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Efficient and safe extraction of microRNAs (miRNAs) from biological samples is pivotal for genetic regulation studies and biotechnological applications. This study focuses on optimizing the microRNA extraction process from the plasma of common carp, a significant species in aquaculture. Recognizing the limitations and hazards of commercial extraction kits, which often employ toxic chemicals like phenol and chloroform, we sought to develop a safer and more effective alternative. Our optimized protocol utilizes guanidinium isothiocyanate (GITC) and sarkosyl, omitting hazardous substances. We explored several parameters including GITC concentration, the addition of sarkosyl, and the role of sodium chloride in enhancing miRNA yield. Our findings demonstrate that optimal conditions involve a GITC concentration of 4.2 M, a 3% sarkosyl concentration, and the use of sodium chloride at 0.5 M. We also investigated the utility of glycogen as a nucleic acid carrier, finding 160 µg to be the optimal concentration. Comparative analysis with commercial kits indicated our method provides higher miRNA yields with reduced cycle threshold values, underscoring the effectiveness of our custom protocol. This optimized approach not only enhances miRNA recovery but also emphasizes safety and cost-effectiveness, making it a valuable method for both research and practical applications in aquaculture.

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Polycystic ovarian syndrome (PCOS) is a prevalent endocrinological disorder affected by ghrelin. This study aimed to investigate the molecular mechanisms underlying the effects of ghrelin on PCOS manifestations in mice and to assess the therapeutic potential of ghrelin. Female C57BL/6 mice were subcutaneously injected with 6 mg/100 g dehydroepiandrosterone (DHEA) for 20 days to induce PCOS. Alterations in reproductive cycles, ovarian morphology, serum sex hormone levels, and related signaling markers were examined. Furthermore, ghrelin-induced effects on granulosa cells and the role of ghrelin/Gq/11/ Yes-associated protein (YAP) signaling were studied by silencing Gαq/11 or YAP using si-RNAs. Finally, we evaluated the therapeutic potential of anti-ghrelin antibodies in DHEA-induced PCOS mice. DHEA administration led to significant PCOS-associated changes including weight gain, disrupted estrous cycles, ovarian morphological alterations, and hormonal imbalances in mice, with elevated Gαq/11 and acylated ghrelin expression, which was also noted in PCOS patients. However, treatment with anti-ghrelin antibodies effectively managed DHEA-induced damage in PCOS mice. In vitro, ghrelin exposure resulted in granulosa cell injury and modulated estrogen receptors alpha (ERα) and YAP protein levels, whereas silencing YAP and Gαq/11 reversed ghrelin-induced detrimental effects and up-regulated ERα expression. This study revealed that DHEA-induced PCOS traits in mice could be improved by anti-ghrelin antibodies, with the ghrelin/Gq/11/YAP signaling pathway identified as a crucial mediator in granulosa cells, affecting ERα transcription to regulate PCOS. These findings suggest a potential therapeutic strategy for the treatment of PCOS.

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Intestinal barrier dysfunction with high serum endotoxin is common in patients with liver fibrosis, but the mechanisms underlying liver fibrosis remain unclear. Melatonin is a well-recognized antioxidant and an anti-inflammatory agent that benefits multiple organs. However, the beneficial effects of melatonin on gut leakiness-associated liver fibrosis have not been systemically studied. Here, we investigated the protective mechanisms of melatonin against thioacetamide (TAA)-induced gut barrier dysfunction and hepatic fibrosis by focusing on posttranslational protein modifications through the gut-liver axis. Our results showed that gut leakiness markers, including decreased gut tight/adherens junction proteins (TJ/AJs) with increased intestinal deformation, apoptosis, and serum endotoxin, were observed early at 1 week after TAA exposure. Liver injury, apoptosis, and fibrosis were prominent at 2 and 4 weeks. Mechanistically, we found that gut TJ/AJs were hyper-acetylated, followed by ubiquitin-dependent proteolysis, leading to their degradation and gut leakiness. Gut dysbiosis, hepatic protein hyper-acetylation, and SIRT1 downregulation were also observed. Consistently, intestinal Sirt1 deficiency greatly enhanced protein hyper-acetylation, gut leakiness, endotoxemia, and liver fibrosis. Pretreatment with melatonin prevented or improved all these changes in both the gut and liver. Furthermore, melatonin blunted protein acetylation and injury in TAA-exposed T84 human intestinal and AML12 mouse liver cells. Overall, this study demonstrated novel mechanisms by which melatonin prevents gut leakiness and liver fibrosis through the gut-liver axis by attenuating the acetylation of intestinal and hepatic proteins. Thus, melatonin consumption can become a potentially safe supplement for liver fibrosis patients by preventing protein hyper-acetylation and gut leakiness.

