Individualized detection of TMPRSS2-ERG fusion status in prostate cancer: a rank-based qualitative transcriptome signature.

BACKGROUND: TMPRSS2-ERG (T2E) fusion is highly related to aggressive clinical features in prostate cancer (PC), which guides individual therapy. However, current fusion prediction tools lacked enough accuracy and biomarkers were unable to be applied to individuals across different platforms due to their quantitative nature. This study aims to identify a transcriptome signature to detect the T2E fusion status of PC at the individual level. METHODS: Based on 272 high-throughput mRNA expression profiles from the Sboner dataset, we developed a rank-based algorithm to identify a qualitative signature to detect T2E fusion in PC. The signature was validated in 1223 samples from three external datasets (Setlur, Clarissa, and TCGA). RESULTS: A signature, composed of five mRNAs coupled to ERG (five ERG-mRNA pairs, 5-ERG-mRPs), was developed to distinguish T2E fusion status in PC. 5-ERG-mRPs reached 84.56% accuracy in Sboner dataset, which was verified in Setlur dataset (n = 455, accuracy = 82.20%) and Clarissa dataset (n = 118, accuracy = 81.36%). Besides, for 495 samples from TCGA, two subtypes classified by 5-ERG-mRPs showed a higher level of significance in various T2E fusion features than subtypes obtained through current fusion prediction tools, such as STAR-Fusion. CONCLUSIONS: Overall, 5-ERG-mRPs can robustly detect T2E fusion in PC at the individual level, which can be used on any gene measurement platform without specific normalization procedures. Hence, 5-ERG-mRPs may serve as an auxiliary tool for PC patient management.

Impact of left atrial appendage thrombus location on diagnostic accuracy of cardiac CT: a single-centre case-control study.

OBJECTIVE: Cardiac CT (CCT) is an emerging non-invasive modality for assessing left atrial appendage (LAA) thrombus, but the results were conflicting. Our study aims to evaluate the accuracy of CCT for detecting LAA thrombus in patients undergoing catheter ablation of atrial fibrillation, using trans-oesophageal echocardiography (TEE) as the reference standard. DESIGN: Case-control study. SETTING: Patient data were collected from a tertiary hospital in China between 2017 and 2022. PARTICIPANTS: The study enrolled 726 patients (male: 60.2%, age: 61±11 years) who had both TEE and CCT before catheter ablation of atrial fibrillation. MEASURES: The CCT protocol consisted of one angiographic phase and one delayed scan 30 s later. LAA thrombi were defined as solid masses on TEE or persistent defects on CCT. The thrombus dimension and location, the LAA filling and emptying flow velocity were assessed by TEE. RESULTS: Of the 57 (7.9%) patients with LAA thrombi identified by TEE, 29 (50.9%) were located at the LAA ostium, and 28 (49.1%) were in the LAA. The former showed higher motility following blood flow and heartbeats than the latter. The CCT detected 14 (48.3%) of the LAA-ostium thrombi but 25 (89.3%) of those in the LAA (p=0.001). The LAA-ostium thrombi with the LAA mean flow velocity >0.35 m/s and maximum diameters <10 mm were more prone to have CCT false-negative results. CONCLUSION: For patients undergoing catheter ablation for atrial fibrillation, CCT with a 30 s delay scan is less sensitive to LAA thrombi than TEE, especially for LAA-ostium thrombi with smaller sizes and higher LAA flow velocity.

Up-regulated SPP1 increases the risk from IPF to lung cancer via activating the pro-tumor macrophages.

