Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression.

Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor ß (TGF-ß) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell-derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications.

Identification of potential causal metabolites associated with atopic dermatitis.

Atopic dermatitis is a chronically recurrent dermatologic disease affected by complex pathophysiology with limited therapeutic options. To identify promising biomarkers for atopic dermatitis, we conducted a Mendelian randomization (MR) study to systematically screen blood metabolome for potential causal mediators of atopic dermatitis and further predict target-mediated side effects. We selected 128 unique blood metabolites from three European-descent metabolome genome-wide association studies (GWASs) with a total of 147 827 participants. Atopic dermatitis dataset originated from a large-scale GWAS including 10 788 cases and 30 047 controls of European ancestry. MR analyses were performed to estimate the associations of blood metabolites with atopic dermatitis. We then applied a phenome-wide MR analysis to ascertain potential on-target side effects of metabolite intervention. Three metabolites were identified as potential causal mediators for atopic dermatitis, including docosahexaenoic acid (odds ratio [OR], 0.87; 95% confidence interval [CI], 0.81-0.94; P = 3.45 × 10-4), arachidonate (OR, 0.30; 95% CI, 0.17-0.53; P = 4.09 × 10-5) and 1-arachidonoylglycerophosphoethanolamine (1-arachidonoyl-GPE) (OR, 0.25; 95% CI, 0.12-0.53; P = 2.58 × 10-4). In the phenome-wide MR analysis, docosahexaenoic acid and arachidonate were also identified to have beneficial or detrimental effects on multiple diseases beyond atopic dermatitis, respectively. No adverse side effects were found for 1-arachidonoyl-GPE. In this systematic MR study, docosahexaenoic acid, arachidonate and 1-arachidonoyl-GPE were identified as potential causal and beneficial mediators in the development of atopic dermatitis. Side-effect profiles were characterized to help inform drug target prioritization, and 1-arachidonoyl-GPE was a promising target for prevention and treatment of atopic dermatitis with no predicted adverse side effects.

The identification of novel schizophrenia-related metabolites using untargeted lipidomics.

Human lipidome still remains largely unexplored among Chinese schizophrenia patients. We aimed to identify novel lipid molecules associated with schizophrenia and cognition among schizophrenia patients. The current study included 96 male schizophrenia patients and 96 gender-matched healthy controls. Untargeted lipidomics profiling was conducted among all participants. Logistic regression models were used to assess metabolite associations with schizophrenia. We further assessed the incremental predictive value of identified metabolites beyond conventional risk factors on schizophrenia status. In addition, identified metabolites were tested for association with cognitive function among schizophrenia patients using linear regression models. A total of 34 metabolites were associated with schizophrenia. Addition of these identified metabolites to age, body mass index, smoking, and education significantly increased the risk reclassification of schizophrenia. Among the schizophrenia-related metabolites, 10 were further associated with cognition in schizophrenia patients, including four metabolites associated with immediate memory, two metabolites associated with delayed memory, three metabolites associated with visuospatial, four metabolites associated with language, one metabolite associated with attention, and two metabolites associated with the total score. Our findings provide novel insights into the biological mechanisms of schizophrenia, suggesting that lipid metabolites may serve as potential diagnostic or therapeutic targets of schizophrenia.

Proteome-wide cellular thermal shift assay reveals unexpected cross-talk between brassinosteroid and auxin signaling.

SignificanceChemical genetics, which investigates biological processes using small molecules, is gaining interest in plant research. However, a major challenge is to uncover the mode of action of the small molecules. Here, we applied the cellular thermal shift assay coupled with mass spectrometry (CETSA MS) to intact Arabidopsis cells and showed that bikinin, the plant-specific glycogen synthase kinase 3 (GSK3) inhibitor, changed the thermal stability of some of its direct targets and putative GSK3-interacting proteins. In combination with phosphoproteomics, we also revealed that GSK3s phosphorylated the auxin carrier PIN-FORMED1 and regulated its polarity that is required for the vascular patterning in the leaf.