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Stratification strategies for chemotherapy plus PD-1 inhibitors in advanced non-small-cell lung cancer (NSCLC) are critically demanded. We performed high-throughput panel-based deep next-generation sequencing and low-pass whole genome sequencing on prospectively collected circulating tumor DNA (ctDNA) specimens from 460 patients in the phase 3 CHOICE-01 study at different time points. We identified predictive markers for chemotherapy plus PD-1 inhibitor, including ctDNA status and genomic features such as blood-based tumor mutational burden, intratumor heterogeneity, and chromosomal instability. Furthermore, we established an integrated ctDNA-based stratification strategy, blood-based genomic immune subtypes (bGIS) scheme, to distinguish patients who benefit from the addition of PD-1 inhibitor to first-line chemotherapy. Moreover, we demonstrated potential applications for the dynamic monitoring of ctDNA. Overall, we proposed a potential therapeutic algorithm based on the ctDNA-based stratification strategy, shedding light on the individualized management of immune-chemotherapies for patients with advanced NSCLC.

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High level of C (ROS) within the tumor microenvironment (TME) not only damage tumor cells but also diminish the efficacy of immunogenic cell death (ICD) and the activity of tumor-infiltrating T lymphocytes, thereby limiting the effectiveness of immunotherapy. Therefore, precise modulation of ROS level is crucial to effectively eliminate tumor cells and activate ICD-induced immunotherapy. Here, an intelligent yolk shell nanoplatform (SPCCM) that features calcium carbonate shells capable of decomposing under acidic TME conditions, thereby releasing the natural antioxidant proanthocyanidins (PAs) and the photosensitizer Ce6 is designed. PAs scavenge ROS within tumors, extending the survival time of T lymphocytes, while Ce6, as an ICD inducer, generates high ROS concentrations upon laser irradiation, thus reaching the toxic threshold within tumor cells and inducing apoptosis. The resulting apoptotic cells serve as tumor-associated antigens, promoting dendritic cells (DCs) maturation, and activating ICD. By effectively neutralizing ROS in the TME, PAs sustainably reduce ROS level, thereby enhancing DCs activation and restoring antitumor immune cell activity suppressed by ROS (resulting in an eightfold increase in DCs activation). This study demonstrates effective synergistic effects between photodynamic therapy and immunotherapy by precisely modulating ROS level.

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BACKGROUND: In the initial analysis of a pivotal phase 2 single-arm study (NCT03861156), befotertinib (D-0316) showed clinical benefit with a manageable safety profile in pretreated patients with EGFR T790M mutated non-small cell lung cancer (NSCLC), including those with brain metastases. METHODS: Eligible patients received oral befotertinib of 50 mg (cohort A) or 75-100 mg (cohort B) once daily until disease progression, withdrawal of informed consent, or death. The primary endpoint for the initial analysis was objective response rate (ORR) assessed by an independent review committee. OS and safety were secondary endpoints. Herein, we present the final OS and safety data. RESULTS: A total of 176 patients in cohort A and 290 patients in cohort B were finally enrolled. At data cutoff (May 31, 2023), the median duration of follow-up was 47.9 months (95 % CI: 47.1-48.3) in cohort A and 36.7 months (35.9-37.9) in cohort B. The median OS was 23.9 months (95 % CI: 21.1-27.2) in cohort A and 31.5 months (26.8-35.3) in cohort B. The median OS for patients with and without brain metastasis in cohort A was 18.6 months (95 % CI: 14.9-26.3) and 26.4 months (95 % CI: 23.0-29.0), respectively. In cohort B, these data was 23.0 months (95 % CI: 18.6-29.1) and 35.5 months (95 % CI: 29.3-NE), respectively. The safety profile of befotertinib remained consistent with previous data. Grade 3 or higher treatment-emergent adverse events were 38.1 % in the cohort A and 50.3 % in the cohort B, and 22.2 % and 31.7 % were related to the study drug. CONCLUSION: Befotertinib demonstrated a more profound OS benefit compared to other 3rd-generation EGFR TKI, despite that cross trial data comparison should be interpreted with caution. The safety profile was manageable and consistent with previously report data in pretreated patients with confirmed T790M mutation-positive NSCLC.