The incidence of lung cancer (LC) in Idiopathic Pulmonary Fibrosis (IPF) patients is more than twice that in non-IPF. This study aims to investigate IPF-to-LC pathogenesis and to develop a predictor for detecting IPF predisposing patients to LC. We conducted unsupervised clustering to detect high-risk subtypes from IPF to LC. Subsequently, we performed single-cell RNA-seq analysis to characterize high-risk IPF by examining the immune microenvironment. We identified 42 common immune function-related pathogenic genes between IPF and LC. We developed an LC risk classifier for IPF patients, comprising five genes: SPP1, MMP9, MMP12, FABP4, and IL1B. The five-gene classifier can successfully distinguish the high-risk population from IPF patients. High-risk IPF patients exhibited an immunosuppressive microenvironment with higher oncogene expression than low-risk patients. Single-cell analysis revealed that SPP1+ macrophages at the terminal of macrophages' developmental trajectory may promote the progression from IPF to LC. The strong crosstalk between SPP1+ macrophages and inflammation-related cancer-associated fibroblasts promoted the tumorigenic process in IPF. In vitro, assays showed that co-culturing macrophages overexpressing SPP1 with MRC-5 cells induced the transition of fibroblasts into cancer-associated fibroblasts. SPP1 produced by macrophages promoted epithelial-mesenchymal transition in alveolar epithelial cells via stimulating the upregulation of N-cadherin and Vimentin in MLE-12 cells. This study provided a novel method to identify the LC risk population from IPF, revealing the cellular interactions involved in the transition from IPF to LC. Our findings highlighted SPP1 as a critical driver in IPF progression, offering a potential target for therapy in fibrosis.

Adsorption and Visible Photocatalytic Synergistic Removal of a Cationic Dye with the Composite Material BiVO4/MgAl-LDHs.

Adsorption and photocatalysis are effective in removing organic pollutants from wastewater. This study is based on the memory effects of MgAl-layered double hydroxides (MgAl-LDHs) after high-temperature calcination. By introducing bismuth vanadate (BiVO4) during the reformation of the layered structure via contact with water, a composite material BiVO4/MgAl-LDHs with enhanced adsorption and visible light catalytic performance was synthesized. The effects of the calcination temperature, ratio, initial methylene blue (MB) concentration, and catalyst dosage on the adsorption and photocatalytic performance were investigated. The BiVO4/MgAl-LDHs showed better photocatalytic performance than the pure BiVO4 and MgAl-LDHs. Under the optimal conditions, the proportion of MB adsorbed in 20 min was 66.1%, and the percentage of MB degraded during 100 min of photolysis was 92.4%. The composite photocatalyst showed good chemical stability and cyclability, and the adsorption-degradation rate was 86% after four cycles. Analyses of the adsorption and photocatalytic mechanisms for the composite material showed that synergistic adsorption and visible light photocatalysis contributed to the excellent catalytic performance of the BiVO4/MgAl-LDHs. A highly adsorbent photocatalytic composite material exhibiting outstanding performance was prepared via a simple, cost-effective, and environmentally friendly method, providing reference information for the removal of organic pollutants from liquids.

Mutant RB1 enhances therapeutic efficacy of PARPis in lung adenocarcinoma by triggering the cGAS/STING pathway.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non-small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.

Identification of a coagulation-related signature correlated with immune infiltration and their prognostic implications in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LUAD) is a fatal form of lung cancer with a poor prognosis. Coagulation system had been confirmed closely related to tumor progression and the hypercoagulable state encouraged the immune infiltration and development of tumor cells, leading to a poor prognosis in cancer patients. However, the use of the coagulation-related genes (CRGs) for prognosis in LUAD has yet to be determined. In this study, we constructed an immune-related signature (CRRS) and identified a potential coagulation-related biomarker (P2RX1). METHODS: We obtained a total of 209 CRGs based on two coagulation-related KEGG pathways, then developed the CRRS signature by using the TCGA-LUAD RNA-seq data via the procedure of LASSO-Cox regression, stepwise-Cox regression, univariate and multivariate Cox regression. Grouped by the CRRS, Kaplan-Meier survival curves and receiver operating characteristic curves were drawn for the training and validation sets, respectively. In addition, single-sample gene set enrichment analysis was exploited to explore immune infiltration level. Moreover, immunophenotypes and immunotherapy grouped by CRRS were further analyzed. RESULTS: We developed an immune-related signature (CRRS) composed of COL1A2, F2, PLAUR, C4BPA, and P2RX1 in LUAD. CRRS was an independent risk factor for overall survival and displayed stable and powerful performance. Additionally, CRRS possessed distinctly superior accuracy than traditional clinical variables and molecular features. Functional analysis indicated that the differentially high expressed genes in the low-risk group significantly enriched in T cell and B cell receptor signaling pathways. The low-risk group was sensitive to anti-PD-1/PD-L1 immunotherapy and displayed abundant immune infiltration and immune checkpoint gene expression. Finally, we identified an independent prognostic gene P2RX1. Low expression of P2RX1 associated with poor overall survival and decreased immune infiltration. CONCLUSIONS: Our study revealed a significant correlation between CRRS and immune infiltration. CRRS could serve as a promising tool to improve the clinical outcomes for individual LUAD patients.

