between chromosomes. Under the assumption that within an individual the probability of being identical-by-descent is equal across all chromosomes, we used a multi-membership model to estimate the deviation of F ROHChr from the average inbreeding effect. This novel approach ensures effect sizes are not overestimated whilst maximising the power of our available dataset of >3000 individuals genotyped on >35,000 autosomal SNPs. We find that most chromosomes confer a minor reduction in fitness-related traits, which when these effects are summed, results in the observed inbreeding depression in birth weight, survival and lifetime breeding success. However, no chromosomes had a significant detrimental effect compared to the overall effect of inbreeding, indicating no major effect loci. We conclude that in this population, inbreeding depression is likely the result of multiple mildly or moderately deleterious mutations spread across all chromosomes, which are difficult to detect with statistical confidence. Such mutations will be inefficiently purged, which may explain the persistence of inbreeding depression in this population., (© 2024 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder. The most devastating variant is bulbar-onset ALS, which portends a median survival of 24 months from the onset of symptoms. Abundant evidence indicates that neuron metabolism and mitochondrial function are impaired in ALS. Metabolic strategies, particularly fasting and ketogenic diet protocols, alter neuron metabolism and mitochondria function in a manner that may mitigate the symptoms of this disorder. We report the case of a 64-year-old man with a 21-month history of progressive, deteriorating bulbar-onset ALS, with an associated pseudobulbar affect, who implemented a time-restricted ketogenic diet (TRKD) for 18 months. During this time, he improved in ALS-related function (7% improvement from baseline), forced expiratory volume (17% improvement), forced vital capacity (13% improvement), depression (normalized), stress levels (normalized), and quality of life (19% improvement), particularly fatigue (23% improvement). His swallowing impairment and neurocognitive status remained stable. Declines were measured in physical function, maximal inspiratory pressure, and maximal expiratory pressure. Weight loss was attenuated and no significant adverse effects occurred. This case study represents the first documented occurrence of a patient with ALS managed with either a fasting or ketogenic diet protocol, co-administered as a TRKD. We measured improved or stabilized ALS-related function, forced expiratory volume, forced vital capacity, swallowing, neurocognitive status, mood, and quality of life. Measurable declines were restricted to physical function, maximal inspiratory pressure, and maximal expiratory pressure. Now over 45 months since symptom onset, our patient remains functionally independent and dedicated to his TRKD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Phillips, Johnston, Simpson, Chang, Mather and Dick.)

Meiotic recombination through chromosomal crossovers ensures proper segregation of homologous chromosomes during meiosis, while also breaking down linkage disequilibrium and shuffling alleles at loci located on the same chromosome. Rates of recombination can vary between species, but also between and within individuals, sex and chromosomes within species. Indeed, the Atlantic salmon genome is known to have clear sex differences in recombination with female biased heterochiasmy and markedly different landscapes of crossovers between males and females. In male meiosis, crossovers occur strictly in the telomeric regions, whereas in female meiosis crossovers tend to occur closer to the centromeres. However, little is known about the genetic control of these patterns and how this differs at the individual level. Here, we investigate genetic variation in individual measures of recombination in > 5000 large full-sib families of a Norwegian Atlantic salmon breeding population with high-density SNP genotypes. We show that females had 1.6 × higher crossover counts (CC) than males, with autosomal linkage maps spanning a total of 2174 cM in females and 1483 cM in males. However, because of the extreme telomeric bias of male crossovers, female recombination is much more important for generation of new haplotypes with 8 × higher intra-chromosomal genetic shuffling than males. CC was heritable in females (h 2  = 0.11) and males (h 2  = 0.10), and shuffling was also heritable in both sex but with a lower heritability in females (h 2  = 0.06) than in males (h 2  = 0.11). Inter-sex genetic correlations for both traits were close to zero, suggesting that rates and distribution of crossovers are genetically distinct traits in males and females, and that there is a potential for independent genetic change in both sexes in the Atlantic Salmon. Together, these findings give novel insights into the genetic architecture of recombination in salmonids and contribute to a better understanding of how rates and distribution of recombination may evolve in eukaryotes more broadly., (© 2023. The Author(s).)

Embryonic lethal mutations are arguably the earliest and most severe manifestation of inbreeding depression, but their impact on wild populations is not well understood. Here, we combined genomic, fitness, and life-history data from 5,925 wild Soay sheep sampled over nearly three decades to explore the impact of embryonic lethal mutations and their evolutionary dynamics. We searched for haplotypes that in their homozygous state are unusually rare in the offspring of known carrier parents and found three putatively semi-lethal haplotypes with 27%-46% fewer homozygous offspring than expected. Two of these haplotypes are decreasing in frequency, and gene-dropping simulations through the pedigree suggest that this is partially due to purifying selection. In contrast, the frequency of the third semi-lethal haplotype remains relatively stable over time. We show that the haplotype could be maintained by balancing selection because it is also associated with increased postnatal survival and body weight and because its cumulative frequency change is lower than in most drift-only simulations. Our study highlights embryonic mutations as a largely neglected contributor to inbreeding depression and provides a rare example of how harmful genetic variation can be maintained through balancing selection in a wild mammal population., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Society for the Study of Evolution (SSE) and European Society for Evolutionary Biology (ESEN).)

The genetic architecture of traits under selection has important consequences for the response to selection and potentially for population viability. Early QTL mapping studies in wild populations have reported loci with large effect on trait variation. However, these results are contradicted by more recent genome-wide association analyses, which strongly support the idea that most quantitative traits have a polygenic basis. This study aims to re-evaluate the genetic architecture of a key morphological trait, birth weight, in a wild population of red deer (Cervus elaphus), using genomic approaches. A previous study using 93 microsatellite and allozyme markers and linkage mapping on a kindred of 364 deer detected a pronounced QTL on chromosome 21 explaining 29% of the variance in birth weight, suggesting that this trait is partly controlled by genes with large effects. Here, we used data for more than 2,300 calves genotyped at >39,000 SNP markers and two approaches to characterise the genetic architecture of birth weight. First, we performed a genome-wide association (GWA) analysis, using a genomic relatedness matrix to account for population structure. We found no SNPs significantly associated with birth weight. Second, we used genomic prediction to estimate the proportion of variance explained by each SNP and chromosome. This analysis confirmed that most genetic variance in birth weight was explained by loci with very small effect sizes. Third, we found that the proportion of variance explained by each chromosome was slightly positively correlated with its size. These three findings highlight a highly polygenic architecture for birth weight, which contradicts the previous QTL study. These results are probably explained by the differences in how associations are modelled between QTL mapping and GWA. Our study suggests that models of polygenic adaptation are the most appropriate to study the evolutionary trajectory of this trait., Competing Interests: Conflicts of interest statement The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Genetics Society of America.)

