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Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Non-invasive prenatal testing (NIPT) employs ultra-low-pass sequencing of maternal plasma cell-free DNA to detect fetal trisomy. Its global adoption has established NIPT as a large human genetic resource for exploring genetic variations and their associations with phenotypes. Here, we present methods for analyzing large-scale, low-depth NIPT data, including customized algorithms and software for genetic variant detection, genotype imputation, family relatedness, population structure inference, and genome-wide association analysis of maternal genomes. Our results demonstrate accurate allele frequency estimation and high genotype imputation accuracy (R 2 >0.84) for NIPT sequencing depths from 0.1× to 0.3×. We also achieve effective classification of duplicates and first-degree relatives, along with robust principal-component analysis. Additionally, we obtain an R 2 >0.81 for estimating genetic effect sizes across genotyping and sequencing platforms with adequate sample sizes. These methods offer a robust theoretical and practical foundation for utilizing NIPT data in medical genetic research., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Methods: Five electronic databases (PubMed (Medline), Web of Science, Embase, Sport Discus, and Cochrane Library) were searched for controlled trials that assessed the MPS response to RE in healthy, adult humans, postabsorptive state. Individual study and random-effects meta-analysis arewere used to inform the effects of RE and covariates on MPS. Results from 79 controlled trials with 237 participants were analysed., Results: Analysis of the pooled effects revealed robust increases in MPS following RE (weighted mean difference (WMD): 0.032% h -1 , 95% CI: [0.024, 0.041] % h -1 , I 2  = 92%, k  = 37, P < 0.001). However, the magnitude of the increase in MPS was lower in older adults (>50 y: WMD: 0.015% h -1 , 95% CI: [0.007, 0.022] % h -1 , I 2  = 76%, k  = 12, P = 0.002) compared to younger adults (<35 y: WMD: 0.041% h -1 , 95% CI: [0.030, 0.052] % h -1 , I 2  = 88%, k  = 25, P < 0.001). Individual studies have reported that the temporal proximity of the RE, muscle group, muscle protein fraction, RE training experience, and the loading parameters of the RE (i.e., intensity, workload, and effort) appeared to affect the MPS response to RE, whereas sex or type of muscle contraction does not., Conclusion: A single bout of RE can sustain measurable increases in postabsorptive MPS soon after RE cessation and up to 48 h post-RE. However, there is substantial heterogeneity in the magnitude and time course of the MPS response between trials, which appears to be influenced by participants' age and/or the loading parameters of the RE itself., Competing Interests: The authors declare that they have no conflicts of interest related to the work submitted for publication., (Copyright © 2024 Robert W. Davies et al.)

Background: Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5'UTRs, correlates with gene dosage sensitivity., Results: We investigate 5'UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5'UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5'UTR length and complexity. Genes that are most intolerant to LoF have longer 5'UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated., Conclusions: Our results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them., (© 2024. The Author(s).)

An analysis of over 1 million old-growth tropical forest trees reveals that ∼2.2% of species comprise 50% of the individuals in Africa, Amazonia, and Southeast Asia, suggesting that the ecological mechanisms underpinning tree community assembly are ubiquitous across the tropics., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An increase in the intake of legumes is recommended in the promotion of plant-sourced (PSP) rather than animal-sourced (ASP) protein intake to produce a more sustainable diet. This study evaluated the quality of novel PSP isolates from pea (PEA) and fava bean (FAVA) and an ASP isolate of whey (WHEY) and compared the magnitude and temporal pattern of peripheral arterial aminoacidemia following ingestion of 0.33 g·kg -1 body mass of protein isolate in healthy young adult men (n = 9). Total indispensable amino acids (IAA) comprised 58% (WHEY), 46% (PEA), and 42% (FAVA) of the total amino acid (AA) composition, with the ingested protein providing 108% (WHEY), 77% (PEA), and 67% (FAVA) of the recommended per diem requirement of IAA. Reflecting the AA composition, the area under the curve (∆AUC 0-180 ), post-ingestion increase in total IAA for WHEY was 41% ( p < 0.001) and 57% ( p < 0.001) greater than PEA and FAVA, respectively, with PEA exceeding FAVA by 28% ( p = 0.003). As a sole-source, single-dose meal-size serving, the lower total IAA for PEA and FAVA would likely evoke a reduced post-prandial anabolic capacity compared to WHEY. Incorporated into a food matrix, the promotion of PSP isolates contributes to a more sustainable diet.

Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling., (© 2023. The Author(s).)

Purpose: To compare the effects of bilateral strength training (BLST) versus unilateral strength training (ULST) on changes in peak force (PF) and interlimb asymmetry (ILA) in the isometric squat at a 120° knee angle (ISq120)., Method: A total of 31 young, recreationally strength-trained men performed either BLST (n = 18) or ULST (n = 13), twice per week for 6 weeks. The total number of repetitions, duty cycle, and effort were standardized between training groups (ie, differing only in the exercises performed). Changes in PF and ILA were assessed pretraining and posttraining., Results: Comparable increases in PF were observed in the BLST group (mean [SD] change; 17.4% [20.5%], P = .001, standardized mean difference [SMD] = 0.45) and the ULST group (11.4% [19.1%], P = .042, SMD = 0.25). No significant changes in symmetry index (SI) scores were observed following BLST (mean [SD] change; 0 [5.7], P = .526, SMD = -0.12) or ULST (+3 [6.0], P = .702, SMD = 0.4). Individual analyses of subjects with marked ILA (ie, baseline SI score > baseline coefficient of variation) revealed a trend toward BLST being more effective at attenuating SI scores in the ISq120., Conclusions: Overall, both BLST and ULST are effective for increasing ISq120 PF. However, it appears that BLST may be more effective at reducing SI scores in those with marked ILA.

Background: Guidelines for the management of polycystic ovary syndrome (PCOS) focus on lifestyle changes, incorporating exercise. Whilst evidence suggests that aerobic exercise may be beneficial, less is known about the effectiveness of resistance training (RT), which may be more feasible for those that have low fitness levels and/or are unable to tolerate/participate in aerobic exercise., Objectives: To identify the available evidence on RT in women with PCOS and to summarise findings in the context of a scoping review., Eligibility Criteria: Studies utilising pre-post designs to assess the effectiveness of RT in PCOS; all outcomes were included., Sources of Evidence: Four databases (PubMed, CENTRAL, CINAHL and SportDiscus) were searched and supplemented by hand searching of relevant papers/reference lists., Charting Methods: Extracted data were presented in tables and qualitatively synthesised., Results: Searches returned 42 papers; of those, 12 papers were included, relating to six studies/trials. Statistical changes were reported for multiple pertinent outcomes relating to metabolic (i.e., glycaemia and fat-free mass) and hormonal (i.e., testosterone and sex hormone-binding globulin) profiles., Conclusions: There is a striking lack of studies in this field and, despite the reported statistical significance for many outcomes, the documented magnitude of changes are small and the quality of the evidence questionable. This highlights an unmet need for rigorously designed/reported and sufficiently powered trials.

The aim of the present study was to evaluate the effect of feeding fava bean ( Vicia faba L.) protein (FBP) on resting and post-exercise myofibrillar fractional synthetic rate (myoFSR). In a parallel, double-blind, randomised control trial, sixteen young, healthy recreationally active adults (age = 25 (5) years, body mass = 70 (15) kg, stature = 1.72 (0.11) m, mean (SD)) ingested 0.33 g·kg -1 FBP ( n = 8) or a negative control (CON, i.e., EAA-free mixture) ( n = 8), immediately after a bout of unilateral knee-extensor resistance exercise. Plasma, saliva, and m. vastus lateralis muscle samples were obtained pre-ingestion and 3 h post-ingestion. MyoFSR was calculated via deuterium labelling of myofibrillar-bound alanine, measured by gas chromatography-pyrolysis-isotope ratio mass spectrometry (GC-Pyr-IRMS). Resistance exercise increased myoFSR ( p = 0.012). However, ingestion of FBP did not evoke an increase in resting (FBP 29 [-5, 63] vs. CON 12 [-25, 49]%, p = 0.409, mean % change [95% CI]) or post-exercise (FBP 78 [33, 123]% vs. CON 58 [9, 107]%, p = 0.732) myoFSR. Ingestion of 0.33 g·kg -1 of FBP does not appear to enhance resting or post-exercise myoFSR in young, healthy, recreationally active adults.

Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6, and GM11545 with bone mineral density, and Psmb9 with weight. However, replication at a nominal threshold of 0.05 between the two component studies was low, with less than one-third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner's Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Leveraging these observations, we integrated information about replication rates, study-specific heterogeneity, and Winner's Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study., (© The Author(s) 2021. Published by Oxford University Press on behalf of Genetics Society of America.)

This study aimed to investigate the test-retest reliability of peak force in the isometric squat across the strength spectrum using coefficient of variation (CV) and intra-class correlation coefficient (ICC). On two separate days, 59 healthy men (mean (SD) age 23.0 (4.1) years; height 1.79 (0.7) m; body mass 84.0 (15.2) kg) performed three maximal effort isometric squats in two positions (at a 120° and a 90° knee angle). Acceptable reliability was observed at both the 120° (CV = 7.5 (6.7), ICC = 0.960 [0.933, 0.977]) and 90° positions (CV = 9.2 (8.8), ICC = 0.920 [0.865, 0.953]). There was no relationship between peak force in the isometric squat and the test-retest reliability at either the 120° (r = 0.052, p = 0.327) or 90° (r = 0.014, p = 0.613) positions. A subgroup of subjects (n = 17) also completed the isometric squat test at a 65° knee angle. Acceptable reliability was observed in this position (CV = 9.6 (9.3), ICC = 0.916 [0.766, 0.970]) and reliability was comparable to the 120° and 90° positions. Therefore, we deem isometric squat peak force output to be a valid and reliable measure across the strength spectrum and in different isometric squat positions.

Ancient genomes anchor genealogies in directly observed historical genetic variation and contextualize ancestral lineages with archaeological insights into their geography and cultural associations. However, the majority of ancient genomes are of lower coverage and cannot be directly built into genealogies. Here, we present a fast and scalable method, Colate, the first approach for inferring ancestral relationships through time between low-coverage genomes without requiring phasing or imputation. Our approach leverages sharing patterns of mutations dated using a genealogy to infer coalescence rates. For deeply sequenced ancient genomes, we additionally introduce an extension of the Relate algorithm for joint inference of genealogies incorporating such genomes. Application to 278 present-day and 430 ancient DNA samples of >0.5x mean coverage allows us to identify dynamic population structure and directional gene flow between early farmer and European hunter-gatherer groups. We further show that the previously reported, but still unexplained, increase in the TCC/TTC mutation rate, which is strongest in West Eurasia today, was already present at similar strength and widespread in the Late Glacial Period ~10k-15k years ago, but is not observed in samples >30k years old. It is strongest in Neolithic farmers, and highly correlated with recent coalescence rates between other genomes and a 10,000-year-old Anatolian hunter-gatherer. This suggests gene-flow among ancient peoples postdating the last glacial maximum as widespread and localizes the driver of this mutational signal in both time and geography in that region. Our approach should be widely applicable in future for addressing other evolutionary questions, and in other species., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Inexpensive genotyping methods are essential to modern genomics. Here we present QUILT, which performs diploid genotype imputation using low-coverage whole-genome sequence data. QUILT employs Gibbs sampling to partition reads into maternal and paternal sets, facilitating rapid haploid imputation using large reference panels. We show this partitioning to be accurate over many megabases, enabling highly accurate imputation close to theoretical limits and outperforming existing methods. Moreover, QUILT can impute accurately using diverse technologies, including long reads from Oxford Nanopore Technologies, and a new form of low-cost barcoded Illumina sequencing called haplotagging, with the latter showing improved accuracy at low coverages. Relative to DNA genotyping microarrays, QUILT offers improved accuracy at reduced cost, particularly for diverse populations that are traditionally underserved in modern genomic analyses, with accuracy nearly doubling at rare SNPs. Finally, QUILT can accurately impute (four-digit) human leukocyte antigen types, the first such method from low-coverage sequence data., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Genetic variation segregates as linked sets of variants or haplotypes. Haplotypes and linkage are central to genetics and underpin virtually all genetic and selection analysis. Yet, genomic data often omit haplotype information due to constraints in sequencing technologies. Here, we present "haplotagging," a simple, low-cost linked-read sequencing technique that allows sequencing of hundreds of individuals while retaining linkage information. We apply haplotagging to construct megabase-size haplotypes for over 600 individual butterflies ( Heliconius erato and H. melpomene ), which form overlapping hybrid zones across an elevational gradient in Ecuador. Haplotagging identifies loci controlling distinctive high- and lowland wing color patterns. Divergent haplotypes are found at the same major loci in both species, while chromosome rearrangements show no parallelism. Remarkably, in both species, the geographic clines for the major wing-pattern loci are displaced by 18 km, leading to the rise of a novel hybrid morph in the center of the hybrid zone. We propose that shared warning signaling (Müllerian mimicry) may couple the cline shifts seen in both species and facilitate the parallel coemergence of a novel hybrid morph in both comimetic species. Our results show the power of efficient haplotyping methods when combined with large-scale sequencing data from natural populations., Competing Interests: Competing interest statement: M.K., A.D., and Y.F.C. declare competing financial interests in the form of patent and employment by the Max Planck Society. The European Research Council provides funding for the research but no other competing interests., (Copyright © 2021 the Author(s). Published by PNAS.)

