Health effects of high serum calcium levels:Updated phenome-wide Mendelian randomisation investigation and review of Mendelian randomisation studies

BACKGROUND: Calcium plays a role in a wide range of biological functions. Here we conducted a phenome-wide Mendelian randomisation (MR-PheWAS) analysis and a systematic review for MR studies to comprehensively investigate the health effects of serum calcium. METHODS: One-hundred and thirty genetic variants strongly associated with serum calcium levels were used as instrumental variables. A phenome-wide association analysis (PheWAS) was conducted to examine the associations of genetically predicted serum calcium with 1473 distinct phenotypes in the UK Biobank including 339,197 individuals. Observed associations in PheWAS were further tested for replication in two-sample MR replication analysis. A systematic review for MR studies on serum calcium was performed to synthesize the published evidence and compare with the current MR-PheWAS findings. FINDINGS: Higher genetically predicted calcium levels were associated with decreased risk of 5 diseases in dermatologic and musculoskeletal systems and increased risk of 17 diseases in circulatory, digestive, endocrine, genitourinary and immune systems. Eight associations were replicated in two-sample MR analysis. These included decreased risk of osteoarthritis and increased risk of coronary artery disease, myocardial infarction, coronary atherosclerosis, hyperparathyroidism, disorder of parathyroid gland, gout, and calculus of kidney and ureter with increased serum calcium. Systematic review of 25 MR studies provided supporting evidence on five out of the eight disease outcomes, while the increased risk of gout, hyperparathyroidism and disorder of parathyroid gland were novel findings. INTERPRETATION: This study found wide-ranged health effects of high serum calcium, which suggests that the benefits and adversities of strategies promoting calcium intake should be assessed. FUNDING: ET is supported by a CRUK Career Development Fellowship (C31250/A22804). XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province. SCL acknowledges research funding from the Swedish Heart Lung Foundation (Hjärt-Lungfonden, 20210351), the Swedish Research Council (Vetenskapsrådet, 2019-00977), and the Swedish Cancer Society (Cancerfonden)

Prenatal Choline Supplementation during High-Fat Feeding Improves Long-Term Blood Glucose Control in Male Mouse Offspring

Maternal obesity increases the risk of metabolic dysregulation in rodent offspring, especially when offspring are exposed to a high-fat (HF), obesogenic diet later in life. We previously demonstrated that maternal choline supplementation (MCS) in HF-fed mouse dams during gestation prevents fetal overgrowth and excess adiposity. In this study, we examined the long-term metabolic influence of MCS. C57BL/6J mice were fed a HF diet with or without choline supplementation prior to and during gestation. After weaning, their pups were exposed to either a HF or control diet for 6 weeks before measurements. Prenatal and post-weaning dietary treatments led to sexually dimorphic responses. In male offspring, while post-weaning HF led to impaired fasting glucose and worse glucose tolerance (p \u3c 0.05), MCS in HF dams (HFCS) attenuated these changes. HFCS (versus maternal normal fat control) appeared to improve metabolic functioning of visceral adipose tissue during post-weaning HF feeding, preventing the elevation in leptin and increasing (p \u3c 0.05) mRNA expression of insulin receptor substrate 1 (Irs1) that promotes peripheral insulin signaling in male offspring. In contrast, MCS had minimal effects on metabolic outcomes of female offspring. In conclusion, MCS during HF feeding in mice improves long-term blood glucose homeostasis in male offspring when they are faced with a postnatal obesogenic environment

Gut microbiota-derived metabolite Trimethylamine-N-oxide (TMAO) and multiple health outcomes:an umbrella review and updated meta-analysis

BACKGROUND: Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO levels are linked to a wide range of health outcomes. OBJECTIVES: This study aimed to summarize health outcomes related to circulating TMAO levels. METHODS: We searched Embase, Medline, Web of Science and Scopus databases from inception to 15 February 2022 to identify and update meta-analyses examining the associations between TMAO and multiple health outcomes. For each health outcome, we estimated the summary effect size, 95% prediction confidence interval (CI), between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate the evidence credibility of the identified associations. RESULTS: This umbrella review identified 24 meta-analyses that investigated the association between circulating TMAO levels and health outcomes including all-cause mortality, cardiovascular diseases, diabetes mellitus, cancer, and renal function. We updated these meta-analyses by including a total of 82 individual studies in 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found six (33%) associations (i.e., all-cause mortality, cardiovascular disease mortality, major adverse cardiovascular events, hypertension, diabetes mellitus, and glomerular filtration rate) to present highly suggestive evidence. CONCLUSIONS: TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension, cardiovascular disease, diabetes, cancer and kidney function. Further studies are needed to investigate whether circulating TMAO levels could be an intervention target for chronic disease

Named Entity Recognition Model Based on k-best Viterbi Decoupling Knowledge Distillation