Erratum: [Corrigendum] MicroRNA­23a inhibits endometrial cancer cell development by targeting SIX1.

[This corrects the article DOI: 10.3892/ol.2019.10694.].

Functional diversity of sodium channel variants in common eastern bumblebee, Bombus impatiens.

For the past decade, Colony Collapse Disorder has been reported worldwide. Insecticides containing pyrethroids may be responsible for a decline in bees, which are more sensitive to pyrethroids compared with other insects. Voltage-gated sodium channels (Nav ) are the major target sites of pyrethroids, and the sodium channel diversity is generated through extensive alternative splicing and RNA editing. In this study, we cloned and analyzed the function of variants of the Nav channel, BiNav , from Bombus impatiens. BiNav covers a 46 kb genome region including 30 exons. Sequence analysis of 56 clones showed that the clones can be grouped into 22 splice types with 11 optional exons (exons j, w, p, q, r, b, e, t, l/k, and z). Here, a special alternative exon w is identified, encoding a stretch of 31 amino acid resides in domain I between S3 and S4. RNA editing generates 18 amino acid changes in different positions in individual variants. Among 56 variants examined, only six variants generated sufficient sodium currents for functional characterization in Xenopus oocytes. In the presence of B. impatiens TipE and TEH1, the sodium current amplitude of BiNav 1-1 increased by fourfold, while TipE of other insect species had no effect on the expression. Abundant alternative splicing and RNA editing of BiNav suggests the molecular and functional pharmacology diversity of the Nav channel for bumblebees. This study provides a theoretical basis for the design of insecticides that specifically target pests without affecting beneficial insects.

Resting-state fMRI reveals changes within the anxiety and social avoidance circuitry of the brain in mice with psoriasis-like skin lesions.

Psoriasis is an autoimmune skin disease that often co-occurs with psychological morbidities such as anxiety and depression, and psychosocial issues also lead psoriasis patients to avoid other people. However, the precise mechanism underlying the comorbidity of psoriasis and anxiety is unknown. Also, whether the social avoidance phenomenon seen in human patients also exists in psoriasis-like animal models remains unknown. In the present study, anxiety-like behaviours and social avoidance-like behaviours were observed in an imiquimod-induced psoriasis-like C57-BL6 mouse model along with typical psoriasis-like dermatitis and itch-like behaviours. The 11.7T resting-state functional magnetic resonance imaging showed differences in brain regions between the model and control group, and voxel-based morphometry showed that the grey matter volume changed in the basal forebrain region, anterior commissure intrabulbar and striatum in the psoriasis-like mice. Seed-based resting state functional connectivity analysis revealed connectivity changes in the amygdala, periaqueductal gray, raphe nuclei and lateral septum. We conclude that the imiquimod-induced psoriasis-like C57-BL6 mouse model is well suited for mechanistic studies and for performing preclinical therapeutic trials for treating anxiety and pathological social avoidance in psoriasis patients.

Synthetic viability induces resistance to immune checkpoint inhibitors in cancer cells.

BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionized the treatment for multiple cancers. However, most of patients encounter resistance. Synthetic viability (SV) between genes could induce resistance. In this study, we established SV signature to predict the efficacy of ICI treatment for melanoma. METHODS: We collected features and predicted SV gene pairs by random forest classifier. This work prioritized SV gene pairs based on CRISPR/Cas9 screens. SV gene pairs signature were constructed to predict the response to ICI for melanoma patients. RESULTS: This study predicted robust SV gene pairs based on 14 features. Filtered by CRISPR/Cas9 screens, we identified 1,861 SV gene pairs, which were also related with prognosis across multiple cancer types. Next, we constructed the six SV pairs signature to predict resistance to ICI for melanoma patients. This study applied the six SV pairs signature to divide melanoma patients into high-risk and low-risk. High-risk melanoma patients were associated with worse response after ICI treatment. Immune landscape analysis revealed that high-risk melanoma patients had lower natural killer cells and CD8+ T cells infiltration. CONCLUSIONS: In summary, the 14 features classifier accurately predicted robust SV gene pairs for cancer. The six SV pairs signature could predict resistance to ICI.

Xylocopa caerulea and Xylocopa auripennis harbor a homologous gut microbiome related to that of eusocial bees.

Background: Eusocial bees, such as bumblebees and honey bees, harbor host-specific gut microbiota through their social behaviors. Conversely, the gut microbiota of solitary bees is erratic owing to their lack of eusocial activities. Carpenter bees (genus Xylocopa) are long-lived bees that do not exhibit advanced eusociality like honey bees. However, they often compete for nests to reproduce. Xylocopa caerulea and Xylocopa auripennis are important pollinators of wild plants on Hainan Island. Whether they have host-specific bacteria in their guts similar to eusocial bees remains unknown. Methods: We targeted the bacterial 16S rRNA V3-V4 region to investigate the diversity of bacterial symbionts in the fore-midgut and hindgut of two carpenter bees, X. caerulea and X. auripennis. Results: A maximum of 4,429 unique amplicon sequence variants (ASVs) were detected from all samples, belonging to 10 different phyla. X. caerulea and X. auripennis shared similar bacterial community profiles, with Lactobacillaceae, Bifidobacteriaceae, and Orbaceae being dominant in their entire guts. X. caerulea and X. auripennis harbor a highly conserved core set of bacteria, including the genera Candidatus Schmidhempelia and Bombiscardovia. These two bacterial taxa from carpenter bees are closely related to those isolated from bumblebees. The LEfSe analysis showed that Lactobacillaceae, Bifidobacteriaceae, and the genus Bombilactobacillus were significantly enriched in the hindguts of both carpenter bees. Functional prediction suggested that the most enriched pathways were involved in carbohydrate and lipid metabolism. Conclusions: Our results revealed the structure of the gut microbiota in two carpenter bees and confirmed the presence of some core bacterial taxa that were previously only found in the guts of social bees.

Risk factors of left ventricular diastolic dysfunction in maintenance hemodialysis patients.

OBJECTIVE: To investigate the risk factors of left ventricular diastolic dysfunction in maintenance hemodialysis (MHD) patients. METHOD: We retrospectively collected data from 363 hemodialysis patients who were on dialysis for at least 3 months at January 1, 2020. According to the echocardiogram results, these patients were divided into left ventricular diastolic dysfunction (LVDD) group and non-LVDD group. The differences in basic data, cardiac structure and functiona between the two groups were analyzed. Logistic regression analysis was used to analyze the risk factors of cardiac diastolic dysfunction in MHD patients. RESULTS: Compared with the non-LVDD group, patients in the LVDD group were older, with an increased proportion of coronary heart disease, more prone to chest tightness, shortness of breath. Simultaneously, they had a significantly increased (p < 0.05) proportion of cardiac structural abnormalities such as left ventricular hypertrophy, left heart enlargement and systolic dysfunction. Multivariate logistic regression analysis showed that the risk of LVDD was significantly increased in elderly MHD patients older than 60 years (OR = 3.86, 95%CI 1.429-10.429), and left ventricular hypertrophy was also significantly associated with LVDD (OR = 2.227, 95% CI 1.383-3.586). CONCLUSION: According to research, both age and left ventricular hypertrophy are risk factors for LVDD in MHD patients. It is recommended that early intervention for LVDD should be implemented to improve the quality of dialysis and reduce the incidence of cardiovascular events in MHD patients.

