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Genome-wide association studies (GWAS) and polygenic score (PGS) development are typically constrained by the data available in biobank repositories in which European cohorts are vastly overrepresented. Here, we increase the utility of non-European participant data within the UK Biobank (UKB) by characterizing the genetic affinities of UKB participants who self-identify as Bangladeshi, Indian, Pakistani, "White and Asian" (WA), and "Any Other Asian" (AOA), towards creating a more robust South Asian sample size for future genetic analyses. We assess the relationships between genetic structure and self-selected ethnic identities resulting in consistent patterns of clustering used to train a support vector machine (SVM). The SVM model was utilized to reassign n = 1,853 AOA and WA participants at the subcontinental level, and increase the sample size of the UKB South Asian group by 1,381 additional participants. We then leverage these samples to assess GWAS performance and PGS development. We further include environmental covariates in the height GWAS by implementing a rigorous covariate selection procedure, and compare the outputs of two GWAS models: GWAS null and GWAS env . We show that PGS performance derived from environmentally adjusted GWAS yields comparable prediction to PGS models developed with an order of magnitude larger training dataset ( R 2 =0.021 vs 0.026). Models with 7 - 8 environmental covariates double the variance explained by PGS alone. In summary, we demonstrate how GWAS performance can be improved by leveraging ambiguous ethnicity codes, ancestry matched imputation panels, and including environmental covariates.

Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process. Polyamine metabolism and hypusination of eIF5A play a pivotal role in sustaining elevated levels of protein synthesis in senescent cells. Mechanistically, we identify a p53-dependent program in senescent cells that maintains hypusination levels of eIF5A. Finally, we demonstrate that functional eIF5A is required for synthesizing mitochondrial ribosomal proteins and monitoring the immune clearance of premalignant senescent cells in vivo. Our findings establish an important role of protein synthesis during cellular senescence and suggest a link between eIF5A, polyamine metabolism, and senescence immune surveillance., (© 2024. The Author(s).)

Background: Facultative bacterial endosymbionts have the potential to influence the interactions between aphids, their natural enemies, and host plants. Among the facultative symbionts found in populations of the grain aphid Sitobion avenae in central Chile, the bacterium Regiella insecticola is the most prevalent. In this study, we aimed to investigate whether infected and cured aphid lineages exhibit differential responses to wheat cultivars containing varying levels of the benzoxazinoid DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one), which is a xenobiotic compound produced by plants. Specifically, we examined the reproductive performance responses of the most frequently encountered genotypes of Sitobion avenae when reared on wheat seedlings expressing low, medium, and high concentrations of DIMBOA., Results: Our findings reveal that the intrinsic rate of population increase (r m ) in cured lineages of Sitobion avenae genotypes exhibits a biphasic pattern, characterized by the lowest r m and an extended time to first reproduction on wheat seedlings with medium levels of DIMBOA. In contrast, the aphid genotypes harbouring Regiella insecticola display idiosyncratic responses, with the two most prevalent genotypes demonstrating improved performance on seedlings featuring an intermediate content of DIMBOA compared to their cured counterparts., Conclusion: This study represents the first investigation into the mediating impact of facultative endosymbionts on aphid performance in plants exhibiting varying DIMBOA contents. These findings present exciting prospects for identifying novel targets for aphid control by manipulating the presence of aphid symbionts. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Despite decades of research resulting in a comprehensive understanding of epicuticular wax metabolism, the function of these almost ubiquitous metabolites in plant-herbivore interactions remains unresolved. In this study, we examined the effects of CRISPR-induced knockout mutations in four Nicotiana glauca (tree tobacco) wax metabolism genes. These mutations cause a wide range of changes in epicuticular wax composition, leading to altered interactions with insects and snails. Three interaction classes were examined: chewing herbivory by seven caterpillars and one snail species, phloem feeding by Myzus persicae (green peach aphid) and oviposition by Bemisia tabaci (whitefly). Although total wax load and alkane abundance did not affect caterpillar growth, a correlation across species, showed that fatty alcohols, a minor component of N. glauca surface waxes, negatively affected the growth of both a generalist caterpillar (Spodoptera littoralis) and a tobacco-feeding specialist (Manduca sexta). This negative correlation was overshadowed by the stronger effect of anabasine, a nicotine isomer, and was apparent when fatty alcohols were added to an artificial lepidopteran diet. By contrast, snails fed more on waxy leaves. Aphid reproduction and feeding activity were unaffected by wax composition but were potentially affected by altered cutin composition. Wax crystal morphology could explain the preference of B. tabaci to lay eggs on waxy wild-type plants relative to both alkane and fatty alcohol-deficient mutants. Together, our results suggest that the varied responses among herbivore classes and species are likely to be a consequence of the co-evolution that shaped the specific effects of different surface wax components in plant-herbivore interactions., (© 2023 The Authors. Plant, Cell & Environment published by John Wiley & Sons Ltd.)