Meeting rising demand for oil palm whilst minimizing the loss of tropical biodiversity and associated ecosystem functions is a core conservation challenge. One potential solution is focusing the expansion of high-yielding crops on presently low-yielding farmlands alongside protecting nearby tropical forests that can enhance provision of ecosystem functions. A key question is how this solution would impact invertebrate functional diversity. We focus on oil palm in the Colombian Llanos, where plantations are replacing improved cattle pastures and forest fragments, and on dung beetles, which play key functional roles in nutrient cycling and secondary seed dispersal. We show that functional richness and functional diversity of dung beetles is greater in oil palm than in cattle pasture, and that functional metrics did not differ between oil palm and remnant forest. The abundance-size class profile of dung beetles in oil palm was more similar to forest than to pasture, which had lower abundances of the smallest and largest dung beetles. The abundance of tunneling and rolling dung beetles did not differ between oil palm and forest, while higher forest cover increased the abundance of diurnal and generalist-feeding beetles in oil palm landscapes. This suggests that prioritizing agricultural development on low-yielding cattle pasture will have positive effects on functional diversity and highlights the need for forest protection to maintain ecosystem functioning within agricultural landscapes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Quantifying and comparing the amount of adaptive evolution among different species is key to understanding how evolution works. Previous studies have shown differences in adaptive evolution across species; however, their specific causes remain elusive. Here, we use improved modeling of weakly deleterious mutations and the demographic history of the outgroup species and ancestral population and estimate that at least 20% of nonsynonymous substitutions between humans and an outgroup species were fixed by positive selection. This estimate is much higher than previous estimates, which did not correct for the sizes of the outgroup species and ancestral population. Next, we jointly estimate the proportion and selection coefficient ( p + and s + , respectively) of newly arising beneficial nonsynonymous mutations in humans, mice, and Drosophila melanogaster by examining patterns of polymorphism and divergence. We develop a novel composite likelihood framework to test whether these parameters differ across species. Overall, we reject a model with the same p + and s + of beneficial mutations across species and estimate that humans have a higher p + s + compared with that of D. melanogaster and mice. We show that this result cannot be caused by biased gene conversion or hypermutable CpG sites. We discuss possible biological explanations that could generate the observed differences in the amount of adaptive evolution across species., (© 2021 Zhen et al.; Published by Cold Spring Harbor Laboratory Press.)

The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.