Bi-directional causal effect between vitamin B12 and non-alcoholic fatty liver disease: Inferring from large population data.

Objectives: Many observational studies evaluate the association between vitamin B12 and non-alcoholic fatty liver disease (NAFLD). However, the causality of this association remains uncertain, especially in European populations. We conducted a bidirectional Mendelian randomization study to explore the association between vitamin B12 and NAFLD. Methods: Two-sample Mendelian randomization study was conducted. Summary statistics for vitamin B12 were acquired from a genome-wide association studies (GWAS) meta-analysis including 45,576 subjects. Summary-level data for NAFLD was obtained from a GWAS meta-analysis of 8,434 cases and 770,180 non-cases and another GWAS meta-analysis of 1,483 cases and 17,781 non-cases. Summary-level data for 4 enzymes including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyltransferase (GGT), was available from the UK Biobank. Inverse variance weighting (as main analysis), weighted median estimate, robust adjusted profile score, MR-Egger, and MR-PRESSO (sensitivity analyses) were performed to calculate causal estimates. Results: Genetically predicted higher vitamin B12 concentrations were consistently associated with an increased NAFLD in two sources. The combined odds ratio (OR) of NAFLD was 1.30 (95% confidence interval (CI), 1.13 to 1.48; p < 0.001) per SD-increase in vitamin B12 concentrations. Genetic liability to NAFLD was also positively associated with vitamin B12 concentrations (Beta 0.08, 95%CI, 0.01 to 0.16; p = 0.034). Sensitivity analyses also revealed consistent results. Genetically predicted vitamin B12 concentrations showed no significant association with liver enzymes. Conclusion: The present study indicates that increased serum vitamin B12 concentrations may play a role in NAFLD risk. NAFLD also has a causal impact on elevated vitamin B12 concentrations in the circulation. Notably, vitamin B12 concentrations imply the levels of vitamin B12 in the circulation, and higher intake of vitamin B12 may not directly lead to higher levels of serum vitamin B12, instead the higher levels of vitamin B12 in the circulation may be caused by the dysregulation of the metabolism of this vitamin in this study. There exist bidirectional causal effects between serum vitamin B12 concentrations and risk of NAFLD in European individuals.

MR-BOIL: Causal inference in one-sample Mendelian randomization for binary outcome with integrated likelihood method.

Mendelian randomization is a statistical method for inferring the causal relationship between exposures and outcomes using an economics-derived instrumental variable approach. The research results are relatively complete when both exposures and outcomes are continuous variables. However, due to the noncollapsing nature of the logistic model, the existing methods inherited from the linear model for exploring binary outcome cannot take the effect of confounding factors into account, which leads to biased estimate of the causal effect. In this article, we propose an integrated likelihood method MR-BOIL to investigate causal relationships for binary outcomes by treating confounders as latent variables in one-sample Mendelian randomization. Under the assumption of a joint normal distribution of the confounders, we use expectation maximization algorithm to estimate the causal effect. Extensive simulations demonstrate that the estimator of MR-BOIL is asymptotically unbiased and that our method improves statistical power without inflating type I error rate. We then apply this method to analyze the data from Atherosclerosis Risk in Communications Study. The results show that MR-BOIL can better identify plausible causal relationships with high reliability, compared with the unreliable results of existing methods. MR-BOIL is implemented in R and the corresponding R code is provided for free download.

Centromere repositioning and shifts in wheat evolution.

