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Background The branched chain amino acids (BCAA) leucine, isoleucine, and valine are essential nutrients that have been associated with diabetes, cancers, and cardiovascular diseases. Observational studies suggest that BCAAs exert homogeneous phenotypic effects, but these findings are inconsistent with results from experimental human and animal studies. Methods Hypothesizing that inconsistencies between observational and experimental BCAA studies reflect bias from shared lifestyle and genetic factors in observational studies, we used data from the UK Biobank and applied multivariable Mendelian randomization causal inference methods designed to address these biases. Results In n  = 97,469 participants of European ancestry (mean age = 56.7 years; 54.1% female), we estimate distinct and often opposing total causal effects for each BCAA. For example, of the 117 phenotypes with evidence of a statistically significant total causal effect for at least one BCAA, almost half (44%, n  = 52) are associated with only one BCAA. These 52 associations include total causal effects of valine on diabetic eye disease [odds ratio = 1.51, 95% confidence interval (CI) = 1.31, 1.76], valine on albuminuria (odds ratio = 1.14, 95% CI = 1.08, 1.20), and isoleucine on angina (odds ratio = 1.17, 95% CI = 1.31, 1.76). Conclusions Our results suggest that the observational literature provides a flawed picture of BCAA phenotypic effects that is inconsistent with experimental studies and could mislead efforts developing novel therapeutics. More broadly, these findings motivate the development and application of causal inference approaches that enable ‘omics studies conducted in observational settings to account for the biasing effects of shared genetic and lifestyle factors. Plain language summary The three branched chain amino acids (BCAAs) leucine, isoleucine, and valine are important building blocks of muscle proteins that are obtained from the diet. Many studies in human populations have examined whether BCAAs affect health and disease. These human studies report results that are inconsistent with results from highly controlled animal studies. Because interest in the therapeutic targeting of BCAAs is growing, we wanted to better understand these discrepancies. Briefly, we used data from a large database that captured many diseases (e.g., cardiovascular disease, cancers, and respiratory disease) and new statistical methods. Our results showed that discrepancies between human studies and animal studies may reflect errors in the ways human studies were designed and conducted. As a result, these human studies may provide a flawed picture of BCAA effects that could mislead efforts developing novel therapeutics. Avery et al. utilize data from the UK Biobank in a multivariable Mendelian randomization study to evaluate the effects of branched chain amino acids (BCAAs) on human disease. Their findings suggest observational studies of BCAA phenotypic effects are prone to substantial error, potentially misleading efforts to develop novel therapeutics.

Advances in technologies to measure a broad set of exposures have led to a range of exposome research efforts. Yet, these efforts have insufficiently integrated methods that incorporate genetic data to strengthen causal inference, despite evidence that many exposome-associated phenotypes are heritable. Objective: We demonstrate how integration of methods and study designs that incorporate genetic data can strengthen causal inference in exposomics research by helping address six challenges: reverse causation and unmeasured confounding, comprehensive examination of phenotypic effects, low efficiency, replication, multilevel data integration, and characterization of tissue-specific effects. Examples are drawn from studies of biomarkers and health behaviors, exposure domains where the causal inference methods we describe are most often applied. Discussion: Technological, computational, and statistical advances in genotyping, imputation, and analysis, combined with broad data sharing and cross-study collaborations, offer multiple opportunities to strengthen causal inference in exposomics research. Full application of these opportunities will require an expanded understanding of genetic variants that predict exposome phenotypes as well as an appreciation that the utility of genetic variants for causal inference will vary by exposure and may depend on large sample sizes. However, several of these challenges can be addressed through international scientific collaborations that prioritize data sharing. Ultimately, we anticipate that efforts to better integrate methods that incorporate genetic data will extend the reach of exposomics research by helping address the challenges of comprehensively measuring the exposome and its health effects across studies, the life course, and in varied contexts and diverse populations. https://doi.org/10.1289/EHP9098.

IntroductionThe independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in >1.5 billion individuals worldwide, but studies have prioritised European populations.MethodsHere, we examined how ancestrally diverse studies could clarify Lp(a)’s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.ResultsFourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a ‘rule out’ for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%–99.9%) across PRS thresholds (80th–99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10−6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects.ConclusionsOur results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps.

Cryptococcosis is a potentially lethal fungal infection of humans caused by organisms within the Cryptococcus neoformans/gattii species complex. Whilst C . neoformans is a relatively common pathogen of immunocompromised individuals, C . gattii is capable of acting as a primary pathogen of immunocompetent individuals. Within the host, both species undergo morphogenesis to form titan cells: exceptionally large cells that are critical for disease establishment. To date, the induction, defining attributes, and underlying mechanism of titanisation have been mainly characterized in C . neoformans . Here, we report the serendipitous discovery of a simple and robust protocol for in vitro induction of titan cells in C . gattii . Using this in vitro approach, we reveal a remarkably high capacity for titanisation within C . gattii , especially in strains associated with the Pacific Northwest Outbreak, and characterise strain-specific differences within the clade. In particular, this approach demonstrates for the first time that cell size changes, DNA amplification, and budding are not always synchronous during titanisation. Interestingly, however, exhibition of these cell cycle phenotypes was correlated with genes associated with cell cycle progression including CDC11 , CLN1 , BUB2 , and MCM6 . Finally, our findings reveal exogenous p-Aminobenzoic acid to be a key inducer of titanisation in this organism. Consequently, this approach offers significant opportunities for future exploration of the underlying mechanism of titanisation in this genus.

