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Abstract Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in GWAS. Using childhood BMI as an example trait, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS of the 12 estimated phenotypes identified 28 genome-wide significant variants at 13 loci, one of which (in DAOA) has not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover unique biological mechanisms influencing quantitative traits.

Conflict of interest: No Introduction and Objectives: Autoimmune hepatitis (AIH) represents the cause in 5-6% of the total amount of liver transplant in Brazilian centers. Factors that impact post-transplant outcomes are not well known. Data from the European registry show an overall survival of 79,4% post AIH liver transplant whereas Latin American numbers are scarce. The aim of this study is to evaluate long-term patient and graft survival after liver transplant due to AIH. Patients / Materials and Methods: This is a retrospective and observational study that included 85 patients with AIH who received liver transplant at a reference center in Brazil, from 1996 to 2023. Demographic data was collected, and survival curves were performed using the Kaplan-Meier method. Results and Discussion: Most of the cohort was composed of white (52,9%) females (71,8%). The median age at transplant timepoint was 27 years, ranging from 11 to 73 years. After LT 15,5% experienced graft lost, with the need of a second or third liver transplant. During the follow-up 32,9% of the patients died, with a mean survival time of 17.5 years (±1.4). The overall survival in 5 years was approximately 80%. There was no difference in survival between males and females. Conversely, patients who were submitted to more than one liver transplant had a poorer overall survival. (Fig.1). Conclusions: Preliminary results show a good overall post-transplant survival for AIH, which is in compass with international reports. The necessity of retransplant conveys a worse prognosis. Other features that might impact overall and graft survival are to be further evaluated in this cohort.

Abstract Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Diabetes mellitus (DM) complications are a burden to health care systems due to the associated consequences of poor glycemic control and the side effects of insulin therapy. Recently. adjuvant therapies, such as vanadium compounds, have gained attention due to their potential to improve glucose homeostasis in patients with diabetes. In order to determine the anti-diabetic and antioxidant effects of the oxidovanadium(IV) complex (Et3NH)2[{VO(OH}2)(ox)2(µ–ox)] or Vox2), rats with streptozotocin (STZ)-induced diabetes were treated with 30 and 100 mg/kg of Vox2, orally administered for 12 days. Vox2 at 100 mg/kg in association with insulin caused a 3.4 times decrease in blood glucose in STZ rats (424 mg/dL), reaching concentrations similar to those in the normoglycemic animals (126 mg/dL). Compared to insulin alone, the association with Vox2 caused an additional decrease in blood glucose of 39% and 65% at 30 and 100 mg/kg, respectively, and an increased pancreatic GSH levels 2.5 times. Vox2 alone did not cause gastrointestinal discomfort, diarrhea, and hepatic or renal toxicity and was not associated with changes in blood glucose level, lipid profile, or kidney or liver function. Our results highlight the potential of Vox2 in association with insulin in treating diabetes.

Abstract Background Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. Methods We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10–18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). Results MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (P difference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. Conclusions Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age.

Introduction and Objectives: Cryptogenic chronic hepatitis is an increasing cause of liver transplantation and affects 5-15% of patients with chronic liver diseases. This study aimed to investigate possible underlying causes of presumed cryptogenic liver disease referred to specialized liver centers by general practitioners in Brazil and to propose a new diagnostic algorithm including metabolic-dysfunction-associated fatty liver disease (MAFLD) definition and lysosomal acid lipase deficiency (LAL-D) investigation. Materials and Methods: A retrospective multicentric Brazilian cohort of patients with presumed chronic cryptogenic hepatitis was reanalyzed with respect to their clinical, laboratory and histological data using Czaja´s algorithm (2011). Results: 326 patients [mean age 60 (46-68) years, 42.9% males] were initially included, 35.7% with cirrhosis. Forty-five individuals were excluded due to an incomplete etiological investigation. Using Czaja´s algorithm, diagnosis of nonalcoholic fatty liver disease could be established in 60 patients (21.3%), alpha-1-antitrypsin deficiency in 9 (3.2%), alcoholic liver disease in 7 (2.7%), autoimmune hepatitis in 5 (1.78%), hemochromatosis in 5 (1.78%), biliary-related hepatitis in 4 (1.4%), viral hepatitis in 4 (1.4%), Budd Chiari in 4 (1.4%), glycogenosis in 3 (1%), drug-induced liver injury in 2 (0.7%), and Wilson disease in 1 (0.35%). LAL-D was demonstrated in 3 individuals (1%). One hundred seventy-five patients remained with cryptogenic hepatitis (53.6%) (FIGURE A). During follow-up, 40 of those patients were submitted to liver transplantation and 19 (47.5%) were retrospectively diagnosed with non-alcoholic steatohepatitis after histopathological examination of the explanted liver. By including MAFLD in the first step of the new algorithm, 100 patients would have been diagnosed (34.9%), reducing the number of individuals without a diagnosis by 18.3% (FIGURE B). Conclusions: One-third of patients with initially presumed cryptogenic liver disease were diagnosed with MAFLD. Despite being a rare disease, LAL-D investigation should be considered for individuals with chronic liver disease of unknown etiology. An updated diagnostic algorithm is proposed for those individuals.