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Hypertension is accompanied by gut microbiota imbalance, but the role of bacteria in the pathogenesis of hypertension requires further study. In this study, we used fecal microbiota transplantation to determine the impact of microbiota composition on blood pressure in spontaneous hypertensive rats (SHRs), using normotensive Wistar Kyoto (WKY) rats as controls. SHRs were randomly divided into two groups (n = 10/group), SHR and SHR-T (SHR plus fecal transplantation) and WKY into WKY and WKY-T (WKY plus fecal transplantation). SHR-T received fecal transplantation from WKY, while WKY-T received fecal transplantation from SHR. Blood pressure was measured from the tail artery in conscious rats. 16S rDNA gene amplicon sequencing was used to analyze bacterial composition. Circulating levels of diamine oxidase, D-lactate, FITC-Dextrans, and lipopolysaccharide were determined. Hematoxylin and eosin (H&E) staining was used to observe structural changes in the intestinal mucosa. Immunofluorescence, Western blot, and RT-PCR were utilized to determine changes in the expression of tight junction proteins. Following cross fecal transplantation, blood pressure decreased in SHR and increased in WKY. Significant differences in gut microbial composition were found between hypertensive and normotensive rats, specifically regarding the relative abundance of lactic and butyric acid-producing bacteria. Changes in gut microbiota composition also impacted the intestinal mucosal barrier integrity. Moreover, fecal transplantation affected the expression of tight junction proteins that may impact intestinal mucosal permeability and structural integrity. Blood pressure may be associated with butyric acid-producing intestinal microbiota and its function in regulating the integrity of intestinal mucosal barrier.

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Ankle moment plays an important role in human gait analysis, patients' rehabilitation process monitoring, and the human-machine interaction control of exoskeleton robots. However, current ankle moment estimation methods mainly rely on inverse dynamics (ID) based on optical motion capture system (OMC) and force plate. These methods rely on fixed instruments in the laboratory, which are difficult to be applied to the control of exoskeleton robots. To solve this problem, this paper developed a new distributed plantar pressure system and proposed an ankle plantar flexion moment estimation method using the plantar pressure system. We integrated eight pressure sensors in each insole to collect the pressure data of the key area of the foot and then used the plantar pressure data to train four neural networks to obtain the ankle moment. The performance of the models was evaluated using normalized root mean square error (NRMSE) and cross-correlation coefficient (ρ). During experiments, eight subjects were recruited for the overground walking tests, and OMC and force plate were used as the gold standard. The results indicate that the Genetic algorithm - Gated recurrent unit estimation algorithm (GA-GRU) was the best estimation model which achieved the highest accuracy in generalized ankle moment estimation (NRMSE = 7.23%, ρ = 0.85) compared with the other models. The designed novel distributed plantar pressure system and the proposed method could serve as a joint moment estimation approach in wearable robot control and human motion state monitoring.

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Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.