Arabidopsis SMO2 modulates ribosome biogenesis by maintaining the RID2 abundance during organ growth.

Ribosome biogenesis is a process of making ribosomes that is tightly linked with plant growth and development. Here, through a suppressor screen for the smo2 mutant, we found that lack of a ribosomal stress response mediator, ANAC082 partially restored growth defects of the smo2 mutant, indicating SMO2 is required for the repression of nucleolar stress. Consistently, the smo2 knock-out mutant exhibited typical phenotypes characteristic of ribosome biogenesis mutants, such as pointed leaves, aberrant leaf venation, disrupted nucleolar structure, abnormal distribution of rRNA precursors, and enhanced tolerance to aminoglycoside antibiotics that target ribosomes. SMO2 interacted with ROOT INITIATION DEFECTIVE 2 (RID2), a methyltransferase-like protein required for pre-rRNA processing. SMO2 enhanced RID2 solubility in Escherichia coli and the loss of function of SMO2 in plant cells reduced RID2 abundance, which may result in abnormal accumulation of FIBRILLARIN 1 (FIB1) and NOP56, two key nucleolar proteins, in high-molecular-weight protein complex. Taken together, our results characterized a novel plant ribosome biogenesis factor, SMO2 that maintains the abundance of RID2, thereby sustaining ribosome biogenesis during plant organ growth.

Genetically Determined Plasma Hepatocyte Growth Factor Levels Are Associated With the Risk and Prognosis of Ischemic Stroke.

BACKGROUND: Observational studies suggest that hepatocyte growth factor (HGF) is associated with the risk and prognosis of ischemic stroke, but the causality of these associations remains unclear. Therefore, we conducted Mendelian randomization (MR) analyses to explore the associations of genetically determined plasma HGF levels with the risk and prognosis of ischemic stroke. METHODS: A total of 13 single-nucleotide polymorphisms associated with plasma HGF were selected as genetic instruments based on the data from a genome-wide association study with 21 758 European participants. Summary data about the risk of ischemic stroke were obtained from the MEGASTROKE (Multiancestry Genome-Wide Association Study of Stroke) Consortium with 34 217 ischemic stroke cases and 406 111 controls of European ancestry, and summary data about the prognosis of ischemic stroke were obtained from the GISCOME study (Genetics of Ischaemic Stroke Functional Outcome) with 6165 European patients with ischemic stroke. We conducted an inverse-variance weighted Mendelian randomization analysis followed by a series of sensitivity analyses to evaluate the associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke. RESULTS: The primary analyses showed that genetically determined high HGF was associated with an increased risk of ischemic stroke (odds ratio per SD increase, 1.11 [95% CI, 1.04-1.19]; P=1.10×10-3) and poor prognosis of ischemic stroke (odds ratio per SD increase, 2.43 [95% CI, 1.76-3.52]; P=6.35×10-8). In the secondary analysis, genetically determined plasma HGF was associated with a high risk of large atherosclerotic stroke (odds ratio per SD increase, 1.39 [95% CI, 1.18-1.63]; P=5.08×10-5) but not small vessel stroke and cardioembolic stroke. Mendelian randomization-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses with different Mendelian randomization methods further confirmed these findings. CONCLUSIONS: We found positive associations of genetically determined plasma HGF with the risk and prognosis of ischemic stroke, suggesting that HGF might be implicated in the occurrence and development of ischemic stroke.

High-Serum Brain-Derived Neurotrophic Factor Levels Are Associated With Decreased Risk of Poststroke Cognitive Impairment.