The distribution of runs of homozygosity (ROH) may be shaped by a number of interacting processes such as selection, recombination and population history, but little is known about the importance of these mechanisms in shaping ROH in wild populations. We combined an empirical dataset of >3000 red deer genotyped at >35,000 genome-wide autosomal SNPs and evolutionary simulations to investigate the influence of each of these factors on ROH. We assessed ROH in a focal and comparison population to investigate the effect of population history. We investigated the role of recombination using both a physical map and a genetic linkage map to search for ROH. We found differences in ROH distribution between both populations and map types indicating that population history and local recombination rate have an effect on ROH. Finally, we ran forward genetic simulations with varying population histories, recombination rates and levels of selection, allowing us to further interpret our empirical data. These simulations showed that population history has a greater effect on ROH distribution than either recombination or selection. We further show that selection can cause genomic regions where ROH is common, only when the effective population size (N e ) is large or selection is particularly strong. In populations having undergone a population bottleneck , genetic drift can outweigh the effect of selection. Overall, we conclude that in this population, genetic drift resulting from a historical population bottleneck is most likely to have resulted in the observed ROH distribution, with selection possibly playing a minor role., (© 2023. The Author(s).)

The rates of mutation, recombination, and transposition are core parameters in models of evolution. They impact genetic diversity, responses to ongoing selection, and levels of genetic load. However, even for key evolutionary model species such as Drosophila melanogaster and Drosophila simulans , few estimates of these parameters are available, and we have little idea of how rates vary between individuals, sexes, or populations. Knowledge of this variation is fundamental for parameterizing models of genome evolution. Here, we provide direct estimates of mutation, recombination, and transposition rates and their variation in a West African and a European population of D. melanogaster and a European population of D. simulans Across 89 flies, we observe 58 single-nucleotide mutations, 286 crossovers, and 89 transposable element (TE) insertions. Compared to the European D. melanogaster , we find the West African population has a lower mutation rate (1.67 × 10 -9 site -1 gen -1 vs. 4.86 × 10 -9 site -1 gen -1 ) and a lower transposition rate (8.99 × 10 -5 copy -1 gen -1 vs. 23.36 × 10 -5 copy -1 gen -1 ), but a higher recombination rate (3.44 cM/Mb vs. 2.06 cM/Mb). The European D. simulans population has a similar mutation rate to European D. melanogaster , but a significantly higher recombination rate and a lower, but not significantly different, transposition rate. Overall, we find paternal-derived mutations are more frequent than maternal ones in both species. Our study quantifies the variation in rates of mutation, recombination, and transposition among different populations and sexes, and our direct estimates of these parameters in D. melanogaster and D. simulans will benefit future studies in population and evolutionary genetics., (© 2023 Wang et al.; Published by Cold Spring Harbor Laboratory Press.)

Meiotic recombination is an important evolutionary mechanism that breaks up linkages between loci and creates novel haplotypes for selection to act upon. Understanding the genetic control of variation in recombination rates is therefore of great interest in both natural and domestic breeding populations. In this study, we used pedigree information and medium-density (∼50K) genotyped data in a large cattle (Bos taurus) breeding population in Norway (Norwegian Red cattle) to investigate recombination rate variation between sexes and individual animals. Sex-specific linkage mapping showed higher rates in males than in females (total genetic length of autosomes = 2,492.9 cM in males and 2,308.9 cM in females). However, distribution of recombination along the genome showed little variation between males and females compared with that in other species. The heritability of autosomal crossover count was low but significant in both sexes (h 2 = 0.04 and 0.09 in males and females, respectively). We identified 2 loci associated with variation in individual crossover counts in female, one close to the candidate gene CEP55 and one close to both MLH3 and NEK9. All 3 genes have been associated with recombination rates in other cattle breeds. Our study contributes to the understanding of how recombination rates are controlled and how they may vary between closely related breeds as well as between species., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Wetlands have been used to treat anthropogenic effluents for decades due to their intense biogeochemical processes that transform and uptake nutrients, organic matter, and toxins. Despite these known functions, we lack generalizable knowledge of effluent-derived dissolved organic matter (DOM) cycling in wetlands. Here, we quantify the cycling of DOM in one of Canada's more economically important wetland complexes (Frank Lake, Alberta), restored to hydrologic permanence in the 1980s using urban and agro-industrial effluents. Optical analyses and PARAFAC (parallel factor analysis) modelling showed a clear compositional change from more bioavailable and protein-like DOM at effluent input sites to more aromatic and humic-like at the wetland outflow, likely due to DOM processing and inputs from marsh plants and wetland soils. Microbial incubations showed that effluent DOM was rapidly consumed, with the half-life of DOM increasing from as low as 35 days for effluent, to 462 days at the outflow, as a function of compositional shifts toward aromatic, humic-like material. Long-term averaged dissolved organic carbon (DOC) export was low compared to many wetlands (10.3 ± 2.0 g C m -2  yr -1 ). Consistent with predictions based on water residence time, our mass balance showed Frank Lake was a net source of DOM across all measured years, but shifted from a source to sink among wet and drought years that respectively shortened or lengthened the water residence and DOM processing times. Overall, Frank Lake processes and transforms effluent DOM, despite being a longer-term net source of DOM to downstream environments., Supplementary Information: The online version contains supplementary material available at 10.1007/s10533-022-01002-x., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s) 2022.)