The centromere is the region of a chromosome that directs its separation and plays an important role in cell division and reproduction of organisms. Elucidating the dynamics of centromeres is an alternative strategy for exploring the evolution of wheat. Here, we comprehensively analyzed centromeres from the de novo-assembled common wheat cultivar Aikang58 (AK58), Chinese Spring (CS), and all sequenced diploid and tetraploid ancestors by chromatin immunoprecipitation sequencing, whole-genome bisulfite sequencing, RNA sequencing, assay for transposase-accessible chromatin using sequencing, and comparative genomics. We found that centromere-associated sequences were concentrated during tetraploidization and hexaploidization. Centromeric repeats of wheat (CRWs) have undergone expansion during wheat evolution, with strong interweaving between the A and B subgenomes post tetraploidization. We found that CENH3 prefers to bind with younger CRWs, as directly supported by immunocolocalization on two chromosomes (1A and 2A) of wild emmer wheat with dicentromeric regions, only one of which bound with CENH3. In a comparison of AK58 with CS, obvious centromere repositioning was detected on chromosomes 1B, 3D, and 4D. The active centromeres showed a unique combination of lower CG but higher CHH and CHG methylation levels. We also found that centromeric chromatin was more open than pericentromeric chromatin, with higher levels of gene expression but lower gene density. Frequent introgression between tetraploid and hexaploid wheat also had a strong influence on centromere position on the same chromosome. This study also showed that active wheat centromeres were genetically and epigenetically determined.

Tachykinin receptor 3 in the lateral habenula alleviates pain and anxiety comorbidity in mice.

The coexistence of chronic pain and anxiety is a common clinical phenomenon. Here, the role of tachykinin receptor 3 (NK3R) in the lateral habenula (LHb) in trigeminal neuralgia and in pain-associated anxiety was systematically investigated. First, electrophysiological recording showed that bilateral LHb neurons are hyperactive in a mouse model of trigeminal neuralgia made by partial transection of the infraorbital nerve (pT-ION). Chemicogenetic activation of bilateral LHb glutamatergic neurons in naive mice induced orofacial allodynia and anxiety-like behaviors, and pharmacological activation of NK3R in the LHb attenuated allodynia and anxiety-like behaviors induced by pT-ION. Electrophysiological recording showed that pharmacological activation of NK3R suppressed the abnormal excitation of LHb neurons. In parallel, pharmacological inhibition of NK3R induced orofacial allodynia and anxiety-like behavior in naive mice. The electrophysiological recording showed that pharmacological inhibition of NK3R activates LHb neurons. Neurokinin B (NKB) is an endogenous high-affinity ligand of NK3R, which binds NK3R and activates it to perform physiological functions, and further neuron projection tracing showed that the front section of the periaqueductal gray (fPAG) projects NKB-positive nerve fibers to the LHb. Optogenetics combined with electrophysiology recordings characterize the functional connections in this fPAG NKB → LHb pathway. In addition, electrophysiological recording showed that NKB-positive neurons in the fPAG were more active than NKB-negative neurons in pT-ION mice. Finally, inhibition of NKB release from the fPAG reversed the analgesic and anxiolytic effects of LHb Tacr3 overexpression in pT-ION mice, indicating that fPAG NKB → LHb regulates orofacial allodynia and pain-induced anxious behaviors. These findings for NK3R suggest the cellular mechanism behind pT-ION in the LHb and suggest that the fPAG NKB → LHb circuit is involved in pain and anxiety comorbidity. This previously unrecognized pathway might provide a potential approach for relieving the pain and anxiety associated with trigeminal neuralgia by targeting NK3R.

Association between homocysteine and nonalcoholic fatty liver disease: Mendelian randomisation study.