BACKGROUND: BDNF (brain-derived neurotrophic factor) is widely implicated in the pathophysiological process of stroke, but the effect of BDNF on poststroke cognitive impairment (PSCI) remains unclear. We aimed to investigate the association between baseline serum BDNF and the risk of PSCI at 3 months in a multicenter study based on a preplanned ancillary study of the CATIS trial (China Antihypertensive Trial in Acute Ischemic Stroke). METHODS: We examined serum BDNF levels at baseline and used the Mini-Mental State Examination and Montreal Cognitive Assessment to evaluate cognitive function at 3-month follow-up after ischemic stroke. PSCI was defined as Mini-Mental State Examination score <27 or Montreal Cognitive Assessment score <25. Logistic regression analyses were performed to evaluate the association between serum BDNF and the risk of 3-month PSCI. RESULTS: In this ancillary study, a total of 660 patients with ischemic stroke with hypertension were included, and 593 patients (mean age, 59.90±10.44 years; 410 males and 183 females) were finally included in this analysis. According to mini-mental state examination score, after adjustment for age, sex, education, baseline National Institutes of Health Stroke Scale score, APOE ɛ4 carriers, and other potential confounders, the odds ratio of PSCI for the highest tertile of BDNF was 0.60 ([95% CI, 0.39-0.94]; P=0.024) compared with the lowest tertile. Multiple-adjusted spline regression model showed a linear association of serum BDNF levels with PSCI at 3 months (P value for linearity=0.010). Adding serum BDNF to conventional prognostic factors slightly improved the risk reclassification of PSCI (net reclassification improvement: 27.46%, P=0.001; integrated discrimination index: 1.02%, P=0.015). Similar significant findings were observed when PSCI was defined by the Montreal Cognitive Assessment score. CONCLUSIONS: Elevated serum BDNF levels were associated with a decreased risk of PSCI at 3 months, suggesting that serum BDNF might be a potential predictive biomarker for PSCI among patients with ischemic stroke with hypertension.

Identification of potential therapeutic targets and mechanisms of COVID-19 through network analysis and screening of chemicals and herbal ingredients.

After experiencing the COVID-19 pandemic, it is widely acknowledged that a rapid drug repurposing method is highly needed. A series of useful drug repurposing tools have been developed based on data-driven modeling and network pharmacology. Based on the disease module, we identified several hub proteins that play important roles in the onset and development of the COVID-19, which are potential targets for repositioning approved drugs. Moreover, different network distance metrics were applied to quantify the relationship between drug targets and COVID-19 disease targets in the protein-protein-interaction (PPI) network and predict COVID-19 therapeutic effects of bioactive herbal ingredients and chemicals. Furthermore, the tentative mechanisms of candidates were illustrated through molecular docking and gene enrichment analysis. We obtained 15 chemical and 15 herbal ingredient candidates and found that different drugs may play different roles in the process of virus invasion and the onset and development of the COVID-19 disease. Given pandemic outbreaks, our method has an undeniable immense advantage in the feasibility analysis of drug repurposing or drug screening, especially in the analysis of herbal ingredients.

Association of Crohn's disease and ulcerative colitis with the risk of neurological diseases: a large-scale Mendelian randomization study.

Observational studies suggested increased risks of Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS) in patients with Crohn's disease (CD) and ulcerative colitis (UC). We aimed to assess the causality for the associations of CD and UC with the risks of AD, PD, and MS through a two-sample Mendelian randomization (MR) study. Independent single nucleotide polymorphisms associated with CD (17,897 cases and 33,977 controls) and UC (13,768 cases and 33,977 controls) were identified as genetic instruments based on a European-descent genome-wide association study (GWAS) released by the International Inflammatory Bowel Disease Genetics Consortium. Summary statistics for AD (combined: 25,881 cases and 256,837 controls), PD (combined: 35,836 cases and 665,686 controls), and MS (combined: 48,477 cases and 285,515 controls) were obtained from the largest GWASs and FinnGen study of European ancestry, respectively. MR estimates were generated using the inverse-variance weighted method in the main analysis with a series of sensitivity analyses. MR analyses were conducted per outcome database and were subsequently meta-analyzed to generate combined estimates. Genetically predicted UC was significantly associated with increased risks of AD (combined: OR, 1.03; 95% CI, 1.01-1.05; P = 1.80 × 10-3) and MS (combined: OR, 1.37; 95% CI, 1.23-1.53; P = 1.18 × 10-8), while there was no association between genetically predicted UC and the risk of PD. In contrast, no significant associations were observed for genetically predicted CD with AD, PD, and MS. MR-Egger regression showed no directional pleiotropy for the identified associations, and sensitivity analyses with different MR methods further confirmed these findings. This study suggested significant adverse effects of UC on AD and MS, highlighting that UC patients should receive early intervention with optimal adjunctive medical therapy to reduce the risks of AD and MS.