Genomic prediction, the technique whereby an individual's genetic component of their phenotype is estimated from its genome, has revolutionised animal and plant breeding and medical genetics. However, despite being first introduced nearly two decades ago, it has hardly been adopted by the evolutionary genetics community studying wild organisms. Here, genomic prediction is performed on eight traits in a wild population of Soay sheep. The population has been the focus of a >30 year evolutionary ecology study and there is already considerable understanding of the genetic architecture of the focal Mendelian and quantitative traits. We show that the accuracy of genomic prediction is high for all traits, but especially those with loci of large effect segregating. Five different methods are compared, and the two methods that can accommodate zero-effect and large-effect loci in the same model tend to perform best. If the accuracy of genomic prediction is similar in other wild populations, then there is a real opportunity for pedigree-free molecular quantitative genetics research to be enabled in many more wild populations; currently the literature is dominated by studies that have required decades of field data collection to generate sufficiently deep pedigrees. Finally, some of the potential applications of genomic prediction in wild populations are discussed., (© 2021 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Vitamin D has a well-established role in skeletal health and is increasingly linked to chronic disease and mortality in humans and companion animals. Despite the clear significance of vitamin D for health and obvious implications for fitness under natural conditions, no longitudinal study has tested whether the circulating concentration of vitamin D is under natural selection in the wild. Here, we show that concentrations of dietary-derived vitamin D 2 and endogenously produced vitamin D 3  metabolites are heritable and largely polygenic in a wild population of Soay sheep (Ovis aries). Vitamin D 2  status was positively associated with female adult survival, and vitamin D 3  status predicted female fecundity in particular, good environment years when sheep density and competition for resources was low. Our study provides evidence that vitamin D status has the potential to respond to selection, and also provides new insights into how vitamin D metabolism is associated with fitness in the wild., (© 2022 The Author. Molecular Ecology published by John Wiley & Sons Ltd.)

In this paper, we consider randomized controlled clinical trials comparing two treatments in efficacy assessment using a time to event outcome. We assume a relatively small number of candidate biomarkers available in the beginning of the trial, which may help define an efficacy subgroup which shows differential treatment effect. The efficacy subgroup is to be defined by one or two biomarkers and cut-offs that are unknown to the investigator and must be learned from the data. We propose a two-stage adaptive design with a pre-planned interim analysis and a final analysis. At the interim, several subgroup-finding algorithms are evaluated to search for a subgroup with enhanced survival for treated versus placebo. Conditional powers computed based on the subgroup and the overall population are used to make decision at the interim to terminate the study for futility, continue the study as planned, or conduct sample size recalculation for the subgroup or the overall population. At the final analysis, combination tests together with closed testing procedures are used to determine efficacy in the subgroup or the overall population. We conducted simulation studies to compare our proposed procedures with several subgroup-identification methods in terms of a novel utility function and several other measures. This research demonstrated the benefit of incorporating data-driven subgroup selection into adaptive clinical trial designs., (© 2022 John Wiley & Sons Ltd.)

Background: Recombination is a fundamental part of mammalian meiosis that leads to the exchange of large segments of DNA between homologous chromosomes and is therefore an important driver of genetic diversity in populations. In breeding populations, understanding recombination is of particular interest because it can break up unfavourable linkage phases between alleles and produce novel combinations of alleles that could be exploited in selection. In this study, we used dense single nucleotide polymorphism (SNP) genotype data and pedigree information to analyse individual and sex-specific variation and genetic architecture of recombination rates within and between five commercially selected pig breeds., Results: In agreement with previous studies, recombination rates were higher in females than in males for all breeds and for all chromosomes, except 1 and 13, for which male rates were slightly higher. Total recombination rate differed between breeds but the pattern of recombination along the chromosomes was well conserved across breeds for the same sex. The autosomal linkage maps spanned a total length of 1731 to 1887 cM for males and of 2231 to 2515 cM for females. Estimates of heritability for individual autosomal crossover count ranged from 0.04 to 0.07 for males and from 0.08 to 0.11 for females. Fourteen genomic regions were found to be associated with individual autosomal crossover count. Of these, four were close to or within candidate genes that have previously been associated with individual recombination rates in pigs and other mammals, namely RNF212, SYCP2 and MSH4. Two of the identified regions included the PRDM7 and MEI1 genes, which are known to be involved in meiosis but have not been previously associated with variation in individual recombination rates., Conclusions: This study shows that genetic variation in autosomal recombination rate persists in domesticated species under strong selection, with differences between closely-related breeds and marked differences between the sexes. Our findings support results from other studies, i.e., that individual crossover counts are associated with the RNF212, SYCP2 and MSH4 genes in pig. In addition, we have found two novel candidate genes associated with the trait, namely PRDM7 and MEI1., (© 2022. The Author(s).)

Detecting microevolutionary responses to natural selection by observing temporal changes in individual breeding values is challenging. The collection of suitable datasets can take many years and disentangling the contributions of the environment and genetics to phenotypic change is not trivial. Furthermore, pedigree-based methods of obtaining individual breeding values have known biases. Here, we apply a genomic prediction approach to estimate breeding values of adult weight in a 35-year dataset of Soay sheep ( Ovis aries) . Comparisons are made with a traditional pedigree-based approach. During the study period, adult body weight decreased, but the underlying genetic component of body weight increased, at a rate that is unlikely to be attributable to genetic drift. Thus cryptic microevolution of greater adult body weight has probably occurred. Genomic and pedigree-based approaches gave largely consistent results. Thus, using genomic prediction to study microevolution in wild populations can remove the requirement for pedigree data, potentially opening up new study systems for similar research.