Knowledge distillation is a general approach to improve the performance of the named entity recognition (NER) models. However, the classical knowledge distillation loss functions are coupled, which leads to poor logit distillation. In order to decouple and effectively improve the performance of logit distillation, this paper proposes an approach, k-best Viterbi decoupling knowledge distillation (kvDKD), which combines k-best Viterbi decoding to improve the computational efficiency, effectively improving the model performance. Additionally, the NER based on deep learning is easy to introduce noise in data augmentation. Therefore, a data augmentation method combining data filtering and entity rebalancing algorithm is proposed, aiming to reduce noise introduced by the original dataset and to enhance the problem of mislabeled data, which can improve the quality of data and reduce overfitting. Based on the above method, a novel named entity recognition model NER-kvDKD (named entity recognition model based on k-best Viterbi decoupling knowledge distillation) is proposed. The comparative experimental results on the datasets of MSRA, Resume, Weibo, CLUENER and CoNLL-2003 show that the proposed method can improve the generalization ability of the model and also effectively improves the student model performance

Association between exposure to the Chinese Famine in different stages of early life and decline in cognitive functioning in adulthood

Objective: To investigate whether exposure to the Chinese Famine in different life stages of early life is associated with cognitive functioning decline in adulthood.Methods: We recruited 1366 adults born between 1952 and 1964 and divided them into fetal-exposed, early childhood-exposed (1-3 years old during the famine), mid childhood-exposed (4-6 years old during the famine), late childhood-exposed (7-9 years old during the famine) and non-exposed groups. A selection of cognitive tests was administered to assess their cognitive performance. Association between malnutrition in different famine exposure periods and adult cognitive performance was estimated by multivariate logistic and multiple linear regression analyses. Results: There were significant differences in cognitive performance between subjects exposed to famine during different life stages. For the general cognitive tests, fetal-exposed period was associated with decreased scores of the Mini-Mental Status Examination (MMSE) and late childhood-exposed with decreased scores of the Montreal Cognitive Assessment (MoCA). We also found exposure to famine during mid and late childhood was associated with worse performance on the Stroop color and word test.Conclusion: Famine exposure in utero and during childhood is associated with overall and specific cognitive decline, affecting selective attention and response inhibition particularly

Data from: New locus reveals the genetic architecture of sex reversal in the Chinese tongue sole (Cynoglossus semilaevis)

Sex reversal in insects, amphibians, reptiles, and fishes is a complicated and interesting biological phenomenon. Sex reversal changes the sex ratio of populations and may complicate breeding schemes. In the Chinese tongue sole (Cynoglossus semilaevis), genetic females may change into pseudomales, thereby increasing aquaculture costs because of the lower growth rate of the males than that of the females. Here, we identify a new locus associated with sex reversal; this single nucleotide polymorphism (SNP) is located in the third intron of the doublesex and mab-3 related transcription factor 1 (Dmrt1) gene on the Z chromosome (named Cyn_Z_8564889) and has two alleles, A and G. Cyn_Z_8564889 regulates sex reversal interactively with our previously detected SNP (Cyn_Z_6676874), with the genetic females simultaneously carrying the T allele of Cyn_Z_6676874 and the A allele of Cyn_Z_8564889 changing into pseudomales. Other Dmrt1 polymorphisms were detected, which formed two haplotypes. Two SNPs in the second exon of Dmrt1 result in amino acid changes, suggesting that Dmrt1 is essential in sex reversal. We also verified that pseudomales produce no or little W sperm. The interaction and linkage between Cyn_Z_6676874 and Cyn_Z_8564889 and the absence of W sperm from pseudomales unravel the genetic architecture of sex reversal in C. semilaevis

sex reversal of tongue sole

supplementary data description File_S1_phenotypes.txt contains fish ID, genotypic sex, phenotypic sex, allele at SNP Cyn_Z_6676874, incidence of sex reversal. File_S2_genotypes.txt contains ID and genotypes of 33410 markers, which are expressed as 012, 0 and 2 stand for homozygotes of each alleles, and 1 for heterozygote. File_S3_SNP_info.txt contains three columns, they are marker name, chromosome, and position in order

Reference Gene Selection for Quantitative Real-Time PCR of Mycelia from Lentinula edodes under High-Temperature Stress

Housekeeping genes are important for measuring the transcription expression of functional genes; 10 traditional reference genes, TUB, TUA, GADPH, EF1, 18S, GTP, ACT, UBI, UBC, and H2A, were tested for their adequacy in Lentinula edodes (L. edodes). Using specific primers, mRNA levels of these candidate housekeeping genes were evaluated in mycelia of L. edodes, which were treated with high-temperature stress at 37°C for 0, 4, 8, 12, 18, and 24 hours. After treatment, expression stability of candidate genes was evaluated using three statistical software programs: geNorm, NormFinder, and BestKeeper. According to geNorm, TUB had the lowest M values in L. edodes strains 18 and 18N44. Using NormFinder, the best candidate reference gene in strain 18 was TUB (0.030), and the best candidate reference gene in strain 18N44 was UBI (0.047). In BestKeeper analysis, the standard deviation (SD) values of UBC, TUA, H2A, EF1, ACT, 18S, and GTP in strain 18 and those of GADPH and GTP in strain 18N44 were greater than 1; thus, these genes were disqualified as reference genes. Taken together, only UBI and TUB were found to be desirable reference genes by BestKeeper software. Based on the results of three software analyses, TUB was the most stable gene under all conditions and was verified as an appropriate reference gene for quantitative real-time polymerase chain reaction in L. edodes mycelia under high-temperature stress