Copyright of Brazilian Journal of Production Engineering / Revista Brasileira de Engenharia de Produção is the property of Brazilian Journal of Production Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Brazilian Journal of Production Engineering / Revista Brasileira de Engenharia de Produção is the property of Brazilian Journal of Production Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Brazilian Journal of Production Engineering / Revista Brasileira de Engenharia de Produção is the property of Brazilian Journal of Production Engineering and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Here, the authors report a multi-ethnic genome wide association meta-analysis of 12 studies from the International Cataract Genetics Consortium. They find six new loci associated with age-related nuclear cataract, in addition to replicating the association at CRYAA, and suggest a strong genetic link between age-related nuclear and congenital cataracts.

Background: Panax ginseng Meyer has widely been used as a traditional herbal medicine because of its diverse health benefits. Amounts of ginseng compounds, mainly ginsenosides, vary according to seasons, varieties, geographical regions, and age of ginseng plants. However, no study has comprehensively determined perturbations of various metabolites in ginseng plants including roots and leaves as they grow. Methods: Nuclear magnetic resonance (1H NMR)–based metabolomics was applied to better understand the metabolic physiology of ginseng plants and their association with climate through global profiling of ginseng metabolites in roots and leaves during whole growing periods. Results: The results revealed that all metabolites including carbohydrates, amino acids, organic acids, and ginsenosides in ginseng roots and leaves were clearly dependent on growing seasons from March to October. In particular, ginsenosides, arginine, sterols, fatty acids, and uracil diphosphate glucose–sugars were markedly synthesized from March until May, together with accelerated sucrose catabolism, possibly associated with climatic changes such as sun exposure time and rainfall. Conclusion: This study highlights the intrinsic metabolic characteristics of ginseng plants and their associations with climate changes during their growth. It provides important information not only for better understanding of the metabolic phenotype of ginseng but also for quality improvement of ginseng through modification of cultivation. Keywords: Metabolic physiology, Metabolomics, NMR, Panax ginseng

The usefulness of genomic prediction (GP) for many animal and plant breeding programs has been highlighted for many studies in the last 20 years. In maize breeding programs, mostly dedicated to delivering more highly adapted and productive hybrids, this approach has been proved successful for both large- and small-scale breeding programs worldwide. Here, we present some of the strategies developed to improve the accuracy of GP in tropical maize, focusing on its use under low budget and small-scale conditions achieved for most of the hybrid breeding programs in developing countries. We highlight the most important outcomes obtained by the University of São Paulo (USP, Brazil) and how they can improve the accuracy of prediction in tropical maize hybrids. Our roadmap starts with the efforts for germplasm characterization, moving on to the practices for mating design, and the selection of the genotypes that are used to compose the training population in field phenotyping trials. Factors including population structure and the importance of non-additive effects (dominance and epistasis) controlling the desired trait are also outlined. Finally, we explain how the source of the molecular markers, environmental, and the modeling of genotype–environment interaction can affect the accuracy of GP. Results of 7 years of research in a public maize hybrid breeding program under tropical conditions are discussed, and with the great advances that have been made, we find that what is yet to come is exciting. The use of open-source software for the quality control of molecular markers, implementing GP, and envirotyping pipelines may reduce costs in an efficient computational manner. We conclude that exploring new models/tools using high-throughput phenotyping data along with large-scale envirotyping may bring more resolution and realism when predicting genotype performances. Despite the initial costs, mostly for genotyping, the GP platforms in combination with these other data sources can be a cost-effective approach for predicting the performance of maize hybrids for a large set of growing conditions.

Abstract Background The selection of hybrids is an essential step in maize breeding. However, evaluating a large number of hybrids in field trials can be extremely costly. However, genomic models can be used to predict the expected performance of un-tested genotypes. Bayesian models offer a very flexible framework for hybrid prediction. The Bayesian methodology can be used with parametric and semi-parametric assumptions for additive and non-additive effects. Furthermore, samples from the posterior distribution of Bayesian models can be used to estimate the variance due to general and specific combining abilities even in cases where additive and non-additive effects are not mutually orthogonal. Also, the use of Bayesian models for analysis and prediction of hybrid performance has remained fairly limited. Results We provided an overview of Bayesian parametric and semi-parametric genomic models for prediction of agronomic traits in maize hybrids and discussed how these models can be used to decompose the genotypic variance into components due to general and specific combining ability. We applied the methodology to data from 906 single cross tropical maize hybrids derived from a convergent population. Our results show that: (1) non-additive effects make a sizable contribution to the genetic variance of grain yield; however, the relative importance of non-additive effects was much smaller for ear and plant height; (2) genomic prediction can achieve relatively high accuracy in predicting phenotypes of un-tested hybrids and in pre-screening. Conclusions Genomic prediction can be a useful tool in pre-screening of hybrids and could contribute to the improvement of the efficiency and efficacy of maize hybrids breeding programs. The Bayesian framework offers a great deal of flexibility in modeling hybrid performance. The methodology can be used to estimate important genetic parameters and render predictions of the expected hybrid performance as well measures of uncertainty about such predictions.