Sexually selected traits show large variation and rapid evolution across the animal kingdom, yet genetic variation often persists within populations despite apparent directional selection. A key step in solving this long-standing paradox is to determine the genetic architecture of sexually selected traits to understand evolutionary drivers and constraints at the genomic level. Antlers are a form of sexual weaponry in male red deer (Cervus elaphus). On the island of Rum, Scotland, males with larger antlers have increased breeding success, yet there has been no evidence of any response to selection at the genetic level. To try and understand the mechanisms underlying this observation, we investigate the genetic architecture of ten antler traits and their principal components using genomic data from >38,000 SNPs. We estimate the heritabilities and genetic correlations of the antler traits using a genomic relatedness approach. We then use genome-wide association and haplotype-based regional heritability to identify regions of the genome underlying antler morphology, and an empirical Bayes approach to estimate the underlying distributions of allele effect sizes. We show that antler morphology is highly repeatable over an individual's lifetime, heritable and has a polygenic architecture and that almost all antler traits are positively genetically correlated with some loci identified as having pleiotropic effects. Our findings suggest that a large mutational target and genetic covariances among antler traits, in part maintained by pleiotropy, are likely to contribute to the maintenance of genetic variation in antler morphology in this population., (© 2021 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Pathogen-mediated selection (PMS) is thought to maintain the high level of allelic diversity observed in the major histocompatibility complex (MHC) class II genes. A comprehensive way to demonstrate contemporary selection is to examine associations between MHC variation and individual fitness. As individual fitness is hard to measure, many studies examine associations between MHC variation and phenotypic traits, including direct or indirect measures of adaptive immunity thought to contribute to fitness. Here, we tested associations between MHC class II variation and five phenotypic traits measured in free-living sheep captured in August: weight, strongyle faecal egg count, and plasma IgA, IgE and IgG immunoglobulin titres against the gastrointestinal nematode parasite Teladorsagia circumcincta. We found no association between MHC class II variation and weight or strongyle faecal egg count. We did, however, find associations between MHC class II variation and immunoglobulin levels which varied with isotype, age and sex. Our results suggest associations between MHC and phenotypic traits are more likely to be found for traits more closely associated with pathogen defence than integrative traits such as bodyweight and highlight the association between MHC variation and antibodies in wild populations., (© 2021 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Investigating the current evolutionary processes acting on a highly polymorphic gene region, such as the major histocompatibility complex (MHC), requires extensive population data for both genotypes and phenotypes. The MHC consists of several tightly linked loci with both allelic and gene content variation, making it challenging to genotype. Eight class IIa haplotypes have previously been identified in the Soay sheep (Ovis aries) of St. Kilda using Sanger sequencing and cloning, but no single locus is representative of all haplotypes. Here, we exploit the closed nature of the island population of Soay sheep and its limited haplotypic variation to identify a panel of SNPs that enable imputation of MHC haplotypes. We compared MHC class IIa haplotypes determined by Sanger sequence-based genotyping of 135 individuals to their SNP profiles generated using the Ovine Infinium HD BeadChip. A panel of 11 SNPs could reliably determine MHC diplotypes, and two additional SNPs within the DQA1 gene enabled detection of a recombinant haplotype affecting only the SNPs downstream of the expressed genes. The panel of 13 SNPs was genotyped in 5951 Soay sheep, of which 5349 passed quality control. Using the Soay sheep pedigree, we were able to trace the origin and inheritance of the recombinant SNP haplotype. This SNP-based method has enabled the rapid generation of locus-specific MHC genotypes for large numbers of Soay sheep. This volume of high-quality genotypes in a well-characterized population of free-living sheep will be valuable for investigating the mechanisms maintaining diversity at the MHC., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

Introduction: The purpose of this study was to compare the metabolism of Streptococcus mutans biofilms after 1-7 days of growth on different orthodontic adhesives., Methods: Specimens of 6 commercial orthodontic adhesives were fabricated in custom-made molds and polymerized using a light-emitting diode light-curing unit. Bioluminescent S mutans (UA159:JM10) biofilms were grown on ultraviolet-sterilized specimens for 1, 3, 5, and 7 days (n = 18 biofilms/d/product) in anaerobic conditions at 37°C. The metabolism of biofilms (relative luminescence unit [RLU]) was measured 0, 2, 4, and 6 minutes after exposure to D-luciferin solution using a microplate reader. A linear mixed-effects model was used to analyze the logarithm of RLU (log RLU). The model included fixed effects of products, days, and minutes. Tukey-Kramer post-hoc tests were then performed on the significant predictors of log RLU (α = 0.05)., Results: Days (P <0.0001) and minutes (P <0.0001) were independent predictors of log RLU, but the products were not (P = 0.5869). After adjusting for minutes, the log RLU was analyzed with a post-hoc test, and all differences between days were significant with the exceptions of day 3 from day 5 (P = 0.0731) and day 5 from day 7 (P = 0.8802). After adjusting for day, log RLU was analyzed with a post-hoc test and all differences in minutes were significant., Conclusions: No significant differences in the metabolism of S mutans biofilms were observed among the 6 orthodontic adhesives. Biofilms that were grown for 3 days demonstrated the highest levels of biofilm metabolism as evidenced by higher mean log RLU values relative to 1, 5, and 7-day growth durations., (Copyright © 2021 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Inbreeding depression is ubiquitous, but we still know little about its genetic architecture and precise effects in wild populations. Here, we combine long-term life-history data with 417 K imputed SNP genotypes for 5952 wild Soay sheep to explore inbreeding depression on a key fitness component, annual survival. Inbreeding manifests in long runs of homozygosity (ROH), which make up nearly half of the genome in the most inbred individuals. The ROH landscape varies widely across the genome, with islands where up to 87% and deserts where only 4% of individuals have ROH. The fitness consequences of inbreeding are severe; a 10% increase in individual inbreeding F ROH is associated with a 60% reduction in the odds of survival in lambs, though inbreeding depression decreases with age. Finally, a genome-wide association scan on ROH shows that many loci with small effects and five loci with larger effects contribute to inbreeding depression in survival.

Runs of homozygosity (ROH) are pervasive in diploid genomes and expose the effects of deleterious recessive mutations, but how exactly these regions contribute to variation in fitness remains unclear. Here, we combined empirical analyses and simulations to explore the deleterious effects of ROH with varying genetic map lengths in wild Soay sheep. Using a long-term dataset of 4879 individuals genotyped at 417K SNPs, we found that inbreeding depression increases with ROH length. A 1% genomic increase in long ROH (>12.5 cM) reduced the odds of first-year survival by 12.4% compared to only 7.7% for medium ROH (1.56-12.5 cM), whereas short ROH (<1.56 cM) had no effect on survival. We show by forward genetic simulations that this is predicted: compared to shorter ROH, long ROH will have higher densities of deleterious alleles, with larger average effects on fitness and lower population frequencies. Taken together, our results are consistent with the idea that the mutation load decreases in older haplotypes underlying shorter ROH, where purifying selection has had more time to purge deleterious mutations. Finally, our study demonstrates that strong inbreeding depression can persist despite ongoing purging in a historically small population., (© 2021 The Authors. Evolution Letters published by Wiley Periodicals LLC on behalf of Society for the Study of Evolution (SSE) and European Society for Evolutionary Biology (ESEB).)