Whole-genome sequencing reveals complex genomic features underlying anti-CD19 CAR T-cell treatment failures in lymphoma.

CD19-directed chimeric antigen receptor (CAR-19) T cells are groundbreaking immunotherapies approved for use against large B-cell lymphomas. Although host inflammatory and tumor microenvironmental markers associate with efficacy and resistance, the tumor-intrinsic alterations underlying these phenomena remain undefined. CD19 mutations associate with resistance but are uncommon, and most patients with relapsed disease retain expression of the wild-type receptor, implicating other genomic mechanisms. We therefore leveraged the comprehensive resolution of whole-genome sequencing to assess 51 tumor samples from 49 patients with CAR-19-treated large B-cell lymphoma. We found that the pretreatment presence of complex structural variants, APOBEC mutational signatures, and genomic damage from reactive oxygen species predict CAR-19 resistance. In addition, the recurrent 3p21.31 chromosomal deletion containing the RHOA tumor suppressor was strongly enriched in patients for whom CAR T-cell therapy failed. Pretreatment reduced expression or monoallelic loss of CD19 did not affect responses, suggesting CAR-19 therapy success and resistance are related to multiple mechanisms. Our study showed that tumor-intrinsic genomic alterations are key among the complex interplay of factors that underlie CAR-19 efficacy and resistance for large B-cell lymphomas.

Oridonin suppresses the growth of glioblastoma cells via inhibiting Hippo/YAP axis.

Glioma is a brain tumor that originates from brain or spine glial cells. Despite alternative treatments, the overall survival rate remains low. Oridonin (ORI) is purified from the Chinese herb Rabdosia rubescens, which has exhibited positive effects on tumors. This study aimed to investigate the effect of ORI on U87MG glioblastoma cells and whether the Hippo/YAP-related signaling pathway was involved. Malignant glioblastoma U87MG cells and male athymic nude mice (BALB/cnu/nu) were used as the experimental models. The YAP inhibitor Verteporfin (VP) and the overexpression of YAP were used to investigate its potential relation with glioma. Here, we found that ORI inhibited cell proliferation and promoted cell apoptosis in a dose-dependent manner in U87MG cells. Moreover, ORI inhibited Bcl-2, YAP, and c-Myc protein expression but increased Bax, caspase-3, and p-YAP protein expression. Furthermore, the effect of ORI was also confirmed in a mouse model bearing glioma. ORI reversed the effect of overexpression of YAP. Collectively, oridonin suppressed glioblastoma oncogenesis via the Hippo/YAP signaling pathway and could be a potential therapeutic target in the treatment of glioblastoma.

Association between Constipation and the Risk of Parkinson's Disease among Participants in the UK Biobank.

