Multi-omics Mendelian randomization integrating GWAS, eQTL, and mQTL data identified genes associated with breast cancer.

Breast cancer (BC) remains a major disease posing a threat to women's health, but the underlying biological interpretation remains largely unknown. Here, we aimed to identify genes associated with breast cancer and analyze their pathophysiological mechanisms based on multi-omics Mendelian randomization (MR). Summary-data-based MR (SMR) was performed to estimate the causal effects of blood and breast mammary tissue expression quantitative trait loci (eQTLs) on BC. External validation analysis was used to validate the identified genes. Integration analyses BC GWAS summaries with eQTLs and DNA methylation QTLs (mQTLs) from the blood were conducted using SMR to prioritize putative blood genes and their regulatory elements associated with BC risk. Finally, two prior genes (ATG10 and RCCD1) from blood tissue reached significant levels in both BCAC (ATG10: ORBRCR = 0.91, PBRCR = 1.29 × 10-11; RCCD1: ORBRCR = 0.90, PBRCR = 3.72 × 10-15) and FinnGen cohorts (ATG10: ORFinnGen = 0.89, PFinnGen = 8.55 × 10-5; RCCD1: ORFinnGen = 0.89, PFinnGen = 2.38 × 10-8). Additionally, those two genes from breast tissues also replicated in both BCAC (ATG10: ORBRCR = 0.95, PBRCR = 1.02 × 10-9; RCCD1: ORBRCR = 0.87, PBRCR = 4.70 × 10-10) and FinnGen cohorts (ATG10: ORFinnGen = 0.93, PFinnGen = 2.38 × 10-4; RCCD1: ORFinnGen = 0.85, PFinnGen = 3.81 × 10-6). Sensitive analysis and external validation analysis validated those two identified genes. Multi-omics MR analysis showed that the SNP signals associated with ATG10 and RCCD1 were significant across the data from BC Genome-wide association study (GWAS), eQTL, and mQTL studies. In conclusion, we identified two priority genes that are potentially associated with BC. These findings improve our limited understanding of the mechanism of BC and shed light on the development of therapeutic agents for treating BC.

Recent advances in the application of Mendelian randomization to chronic kidney disease.

OBJECTIVE: Chronic kidney disease (CKD) is a condition influenced by both genetic and environmental factors and has been a focus of extensive research. Utilizing Mendelian randomization, researchers have begun to untangle the complex causal relationships underlying CKD. This review delves into the advances and challenges in the application of MR in the field of nephrology, shifting from a mere summary of its principles and limitations to a more nuanced exploration of its contributions to our understanding of CKD. METHODS: Key findings from recent studies have been pivotal in reshaping our comprehension of CKD. Notably, evidence indicates that elevated testosterone levels may impair renal function, while higher sex hormone-binding globulin (SHBG) levels appear to be protective, predominantly in men. Surprisingly, variations in plasma glucose and glycated hemoglobin levels seem unaffected by genetically induced changes in the estimated glomerular filtration rate (eGFR), suggesting an independent pathway for renal function impairment. RESULTS: Furthermore, lifestyle factors such as physical activity and socioeconomic status emerge as significant influencers of CKD risk and kidney health. The relationship between sleep duration and CKD is nuanced; short sleep duration is linked to increased risk, while long sleep duration does not exhibit a clear causal effect. Additionally, lifestyle factors, including diet, exercise, and mental wellness activities, play a crucial role in kidney health. New insights also reveal a substantial causal connection between both central and general obesity and CKD onset, while no significant links were found between genetically modified LDL cholesterol or triglyceride levels and kidney function. CONCLUSION: This review not only presents the recent achievements of MR in CKD research but also illuminates the path forwards, underscoring critical unanswered questions and proposing future research directions in this dynamic field.

Engineering Logic DNA Nanoprobes on Live Cell Membranes for Simultaneously Monitoring Extracellular pH and Precise Drug Delivery.