Background: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and succumb to the disease. Therefore, efforts to identify new therapeutic targets are underway. Due to its role in stabilizing several oncoproteins' mRNA, the human antigen R (HuR) has been shown as a promising molecular target for cancer therapy. However, little is known about its potential role in melanoma treatment., Methods: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro. Cells were treated with HuR siRNA encapsulated in a lipid nanoparticle (NP) either alone or in combination with MEK inhibitor (U0126) and subjected to cell viability, cell-cycle, apoptosis, Western blotting, and cell migration and invasion assays. Cells that were untreated or treated with control siRNA-NP (C-NP) were included as controls., Results: HuR-NP treatment significantly reduced the expression of HuR and HuR-regulated oncoproteins, induced G1 cell cycle arrest, activated apoptosis signaling cascade, and mitigated melanoma cells' aggressiveness while sparing normal melanocytes. Furthermore, we demonstrated that HuR-NP treatment significantly reduced the expression of the microphthalmia-associated transcription factor (MITF) in both MeWo and MITF-overexpressing MeWo cells ( p < 0.05). Finally, combining HuR-NP with U0126 resulted in synergistic antitumor activity against MeWo cells ( p < 0.01)., Conclusion: HuR-NP exhibited antitumor activity in melanoma cells independent of their oncogenic B-RAF mutational status. Additionally, combinatorial therapy incorporating MEK inhibitor holds promise in overriding MITF-mediated drug resistance in melanoma.

The transfer of antibodies from mother to offspring provides crucial protection against infection to offspring during early life in humans and domestic and laboratory animals. However, few studies have tested the consequences of variation in maternal antibody transfer for offspring fitness in the wild. Further, separating the immunoprotective effects of antibodies from their association with nutritional resources provided by mothers is difficult. Here, we measured plasma levels of total and parasite-specific antibodies in neonatal (less than 10 days old) wild Soay sheep over 25 years to quantify variation in maternal antibody transfer and test its association with offspring survival. Maternal antibody transfer was predicted by maternal age and previous antibody responses, and was consistent within mothers across years. Neonatal total IgG antibody levels were positively related to early growth, suggesting they reflected nutritional transfer. Neonatal parasite-specific IgG levels positively predicted first-year survival, independent of lamb weight, total IgG levels and subsequent lamb parasite-specific antibody levels. This relationship was partly mediated via an indirect negative association with parasite burden. We show that among-female variation in maternal antibody transfer can have long-term effects on offspring growth, parasite burden and fitness in the wild, and is likely to impact naturally occurring host-parasite dynamics.

Sporadic inclusion body myositis (IBM) is a chronic inflammatory and degenerative muscle disease with limited treatment options; no therapy can alter its natural course. Ketogenic diets are theoretically capable of suppressing inflammation, enhancing cell bioenergetics, alleviating mitochondria dysfunction, and stimulating autophagy, which may be beneficial in IBM. We report the case of a 52-year-old woman with worsening IBM who pursued a modified ketogenic diet for 1 year. Adverse effects were mild and resolved 3 weeks into the diet. Prior to starting her ketogenic diet, despite the use of a walking stick at all times, she was experiencing one to two falls per week as well as swallowing difficulties, musculoskeletal pain, and depression. Moreover, magnetic resonance imaging (MRI) of the bilateral thighs during the year prior to the diet indicated worsening muscle inflammation and a 14% decrease in thigh muscle volume, which corresponded to a 4% decrease in the ratio of thigh muscle to thigh total volume. After 1 year on her ketogenic diet, our patient regained independent walking, and her swallowing difficulties, pain, and depression resolved. She maintained her strength, improved in every test of function, enhanced her quality of life, and lowered her blood creatine kinase. MRI of the bilateral thighs during the year of the diet indicated stabilized muscle inflammation and a 2.9% decrease in thigh muscle volume, which in the context of diet-induced fat loss corresponded to a sustained 1% increase in the ratio of thigh muscle to thigh total volume. This case is unique in that a ketogenic diet was utilized as the primary treatment strategy for a patient with confirmed IBM, culminating in substantial clinical improvement, stabilized muscle inflammation, and a slowed rate of muscle atrophy. Our patient has remained on her ketogenic diet for over 2 years now and continues to enjoy a full and independent life., (Copyright © 2020 Phillips, Murtagh, Ziad, Johnston and Moon.)

The release of captive-bred animals into the wild is commonly practised to restore or supplement wild populations but comes with a suite of ecological and genetic consequences. Vast numbers of hatchery-reared fish are released annually, ostensibly to restore/enhance wild populations or provide greater angling returns. While previous studies have shown that captive-bred fish perform poorly in the wild relative to wild-bred conspecifics, few have measured individual lifetime reproductive success (LRS) and how this affects population productivity. Here, we analyse data on Atlantic salmon from an intensely studied catchment into which varying numbers of captive-bred fish have escaped/been released and potentially bred over several decades. Using a molecular pedigree, we demonstrate that, on average, the LRS of captive-bred individuals was only 36% that of wild-bred individuals. A significant LRS difference remained after excluding individuals that left no surviving offspring, some of which might have simply failed to spawn, consistent with transgenerational effects on offspring survival. The annual productivity of the mixed population (wild-bred plus captive-bred) was lower in years where captive-bred fish comprised a greater fraction of potential spawners. These results bolster previous empirical and theoretical findings that intentional stocking, or non-intentional escapees, threaten, rather than enhance, recipient natural populations.