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The prognostic significance of the signet-ring cell component in gallbladder carcinoma (GBC) has not been systematically evaluated. The aim of this study was to assess the similarities and differences between gallbladder signet-ring cell carcinoma (GBSRCA) and gallbladder adenocarcinoma (GBAC) in terms of clinicopathological features and long-term survival. Using the Surveillance, Epidemiology, and End Results (SEER) database, we analyzed 6,612 patients diagnosed with gallbladder cancer between 2000 and 2021. The cohort included 147 patients with GBSRCA and 6,465 with GBAC. Patients with GBSRCA were significantly younger, with 33.3% being age 60 or younger compared to 23.9% of patients with GBAC (p = 0.009). There was a higher proportion of females in the GBSRCA group (77.6%) compared to the GBAC group (70.1%, p = 0.049). GBSRCA was associated with a more advanced tumor stage (T3-T4: 56.5% vs. 44.4%, P = 0.004), higher rates of lymph node metastasis (43.5% vs. 28.0%, P < 0.001), and poorer differentiation status (poorly to undifferentiated: 80.3% vs. 29.7%, P < 0.001). Survival analysis revealed that patients with GBSRCA had significantly worse overall survival (OS) and cancer-specific survival (CSS) compared to patients with GBAC (p < 0.001). GBSRCA was an independent prognostic factor for OS (P = 0.001) in the entire cohort, while the T stage and N stage were independent prognostic factors for OS and CSS in patients with GBSRCA. Even after propensity score matching, patients with GBSRCA still had a poorer prognosis.

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Human-induced disturbances such as dam construction and regulation have led to widespread alterations in hydrological processes and thus substantially influence plant characteristics in the hydro-fluctuation zones (HFZs). To reveal utilization of limited resources and mechanisms of inter-specific competition and species co-existence of plant communities based on niche breadth and overlap under the different HFZs of the Three Gorges Reservoir (TGR) in China, we conducted a field investigation with 368 quadrats on the effects of hydrological alterations on plant diversity and niche characteristics. The results showed anti-seasonal flooding precipitated the gradual disappearance of the original diverse niches, resulting in the reduction of plant species richness and functional diversity and more obvious competition among plant species with similar resource requirements. Annuals, perennials and shrubs accounted for 71.23%, 27.39% and 1.37%, respectively, suggesting that annuals and flood-tolerant riparian herbs were favored under such novel flooding conditions. A consistent increase in species number, Shannon-Wiener diversity index and Simpson dominance index with altitude was inconsistent with hump-shaped diversity-disturbance relationship of the intermediate disturbance hypothesis, while the opposite trend was observed for the Pielou evenness index. This species distribution pattern might be caused by several synergetic attributes (e.g., the submergence depth, plant tolerant capacity to flooding, life form, dispersal mode and inter-specific competition). Vegetation types shifted from xerophytes to mesophytes and eventually to hygrophytes with the increasing flooding time in the HFZs. Hydrological alterations proved to be the paramount driver of vegetation distribution in the different HFZs. The niche analysis provided the first insights on the mechanisms of resource utilization and inter-specific competition, of which annuals could germinate quickly after soil drainage to achieve the greatest competitive advantages and occupy a larger niche space than other plants. Vegetation was still in the early stage of primary succession in the novel riparian forests. Therefore, vegetation restoration strategies should be biased towards herbaceous plants, due to annuals with better environmental adaptability, supplemented by shrubs and small trees. To establish a complete reference system for vegetation restoration, natural vegetation monitory plots in the different succession stages should be established in the different HFZs of the TGR, and their environmental conditions, community structures and inter-specific relationships further analyzed.

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Disrupted connectivity in the default mode network (DMN) during resting-state functional MRI (rs-fMRI) is well-documented in schizophrenia (SCZ). The amygdala, a key component in the neurobiology of SCZ, comprises distinct subregions that may exert varying effects on the disorder. This study aimed to investigate variations in functional connectivity (FC) between distinct amygdala subregions and the DMN in SCZ individuals and explore the effects of treatment on these connections. Fifty-six SCZ patients and 51 healthy controls underwent FC analysis and questionnaire surveys during resting state. The amygdala was selected as the region of interest (ROI) and subdivided into four parts. Changes in FC were examined, and correlations between questionnaire scores and brain activity were explored. Pre-treatment, SCZ patients exhibited reduced FC between the amygdala and DMN compared to HCs. After treatment, significant differences persisted in the right medial amygdala, while other regions did not differ significantly from controls. In addition, PANSS scores positively correlated with FC between the Right Medial Amygdala and the left SMFC (r = .347, p = .009), while RBANS5A scores showed a positive correlation with FC between the Left Lateral Amygdala and the right MTG (rho = -.347, p = .009). The rsFC between the amygdala and the DMN plays a crucial role in the treatment mechanisms of SCZ. This could provide a promising predictive indicator for understanding the neural mechanisms behind treatment and symptomatic improvement.