BACKGROUND: Many observational studies explore the relationship between homocysteine (Hcy) and nonalcoholic fatty liver disease (NAFLD), whereas the causality of this association remains uncertain, especially in European populations. We performed a bidirectional Mendelian randomisation study to elucidate the causal association between Hcy and NAFLD. Furthermore, we explored the relationship of Hcy with liver enzymes, including alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate aminotransferase (AST). METHODS: Two-sample Mendelian randomisation study was conducted. Summary statistics for Hcy were obtained from a genome-wide association studies (GWAS) meta-analysis comprising 44,147 subjects. Summary-level data for NAFLD were acquired from a GWAS meta-analysis of 8434 cases and 770,180 noncases and another GWAS meta-analysis of 1483 cases and 17,781 noncases. Summary-level data for three liver enzymes were available from the UK Biobank. RESULTS: Genetic associations of Hcy concentrations with NAFLD and liver enzymes were observed. Genetically predicted higher Hcy concentrations were consistently associated with an increased NAFLD risk in two data sources. The combined odds ratio of NAFLD was 1.25 (95% confidence interval [CI], 1.05-1.45) per SD increase in Hcy concentrations. Genetically predicted higher Hcy concentrations showed significant association with ALP (Beta .69; 95% CI, 0.04-1.34), ALT (Beta 0.56; 95% CI, 0.15-0.97) and AST levels (Beta .57; 95% CI, 0.10-1.04). Genetic liability to NAFLD was not associated with Hcy concentrations. CONCLUSIONS: This study has clinical implications as it indicates that increased Hcy concentrations increase the relevant liver enzymes and may play a role in NAFLD risk in European populations.

Causal effects of B vitamins and homocysteine on obesity and musculoskeletal diseases: A Mendelian randomization study.

Objectives: Although homocysteine (Hcy) increases the risk of cardiovascular diseases, its effects on obesity and musculoskeletal diseases remain unclear. We performed a Mendelian randomization study to estimate the associations between Hcy and B vitamin concentrations and their effects on obesity and musculoskeletal-relevant diseases in the general population. Methods: We selected independent single nucleotide polymorphisms of Hcy (n = 44,147), vitamin B12 (n = 45,576), vitamin B6 (n = 1864), and folate (n = 37,465) at the genome-wide significance level as instruments and applied them to the studies of summary-level data for fat and musculoskeletal phenotypes from the UK Biobank study (n = 331,117), the FinnGen consortium (n = 218,792), and other consortia. Two-sample Mendelian randomization (MR) approaches were utilized in this study. The inverse variance weighting (IVW) was adopted as the main analysis. MR-PRESSO, MR-Egger, the weighted median estimate, bidirectional MR, and multivariable MR were performed as sensitivity methods. Results: Higher Hcy concentrations were robustly associated with an increased risk of knee osteoarthritis [odds ratio (OR) 1.119; 95% confidence interval (CI) 1.032-1.214; P = 0.007], hospital-diagnosed osteoarthritis (OR 1.178; 95% CI 1.012-1.37; P = 0.034), osteoporosis with pathological fracture (OR 1.597; 95% CI 1.036-2.46; P = 0.034), and soft tissue disorder (OR 1.069; 95% CI 1.001-1.141; P = 0.045) via an inverse variance weighting method and other MR approaches. Higher vitamin B12 levels were robustly associated with decreased body fat percentage and its subtypes (all P < 0.05). Bidirectional analyses showed no reverse causation. Multivariable MR analyses and other sensitivity analyses showed directionally similar results. Conclusions: There exist significant causal effects of vitamin B12 in the serum and Hcy in the blood on fat and musculoskeletal diseases, respectively. These findings may have an important insight into the pathogenesis of obesity and musculoskeletal diseases and other possible future therapies.

Inferring causal effects of homocysteine and B-vitamin concentrations on bone mineral density and fractures: Mendelian randomization analyses.