Objective: In the healthy spine, the spinal cord moves unimpeded with spinal fluid pulsation in the rostral and caudal directions. When a portion of the spinal cord becomes attached to lesions within the spinal column, excess strain can cause signs and symptoms such as pain, motor deficits, sensory deficits, bladder dysfunction, and bowel dysfunction. This condition is termed tethered cord syndrome. There are no clear guidelines for offering surgical intervention, although there is a general consensus that worsening signs and symptoms increase the likelihood that patients will need surgery., Methods: In this article, we conduct a systematic review and meta-analysis for all available literature within the Ovid (MEDLINE), PubMed, and Google Scholar databases to evaluate common symptoms among patients with tethered cord and to examine how surgery affects symptoms., Results: Within the cohort of 730 patients, 708 (97%) were treated surgically by a detethering procedure. The most common preoperative sign or symptom was pain (81%), followed by motor deficits (63%), sensory deficits (61%), bladder dysfunction (56%), and bowel dysfunction (15%). One percent of patients had no deficit or symptom. Pain was the symptom that was most responsive to surgery, with 81% of patients reporting that their pain improved after detethering., Conclusions: Tethered cord syndrome should be included in the differential diagnosis in patients presenting with back or leg pain, somatosensory symptoms of the lower extremities, muscular weakness, urodynamic dysfunction, or bowel dysfunction. After a definitive diagnosis is made, patients should be counseled about surgical detethering as an option., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Much of our knowledge of the drivers of immune variation, and how these responses vary over time, comes from humans, domesticated livestock or laboratory organisms. While the genetic basis of variation in immune responses have been investigated in these systems, there is a poor understanding of how genetic variation influences immunity in natural, untreated populations living in complex environments. Here, we examine the genetic architecture of variation in immune traits in the Soay sheep of St Kilda, an unmanaged population of sheep infected with strongyle gastrointestinal nematodes. We assayed IgA, IgE and IgG antibodies against the prevalent nematode Teladorsagia circumcincta in the blood plasma of > 3,000 sheep collected over 26 years. Antibody levels were significantly heritable (h2 = 0.21 to 0.57) and highly stable over an individual's lifespan. IgA levels were strongly associated with a region on chromosome 24 explaining 21.1% and 24.5% of heritable variation in lambs and adults, respectively. This region was adjacent to two candidate loci, Class II Major Histocompatibility Complex Transactivator (CIITA) and C-Type Lectin Domain Containing 16A (CLEC16A). Lamb IgA levels were also associated with the immunoglobulin heavy constant loci (IGH) complex, and adult IgE levels and lamb IgA and IgG levels were associated with the major histocompatibility complex (MHC). This study provides evidence of high heritability of a complex immunological trait under natural conditions and provides the first evidence from a genome-wide study that large effect genes located outside the MHC region exist for immune traits in the wild., Competing Interests: The authors have declared that no competing interests exist.

The N-terminal regions (tails) of histone proteins are dynamic elements that protrude from the nucleosome and are involved in many aspects of chromatin organization. Their epigenetic role is well-established, and post-translational modifications present on these regions contribute to transcriptional regulation. Considering their biological significance, relatively few structural details have been established for histone tails, mainly because of their inherently disordered nature. Although hydrogen/deuterium exchange mass spectrometry (HX-MS) is well-suited for the analysis of dynamic structures, it has seldom been employed in this context, presumably because of the poor N-terminal coverage provided by pepsin. Inspired from histone-clipping events, we profiled the activity of cathepsin-L under HX-MS quench conditions and characterized its specificity employing the four core histones (H2A, H2B, H3 and H4). Cathepsin-L demonstrated cleavage patterns that were substrate- and pH-dependent. Cathepsin-L generated overlapping N-terminal peptides about 20 amino acids long for H2A, H3, and H4 proving its suitability for the analysis of histone tails dynamics. We developed a comprehensive HX-MS method in combination with pepsin and obtained full sequence coverage for all histones. We employed our method to analyze histones H3 and H4. We observe rapid deuterium exchange of the N-terminal tails and cooperative unfolding (EX1 kinetics) in the histone-fold domains of histone monomers in-solution. Overall, this novel strategy opens new avenues for investigating the dynamic properties of histones that are not apparent from the crystal structures, providing insights into the structural basis of the histone code., (© 2019 Papanastasiou et al.)

Comparing observed versus theoretically expected evolutionary responses is important for our understanding of the evolutionary process, and for assessing how species may cope with anthropogenic change. Here, we document directional selection for larger female size in Atlantic salmon, using pedigree-derived estimates of lifetime reproductive success as a fitness measure. We show the trait is heritable and, thus, capable of responding to selection. The Breeder's Equation, which predicts microevolution as the product of phenotypic selection and heritability, predicted evolution of larger size. This was at odds, however, with the observed lack of either phenotypic or genetic temporal trends in body size, a so-called "paradox of stasis." To investigate this paradox, we estimated the additive genetic covariance between trait and fitness, which provides a prediction of evolutionary change according to Robertson's secondary theorem of selection (STS) that is unbiased by missing variables. The STS prediction was consistent with the observed stasis. Decomposition of phenotypic selection gradients into genetic and environmental components revealed a potential upward bias, implying unmeasured factors that covary with trait and fitness. These results showcase the power of pedigreed, wild population studies-which have largely been limited to birds and mammals-to study evolutionary processes on contemporary timescales., Competing Interests: The authors declare they have no conflicting interests with the work herein.

Tryptophan biosynthesis is one of the most characterized processes in bacteria, in which the enzymes from Salmonella typhimurium and Escherichia coli serve as model systems. Tryptophan synthase (TrpAB) catalyzes the final two steps of tryptophan biosynthesis in plants, fungi and bacteria. This pyridoxal 5'-phosphate (PLP)-dependent enzyme consists of two protein chains, α (TrpA) and β (TrpB), functioning as a linear αββα heterotetrameric complex containing two TrpAB units. The reaction has a complicated, multistep mechanism resulting in the β-replacement of the hydroxyl group of l-serine with an indole moiety. Recent studies have shown that functional TrpAB is required for the survival of pathogenic bacteria in macrophages and for evading host defense. Therefore, TrpAB is a promising target for drug discovery, as its orthologs include enzymes from the important human pathogens Streptococcus pneumoniae , Legionella pneumophila and Francisella tularensis , the causative agents of pneumonia, legionnaires' disease and tularemia, respectively. However, specific biochemical and structural properties of the TrpABs from these organisms have not been investigated. To fill the important phylogenetic gaps in the understanding of TrpABs and to uncover unique features of TrpAB orthologs to spearhead future drug-discovery efforts, the TrpABs from L. pneumophila , F. tularensis and S. pneumoniae have been characterized. In addition to kinetic properties and inhibitor-sensitivity data, structural information gathered using X-ray crystallo-graphy is presented. The enzymes show remarkable structural conservation, but at the same time display local differences in both their catalytic and allosteric sites that may be responsible for the observed differences in catalysis and inhibitor binding. This functional dissimilarity may be exploited in the design of species-specific enzyme inhibitors.