The quality and nutritional value of dietary proteins are determined by the quantity, digestibility and bioavailability of essential amino acids (EAA), which play a critical role in human growth, longevity and metabolic health. Plant-source protein is often deficient in one or more EAAs (e.g., branched-chain amino acids, lysine, methionine and/or tryptophan) and, in its natural form, is less digestible than animal-source protein. Nevertheless, dietary intake of plant-source protein has been promoted because of its potential health benefits, lower cost of production and lower environmental impact compared to animal-source protein. Implementation of dietary strategies that improve both human and planetary health are of critical importance and subject to growing interest from researchers and consumers. Therefore, in this review we analyse current plant protein intake patterns and discuss possible countermeasures that can enhance plant protein nutrition, examples include: (1) combining different plant proteins with complementary EAA profiles; (2) identification and commercial cultivation of new and novel high-quality plant proteins; (3) industrial and domestic processing methods; and (4) genome-editing techniques.

Sharing human genotype and phenotype data is essential to discover otherwise inaccessible genetic associations, but is a challenge because of privacy concerns. Here, we present a method of homomorphic encryption that obscures individuals' genotypes and phenotypes, and is suited to quantitative genetic association analysis. Encrypted ciphertext and unencrypted plaintext are analytically interchangeable. The encryption uses a high-dimensional random linear orthogonal transformation key that leaves the likelihood of quantitative trait data unchanged under a linear model with normally distributed errors. It also preserves linkage disequilibrium between genetic variants and associations between variants and phenotypes. It scrambles relationships between individuals: encrypted genotype dosages closely resemble Gaussian deviates, and can be replaced by quantiles from a Gaussian with negligible effects on accuracy. Likelihood-based inferences are unaffected by orthogonal encryption. These include linear mixed models to control for unequal relatedness between individuals, heritability estimation, and including covariates when testing association. Orthogonal transformations can be applied in a modular fashion for multiparty federated mega-analyses where the parties first agree to share a common set of genotype sites and covariates prior to encryption. Each then privately encrypts and shares their own ciphertext, and analyses all parties' ciphertexts. In the absence of private variants, or knowledge of the key, we show that it is infeasible to decrypt ciphertext using existing brute-force or noise-reduction attacks. We present the method as a challenge to the community to determine its security., (Copyright © 2020 Mott et al.)

Background: The aim of this study was to investigate the effect of whey protein supplementation on myofibrillar protein synthesis (myoPS) and muscle recovery over a 7-d period of intensified resistance training (RT)., Methods: In a double-blind randomised parallel group design, 16 resistance-trained men aged 18 to 35 years completed a 7-d RT protocol, consisting of three lower-body RT sessions on non-consecutive days. Participants consumed a controlled diet (146 kJ·kg -1 ·d -1 , 1.7 g·kg -1 ·d -1 protein) with either a whey protein supplement or an isonitrogenous control (0.33 g·kg -1 ·d -1 protein). To measure myoPS, 400 ml of deuterium oxide (D 2 O) (70 atom %) was ingested the day prior to starting the study and m. vastus lateralis biopsies were taken before and after RT-intervention. Myofibrillar fractional synthetic rate (myoFSR) was calculated via deuterium labelling of myofibrillar-bound alanine, measured by gas chromatography-pyrolysis-isotope ratio mass spectrometry (GC-Pyr-IRMS). Muscle recovery parameters (i.e., countermovement jump height, isometric-squat force, muscle soreness and serum creatine kinase) were assessed daily., Results: MyoFSR PRE was 1.6 (0.2) %∙d -1 (mean (SD)). Whey protein supplementation had no effect on myoFSR ( p = 0.771) or any recovery parameter ( p = 0.390-0.989)., Conclusions: Over an intense 7-d RT protocol, 0.33 g·kg -1 ·d -1 of supplemental whey protein does not enhance day-to-day measures of myoPS or postexercise recovery in resistance-trained men.

During meiotic recombination, homologue-templated repair of programmed DNA double-strand breaks (DSBs) produces relatively few crossovers and many difficult-to-detect non-crossovers. By intercrossing two diverged mouse subspecies over five generations and deep-sequencing 119 offspring, we detect thousands of crossover and non-crossover events genome-wide with unprecedented power and spatial resolution. We find that both crossovers and non-crossovers are strongly depleted at DSB hotspots where the DSB-positioning protein PRDM9 fails to bind to the unbroken homologous chromosome, revealing that PRDM9 also functions to promote homologue-templated repair. Our results show that complex non-crossovers are much rarer in mice than humans, consistent with complex events arising from accumulated non-programmed DNA damage. Unexpectedly, we also find that GC-biased gene conversion is restricted to non-crossover tracts containing only one mismatch. These results demonstrate that local genetic diversity profoundly alters meiotic repair pathway decisions via at least two distinct mechanisms, impacting genome evolution and Prdm9-related hybrid infertility.

