Heterozygote Advantage for Fecundity

Heterozygote advantage, or overdominance, remains a popular and persuasive explanation for the maintenance of genetic variation in natural populations in the face of selection. However, despite being first proposed more than 80 years ago, there remain few examples that fit the criteria for heterozygote advantage, all of which are associated with disease resistance and are maintained only in the presence of disease or other gene-by-environment interaction. Here we report five new examples of heterozygote advantage, based around polymorphisms in the BMP15 and GDF9 genes that affect female fecundity in domesticated sheep and are not reliant on disease for their maintenance. Five separate mutations in these members of the transforming growth factor β (TGFβ) superfamily give phenotypes with fitness differentials characteristic of heterozygous advantage. In each case, one copy of the mutant allele increases ovulation rate, and ultimately litter size per ewe lambing, relative to the wildtype. However, homozygous ewes inheriting mutant alleles from both parents have impaired oocyte development and maturation, which results in small undeveloped ovaries and infertility. Using data collected over many years on ovulation rates, litter size, and lambing rates, we have calculated the equilibrium solution for each of these polymorphisms using standard population genetic theory. The predicted equilibrium frequencies obtained for these mutant alleles range from 0.11 to 0.23, which are amongst the highest yet reported for a polymorphism maintained by heterozygote advantage. These are amongst the most frequent and compelling examples of heterozygote advantage yet described and the first documented examples of heterozygote advantage that are not reliant on a disease interaction for their maintenance

Pre-cooling for endurance exercise performance in the heat: a systematic review.

PMCID: PMC3568721The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1741-7015/10/166. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Endurance exercise capacity diminishes under hot environmental conditions. Time to exhaustion can be increased by lowering body temperature prior to exercise (pre-cooling). This systematic literature review synthesizes the current findings of the effects of pre-cooling on endurance exercise performance, providing guidance for clinical practice and further research

One-Loop Calculation of the Oblique S Parameter in Higgsless Electroweak Models

We present a one-loop calculation of the oblique S parameter within Higgsless models of electroweak symmetry breaking and analyze the phenomenological implications of the available electroweak precision data. We use the most general effective Lagrangian with at most two derivatives, implementing the chiral symmetry breaking SU(2)_L x SU(2)_R -> SU(2)_{L+R} with Goldstones, gauge bosons and one multiplet of vector and axial-vector massive resonance states. Using the dispersive representation of Peskin and Takeuchi and imposing the short-distance constraints dictated by the operator product expansion, we obtain S at the NLO in terms of a few resonance parameters. In asymptotically-free gauge theories, the final result only depends on the vector-resonance mass and requires M_V > 1.8 TeV (3.8 TeV) to satisfy the experimental limits at the 3 \sigma (1\sigma) level; the axial state is always heavier, we obtain M_A > 2.5 TeV (6.6 TeV) at 3\sigma (1\sigma). In strongly-coupled models, such as walking or conformal technicolour, where the second Weinberg sum rule does not apply, the vector and axial couplings are not determined by the short-distance constraints; but one can still derive a lower bound on S, provided the hierarchy M_V < M_A remains valid. Even in this less constrained situation, we find that in order to satisfy the experimental limits at 3\sigma one needs M_{V,A} > 1.8 TeV.Comment: 34 pages, 9 figures. Version published in JHEP. Some references and sentences have been added to facilitate the discussio