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BACKGROUND: Sleep remains a cornerstone for sociopsychological well-being, but it is in decline, especially among today's youth. Simultaneously, engagement with social media is escalating. Research has identified a link between social networking sites use and sleep problems; however, the nature and direction of the relations remain obscure. Therefore, it is imperative to pursue longitudinal research to elucidate this correlation and guide suitable intervention practices. The present study aimed to examine the reciprocal relationship between social networking sites use and sleep problems. METHODS: By adopting a three-stage cross-lagged design across four time points, assessment results from 194 university students were gathered at four-week intervals. RESULTS: The findings indicate that (1) Social networking sites use was significantly greater in females than in males at all four time points, while sleep problems were significantly greater in females than in males at Time 3 and Time 4. (2) Sleep problems at the second time point serve as a positive predictor of subsequent social networking sites use at the third time point. (3) Social networking sites use at the initial time point could marginally significantly predict sleep problems at the fourth time point. CONCLUSIONS: This study elucidates the dynamic relationship between social networking sites use and sleep problems across an academic term, suggesting the need for temporally tailored interventions.

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RATIONALE: Acquired resistance still inevitably occurs in patients treated with third-generation TKI osimertinib. Although the EGFR L718Q mutation has been reported as a scarce mechanism of osimertinib resistance, advanced therapeutic strategies are still in development. In this report, we included 2 cases of patients who acquired EGFR L858R/L718Q mutation after osimertinib and were overcome by dacomitinib. PATIENT CONCERNS: Case 1: A 77-year-old woman was diagnosed with stage IV lung adenocarcinoma. Case 2: A 64-year-old woman was diagnosed with stage IV lung adenocarcinoma. DIAGNOSES: Case 1: The patient was diagnosed with adenocarcinoma with EGFR L858R mutation. Since then, treatment with gefitinib was administrated, leading to a progression-free survival of 18 months. The treatment was switched to osimertinib based on the detection of EGFR T790M mutation, resulting in a progression-free survival of 24 months. Subsequently, EGFR L718Q mutation was detected. Case 2: The patient was diagnosed with adenocarcinoma with EGFR L858R mutation. Icotinib was used as the first-line treatment for 7 months. Osimertinib was applied as the second-line treatment for 13 months based on the EGFR T790M mutation. Subsequently, EGFR L718Q mutation was detected. INTERVENTIONS: Case 1: Dacomitinib was administered. Case 2: Dacomitinib was administered. OUTCOMES: Case 1:The progression-free survival was 8 months. Case 2: The progression-free survival was 3 months. LESSONS: Dacomitinib is a potential treatment option for NSCLC patients with EGFR L718Q mutation after resistance to Osimertinib. Further research is needed to validate the efficacy of Dacomitinib in this context.

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The present study utilized the spared nerve injury (SNI) to create a mouse model of depression to investigate the impact of esketamine on depressive-like behaviors, on the expression of PSD-95 and CRMP2 proteins, and on changes in neuronal dendritic spine plasticity in the prefrontal cortex (PFC). Depressive-like behavioral tests were performed 1 h after esketamine treatment, and the PFC tissues were obtained on the fourth day after completing the behavioral tests. Then, dendritic spine density and morphology in the PFC were measured using Golgi staining, and CRMP2 and PSD-95 proteins were obtained from PFC tissue by western blotting. The results of this study showed that esketamine significantly increased the immobility time in the forced swimming test and tail suspension test. In the open field test, esketamine increased the time spent in the open arms, the time spent in the central area, and the total distance covered. It also increased the protein expression levels of CRMP2 and PSD-95 in addition to the total and mature dendritic spine density of the PFC in SNI-depressed mice. Esketamine can significantly improve depression-like behaviors in SNI-depressed mice and promote an increase in dendritic spine density and maturation in the PFC. These effects may be associated with changes in CRMP2 and PSD-95 expression.