The aim of this study was to test the effects of two disparate isonitrogenous, isocaloric pre-exercise feeds on deuterium-oxide (D 2 O) derived measures of myofibrillar protein synthesis (myoPS) in humans. Methods: In a double-blind parallel group design, 22 resistance-trained men aged 18 to 35 years ingested a meal (6 kcal·kg -1 , 0.8 g·kg -1 carbohydrate, 0.2 g·kg -1 fat) with 0.33 g·kg -1 nonessential amino acids blend (NEAA) or whey protein (WHEY), prior to resistance exercise (70% 1RM back-squats, 10 reps per set to failure, 25% duty cycle). Biopsies of M. vastus lateralis were obtained pre-ingestion (PRE) and +3 h post-exercise (POST). The myofibrillar fractional synthetic rate (myoFSR) was calculated via deuterium labelling of myofibrillar-bound alanine, measured by gas chromatography-pyrolysis-isotope ratio mass spectrometry (GC-Pyr-IRMS). Data are a mean percentage change (95% CI). Results: There was no discernable change in myoFSR following NEAA (10(-5, 25) %, p = 0.235), whereas an increase in myoFSR was observed after WHEY (28 (13, 43) %, p = 0.003). Conclusions: Measured by a D 2 O tracer technique, a disparate myoPS response was observed between NEAA and WHEY. Pre-exercise ingestion of whey protein increased post-exercise myoPS, whereas a NEAA blend did not, supporting the use of NEAA as a viable isonitrogenous negative control.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies (ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels. In the clinical sample, we identify and directly phase two non-synonymous de novo variants in SAMD9L, (OMIM #159550) inferring that they lie on the same paternal haplotype. Whilst consensus SNV-calling error rates from ONT data remain substantially higher than those from short-read methods, we demonstrate the substantial benefits of analytical innovation. Ongoing improvements to base-calling and SNV-calling methodology must continue for nanopore sequencing to establish itself as a primary method for clinical WGS.

Twenty-three resistance trained men 18-35 years (23 [3] years, 1.8 [0.1] m, 81 [10] kg body mass, 2.3 [1.1] years resistance training experience; mean [SD]) performed repeated maximal voluntary isometric squats (ISQ) and countermovement jumps (CMJ) pre- and +30 minutes post a unilateral microbiopsy of m. vastus lateralis. ISQ and CMJ were simultaneously measured by two force plates sampling ipsilateral (biopsied) and contralateral (non-biopsied) limb force. Bilateral limb force (ipsilateral + contralateral) and imbalance (ipsilateral/bilateral) data are reported as % change from pre-biopsy (mean [95% CI]). A post-biopsy reduction in bilateral ISQ peak force (-17 [-23, -11] %; P < 0.001), ISQ rate of force development (RFD; -28 [-41, -15] %, P = 0.002) and CMJ peak take-off force (-7 [-13, -1]%, P = 0.019) occurred. Imbalance was observed for ISQ peak force (3.2 [2.1, 4.3] %, P < 0.001), RFD (2.8 [1.6, 4.0] %, P < 0.001) and CMJ landing (3.3 [1.0, 5.6] %, P = 0.009), resultant of a force transfer from the ipsilateral (biopsied) to the contralateral (non-biopsied) limb. These data suggest that in young, resistance trained men a modulatory influence on maximal voluntary static and dynamic lower-body contractile function is evoked acutely (+30 minutes) following a microbiopsy of m. vastus lateralis., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