Unconstrained three-dimensional reaching in Rhesus monkeys

To better understand normative behavior for quantitative evaluation of motor recovery after injury, we studied arm movements by non-injured Rhesus monkeys during a food-retrieval task. While seated, monkeys reached, grasped, and retrieved food items. We recorded three-dimensional kinematics and muscle activity, and used inverse dynamics to calculate joint moments due to gravity, segmental interactions, and to the muscles and tissues of the arm. Endpoint paths showed curvature in three dimensions, suggesting that maintaining straight paths was not an important constraint. Joint moments were dominated by gravity. Generalized muscle and interaction moments were less than half of the gravitational moments. The relationships between shoulder and elbow resultant moments were linear during both reach and retrieval. Although both reach and retrieval required elbow flexor moments, an elbow extensor (triceps brachii) was active during both phases. Antagonistic muscles of both the elbow and hand were co-activated during reach and retrieval. Joint behavior could be described by lumped-parameter models analogous to torsional springs at the joints. Minor alterations to joint quasi-stiffness properties, aided by interaction moments, result in reciprocal movements that evolve under the influence of gravity. The strategies identified in monkeys to reach, grasp, and retrieve items will allow the quantification of prehension during recovery after a spinal cord injury and the effectiveness of therapeutic interventions

Evidence for Oxidative Stress and Defective Antioxidant Response in Guinea Pigs with Tuberculosis

The development of granulomatous inflammation with caseous necrosis is an important but poorly understood manifestation of tuberculosis in humans and some animal models. In this study we measured the byproducts of oxidative stress in granulomatous lesions as well as the systemic antioxidant capacity of BCG vaccinated and non-vaccinated guinea pigs experimentally infected with Mycobacterium tuberculosis. In non-vaccinated guinea pigs, oxidative stress was evident within 2 weeks of infection as measured by a decrease in the serum total antioxidant capacity and blood glutathione levels accompanied by an increase in malondialdehyde, a byproduct of lipid peroxidation, within lesions. Despite a decrease in total and reduced blood glutathione concentrations, there was an increase in lesion glutathione by immunohistochemistry in response to localized oxidative stress. In addition there was an increase in the expression of the host transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), which regulates several protein and non-proteins antioxidants, including glutathione. Despite the increase in cytoplasmic expression of Nrf2, immunohistochemical staining revealed a defect in Nrf2 nuclear translocation within granulomatous lesions as well as a decrease in the expression of the Nrf2-regulated antioxidant protein NQO1. Treating M. tuberculosis–infected guinea pigs with the antioxidant drug N-acetyl cysteine (NAC) partially restored blood glutathione concentrations and the serum total antioxidant capacity. Treatment with NAC also decreased spleen bacterial counts, as well as decreased the lung and spleen lesion burden and the severity of lesion necrosis. These data suggest that the progressive oxidative stress during experimental tuberculosis in guinea pigs is due in part to a defect in host antioxidant defenses, which, we show here, can be partially restored with antioxidant treatment. These data suggest that the therapeutic strategies that reduce oxidant-mediated tissue damage may be beneficial as an adjunct therapy in the treatment and prevention of tuberculosis in humans

A Large Gene Network in Immature Erythroid Cells Is Controlled by the Myeloid and B Cell Transcriptional Regulator PU.1

PU.1 is a hematopoietic transcription factor that is required for the development of myeloid and B cells. PU.1 is also expressed in erythroid progenitors, where it blocks erythroid differentiation by binding to and inhibiting the main erythroid promoting factor, GATA-1. However, other mechanisms by which PU.1 affects the fate of erythroid progenitors have not been thoroughly explored. Here, we used ChIP-Seq analysis for PU.1 and gene expression profiling in erythroid cells to show that PU.1 regulates an extensive network of genes that constitute major pathways for controlling growth and survival of immature erythroid cells. By analyzing fetal liver erythroid progenitors from mice with low PU.1 expression, we also show that the earliest erythroid committed cells are dramatically reduced in vivo. Furthermore, we find that PU.1 also regulates many of the same genes and pathways in other blood cells, leading us to propose that PU.1 is a multifaceted factor with overlapping, as well as distinct, functions in several hematopoietic lineages

A Horizon Scan to Support Chemical Pollution–Related Policymaking for Sustainable and Climate-Resilient Economies