Abstract Background Genetic and environmental risk factors contribute to periodontal disease, but the underlying susceptibility pathways are not fully understood. Epigenetic mechanisms are malleable regulators of gene function that can change in response to genetic and environmental stimuli, thereby providing a potential mechanism for mediating risk effects in periodontitis. The aim of this study is to identify epigenetic changes across tissues that are associated with periodontal disease. Methods Self-reported gingival bleeding and history of gum disease, or tooth mobility, were used as indicators of periodontal disease. DNA methylation profiles were generated using the Infinium HumanMethylation450 BeadChip in whole blood, buccal, and adipose tissue samples from predominantly older female twins (mean age 58) from the TwinsUK cohort. Epigenome-wide association scans (EWAS) of gingival bleeding and tooth mobility were conducted in whole blood in 528 and 492 twins, respectively. Subsequently, targeted candidate gene analysis at 28 genomic regions was carried out testing for phenotype-methylation associations in 41 (tooth mobility) and 43 (gingival bleeding) buccal, and 501 (tooth mobility) and 556 (gingival bleeding) adipose DNA samples. Results Epigenome-wide analyses in blood identified one CpG-site (cg21245277 in ZNF804A) associated with gingival bleeding (FDR = 0.03, nominal p value = 7.17e−8) and 58 sites associated with tooth mobility (FDR

Abstract Background Intermittent fasting and time-restricted diets are associated with lower risk biomarkers for cardio-metabolic disease. The shared mechanisms underpinning the similar physiological response to these events is not established, but circadian rhythm could be involved. Here we investigated the transcriptional response to fasting in a large cross-sectional study of adipose and skin tissue from healthy volunteers (N = 625) controlling for confounders of circadian rhythm: time of day and season. Results We identified 367 genes in adipose and 79 in skin whose expression levels were associated (FDR

Genome-wide association studies (GWAS) is one of the most popular methods of studying the genetic control of traits. This methodology has been intensely performed on inbred genotypes to identify causal variants. Nonetheless, the lack of covariance between the phenotype of inbred lines and their offspring in cross-pollinated species (such as maize) raises questions on the applicability of these findings in a hybrid breeding context. To address this topic, we incorporated previously reported parental lines GWAS information into the prediction of a low heritability trait in hybrids. This was done by marker-assisted selection based on significant markers identified in the lines and by genomic prediction having these markers as fixed effects. Additive-dominance GWAS of hybrids, a non-conventional procedure, was also performed for comparison purposes. Our results suggest that incorporating information from parental inbred lines GWAS led to decreases in the predictive ability of hybrids. Correspondingly, inbred lines and hybrids-based GWAS yielded different results. These findings do not invalidate GWAS on inbred lines for selection purposes, but mean that it may not be directly useful for hybrid breeding.

Abstract Background Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet. Methods Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS). Results We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10–6 for rs612529 for association to atopic dermatitis (AD). Conclusion Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.

Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.

Several studies have shown differences in the abilities of maize genotypes to facilitate or impede Azospirillum brasilense colonization and to receive benefits from this association. Hence, our aim was to study the genetic control, heterosis effect and the prediction accuracy of the shoot and root traits of maize in response to A. brasilense. For that, we evaluated 118 hybrids under two contrasting scenarios: i) N stress (control) and ii) N stress plus A. brasilense inoculation. The diallel analyses were performed using mixed model equations, and the genomic prediction models accounted for the general and specific combining ability (GCA and SCA, respectively) and the presence or not of G×E effects. In addition, the genomic models were fitted considering parametric (G-BLUP) and semi-parametric (RKHS) kernels. The genotypes showed significant inoculation effect for five root traits, and the GCA and SCA were significant for both. The GCA in the inoculated treatment presented a greater magnitude than the control, whereas the opposite was observed for SCA. Heterosis was weakly influenced by the inoculation, and the heterozygosity and N status in the plant can have a role in the benefits that can be obtained from this Plant Growth-Promoting Bacteria (PGPB). Prediction accuracies for N stress plus A. brasilense ranged from 0.42 to 0.78, depending on the scenario and trait, and were higher, in most cases, than the non-inoculated treatment. Finally, our findings provide an understanding of the quantitative variation of maize responsiveness to A. brasilense and important insights to be applied in maize breeding aiming the development of superior hybrids for this association.