INTRODUCTION: Constipation is common in patients with Parkinson's disease (PD), but its impact on incident PD remains uncertain. We aimed to prospectively investigate constipation symptoms and the risk of PD. METHODS: Participants without PD at baseline from the UK Biobank were included in the study. Information on the regular use of laxatives, bowel movement frequency, and the frequency of hard or lumpy stools was collected. Incident PD was defined by the ICD-10 code. Cox proportional hazards models were used to assess the association between constipation symptoms and incident PD. RESULTS: In the analysis of regular laxative use and PD, 490,797 participants were included and 2,735 incident PD were detected. The multivariable adjusted HR of PD in participants who regularly used laxatives was 1.99 (95% confidence interval [CI], 1.70-2.33) compared with those who did not. In the analysis of bowel movement frequency and hard or lumpy stools and PD, 170,017 participants were included and 519 incident PD were detected. The multivariable adjusted HRs were 2.16 (95% CI, 1.74-2.68) and 2.57 (95% CI, 2.00-3.31) for participants with a bowel movement frequency of 3-6 times/week and <3 times/week, respectively, compared with those with a bowel movement frequency of ≥7 times/week; compared with participants who never had hard or lumpy stools, multivariable adjusted HRs were 1.31 (95% CI, 1.07-1.60), 2.32 (95% CI, 1.77-3.05), and 2.94 (95% CI, 2.14-4.05) for those who sometimes had hard or lumpy stools, often had hard or lumpy stools, and most of time/always had hard or lumpy stools, respectively. CONCLUSIONS: Constipation measured by the regular use of laxatives, bowel movement frequency, and the frequency of hard or lumpy stools was significantly associated with an increased risk of incident PD.

Association between Physical Activity and Parkinson's Disease: A Prospective Cohort Study.

BACKGROUND: The burden of Parkinson's disease (PD) is still increasing, and physical activity is a modifiable factor for health benefits. The benefits of physical activity in PD are not well established. Therefore, this study aimed to investigate the association between various types of physical activity and the risk of developing PD. METHODS: Data from 432,497 participants in UK Biobank, who were free of PD at baseline, were analyzed. Physical activity levels were assessed by measuring the duration of walking for pleasure, light and heavy do-it-yourself (DIY) activities, strenuous sports, and other exercises. Physical activity was categorized into daily living activities (walking for pleasure, light DIY, and heavy DIY) and structured exercises (strenuous sports and other exercises). Association between different types of physical activity and PD risk was examined using multivariable adjusted restricted cubic splines and Cox proportional risk models. RESULTS: Over a median follow-up of 13.7 years, 2,350 PD cases were identified. Cubic spline analyses revealed negative linear associations between PD risk and total physical activity, daily living activities, and structured exercise. After multivariable adjustment, the hazard ratios and 95% confidence intervals for incident PD associated with the highest quartile of total physical activity, daily living activities, and structured exercise were 0.72 (0.64-0.81), 0.75 (0.67-0.84), and 0.78 (0.67-0.90), respectively, compared to those in the lowest quartile. Sensitivity analysis confirmed these findings. CONCLUSIONS: Higher levels of both daily living activities and structured exercise were associated with a reduced incidence of PD, underscoring the importance of maintaining physical activity to prevent PD.

Optimal dosage of rituximab for children with Burkitt lymphoma.