It remains a challenge to use a single probe to simultaneously detect extracellular pH fluctuations and specifically recognize cancer cells for precise drug delivery. Here, we engineered a tetrahedral framework nucleic acid-based logic nanoprobe (isgc8-tFNA) on live cell membranes for simultaneously monitoring extracellular pH and targeted drug delivery. Isgc8-tFNA was anchored stably on the cell surface through three cholesterol molecules inserting into the bilayer of the cell membrane. Once responding to the acidic tumor microenvironment, isgc8-tFNA formed an i-motif structure, leading to turn-on FRET signals for monitoring changes of extracellular pH. The nanoprobe exhibited a narrow pH-response window and excellent reversibility. Moreover, the nanoprobe could execute logic identification on the cell surface for precise drug delivery. Only if both in the acidic microenvironment and aptamer-targeting marker are present on the cell surface, the sgc8-ASO-chimera strand, carrying an antisense oligonucleotide drug, was released from the nanoprobe and entered into targeted cancer cells for gene silence. Additionally, the in situ drug release facilitated the uptake of drugs mediated by the interaction between sgc8 aptamer and membrane proteins, resulting in enhanced inhibition of cancer cell migration and proliferation. This logic nanoprobe will provide inspiration for designing smart devices for diagnosis of pH-related diseases and targeted drug delivery.

Parkinson's disease patients with absence of normal dipping status were more vulnerable to cognitive impairment from the early stages.

INTRODUCTION: The objective of this study was to determine the characteristics of cognitive function in Parkinson's disease (PD) patients with different dipping statuses. METHODS: Consecutive PD patients were recruited for this study. All participants underwent 24-h ambulatory blood pressure monitor (ABPM). Corresponding scales were employed to evaluate both motor and non-motor symptoms. The subjects were categorized into reverse, reduced, normal, and extreme dipping groups based on dipping patterns. Additionally, they were divided into early and non-early stage groups according to the disease duration being more than 5 years. RESULTS: The proportions of the four dipping groups in the early and non-early stage groups exhibited no significant differences. The Montreal Cognitive Assessment (MoCA) scores in the reverse group were significantly lower than those in the normal dipping group (16.2 ± 5.8 vs 21.1 ± 6.1,P = 0.003). The attention as well as delayed recall scores in the reverse dipping group were significant lower than those in the normal dipping group (P = 0.042; P < 0.001). The multivariate linear regression analysis revealed that absence of normal dipping was an independent risk factor (OR = -2.252; P = 0.027) for MoCA scores for PD patients. CONCLUSIONS: PD patients with absence of normal dipping status were more vulnerable to cognitive impairment from the early stages of the disease. The 24-h ABPM is recommended for early detection of abnormal dipping status and identification of individuals at risk for cognitive decline.

A Self-Consistent Framework for Tailored Single-Atom Catalysts in Electrocatalytic Nitrogen Reduction.

The catalytic activity of single-atom catalysts (SACs) is crucially affected by the actual ligand configurations under the reaction condition; thus, carefully considering the reaction condition is crucial for the theoretical design of SACs. With single metal atoms supported by g-C3N4 as a model system, a self-consistent screening framework is proposed for the theoretical design of SACs with respect to the nitrogen reduction reaction (NRR). Pourbaix diagrams are constructed on the basis of various co-adsorption configurations of N2, H, and OH. Possible stable configurations containing N2 under the expected reaction condition are considered to obtain the limiting potential of NRR, and the stability of the configuration at the calculated UL is rechecked. With this framework, AC stacking of double-layer g-C3N4-supported Nb and AA stacking and AB stacking of double-layer g-C3N4-supported W are predicted to exhibit superior NRR activity with UL values of -0.36, -0.45, and -0.52 V, respectively. This procedure can be widely applied to the screening of SACs for electrocatalytic reactions.

Causal relationship between female reproductive factors, sex hormones and uterine leiomyoma: a Mendelian randomization study.

RESEARCH QUESTION: Are the observed associations between female reproductive factors and sex hormones with the risk of uterine leiomyoma truly causal associations? DESIGN: The putative causal relationships between female reproductive factors and sex hormones with uterine leiomyoma were investigated using two-sample Mendelian randomization. Statistics on exposure-associated genetic variants were obtained from genome-wide association studies (GWAS). The uterine leiomyoma GWAS from the FinnGen and FibroGENE consortia were used as outcome data for discovery and replication analyses, respectively. Results were pooled by meta-analysis. Sensitivity analyses ensured robustness of the Mendelian randomization analysis. RESULTS: When FinnGen GWAS were used as outcome data, a causal relationship was found between age at menarche (OR 0.84, P < 0.0001), age at menopause (OR 1.08, P < 0.0001), number of live births (OR 0.25, P < 0.001) and total testosterone levels (OR 0.90, P < 0.001) with the risk of uterine leiomyoma. When FibroGENE GWAS were used as outcome data, Mendelian randomization results for age at menopause, the number of live births and total testosterone levels were replicated. In the meta-analysis, a later age at menopause (OR 1.08, P < 0.0001) was associated with an increased risk of uterine leiomyoma. A higher number of live births (OR 0.25, P < 0.0001) and higher total testosterone levels (OR 0.90, P < 0.0001) were associated with a decreased risk of uterine leiomyoma. CONCLUSIONS: A causal relationship between later age at menopause, lower number of live births and lower total testosterone levels with increased risk of uterine leiomyoma was found.