Nutritional immunity describes the host-driven manipulation of essential micronutrients, including iron, zinc and manganese. To withstand nutritional immunity and proliferate within their hosts, pathogenic microbes must express efficient micronutrient uptake and homeostatic systems. Here we have elucidated the pathway of cellular zinc assimilation in the major human fungal pathogen Candida albicans. Bioinformatics analysis identified nine putative zinc transporters: four cytoplasmic-import Zip proteins (Zrt1, Zrt2, Zrt3 and orf19.5428) and five cytoplasmic-export ZnT proteins (orf19.1536/Zrc1, orf19.3874, orf19.3769, orf19.3132 and orf19.52). Only Zrt1 and Zrt2 are predicted to localise to the plasma membrane and here we demonstrate that Zrt2 is essential for C. albicans zinc uptake and growth at acidic pH. In contrast, ZRT1 expression was found to be highly pH-dependent and could support growth of the ZRT2-null strain at pH 7 and above. This regulatory paradigm is analogous to the distantly related pathogenic mould, Aspergillus fumigatus, suggesting that pH-adaptation of zinc transport may be conserved in fungi and we propose that environmental pH has shaped the evolution of zinc import systems in fungi. Deletion of C. albicans ZRT2 reduced kidney fungal burden in wild type, but not in mice lacking the zinc-chelating antimicrobial protein calprotectin. Inhibition of zrt2Δ growth by neutrophil extracellular traps was calprotectin-dependent. This suggests that, within the kidney, C. albicans growth is determined by pathogen-Zrt2 and host-calprotectin. As well as serving as an essential micronutrient, zinc can also be highly toxic and we show that C. albicans deals with this potential threat by rapidly compartmentalising zinc within vesicular stores called zincosomes. In order to understand mechanistically how this process occurs, we created deletion mutants of all five ZnT-type transporters in C. albicans. Here we show that, unlike in Saccharomyces cerevisiae, C. albicans Zrc1 mediates zinc tolerance via zincosomal zinc compartmentalisation. This novel transporter was also essential for virulence and liver colonisation in vivo. In summary, we show that zinc homeostasis in a major human fungal pathogen is a multi-stage process initiated by Zrt1/Zrt2-cellular import, followed by Zrc1-dependent intracellular compartmentalisation.

[This corrects the article DOI: 10.1371/journal.ppat.1010321.].

[This corrects the article DOI: 10.1371/journal.ppat.1010321.].

BackgroundThe Brain Trauma Foundation (BTF) Guidelines for the Management of Severe Traumatic Brain Injury (TBI) include intracranial pressure monitoring (ICPM), yet very little is known about ICPM in older adults. Our objectives were to characterize the utilization of ICPM in older adults and identify factors associated with ICPM in those who met the BTF guidelines.MethodsWe analyzed data from the American Association for the Surgery of Trauma Geriatric TBI Study, a registry study conducted among individuals with isolated, CT-confirmed TBI across 45 trauma centers. The analysis was restricted to those aged ≥60. Independent factors associated with ICPM for those who did and did not meet the BTF guidelines were identified using logistic regression.ResultsOur sample was composed of 2303 patients, of whom 66 (2.9%) underwent ICPM. Relative to Glasgow Coma Scale (GCS) score of 13 to 15, GCS score of 9 to 12 (OR 10.2; 95% CI 4.3 to 24.4) and GCS score of <9 (OR 15.0; 95% CI 7.2 to 31.1), intraventricular hemorrhage (OR 2.4; 95% CI 1.2 to 4.83), skull fractures (OR 3.6; 95% CI 2.0 to 6.6), CT worsening (OR 3.3; 95% CI 1.8 to 5.9), and neurosurgical interventions (OR 3.8; 95% CI 2.1 to 7.0) were significantly associated with ICPM. Restricting to those who met the BTF guidelines, only 43 of 240 (18%) underwent ICPM. Factors independently associated with ICPM included intraparenchymal hemorrhage (OR 2.2; 95% CI 1.0 to 4.7), skull fractures (OR 3.9; 95% CI 1.9 to 8.2), and neurosurgical interventions (OR 3.5; 95% CI 1.7 to 7.2).DiscussionWorsening GCS, intraparenchymal/intraventricular hemorrhage, and skull fractures were associated with ICPM among older adults with TBI, yet utilization of ICPM remains low, especially among those meeting the BTF guidelines, and potential benefits remain unclear. This study highlights the need for better understanding of factors that influence compliance with BTF guidelines and the risks versus benefits of ICPM in this population.Level of evidencePrognostic and epidemiological, level III.

The dynamic field of flavin and flavoprotein biochemistry has seen rapid advancement in recent years. This second book of the two volume set is focussing on complex flavoproteins and physical methods. It gives important new insights into the reaction mechanisms of flavin-containing enzymes and the role of flavoproteins in cell signalling pathways, and is an essential reference for all researchers in biochemistry, chemistry, photochemistry and photophysics working on flavoenzymes.