Cancer cell survival is highly dependent on its metabolic reprogramming, which supports not only cell growth but also confers to the tumor cells characteristics to initiate migration and colonization. Among the different mechanisms that are involved, translational control plays a significant role in oncogenesis; however, its impact on cancer progression still remains poorly understood. A study by Navickas and colleagues revealed that the RNA-binding protein heterogeneous nuclear ribonucleoprotein C (HNRNPC) functions as a translational regulator, and its downregulation in highly metastatic cells leads to the lengthening of 3' untranslated regions in HNRNPC-bound mRNAs, resulting in translational repression mediated by the AGO-miRNA RNA-induced silencing complex., (©2023 American Association for Cancer Research.)

Objectives: Collecting skeletal measurements from medical imaging databases remains a tedious task, limiting the research utility of biobank-level data. Here we present an automated phenotyping pipeline for obtaining skeletal measurements from DXA scans and compare its performance to manually collected measurements., Materials and Methods: A pipeline that extends the Advanced Normalization Tools (ANTs) framework was developed on 341 whole-body DXA scans of UK Biobank South Asian participants. A set of 10 measurements throughout the skeleton was automatically obtained via this process, and the performance of the method was tested on 20 additional DXA images by calculating percent error and concordance correlation coefficients (CCC) for manual and automated measurements. Stature was then regressed on the automated femoral and tibia lengths and compared to published stature regressions to further assess the reliability of the automated measurements., Results: Based on percent error and CCC, the performance of the automated measurements falls into three categories: poor (sacral and acetabular breadths), variable (trunk length, upper thoracic breadth, and innominate height), and high (maximum pelvic aperture breadth, bi-iliac breadth, femoral maximum length, and tibia length). Stature regression plots indicate that the automated measurements reflect realistic body proportions and appear consistent with published data reflecting these relationships in South Asian populations., Discussion: Based on the performance of this pipeline, a subset of measurements can be reliably extracted from DXA scans, greatly expanding the utility of biobank-level data for biological anthropologists and medical researchers., (© 2023 Wiley Periodicals LLC.)

Background: To reduce the arbitrariness in the allocation of rare resources in intensive care units (ICU) in the context of the pandemic, tiebreakers were considered in some COVID-19 triage algorithms. They were also contemplated to facilitate the tragic decisions of healthcare workers when faced with two patients with similar prognosis and only one ICU bed available. Little is known about the public's perspective on tiebreakers., Objectives: To consolidate the available scientific literature on public consultations, particularly on tiebreakers and their underlying values. Also, to obtain an overview of the key arguments presented by the participating public and to identify potential gaps related to this topic., Methods: The steps described by Arksey and O'Malley was the preferred method to our approach. Seven electronic databases were searched from January 2020 to April 2022, using keywords for each database: PubMed, Medline, EMBASE, Web of Science, PsycINFO, EBM reviews, CINAHL complete. We also searched in Google and Google Scholar, and in the references of the articles found. Our analysis was mainly qualitative. A thematic analysis was performed to consider the public's perspectives on tiebreakers and their underlying values, according to these studies., Results: Of 477 publications found, 20 were selected. They carried out public consultations through various methods: surveys (80%), interviews (20%), deliberative processes (15%) and others (5%) in various countries: Australia, Brazil, Canada, China, France, Germany, India, Iran, Italy, Japan, Korea, Netherlands, Portugal, Spain, Switzerland, Thailand, United Kingdom, and United States. Five themes emerged from our analysis. The public favored the life cycle (50%) and absolute age (45%) as a tiebreaker. Other values considered important were reciprocity, solidarity, equality, instrumental value, patient merit, efficiency, and stewardship. Among the new findings were a preference for patient nationality and those affected by COVID-19., Conclusions: There is a preference for favoring younger patients over older patients when there is a tie between similar patients, with a slight tendency to favor intergenerational equity. Variability was found in the public's perspectives on tiebreakers and their values. This variability was related to socio-cultural and religious factors. More studies are needed to understand the public's perspective on tiebreakers., Supplementary Information: The online version contains supplementary material available at 10.1007/s44250-023-00027-9., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© Crown 2023.)