Novel insights into causal effects of serum lipids and lipid-modifying targets on cholelithiasis.

OBJECTIVE: Different serum lipids and lipid-modifying targets should affect the risk of cholelithiasis differently, however, whether such effects are causal is still controversial and we aimed to answer this question. DESIGN: We prospectively estimated the associations of four serum lipids with cholelithiasis in UK Biobank using the Cox proportional hazard model, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Furthermore, we estimated the causal associations of the genetically predicted serum lipids with cholelithiasis in Europeans using the Mendelian randomisation (MR) design. Finally, both drug-target MR and colocalisation analyses were performed to estimate the lipid-modifying targets' effects on cholelithiasis, including HMGCR, NPC1L1, PCSK9, APOB, LDLR, ACLY, ANGPTL3, MTTP, PPARA, PPARD and PPARG. RESULTS: We found that serum levels of LDL-C and HDL-C were inversely associated with cholelithiasis risk and such associations were linear. However, the serum level of TC was non-linearly associated with cholelithiasis risk where lower TC was associated with higher risk of cholelithiasis, and the serum TG should be in an inverted 'U-shaped' relationship with it. The MR analyses supported that lower TC and higher TG levels were two independent causal risk factors. The drug-target MR analysis suggested that HMGCR inhibition should reduce the risk of cholelithiasis, which was corroborated by colocalisation analysis. CONCLUSION: Lower serum TC can causally increase the risk of cholelithiasis. The cholelithiasis risk would increase with the elevation of serum TG but would decrease when exceeding 2.57 mmol/L. The use of HMGCR inhibitors should prevent its risk.

Metagenomic next-generation sequencing for diagnosis of infectious encephalitis and meningitis: a retrospective study of 90 patients.

BACKGROUND: Infections of the central nervous system (CNS) are potentially life-threatening and can cause serious morbidity. We evaluated the clinical value of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis and explored the factors affecting the results of mNGS. METHODS: Patients with suspected cases of encephalitis or meningitis who presented in Northern Jiangsu People's Hospital from 1 March 2018 to 30 September 2022 were collected. Demographic, historical, and clinical information were obtained, and cerebrospinal fluid (CSF) samples were treated with mNGS. The pathogen was identified using National Center for Biotechnology Information (NCBI) GenBank sequence data. RESULTS: Ninety-six patients were screened and finally 90 subjects enrolled. Of the 90 enrolled cases, 67 (74.4%) were diagnosed with central nervous system infections, which included 48 cases (71.6%) of viral infection, 11 (12.2%) of bacterial infection, 5 (7.5%) of mycobacterium tuberculosis, 2 (3.0%) of fungal infection, and 1 (1.5%) of rickettsia infection. From these cases, mNGS identified 40 (44.4%) true-positive cases, 3 (3.3%) false-positive case, 22 (24.4%) true-negative cases, and 25 (27.8%) false-negative cases. The sensitivity and specificity of mNGS were 61.5% and 88%, respectively. mNGS of CSF could show a higher positive rate in patients with marked CSF abnormalities, including elevated protein concentrations and monocyte counts. CONCLUSION: mNGS of CSF is an effective method for detecting infectious encephalitis and meningitis, and the results should be analyzed combined with conventional microbiological testing results.

Common gastrointestinal diseases and chronic obstructive pulmonary disease risk: a bidirectional Mendelian randomization analysis.