The current chemotherapy treatments have led to an improvement in survival rates for pediatric Burkitt's lymphoma (BL). Survival in children with high-grade, mature B-cell non-Hodgkin's lymphoma (B-NHL) has been prolonged by six rituximab doses combined with chemotherapy, whereas the efficacy of four doses has not been reported. This study aimed to explore optimal therapeutic strategies-the number of doses of rituximab based on different risk groups-and also aim to investigate the clinical characteristics of Chinese pediatric BL. This study consecutively enrolled children with BL in Beijing Children's Hospital who received French-American-British mature B-cell lymphoma 96 (FAB/LMB96). The patients were divided into three groups: R0 group (chemotherapy alone), R6 group (chemotherapy combined with six rituximab doses), and R4 group (chemotherapy combined with four rituximab doses). The clinical characteristics and outcomes were evaluated. Univariate and multivariate analyses and prognostic nomogram were used to assess prognostic factors. A nomogram was developed that predicted overall survival based on the Cox proportional hazards model, and the concordance index (C-index) and a calibration curve were used to determine its predictive and discriminatory capacity. We enrolled 385 boys and 71 girls, with a median age of 6 years (1-14 years). Of these, 296 patients (65%) had initial abdominal symptoms, 182 (40%) had bulky disease, 46 (10%) had B symptoms, 77 (16.9%) had BL-ALL (blasts ≥ 25% in bone marrow (BM)), 96 (21%) had central nervous system (CNS) disease, 406 (89%) were in stages III-IV, 378 (83%) were in group C, 170 (37.2%) had lactate dehydrogenase (LDH) levels ≥ 1000 U/L at initial diagnosis, and 137 (30%) had tumor lysis syndrome. The R0, R6, and R4 groups included 79, 144, and 227 patients, respectively. Six patients were excluded due to treatment withdrawal for various reasons. The 3-year overall survival (OS) and event-free survival (EFS) percentages were 92% ± 1.3% and 91.3% ± 1.3%, respectively, in all cohorts, whereas the 3-year EFS percentage was 83.5% ± 4.2%, 93% ± 2.1%, and 92.9% ± 1.8% in the R0, R6, and R4 groups, respectively (P = 0.025). The nomogram included four important variables based on a multivariate analysis of the primary cohort: course of disease ≤ 20 days, presence of bulky disease at the beginning of diagnosis, central nervous system(CNS) invasion, and dosage of rituximab. The calibration curve showed that the nomogram was able to predict 3-year OS accurately. The C-index of the nomogram for OS prediction was 0.79 for both cohorts. In our hospital, pediatric BL was more commonly observed in school-age boys with an abdominal mass and mostly in advanced stages at initial diagnosis. The FAB/LMB96 regimen combined with rituximab significantly increased survival outcomes. We observed no significant differences between four and six doses of rituximab in terms of treatment outcomes. The proposed nomogram provides an individualized risk estimate of OS in patients with BL and may assist treatment decision-making or rituximab dose design.

Photo-Driven Regiodivergent Arylation/Cyclization and Arylation/Hydroxylation of N-Aryl Methacrylamides with Aryltriazenes: Access to Functionalized 3,3-Disubstituted Oxindoles and α-Hydroxylamides.

A metal-free, light-induced regiodivergent functionalization of α,ß-unsaturated amides with aryltriazenes under ambient conditions was developed. The visible light and B(C6F5)3 cocatalyzed radical cascade arylation/cyclization of N-alkyl-N-arylmethacrylamides can obtain functionalized 3,3-disubstituted oxindoles with the assistance of photocatalyst eosin Y-Na2. In the absence of any catalyst, with purple light irradiation and electron-donor-acceptor (EDA) complex initiation, the radical cascade arylation/hydroxylation of N-arylmethacrylamides affords α-hydroxylamides. This methodology highlights the arts in accessing different regioisomers by altering the substrates and photocatalytic strategies.

Visible-Light-Driven Bifunctional Photocatalytic Radical-Cascade Selenocyanation/Cyclization of Acrylamides with KSeCN.

A visible-light-induced radical-cascade selenocyanation/cyclization of N-alkyl-N-methacryloyl benzamides, 2-aryl-N-acryloyl indoles, and N-methacryloyl-2-phenylbenzimidazoles with potassium isoselenocyanate (KSeCN) was developed. The reactions were carried out with inexpensive KSeCN as a selenocyanation reagent, potassium persulfate as an oxidant, 2,4,6-triphenylpyrylium tetrafluoroborate as a bifunctional catalyst for phase-transfer catalysis, and photocatalysis. A library of selenocyanate-containing isoquinoline-1,3(2H,4H)-diones, indolo[2,1-a]isoquinoline-6(5H)-ones, and benzimidazo[2,1-a]isoquinolin-6(5H)-ones were achieved in moderate to excellent yields at room temperature under visible-light and ambient conditions. Importantly, the present protocol features mild reaction conditions, large-scale synthesis, simple manipulation, product derivatization, good functional group, and heterocycle tolerance.

Electrochemical Oxidative 1,2-Dithiocyanation: Access to Functionalized Alkenes and Alkynes.