Background: Little is known about factors affecting implementation of patient safety programmes in low and middle-income countries. The goal of our study was to evaluate the implementation of a patient safety programme for paediatric care in Guatemala., Methods: We used a mixed methods design to examine the implementation of a patient safety programme across 11 paediatric units at the Roosevelt Hospital in Guatemala. The safety programme included: (1) tools to measure and foster safety culture, (2) education of patient safety, (3) local leadership engagement, (4) safety event reporting systems, and (5) quality improvement interventions. Key informant staff (n=82) participated in qualitative interviews and quantitative surveys to identify implementation challenges early during programme deployment from May to July 2018, with follow-up focus group discussions in two units 1 year later to identify opportunities for programme modification. Data were analysed using thematic analysis, and integrated using triangulation, complementarity and expansion to identify emerging themes using the Consolidated Framework for Implementation Research. Salience levels were reported according to coding frequency, with valence levels measured to characterise the degree to which each construct impacted implementation., Results: We found several facilitators to safety programme implementation, including high staff receptivity, orientation towards patient-centredness and a desire for protocols. Key barriers included competing clinical demands, lack of knowledge about patient safety, limited governance, human factors and poor organisational incentives. Modifications included use of tools for staff recognition, integration of education into error reporting mechanisms and designation of trained champions to lead unit-based safety interventions., Conclusion: Implementation of safety programmes in low-resource settings requires recognition of facilitators such as staff receptivity and patient-centredness as well as barriers such as lack of training in patient safety and poor organisational incentives. Embedding an implementation analysis during programme deployment allows for programme modification to enhance successful implementation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Aphids (Hemiptera: Aphididae) are insects with one of the highest potentials for invasion. Several aphid species are present globally due to introduction events; they represent important pests of agroecosystems. The bird cherry-oat aphid Rhopalosiphum padi (Linnaeus) is a major pest of cereals and pasture grasses worldwide. Here, we report the genetic features of populations of R. padi that colonize different cereal crops in central Chile., Methods: Rhopalosiphum padi individuals were collected in central Chile and genotyped at six microsatellite loci. The most frequent multilocus genotype (MLG) was then studied further to assess its reproductive performance across cereal hosts under laboratory conditions., Results: Populations of R. padi in Chile are characterized by a low clonal diversity ( G / N = 62/377 = 0.16) and the overrepresentation of a few widely distributed MLGs. One of the MLGs constituted roughly half of the sample and was observed in all sampled populations at high frequencies. Furthermore, this putative aphid "superclone" exhibited variations in its reproductive performance on cereals most commonly cultivated in Chile. The sampled populations also exhibited weak signs of genetic differentiation among hosts and localities. Our findings suggest that (1) obligate parthenogenesis is the primary reproductive mode of R. padi in Chile in the sampled range and (2) its introduction involved the arrival of a few genotypes that multiplied asexually., Competing Interests: The authors declare that they have no competing interests.

Initially identified as a factor involved in tyrosine kinase receptor signaling, Grb10-interacting GYF protein 2 (GIGYF2) has later been shown to interact with the 5' cap-binding protein 4EHP as part of a translation repression complex, and to mediate post-transcriptional repression of tethered reporter mRNAs. A current model proposes that GIGYF2 is indirectly recruited to mRNAs by specific RNA-binding proteins (RBPs) leading to translation repression through its association with 4EHP. Accordingly, we recently observed that GIGYF2 also interacts with the miRNA-induced silencing complex and probably modulates its translation repression activity. Here we have further investigated how GIGYF2 represses mRNA function. In a tethering reporter assay, we identify three independent domains of GIGYF2 with repressive activity. In this assay, GIGYF2-mediated repression is independent of 4EHP but largely dependent on the CCR4/NOT complex that GIGYF2 recruits through multiple interfaces. Importantly, we show that GIGYF2 is an RBP and identify for the first time endogenous mRNA targets that recapitulate 4EHP-independent repression. Altogether, we propose that GIGYF2 has two distinct mechanisms of repression: one depends on 4EHP binding and mainly affects translation; the other is 4EHP-independent and involves the CCR4/NOT complex and its deadenylation activity.

Programmes to modify the safety culture have led to lasting improvements in patient safety and quality of care in high-income settings around the world, although their use in low-income and middle-income countries (LMICs) has been limited. This analysis explores (1) how to measure the safety culture using a health culture survey in an LMIC and (2) how to use survey data to develop targeted safety initiatives using a paediatric nephrology unit in Guatemala as a field test case. We used the Safety, Communication, Operational Reliability, and Engagement survey to assess staff views towards 13 health climate and engagement domains. Domains with low scores included personal burnout, local leadership, teamwork and work-life balance. We held a series of debriefings to implement interventions targeted towards areas of need as defined by the survey. Programmes included the use of morning briefings, expansion of staff break resources and use of teamwork tools. Implementation challenges included the need for education of leadership, limited resources and hierarchical work relationships. This report can serve as an operational guide for providers in LMICs for use of a health culture survey to promote a strong safety culture and to guide their quality improvement and safety programmes., Competing Interests: Competing interests: None declared.

Understanding the function of the thousands of cellular proteins is a central question in molecular cell biology. As proteins are typically part of multiple dynamic and often overlapping macromolecular complexes exerting distinct functions, the identification of protein-protein interactions (PPI) and their assignment to specific complexes is a crucial but challenging task. We present a protein fragments complementation assay integrated with the proximity-dependent biotinylation technique BioID. Activated on the interaction of two proteins, split-BioID is a conditional proteomics approach that allows in a single and simple assay to both experimentally validate binary PPI and to unbiasedly identify additional interacting factors. Applying our method to the miRNA-mediated silencing pathway, we can probe the proteomes of two distinct functional complexes containing the Ago2 protein and uncover the protein GIGYF2 as a regulator of miRNA-mediated translation repression. Hence, we provide a novel tool to study dynamic spatiotemporally defined protein complexes in their native cellular environment.