Background: Observational studies suggest an association between gastrointestinal diseases and chronic obstructive pulmonary disease (COPD), but the causal relationship remains unclear. Methods: We conducted bidirectional Mendelian randomization (MR) analysis using summary data from genome-wide association study (GWAS) to explore the causal relationship between common gastrointestinal diseases and COPD. Gastrointestinal diseases included gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), irritable bowel syndrome (IBS), Crohn's disease (CD), ulcerative colitis (UC), functional dyspepsia (FD), non-infectious gastroenteritis (NGE), and constipation (CP). Significant MR analysis results were replicated in the COPD validation cohort. Results: Bidirectional MR analysis supported a bidirectional causal relationship between GERD and COPD, and COPD was also found to increase the risk of IBS and CP. Our study also provided evidence for a bidirectional causal relationship between PUD and COPD, although the strength of evidence may be insufficient. Furthermore, we provided evidence that there is no causal association between CD, UC, FD, NGE, and COPD. Conclusion: This study offers some evidence to clarify the causal relationship between common gastrointestinal diseases and COPD. Further research is needed to understand the underlying mechanisms of these associations.

Multidisciplinary team collaboration impact on NGF, BDNF, serum IGF-1, and life quality in patients with hemiplegia after stroke.

This study aimed to study the impact of multidisciplinary team collaboration on NGF, BDNF, serum IGF-1, and life quality in patients with hemiplegia after stroke. For this purpose, 200 post-stroke hemiplegic patients admitted from March 2022 to February 2023 were selected and randomly divided into a control group (100) and an observation group (100). The control group was given routine nursing care, while the observation group was given a multidisciplinary team collaboration model. The neurotroph in [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1)] and nutritional status [hemoglobin (HGB), serum albumin (ALB), transferrin (TRF)] of patients were compared before and after the intervention on the second day of admission and on the 30th day of intervention. The FUGL Meyer (FM) motor function assessment scale, NIHSS National Institutes of Health Stroke Scale, and the Specialized Quality of Life Scale (SS-QIL) for stroke patients were used to assess limb motor function, balance function, degree of neurological impairment, and life quality. Results showed that before intervention, there was no statistically significant difference in the levels of NGF, BDNF, IGF-1, HGB, ALB, TRF, limb motor function, balance function, neurological deficits, and quality of life scores between the two (P>0.05); After intervention, the levels of NGF, BDNF, IGF-1, HGB, ALB, and TRF in the observation group were significantly higher (P<0.05); The FM and SS-QOL of patients in the observation group were significantly higher (P<0.05); The NIHSS score of patients in the observation group was significantly lower (P<0.05). In conclusion, multidisciplinary team cooperation can significantly improve the level of neurotrophin, reduce the degree of nerve defect, and promote the recovery of limb function, balance function and life quality for stroke patients with hemiplegia.

Associations of 10 dietary habits with breast cancer: a Mendelian randomization study.

Introduction: Epidemiological studies have revealed a link between dietary habits and the breast cancer risk. The causality of the association between food consumption and breast cancer requires further investigation. Methods: Using Mendelian randomization, we assessed the causal effects of 10 dietary habits on the risks of breast cancer and its subtypes (estrogen receptor [ER] + and ER- breast cancer). We obtained dietary pattern data in 2018 (number of single-nucleotide polymorphisms [SNPs] = 9,851,867) and breast cancer data in 2017 (number of SNPs = 10,680,257) from IEU OpenGWAS. Rigorous sensitivity analyses were conducted to ensure that the study results were credible and robust. Results: We identified that genetic predisposition to higher dried fruit intake was linked to a reduced risk of overall breast cancer (inverse variance-weighted [IVW] odds ratio [OR] = 0.55; 95% confidence interval [CI]: 0.43-0.70; p = 1.75 × 10-6), ER+ breast cancer (IVW OR = 0.62; 95% CI: 0.47-0.82; p = 8.96 × 10-4) and ER- breast cancer (IVW OR = 0.48; 95% CI: 0.34-0.68; p = 3.18 × 10-5), whereas genetic predisposition to more oily fish intake was linked to a lower risk of ER+ breast cancer (IVW OR = 0.73; 95% CI: 0.53-0.99; p = 0.04). Discussion: Our findings suggest that a genetic predisposition for dried fruit and oily fish consumption may be protective against breast cancer; however, further investigation is required.

Quantitative detection of microRNA-21 in vivo using in situ assembled photoacoustic and SERS nanoprobes.