Objectives: In the progress of bone metabolism, homocysteine (Hcy) and B vitamins play substantial roles. However, the causal associations of homocysteine, B-vitamin concentrations with bone mineral density (BMD), and fractures remain unclear. Therefore, we employed a two-sample Mendelian randomization (MR) design to infer the causal effects of Hcy and B vitamins on BMD and fractures. Methods: We selected instrumental variables from large genome-wide association studies (GWASs). Specifically, the exposures mainly included Hcy (sample size: 44,147), vitamin B12 (sample size: 45,576), folate (sample size: 37,465), and vitamin B6 (sample size: 1,864). The outcome variables included total body BMD (sample size: 66,628), heel BMD (sample size: 142,487), femoral neck BMD (sample size: 32,735), lumbar spine BMD (sample size: 28,498), and forearm BMD (sample size: 8143). Additionally, the total body BMD in several age strata was also included. Furthermore, the fractures of the forearm, femoral neck, lumbar spine, heel corresponding with the BMD regions, and femoral neck and lumbar spine BMD in men and women, separately, were added as additional outcomes. Two-sample MR approaches were utilized in this study. Inverse variance weighting (IVW) was adopted as the main analysis. MR-PRESSO, MR-Egger, the weighted median estimate, and multivariable MR were performed as sensitivity methods. Results: In the main analysis, Hcy concentrations have an inverse association with heel BMD (Beta = 0.046, 95% confidence interval (CI) -0.073 to -0.019, P = 9.59E-04) per SD unit. In addition, for one SD increase of vitamin B12, the total body BMD decreased 0.083 unit (95%CI -0.126 to -0.040, P = 1.65E-04). The trend was more obvious in age over 45 years (Beta = -0.135, 95%CI -0.203-0.067, P = 9.86E-05 for age 45-60; Beta = -0.074, 95%CI -0.141 to -0.007, P = 0.031 for age over 60 years). No association of B vitamins and Hcy levels with the risk of fractures and femoral neck and lumbar spine BMD in men and women was found in this study. Other sensitivity MR methods elucidated consistent results. Conclusions: Our findings indicated that there exist the inversely causal effects of Hcy and vitamin B12 on BMD in certain body sites and age strata. These give novel clues for intervening bone-related diseases in public health and nutrition.

Molecular characterization of the genome-wide BOR transporter family and their responses to boron conditions in common wheat (Triticum aestivum L.).

Boron (B) deficiency is an agricultural problem that causes significant yield losses in many countries. B transporters (BORs) are responsible for B uptake and distribution and play important roles in yield formation. A comprehensive analysis of the BOR family members in common wheat is still lacking. In the present study, to clarify the molecular characterization and response to B status, genome-wide TaBOR genes and expression patterns were investigated. Fourteen TaBOR genes were identified in common wheat by a homology search. The corresponding phylogenetic tree indicated that 14 TaBOR genes were separately classified into subfamilies of TaBOR1, TaBOR3, and TaBOR4. All TaBOR genes had 12-14 extrons and 11-13 introns. Most TaBOR proteins contained 10 conserved motifs, and motifs 1, 2, 3, 4, and 6 constituted the conserved bicarbonate (HCO3 -) domain. Fourteen TaBOR genes were mapped on 13 chromosomes mainly distributed in the first, third, fifth, and seventh homologous groups. The promoters of TaBOR genes consisted of phytohormones, light responses, and stress-related cis-elements. GO analysis indicated that TaBOR genes were enriched in terms of transmembrane transport and ion homeostasis. TaBOR genes showed diverse expression profiles in different tissues. The members of the TaBOR1 subfamily showed high expression in grains, leaves, roots, stems, and spikes, but members of the TaBOR4 subfamily were highly expressed only in spikes and grains. RT-qPCR indicated that TaBOR1-5A, TaBOR1-5B, and TaBOR1-5D were induced by low B concentrations and had much higher expression in roots than in shoots. TaBOR3-3A, TaBOR3-3B, TaBOR3-3D, TaBOR4-1A, TaBOR4-1B, TaBOR4-1D, and TaBOR3-4B were induced by low and high B concentrations and had high expression in roots and shoots. TaBOR3-4D and TaBOR3-7B were upregulated by low and high B concentrations, respectively, but had expression only in roots. Our results provide basic information on the TaBOR family, which is beneficial for elucidating the functions of TaBOR genes to overcome the problem of B deficiency.