Data Availability Statement: All data are included in the Supporting Information for publication online.Supporting Information is available online at https://setac.onlinelibrary.wiley.com/doi/10.1002/etc.5620#support-information-section .Copyright © 2023 Crown copyright and The Authors. While chemicals are vital to modern society through materials, agriculture, textiles, new technology, medicines, and consumer goods, their use is not without risks. Unfortunately, our resources seem inadequate to address the breadth of chemical challenges to the environment and human health. Therefore, it is important we use our intelligence and knowledge wisely to prepare for what lies ahead. The present study used a Delphi-style approach to horizon-scan future chemical threats that need to be considered in the setting of chemicals and environmental policy, which involved a multidisciplinary, multisectoral, and multinational panel of 25 scientists and practitioners (mainly from the United Kingdom, Europe, and other industrialized nations) in a three-stage process. Fifteen issues were shortlisted (from a nominated list of 48), considered by the panel to hold global relevance. The issues span from the need for new chemical manufacturing (including transitioning to non-fossil-fuel feedstocks); challenges from novel materials, food imports, landfills, and tire wear; and opportunities from artificial intelligence, greater data transparency, and the weight-of-evidence approach. The 15 issues can be divided into three classes: new perspectives on historic but insufficiently appreciated chemicals/issues, new or relatively new products and their associated industries, and thinking through approaches we can use to meet these challenges. Chemicals are one threat among many that influence the environment and human health, and interlinkages with wider issues such as climate change and how we mitigate these were clear in this exercise. The horizon scan highlights the value of thinking broadly and consulting widely, considering systems approaches to ensure that interventions appreciate synergies and avoid harmful trade-offs in other areas. We recommend further collaboration between researchers, industry, regulators, and policymakers to perform horizon scanning to inform policymaking, to develop our ability to meet these challenges, and especially to extend the approach to consider also concerns from countries with developing economies. Environ Toxicol Chem 2023;00:1–17. © 2023 Crown copyright and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.Department for Environment, Food and Rural Affair

Community shift of ammonia-oxidizing bacteria along an anthropogenic pollution gradient from the Pearl River Delta to the South China Sea

The phylogenetic diversity and abundance of ammonia-oxidizing beta-proteobacteria (beta-AOB) was analyzed along an anthropogenic pollution gradient from the coastal Pearl River Delta to the South China Sea using the ammonia monooxygenase subunit A (amoA) gene. Along the gradient from coastal to the open ocean, the phylogenetic diversity of the dominant genus changed from Nitrosomonas to Nitrosospira, indicating the niche specificity by these two genera as both salinity and anthropogenic influence were major factors involved. The diversity of bacterial amoA gene was also variable along the gradient, with the highest in the deep-sea sediments, followed by the marshes sediments and the lowest in the coastal areas. Within the Nitrosomonas-related clade, four distinct lineages were identified including a putative new one (A5-16) from the different sites over the large geographical area. In the Nitrosospira-related clade, the habitat-specific lineages to the deep-sea and coastal sediments were identified. This study also provides strong support that Nitrosomonas genus, especially Nitrosomonas oligotropha lineage (6a) could be a potential bio-indicator species for pollution or freshwater/wastewater input into coastal environments. A suite of statistical analyses used showed that water depth and temperature were major factors shaping the community structure of beta-AOB in this study area

Oblique S and T Constraints on Electroweak Strongly-Coupled Models with a Light Higgs

Using a general effective Lagrangian implementing the chiral symmetry breaking SU(2)L x SU(2)R -> SU(2){L+R}, we present a one-loop calculation of the oblique S and T parameters within electroweak strongly-coupled models with a light scalar. Imposing a proper ultraviolet behaviour, we determine S and T at next-to-leading order in terms of a few resonance parameters. The constraints from the global fit to electroweak precision data force the massive vector and axial-vector states to be heavy, with masses above the TeV scale, and suggest that the W+W- and ZZ couplings of the Higgs-like scalar should be close to the Standard Model value. Our findings are generic, since they only rely on soft requirements on the short-distance properties of the underlying strongly-coupled theory, which are widely satisfied in more specific scenarios