Accurately quantifying microRNA levels in vivo is of great importance for cancer staging and prognosis. However, the low abundance of microRNAs and interference from the complex tumor microenvironment usually limit the real-time quantification of microRNAs in vivo. Herein, for the first time, we develop an ultrasensitive microRNA (miR)-21 activated ratiometric nanoprobe for quantification of the miR-21 concentration in vivo without signal amplification as well as dynamic tracking of its distribution. The core-satellite nanoprobe by miR-21 triggered in situ self-assembly was built on nanogapped gold nanoparticles (AuNNP probe) and gold nanoparticles (AuNP probe). The AuNP probe generated a photoacoustic (PA) signal and ratiometric SERS signal with the variation of miR-21, whereas the AuNNP probe served as an internal standard, enabling ratiometric SERS imaging of miR-21. The absolute concentration of miR-21 in MCF-7 tumor-bearing mice was quantified to be 83.8 ± 24.6 pM via PA and ratiometric SERS imaging. Our strategy provides a powerful approach for the quantitative detection of microRNAs in vivo, providing a reference for the clinical treatment of cancer.

Causal pathways linking polycystic ovary syndrome to distinct breast cancer subtypes through mediator factors: a multivariable mendelian randomization analysis.

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterized by ovarian cysts, high androgen levels, and irregular menstruation. The causality between PCOS and breast cancer (BC) has been widely discussed as they share a significant intersection in clinical manifestations. Previous epidemiological studies have not provided consistent conclusions in association between PCOS and BC, while mendelian randomization (MR) analyses have confirmed the causality between PCOS and estrogen receptor-positive breast cancer (ER + BC), but among a series of clinical manifestations resulting from PCOS, which related traits mediate the causal effect remains unknown. In this study, we conducted multivariable mendelian randomization (MVMR) analysis to explore the potential mediator variables in the mechanism linking PCOS to distinct subtypes of BC, and calculated the mediating effects proportion. We analyzed 13 PCOS-related traits and found that age at menopause may mediate PCOS-induced ER + BC (with -4.82% proportion) with a weak protective effect through the repair of DNA double-strand breaks by homologous recombination. This study helps to better comprehend the shared mechanisms contributing to the development of both PCOS and BC, and to screen high-risk populations for BC and take appropriate preventive measures.

Diet-derived antioxidants and osteoporosis: A Mendelian randomization study.

BACKGROUND: Antioxidants can prevent osteoporosis, but the association between serum antioxidants and the cause of osteoporosis remains unknown. We aimed to utilize Mendelian randomization (MR) to determine whether genetically predicted serum levels of diet-derived antioxidants can affect the risk of osteoporosis, to determine the effect of dietary supplementation of antioxidants. METHODS: Genetic variants associated with diet-derived antioxidants were selected from the genome-wide association studies. A total of 12,946 osteoporosis cases and 506,624 healthy controls were obtained from UK Biobank (UKB) and Genetic Factors of Osteoporosis (GEFOS) consortia. We implemented a two-sample MR design and performed several sensitivity analyses to evaluate the causal relationship. RESULTS: In UKB, the genetically predicted higher ß-carotene (OR = 0.863, p = 7.37 × 10-6, power = 100%) and γ-tocopherol (OR = 0.701, p = 0.021, power = 5%) had an inverse relationship with osteoporosis. However, only the association of serum ß-carotene passed FDR correction. In GEFOS, there were no significant diet-derived antioxidants. The direction of the association of ß-carotene with osteoporosis (OR = 0.844, p = 0.106, power = 87%) was consistent with that in the UKB dataset. A fixed-effects meta-analysis confirmed that ß-carotene (OR = 0.862, p = 2.21 × 10-6) and γ-tocopherol (OR = 0.701, p = 2.31 × 10-2) could decrease the risk of osteoporosis. To reduce exclusion limit bias, we used total body bone mineral density, lumbar spine bone mineral density and femoral neck bone mineral density as surrogates and found that the genetically elevated circulating ß-carotene level could increase total body BMD (beta = 0.043, p-value = 8.26 x 10-5, power = 100%), lumbar spine BMD (beta = 0.226, p-value = 0.001, power = 100%) and femoral neck BMD(beta = 0.118, p-value = 0.016, power = 100%). CONCLUSIONS: We observed that genetically predicted serum ß-carotene could elevate BMD and prevent osteoporosis.

Optimization of structural connectomes and scaled patterns of structural-functional decoupling in Parkinson's disease.