ABSTRACT White mold, caused by Sclerotinea sclerotiorum (Lib.) de Bary is one of the most important diseases of the common bean (Phaseolus vulgaris L.) worldwide. Physiological resistance and traits related to disease avoidance such as architecture contribute to field resistance. The aim of this study was to verify the efficiency of recurrent selection in physiological resistance to white mold, “Carioca” grain type and upright habit in common bean. Thirteen common bean lines with partial resistance to white mold were intercrossed by means of a circulant diallel table, and seven recurrent selection cycles were obtained. Of these cycles, progenies of the S0:1, S0:2 and S0:3 generations of cycles III, IV, V and VI were evaluated. The best (8 to 10) progenies of the seven cycles were also evaluated, in two experiments, one in the greenhouse and one in the field. Lattice and/or randomized block experimental designs were used. The traits evaluated were: resistance to white mold by the straw test method, growth habit and grain type. The most resistant progenies were selected based on the average score of resistance to white mold. Subsequently, they were evaluated with regard to grain type and growth habit. Recurrent selection allowed for genetic progress of about 11 % per year for white mold resistance and about 15 % per year for the plant architecture. There was no gain among cycles for grain type. Progeny selection and recurrent selection were efficient for obtaining progenies with a high level of resistance to white mold with “Carioca” grain type and upright habit.

The objectives of this study were to verify the resistance of common bean lines derived from recurrent selection for white mold resistance and to identify those more stable to different isolates; to compare the aggressiveness of different Sclerotinia sclerotiorum isolates; and to verify isolates x lines interaction. Fifteen common bean lines were evaluated, twelve derived from recurrent selection for white mold resistance, one non-adapted source of resistance (Cornell 605), one moderately resistant and adapted (VC-16) and one susceptible to white mold (Corujinha). Ten isolates were used to inoculate the common bean lines through the straw test. A total of ten experiments were performed, one for each isolate. The randomized complete block design with three replications was used in each experiment. Each plot had five plants inoculated in two main branches, therefore the plot data was the average of the ten evaluations through a scale of nine grades. Diallel analysis were used to estimate the general reaction capacity (lines) and general aggressiveness capacity (isolates) to measure the resistance to white mold and the aggressiveness of the isolates, respectively. The GGE biplot analysis was used to group the common bean lines based on their resistance alleles and identify those more instable to the isolates. The resistance of the lines P4 and P10 was similar to Cornell 605, and they had stable reaction to different isolates and "Carioca" grain type. The lines of the advanced cycles of recurrent selection accumulated more favorable alleles than those of the first cycles, confirming the efficiency of the recurrent selection to increase white mold resistance in common bean. In addition, it was identified more aggressive isolates, UFLA 109 and UFLA 116, and a small magnitude of isolates x lines interaction, indicating a predominance of the horizontal resistance of the lines.

Chronic hyperglycemia, which is present in all types of diabetes, increases the formation of advanced glycation end-products (AGEs). The interaction of AGEs with receptor of advanced glycation end-products (RAGE) initiates a cascade of pro-inflammatory and pro-coagulant processes that result in oxidative stress, stimulating the formation and accumulation of more AGE molecules. This cyclic process, denominated metabolic memory, may explain the persistency of diabetic vascular complications in patients with satisfactory glycemic control. The RAGE found in several cell membranes is also present in soluble isoforms (esRAGE and cRAGE), which are generated by alternative deoxyribonucleic acid splicing or by proteolytic cleavage. This review focuses on new research into these mediators as potential biomarkers for vascular complications in diabetes.

A backcross breeding program between commercial common bean cultivars (VC3 and M20) and sources of resistance(Ex-Rico 23 and G122) was conducted with a view toward selecting carioca (beige with brown stripes) progenies resistant to whitemold. Forty-eight progenies (27 F2:6 BC1 and 21 F1:5 BC2) were evaluated for yield, growth habit, grain type and pathogen responseby two methodologies for assessment (“straw test” and “oxalic acid”). The methods were effective in discriminating the progenies,showing differing results, for they may assess different resistance mechanisms. Thus, they should be used together. Simultaneousselection for yield, growth habit, grain type and white mold resistance proved to be viable. The most appropriate strategy was to uselower intensities of selection and prioritize traits such as resistance and grain type, which are essential for commercial acceptance.Two progenies proved their superiority for the breeding program for they combine the traits of resistance and favorable grain type.

[This corrects the article DOI: 10.1371/journal.pgen.1005378.].