A long-held, but poorly tested, assumption in natural populations is that individuals that disperse into new areas for reproduction are at a disadvantage compared to individuals that reproduce in their natal habitat, underpinning the eco-evolutionary processes of local adaptation and ecological speciation. Here, we capitalize on fine-scale population structure and natural dispersal events to compare the reproductive success of local and dispersing individuals captured on the same spawning ground in four consecutive parent-offspring cohorts of wild Atlantic salmon ( Salmo salar ). Parentage analysis conducted on adults and juvenile fish showed that local females and males had 9.6 and 2.9 times higher reproductive success than dispersers, respectively. Our results reveal how higher reproductive success in local spawners compared to dispersers may act in natural populations to drive population divergence and promote local adaptation over microgeographic spatial scales without clear morphological differences between populations.

An effective immune response is expected to confer fitness benefits through improved resistance to parasites but also incur energetic costs that negatively impact fitness-related traits, such as reproduction. The fitness costs and benefits of an immune response are likely to depend on host age, sex, and levels of parasite exposure. Few studies have examined the full extent to which patterns of natural selection on immune phenotypes vary across demographic groups and environments in the wild. Here, we assessed natural selection on plasma levels of three functionally distinct isotypes (IgA, IgE, and IgG) of antibodies against a prevalent nematode parasite measured in a wild Soay sheep population over 26 years. We found little support for environment-dependent selection or reproductive costs. However, antibody levels were negatively associated with parasite egg counts and positively associated with subsequent survival, albeit in a highly age- and isotype-dependent manner. Raised levels of antiparasite IgA best predicted reduced egg counts, but this did not predict survival in lambs. In adults increased antiparasite IgG predicted reduced egg counts, and in adult females IgG levels also positively predicted overwinter survival. Our results highlight the potential importance of age- and sex-dependent selection on immune phenotypes in nature and show that patterns of selection can vary even among functionally related immune markers.

Increased expression of the Tribbles pseudokinase 1 gene ( TRIB1 ) is associated with lower plasma levels of LDL cholesterol and triglycerides, higher levels of HDL cholesterol and decreased risk of coronary artery disease and myocardial infarction. We identified a class of tricyclic glycal core-based compounds that upregulate TRIB1 expression in human HepG2 cells and phenocopy the effects of genetic TRIB1 overexpression as they inhibit expression of triglyceride synthesis genes and ApoB secretion in cells. In addition to predicted effects related to downregulation of VLDL assembly and secretion these compounds also have unexpected effects as they upregulate expression of LDLR and stimulate LDL uptake. This activity profile is unique and favorably differs from profiles produced by statins or other lipoprotein targeting therapies. BRD8518, the initial lead compound from the tricyclic glycal class, exhibited stereochemically dependent activity and the potency far exceeding previously described benzofuran BRD0418. Gene expression profiling of cells treated with BRD8518 demonstrated the anticipated changes in lipid metabolic genes and revealed a broad stimulation of early response genes. Consistently, we found that BRD8518 activity is MEK1/2 dependent and the treatment of HepG2 cells with BRD8518 stimulates ERK1/2 phosphorylation. In agreement with down-regulation of genes controlling triglyceride synthesis and assembly of lipoprotein particles, the mass spectrometry analysis of cell extracts showed reduced rate of incorporation of stable isotope labeled glycerol into triglycerides in BRD8518 treated cells. Furthermore, we describe medicinal chemistry efforts that led to identification of BRD8518 analogs with enhanced potency and pharmacokinetic properties suitable for in vivo studies.

Objective: Inflammatory and immunologic cytokines and vagal activity have important roles in health and mental health, and may influence each other. The authors assessed relationships of representative biomarkers linked to disaster exposure-heart rate variability (HRV) with Interleukin-2 (IL-2, cell-medicated immunity) and Interleukin-6 (IL-6, pro-inflammatory and pro-immunologic), stratified by psychiatric diagnosis., Design: Participants were assessed for psychiatric diagnosis, IL-2, IL-6, HRV, and HR reactivity to trauma reminders., Setting: Outpatient university psychiatry clinics in Oklahoma City and Tulsa., Participants: Relocated Katrina survivors and demographically matched controls, not on psychiatric, cardiovascular, or inflammatory medications., Main Outcome Measures: SCID-IV, baseline serum IL-2 and IL-6, HRV through power spectral analysis., Results: Survivors had higher sympathetic and lower parasympathetic activity at baseline and lower parasympathetic HR reactivity than controls, with flattened parasympathetic reactivity in the presence of depression and of post-traumatic stress disorder (PTSD). Survivors' IL-2 and IL-6 did not differ from controls and did not differ in PTSD or depression. Depressed survivors' sympathetic reactivity correlated negatively with IL-2 and parasympathetic reactivity correlated positively with IL-2., Conclusions: HRV differed after hurricane exposure and with survivors& depression and/or PTSD, more sensitively capturing somatic sequelae than assessed cytokines. Higher sympathetic HR reactivity associated with lower immuno-logic IL-2 may indicate a double biological "hit" in depressed disaster survivors, possibly rendering them more vulnerable to cardiovascular and immunologic illness as well as depression. Associations of HRV with IL-2 may support reciprocal influences of cytokines and vagal activity. Lack of significant correlations of IL-6 with HRV measures is consistent with its pleiotropic role.