Reported herein is the 1,2-dithiocyanation of alkenes and alkynes via an efficient and facile electrochemical method. This approach not only showed a broad substrate scope and good functional-group compatibility but also avoided stoichiometric oxidants. Different from previous reports, various internal alkynes could be tolerated to provide tetra-substituted alkenes. Further gram-scale-up experiments and synthetic transformation demonstrated a potential application in organic synthesis. This process underwent a radical pathway, as evidenced by our mechanistic studies.

Mendelian randomization analysis implicates bidirectional associations between brain imaging-derived phenotypes and ischemic stroke.

Brian imaging-derived phenotypes (IDPs) have been suggested to be associated with ischemic stroke, but the causality between them remains unclear. In this bidirectional two-sample Mendelian randomization (MR) study, we explored the potential causal relationship between 461 imaging-derived phenotypes (n = 33,224, UK Biobank) and ischemic stroke (n = 34,217 cases/406,111 controls, Multiancestry Genome-Wide Association Study of Stroke). Forward MR analyses identified five IDPs associated with ischemic stroke, including mean diffusivity (MD) in the right superior fronto-occipital fasciculus (1.22 [95% CI, 1.11-1.34]), MD in the left superior fronto-occipital fasciculus (1.30 [1.17-1.44]), MD in the anterior limb of the right internal capsule (1.36 [1.22-1.51]), MD in the right anterior thalamic radiation (1.17 [1.09-1.26]), and MD in the right superior thalamic radiation (1.23 [1.11-1.35]). In the reverse MR analyses, ischemic stroke was identified to be associated with three IDPs, including high isotropic or free water volume fraction in the body of corpus callosum (beta, 0.189 [95% confidence interval, 0.107-0.271]), orientation dispersion index in the pontine crossing tract (0.175 [0.093-0.257]), and volume of the third ventricle (0.219 [0.138-0.301]). This bidirectional two-sample MR study suggested five predictors and three diagnostic markers for ischemic stroke at the brain-imaging level. Further studies are warranted to replicate our findings and clarify underlying mechanisms.

The bidirectional association between frailty index and cardiovascular disease: A Mendelian randomization study.

BACKGROUND AND AIM: Observational studies have suggested a relationship between frailty and cardiovascular disease (CVD), but the causality is still uncertain. We used bidirectional Mendelian randomization (MR) design to investigate the potential causal associations between frailty and four main CVDs, including hypertension, myocardial infarction (MI), heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Independent single-nucleotide polymorphisms for frailty index (FI) and CVDs (hypertension, MI, HF, and AF) were selected as genetic instruments based on European-descent genome-wide association studies (GWASs). Summary-level data for outcomes on FI (n = 175,226), hypertension (n = 463,010), MI (n = 171,875), HF (n = 977323), and AF (n = 1,030,836) was derived from five large-scale GWASs of European ancestry. We used the inverse-variance weighted (IVW) method to examine the bidirectional associations between FI and CVDs in the main analyses. In the IVW MR analyses, genetically determined high FI was significantly associated with increased risks of hypertension (odds ratio [OR] per 1-SD increase: 1.07 [95 % confidence interval, 1.05-1.08]), MI (OR per 1-SD increase: 1.74 [1.21-2.51]), HF (OR per 1-SD increase: 1.28 [1.10-1.48]), and AF (OR per 1-SD increase: 1.20 [1.08-1.33]). In addition, genetically determined hypertension (beta: 1.406 [1.225-1.587]), MI (beta: 0.045 [0.023-0.067]), HF (beta: 0.105 [0.066-0.143]) and AF (beta: 0.021 [0.012-0.031]) were significantly associated with high FI. These findings were robustly supported by a series of sensitivity analyses with different MR models. CONCLUSIONS: We found potential bidirectional causal associations between elevated FI and increased risks of CVD, suggesting mutual risk factors between frailty and CVD.