To investigate sex differences in the temporal recovery of neuromuscular function following resistance training (RT), eleven men and eight women 18-35 years completed a single RT bout (barbell back-squats, 80 % 1RM, 5 sets × 5 reps, 25 % duty cycle, then 1 set × max reps). Measures of muscle function (isometric, concentric, eccentric knee extensor strength, and countermovement jump (CMJ) height), serum creatine kinase activity (CK) and lower-body muscle pain were assessed before RT (0 h), +4 h, +24 h, +48 h, and +72 h post-RT. Data are mean % change from PRE (SD) and effect size (ω 2 , d). Men and women had similar RT-experience (men, 2.1 (0.8) years vs. women 2.4 (1.0) years, P = 0.746, and d = 0.3) and 1RM strength per kg lean mass (men, 1.9 (0.2) kg⋅kg -1 vs. women, 1.8 (0.3) kg⋅kg -1 , P = 0.303, and d = 0.3). A 36 (12)% increase in lower-body muscle pain was reported following RT ( P < 0.05, d > 0.9). There was an absence of any overt change in CK [+24 h, 74 (41) IU⋅L -1 ; pooled mean (SD)]. Decrements in knee extensor strength and CMJ height were observed +4 to +72 h for both men and women ( P < 0.05, ω 2 = 0.19-0.69). Sex differences were apparent for CMJ height (+24 h men, -10 (6)% vs. women, -20 (11)%, P < 0.001, and d = 1.8) and isokinetic concentric strength (+24 h men, -10 (13)% vs. women -25 (14)%, P = 0.006, and d = 1.8), with a more pronounced loss and prolonged recovery in women compared to men (e.g., CMJ + 72 h men, -3 (6)% vs. women, -13 (12)%, P = 0.051, and d = 1.1). We conclude that the different temporal recovery patterns between men and women are not explicable by differences in muscle strength, RT performance, experience, muscle damage or fatigability.

We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We present a bioluminescence method, based on the calcium-reporter Aequorin (AEQ), that exploits targeted transgenic expression patterns to identify activity of specific neural groups in the larval Drosophila nervous system. We first refine, for intact but constrained larva, the choice of Aequorin transgene and method of delivery of the co-factor coelenterazine and assay the luminescence signal produced for different neural expression patterns and concentrations of co-factor, using standard photo-counting techniques. We then develop an apparatus that allows simultaneous measurement of this neural signal while video recording the crawling path of an unconstrained animal. The setup also enables delivery and measurement of an olfactory cue (CO 2 ) and we demonstrate the ability to record synchronized changes in Kenyon cell activity and crawling speed caused by the stimulus. Our approach is thus shown to be an effective and affordable method for studying the neural basis of behavior in Drosophila larvae.

The effects of nutrition on exercise metabolism and performance remain an important topic among sports scientists, clinical, and athletic populations. Recently, fasted exercise has garnered interest as a beneficial stimulus which induces superior metabolic adaptations to fed exercise in key peripheral tissues. Conversely, pre-exercise feeding augments exercise performance compared with fasting conditions. Given these seemingly divergent effects on performance and metabolism, an appraisal of the literature is warranted. This review determined the effects of fasting vs pre-exercise feeding on continuous aerobic and anaerobic or intermittent exercise performance, and post-exercise metabolic adaptations. A search was performed using the MEDLINE and PubMed search engines. The literature search identified 46 studies meeting the relevant inclusion criteria. The Delphi list was used to assess study quality. A meta-analysis and meta-regression were performed where appropriate. Findings indicated that pre-exercise feeding enhanced prolonged (P = .012), but not shorter duration aerobic exercise performance (P = .687). Fasted exercise increased post-exercise circulating FFAs (P = .023) compared to fed exercise. It is evidenced that pre-exercise feeding blunted signaling in skeletal muscle and adipose tissue implicated in regulating components of metabolism, including mitochondrial adaptation and substrate utilization. This review's findings support the hypothesis that the fasted and fed conditions can divergently influence exercise metabolism and performance. Pre-exercise feeding bolsters prolonged aerobic performance, while seminal evidence highlights potential beneficial metabolic adaptations that fasted exercise may induce in peripheral tissues. However, further research is required to fully elucidate the acute and chronic physiological adaptations to fasted vs fed exercise., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Whey protein (WP) is a widely consumed nutritional supplement, known to enhance strength and muscle mass during resistance training (RT) regimens. Muscle protein anabolism is acutely elevated following RT, which is further enhanced by WP. As a result, there is reason to suggest that WP supplementation may be an effective nutritional strategy for restoring the acute loss of contractile function that occurs following strenuous RT. This systematic review and meta-analysis provides a synthesis of the literature to date, investigating the effect of WP supplementation on the recovery of contractile function in young, healthy adults. Eight studies, containing 13 randomised control trials (RCTs) were included in this review and meta-analysis, from which individual standardised effect sizes (ESs) were calculated, and a temporal overall ES was determined using a random-effects model. Whilst only half of the individual studies reported beneficial effects for WP, the high-quality evidence taken from the 13 RCTs was meta-analysed, yielding overall positive small to medium effects for WP from < 24 to 96 h (ES range = 0.4 to 0.7), for the temporal restoration of contractile function compared to the control treatment. Whilst the effects for WP were shown to be consistent over time, these results are limited to 13 RCTs, principally supporting the requirement for further comprehensive research in this area.