Parkinson's disease (PD) is manifested with disrupted topology of the structural connection network (SCN) and the functional connection network (FCN). However, the SCN and its interactions with the FCN remain to be further investigated. This multimodality study attempted to precisely characterize the SCN using diffusion kurtosis imaging (DKI) and further identify the neuropathological pattern of SCN-FCN decoupling, underscoring the neurodegeneration of PD. Diffusion-weighted imaging and resting-state functional imaging were available for network constructions among sixty-nine patients with PD and seventy demographically matched healthy control (HC) participants. The classification performance and topological prosperities of both the SCN and the FCN were analyzed, followed by quantification of the SCN-FCN couplings across scales. The SCN constructed by kurtosis metrics achieved optimal classification performance (area under the curve 0.89, accuracy 80.55 %, sensitivity 78.40 %, and specificity 80.65 %). Along with diverse alterations of structural and functional network topology, the PD group exhibited decoupling across scales including: reduced global coupling; increased nodal coupling within the sensorimotor network (SMN) and subcortical network (SN); higher intramodular coupling within the SMN and SN and lower intramodular coupling of the default mode network (DMN); decreased coupling between the modules of DMN-fronto-parietal network and DMN-visual network, but increased coupling between the SMN-SN module. Several associations between the coupling coefficient and topological properties of the SCN, as well as between network values and clinical scores, were observed. These findings validated the clinical implementation of DKI for structural network construction with better differentiation ability and characterized the SCN-FCN decoupling as supplementary insight into the pathological process underlying PD.

Proteome-wide Mendelian randomization highlights AIF1 and HLA-DQA2 as targets for primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a kind of cholestatic liver disease without effective therapies and its pathogenesis is largely unknown. METHODS: We performed the proteome-wide Mendelian randomization (MR) design to estimate the causal associations of protein levels with PSC risk. Therein, genetic associations with 4,907 plasma protein levels were extracted from a proteome-wide genome-wide association study (GWAS) with 35,559 individuals and those with PSC were obtained from the International PSC Study Group (2,871 cases and 12,019 controls) and the FinnGen study (1,491 cases and 301,383 controls). The colocalization analysis was performed to detect causal variants shared by proteins and PSC. The identified proteins were further enriched in pathways and diseases. A phenome-wide association screening was performed and potential drugs were assessed as well. RESULTS: The results indicated that genetically predicted plasma levels of 14 proteins were positively associated with an increased risk of PSC and 8 proteins were inversely associated with PSC risk in both PSC GWAS data sets, and they all survived in sensitivity analyses. The colocalization indicated that AIF1 (allograft inflammatory factor 1) and HLA-DQA2 (major histocompatibility complex, class II, DQ alpha 2) were shared proteins with PSC, and they should be direct targets for PSC. The phenome-wide screening suggested that variants located at AIF1 or HLA-DQA2 region were closely associated with several autoimmune diseases, such as rheumatoid arthritis, implicating the shared pathogenesis among them. CONCLUSIONS: Our study highly pinpointed two candidate targets (AIF1 and HLA-DQA2) for PSC.

Suitable ultrasound screening method for older adults with disability to identify low muscle mass.

Objective: This study aimed to investigate the accuracy and consistency of different ultrasound protocols for the measurement of gastrocnemius muscle (GM) thickness and to identify a suitable ultrasound scheme that can be used to detect the low muscle mass in older with disability. Materials and methods: In this cross-sectional study, each participant underwent three different ultrasound protocols for the measurement of the GM thickness, and each measurement was repeated three times. The three measurement schemes were as follows: method A, lying on the examination bed in a prone position with legs stretched and relaxed and feet hanging outside the examination bed; method B, lateral right side lying position with legs separated (left leg flexed and right leg in a relaxed state); and method C, right side lying position with legs together and lower limb muscles in a relaxed state. The low muscle mass was determined by averaging two or three measurements of the GM thickness determined using different sonographic protocols. Results: The study included 489 participants. The difference in the prevalence of low muscle mass identified between two and three replicates of the same measurement protocol ranged from 0 to 1.3%. Considering the three repeated measurements of the method A as the reference, the area under the curve (AUC) in different measurement schemes were 0.977-1 and 0.973-1 in males and females, respectively. Furthermore, male and female Kappa values from low to high were 0.773, 0.801, 0.829, 0.839, and 0.967 and 0.786, 0.794, 0.804, 0.819, and 0.984, respectively. Conclusion: Different ultrasound measurement protocols showed high accuracy and consistency in identifying low muscle mass. Repeating the measurements two or three times was found to be feasible.

Targeting Pyroptosis through Lipopolysaccharide-Triggered Noncanonical Pathway for Safe and Efficient Cancer Immunotherapy.