Recombination is a fundamental feature of sexual reproduction, ensuring proper disjunction, preventing mutation accumulation and generating new allelic combinations upon which selection can act. However it is also mutagenic, and breaks up favorable allelic combinations previously built up by selection. Identifying the genetic drivers of recombination rate variation is a key step in understanding the causes and consequences of this variation, how loci associated with recombination are evolving and how they affect the potential of a population to respond to selection. However, to date, few studies have examined the genetic architecture of recombination rate variation in natural populations. Here, we use pedigree data from ∼ 2,600 individuals genotyped at ∼ 38,000 SNPs to investigate the genetic architecture of individual autosomal recombination rate in a wild population of red deer ( Cervus elaphus ). Female red deer exhibited a higher mean and phenotypic variance in autosomal crossover counts (ACC). Animal models fitting genomic relatedness matrices showed that ACC was heritable in females ([Formula: see text] = 0.12) but not in males. A regional heritability mapping approach showed that almost all heritable variation in female ACC was explained by a genomic region on deer linkage group 12 containing the candidate loci REC8 and RNF212B , with an additional region on linkage group 32 containing TOP2B approaching genome-wide significance. The REC8/RNF212B region and its paralogue RNF212 have been associated with recombination in cattle, mice, humans and sheep. Our findings suggest that mammalian recombination rates have a relatively conserved genetic architecture in both domesticated and wild systems, and provide a foundation for understanding the association between recombination loci and individual fitness within this population., (Copyright © 2018 Johnston et al.)

Recombination, the exchange of DNA between maternal and paternal chromosomes during meiosis, is an essential feature of sexual reproduction in nearly all multicellular organisms. While the role of recombination in the evolution of sex has received theoretical and empirical attention, less is known about how recombination rate itself evolves and what influence this has on evolutionary processes within sexually reproducing organisms. Here, we explore the patterns of, and processes governing recombination in eukaryotes. We summarize patterns of variation, integrating current knowledge with an analysis of linkage map data in 353 organisms. We then discuss proximate and ultimate processes governing recombination rate variation and consider how these influence evolutionary processes. Genome-wide recombination rates (cM/Mb) can vary more than tenfold across eukaryotes, and there is large variation in the distribution of recombination events across closely related taxa, populations and individuals. We discuss how variation in rate and distribution relates to genome architecture, genetic and epigenetic mechanisms, sex, environmental perturbations and variable selective pressures. There has been great progress in determining the molecular mechanisms governing recombination, and with the continued development of new modelling and empirical approaches, there is now also great opportunity to further our understanding of how and why recombination rate varies.This article is part of the themed issue 'Evolutionary causes and consequences of recombination rate variation in sexual organisms'., (© 2017 The Authors.)

Recombination, the process by which DNA strands are broken and repaired, producing new combinations of alleles, occurs in nearly all multicellular organisms and has important implications for many evolutionary processes. The effects of recombination can be good , as it can facilitate adaptation, but also bad when it breaks apart beneficial combinations of alleles, and recombination is highly variable between taxa, species, individuals and across the genome. Understanding how and why recombination rate varies is a major challenge in biology. Most theoretical and empirical work has been devoted to understanding the role of recombination in the evolution of sex-comparing between sexual and asexual species or populations. How recombination rate evolves and what impact this has on evolutionary processes within sexually reproducing organisms has received much less attention. This Theme Issue focusses on how and why recombination rate varies in sexual species, and aims to coalesce knowledge of the molecular mechanisms governing recombination with our understanding of the evolutionary processes driving variation in recombination within and between species. By integrating these fields, we can identify important knowledge gaps and areas for future research, and pave the way for a more comprehensive understanding of how and why recombination rate varies., (© 2017 The Authors.)

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD L ), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD L expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

New antibiotics with novel targets are greatly needed. Bacteria have numerous essential functions, but only a small fraction of such processes-primarily those involved in macromolecular synthesis-are inhibited by current drugs. Targeting metabolic enzymes has been the focus of recent interest, but effective inhibitors have been difficult to identify. We describe a synthetic azetidine derivative, BRD4592, that kills Mycobacterium tuberculosis (Mtb) through allosteric inhibition of tryptophan synthase (TrpAB), a previously untargeted, highly allosterically regulated enzyme. BRD4592 binds at the TrpAB α-β-subunit interface and affects multiple steps in the enzyme's overall reaction, resulting in inhibition not easily overcome by changes in metabolic environment. We show that TrpAB is required for the survival of Mtb and Mycobacterium marinum in vivo and that this requirement may be independent of an adaptive immune response. This work highlights the effectiveness of allosteric inhibition for targeting proteins that are naturally highly dynamic and that are essential in vivo, despite their apparent dispensability under in vitro conditions, and suggests a framework for the discovery of a next generation of allosteric inhibitors.

High-density linkage maps are an important tool to gain insight into the genetic architecture of traits of evolutionary and economic interest, and provide a resource to characterize variation in recombination landscapes. Here, we used information from the cattle genome and the 50 K Cervine Illumina BeadChip to inform and refine a high-density linkage map in a wild population of red deer ( Cervus elaphus ). We constructed a predicted linkage map of 38,038 SNPs and a skeleton map of 10,835 SNPs across 34 linkage groups. We identified several chromosomal rearrangements in the deer lineage relative to sheep and cattle, including six chromosome fissions, one fusion, and two large inversions. Otherwise, our findings showed strong concordance with map orders in the cattle genome. The sex-averaged linkage map length was 2739.7 cM and the genome-wide autosomal recombination rate was 1.04 cM/Mb. The female autosomal map length was 1.21 longer than that of males (2767.4 cM vs. 2280.8 cM, respectively). Sex differences in map length were driven by high female recombination rates in peri-centromeric regions, a pattern that is unusual relative to other mammal species. This effect was more pronounced in fission chromosomes that would have had to produce new centromeres. We propose two hypotheses to explain this effect: (1) that this mechanism may have evolved to counteract centromeric drive associated with meiotic asymmetry in oocyte production; and/or (2) that sequence and structural characteristics suppressing recombination in close proximity to the centromere may not have evolved at neo-centromeres. Our study provides insight into how recombination landscapes vary and evolve in mammals, and will provide a valuable resource for studies of evolution, genetic improvement, and population management in red deer and related species., (Copyright © 2017 Johnston et al.)