Longitudinal change in body composition for elite-level inter-county hurlers was reported over a single season and four consecutive seasons. Body composition measured by dual-energy x-ray absorptiometry (DXA) of 66 senior, male, outfield players was obtained. Four successive measurements were taken: off-season (OFF 1 ), pre-season (PRE), mid-season (MID) and the off-season of the following season (OFF 2 ). A subsample of 11 hurlers were measured at all time points over 4 consecutive seasons. DXA-derived estimates of fat and lean mass were normalised to stature for analysis (kg∙m ‒2 ); data are (mean [lower: upper, 95% confidence interval]). A concurrent increase of lean mass (0.31 [0.19: 0.43] kg∙m ‒2 ) and loss of fat mass occurred (-0.38 [-0.50: -0.26] kg∙m ‒2 ) OFF 1 to PRE. Lean mass accrual was maintained PRE to OFF 2 while the initial loss of fat mass was restored MID to OFF 2 (0.52 [0.40: 0.64] kg ∙ m ‒2 ), with the trunk acting as the primary region of change. Over the four seasons, a net increase of lean mass was observed (~ 0.9 [0.4: 1.4] kg per annum) with a negligible overall change for fat mass over time. However, the cycling of fat mass (OFF to PRE and MID to OFF) within each season was recurrent season-to-season.

Inexpensive genotyping methods are essential for genetic studies requiring large sample sizes. In human studies, array-based microarrays and high-density haplotype reference panels allow efficient genotype imputation for this purpose. However, these resources are typically unavailable in non-human settings. Here we describe a method (STITCH) for imputation based only on sequencing read data, without requiring additional reference panels or array data. We demonstrate its applicability even in settings of extremely low sequencing coverage, by accurately imputing 5.7 million SNPs at a mean r(2) value of 0.98 in 2,073 outbred laboratory mice (0.15× sequencing coverage). In a sample of 11,670 Han Chinese (1.7× coverage), we achieve accuracy similar to that of alternative approaches that require a reference panel, demonstrating that our approach can work for genetically diverse populations. Our method enables straightforward progression from low-coverage sequence to imputed genotypes, overcoming barriers that at present restrict the application of genome-wide association study technology outside humans., Competing Interests: The authors declare no competing financial interests.

Two bottlenecks impeding the genetic analysis of complex traits in rodents are access to mapping populations able to deliver gene-level mapping resolution and the need for population-specific genotyping arrays and haplotype reference panels. Here we combine low-coverage (0.15×) sequencing with a new method to impute the ancestral haplotype space in 1,887 commercially available outbred mice. We mapped 156 unique quantitative trait loci for 92 phenotypes at a 5% false discovery rate. Gene-level mapping resolution was achieved at about one-fifth of the loci, implicating Unc13c and Pgc1a at loci for the quality of sleep, Adarb2 for home cage activity, Rtkn2 for intensity of reaction to startle, Bmp2 for wound healing, Il15 and Id2 for several T cell measures and Prkca for bone mineral content. These findings have implications for diverse areas of mammalian biology and demonstrate how genome-wide association studies can be extended via low-coverage sequencing to species with highly recombinant outbred populations., Competing Interests: The authors declare no competing financial interests.