Inducing pyroptosis in cancer cells holds great potential in cancer immunotherapy. Lipopolysaccharide (LPS)-sensing noncanonical pathways are an important mechanism of pyroptosis to eliminate damaged cells, which has not yet been explored for cancer immunotherapy. Here, we utilize bacterial outer membrane vesicles (OMVs) as a natural LPS carrier to trigger a noncanonical pyroptosis pathway for immunotherapy. To address the concern of systemic toxicity, molecule engineered OMVs were designed by equipping DNA aptamers on the OMVs (Apt-OMVs). In addition to improving capacity to target tumors, Apt-OMVs also took advantage of the spherical nucleic acid structure to shield OMVs against nonspecific immune recognition and evade immunogenicity. The selective pyroptosis enhanced tumor immunogenicity, not only promoting the infiltration of effector T cells but also reducing the amount of immunosuppressive regulatory T cells, which remarkably suppressed tumor growth. This work reports the first pyroptosis inducer by the noncanonical pathway, offering inspiration for safe and efficient pyroptosis-mediated immunotherapy.

Causality of Diabetic Nephropathy and Age-Related Macular Degeneration: A Mendelian Randomization Study.

PURPOSE: Age-related macular degeneration (AMD) currently stands as the leading cause of irreversible vision loss in the present era. The primary objective of this study was to investigate the causal relationships between diabetic nephropathy (DN), its associated risk factors, and AMD among participants of European descent. METHODS: Genetic variants associated with DN and its risk factors, encompassing glycemic traits, lipidemic traits, systolic/diastolic blood pressure, obesity, and urate, were obtained from previously published genome-wide association studies. Summary-level statistics for AMD were acquired from the FinnGen database. Univariable and multivariable Mendelian randomization (MR) were employed to conduct this investigation. RESULTS: Our MR analyses indicated that per 1-standard deviation (SD) increase of DN heightened the risk of overall AMD (p = 1.03 × 10-8, OR = 1.24). And these findings remained consistent when examining both dry AMD (p = 2.27 × 10-4, OR = 1.17) and wet AMD (p = 5.15 × 10-6, OR = 1.33). Additionally, there was a causal association between high-density lipoprotein-cholesterol (HDL-C) levels and an increased risk of AMD (p = 2.69 × 10-3, OR = 1.23), while triglycerides were found to mitigate the risk (p = 0.02, OR = 0.83). Notably, no significant associations were observed between other risk factors of DN and AMD. CONCLUSIONS: These findings suggest that the impact of DN on the development of AMD may be more substantial than previously believed. Furthermore, elevated HDL-C levels appear to heighten the risk of AMD, whereas triglycerides may provide a protective effect.

Genetic liability to multiple factors and uterine leiomyoma risk: a Mendelian randomization study.

Background and objective: Uterine leiomyoma is the most common benign tumor in females of reproductive age. However, its causes have never been fully understood. The objective of our study was to analyze the causal association between various factors and uterine leiomyoma using Mendelian randomization (MR). Methods: Genetic variables associated with risk factors were obtained from genome-wide association studies. Summary-level statistical data for uterine leiomyoma were obtained from FinnGen and the UK Biobank (UKB) consortium. We used inverse variance weighted, MR-Egger, and weighted median methods in univariate analysis. Multivariable MR analysis was used to identify independent risk factors. A fixed-effect model meta-analysis was used to combine the results of the FinnGen and UKB data. Results: In the FinnGen data, higher genetically predicted age at natural menopause, systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting insulin were associated with an increased risk of uterine leiomyoma, while higher age at menarche was associated with a reduced risk of uterine leiomyoma. Multivariable MR analysis of SBP and DBP showed that higher DBP might be an independent risk factor of uterine leiomyoma. In the UKB data, the results for age at natural menopause, SBP, DBP, and age at menarche were replicated. The result of the meta-analysis suggested that uterine leiomyoma could also be affected by polycystic ovary syndrome (PCOS), endometriosis, and 2-hour glucose level. Conclusion: Our MR study confirmed that earlier menstrual age, hypertension, obesity, and elevated 2-hour glucose post-challenge were risk factors for uterine leiomyoma, and the causal relationship between smoking and uterine leiomyoma was ruled out. In addition, later age of menopause and endometriosis were found to increase the risk of uterine leiomyoma, while PCOS was found to decrease the risk.