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Objective: To investigate the therapeutic effect of Cf-252 neutron intracavitary brachytherapy (ICBT) in the treatment of primary vaginal carcinoma of stage I-III, along with advanced complications. Methods: Between August 2009 and August 2013, 41 patients with intact primary vaginal carcinoma based on the histological diagnosis at the Second Cancer Hospital of Heilongjiang Province (Beidahuang Group General Hospital) and the Daping Hospital of the Third Military Medical University were included in this study. Among them, 32 patients were squamous cell carcinoma, and 9 adenocarcinomas. Stage I patients were treated with ICBT alone. Patients at stages II and III were treated using ICBT combined with external beam radiotherapy (EBRT). Results: The mean age, the rate of the 5-year local control, the rate of the 5-year overall survival was increased. The rate of the 5-year tumor-free survival was 56.1%, and the incidence of advanced serious complications (grade II and above radiation cystitis, proctitis, etc.) was 29.3%. Compared to later stages, early-stage patients are in better physical shape, so they are better able to withstand the toxic side effects of treatment. The local control (LC), overall survival (OS), or disease-free survival (DFS) rate in stage III patients was significantly lower than those in stage I and stage II. The rate of OS in stage I patients was 90.9% (10/11), which was significantly higher than that in all patients (56.1%; 23/41). Moreover, the mean survival time was significantly different between stage III and stage I. In addition, the survival status of squamous cell carcinoma and adenocarcinoma was also very different. Conclusion: In summary, the use of Cf-252 ICBT radiotherapy resulted in a higher rate of local control of vaginal cancer and a lower rate of recurrence, better-shrinking effect, and efficacy for advanced tumors, and has clinical prospects.

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Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/ß-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis.

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BACKGROUND: Default mode network (DMN) is one of the most recognized resting-state networks in major depressive disorder (MDD). However, the homogeneity of this network in MDD remains incompletely explored. Therefore, this study aims to determine whether there is abnormal network homogeneity (NH) of the DMN in MDD patients. At the same time, correlations between clinical variables and brain functional connectivity are examined. METHODS: We enrolled 42 patients diagnosed with MDD and 42 HCs. A variety of clinical variables were collected, and data analysis was conducted using the NH and independent component analysis methods. RESULTS: The study shows that MDD patients have higher NH values in the left superior medial prefrontal cortex (MPFC) and left posterior cingulate cortex (PCC) compared to HCs. Additionally, there is a positive correlation between NH values of the left superior MPFC and Eysenck Personality Questionnaire values. NH values of the left PCC are positively linked to CHOL levels, LDL levels, and utilization scores. However, these correlations lose significance after the Bonferroni correction. CONCLUSION: Our findings indicate the presence of abnormal DMN homogeneity in MDD, underscoring the significance of DMN in the pathophysiology of MDD. Simultaneously, the study provides preliminary evidence for the correlation between clinical variables and brain functional connectivity.

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PURPOSE: Greater white matter hyperintensities (WMH) in older adults have been associated with reduced bone mineral density (BMD) and increased fractures and falls. However, it is unclear whether there is a causal relationship between BMD reduction and WMH. In this study, Mendelian randomization (MR) was used to find the causality between WMH and estimated BMD (eBMD). METHODS: We performed a two-sample bidirectional MR analysis using statistical data obtained from publicly available genome-wide association studies (GWAS). The main method of MR analysis is the inverse-variance weighted (IVW) method. To identify and account for the impact of horizontal pleiotropy, we also employed MR-Egger regression, MR pleiotropy residual sum, and outlier (MR-PRESSO). RESULTS: MR analysis found a causal relationship between eBMD and WMH (IVW OR = 0.938, 95 % CI: 0.889-0.990, p = 0.020). Our causal estimates are unlikely to be distorted by horizontal pleiotropy according to heterogeneity test (both p > 0.05) and MR-Egger regression (p > 0.05). However, in the reverse MR analysis, there was no evidence that WMH was causally correlated with eBMD (IVW OR = 0.979, 95 % CI: 0.954-1.005, p = 0.109). CONCLUSION: Our results suggest that low eBMD increased the risk of WMH; conversely, no evidence that WMH causally affects eBMD was found.

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