Dissecting the shared genetic architecture between anti-Müllerian hormone and age at menopause based on genome-wide association study.

BACKGROUND: While the phenotypic association between anti-Müllerian hormone (AMH) and age at menopause has been widely studied, the role of AMH in predicting the age at menopause is currently controversial, and the genetic architecture or causal relationships underlying these two traits is not well understood. AIM: We aimed to explore the shared genetic architecture between AMH and age at menopause, to identify shared pleiotropic loci and genes, and to investigate causal association and potential causal mediators. STUDY DESIGN: Using summary statistics from publicly available genome-wide association studies on AMH (N=7,049) and age at menopause (N=201,323) in Europeans, we investigated the global genetic architecture between AMH and age at menopause through linkage disequilibrium score regression. We employed pleiotropic analysis under composite null hypothesis (PLACO), Functional Mapping and Annotation of Genetic Associations (FUMA), Multimarker analysis of GenoMic annotation (MAGMA), and colocalization analysis to identify loci and genes with pleiotropic effects. Tissue enrichment analysis based on GTEx data was conducted using the Linkage Disequilibrium Score for the specific expression of genes analysis (LDSC-SEG). Functional genes that were shared were additionally identified through summary data-based Mendelian randomization (SMR). The relationship between AMH and age at menopause was examined through two-sample Mendelian randomization (MR), and potential mediators were further explored using colocalization and metabolite-mediated analysis. RESULTS: A positive genetic association (correlation coefficient = 0.88, P = 1.33 × 10-5) was observed between AMH and age at menopause. By using PLACO and FUMA, 42 significant pleiotropic loci were identified that were associated with AMH and age at menopause, and ten of these (rs10734411, rs61913600, rs2277339, rs75770066, rs28416520, rs9796, rs11668344, rs403727, rs6011452, and rs62237617) had colocalized loci. Additionally, 245 significant pleiotropic genes were identified by MAGMA. Genetic associations between AMH and age at menopause were markedly concentrated in various tissues including whole blood, brain, heart, liver, muscle, pancreas, and kidneys. Further, SMR analysis revealed nine genes that may have a causative effect on both AMH and age at menopause. A potential causal effect of age at menopause on AMH was suggested by two-sample MR analysis, with very-low-density lipoprotein identified as a potential mediator. CONCLUSIONS: Our study revealed a shared genetic architecture between AMH and age at menopause, providing a basis for experimental investigations and individual therapies to enhance reproductive outcomes. Furthermore, our findings emphasized that relying solely on AMH is not sufficient for accurately predicting the age at menopause, and a combination of other factors needs to be considered. Exploring new therapeutics aimed at delaying at the onset of menopause holds promise, particularly when targeting shared genes based on their shared genetic architecture.

Maternal smoking, consumption of alcohol, and caffeinated beverages during pregnancy and the risk of childhood brain tumors: a meta-analysis of observational studies.

BACKGROUND: We conducted this meta-analysis to investigate the potential association between maternal smoking, alcohol and caffeinated beverages consumption during pregnancy and the risk of childhood brain tumors (CBTs). METHODS: A thorough search was carried out on PubMed, Embase, Web of Science, Cochrane Library, and China National Knowledge Internet to identify pertinent articles. Fixed or random effects model was applied to meta-analyze the data. RESULTS: The results suggested a borderline statistically significant increased risk of CBTs associated with maternal smoking during pregnancy (OR 1.04, 95% CI 0.99-1.09). We found that passive smoking (OR 1.12, 95% CI 1.03-1.20), rather than active smoking (OR 1.00, 95% CI 0.93-1.07), led to an increased risk of CBTs. The results suggested a higher risk in 0-1 year old children (OR 1.21, 95% CI 0.94-1.56), followed by 0-4 years old children (OR 1.12, 95% CI 0.97-1.28) and 5-9 years old children (OR 1.11, 95% CI 0.95-1.29). This meta-analysis found no significant association between maternal alcohol consumption during pregnancy and CBTs risk (OR 1.00, 95% CI 0.80-1.24). An increased risk of CBTs was found to be associated with maternal consumption of caffeinated beverages (OR 1.16, 95% CI 1.07-1.26) during pregnancy, especially coffee (OR 1.18, 95% CI 1.00-1.38). CONCLUSIONS: Maternal passive smoking, consumption of caffeinated beverages during pregnancy should be considered as risk factors for CBTs, especially glioma. More prospective cohort studies are warranted to provide a higher level of evidence.

A pathological joint-liver axis mediated by matrikine-activated CD4+ T cells.

The knee joint has long been considered a closed system. The pathological effects of joint diseases on distant organs have not been investigated. Herein, our clinical data showed that post-traumatic joint damage, combined with joint bleeding (hemarthrosis), exhibits a worse liver function compared with healthy control. With mouse model, hemarthrosis induces both cartilage degeneration and remote liver damage. Next, we found that hemarthrosis induces the upregulation in ratio and differentiation towards Th17 cells of CD4+ T cells in peripheral blood and spleen. Deletion of CD4+ T cells reverses hemarthrosis-induced liver damage. Degeneration of cartilage matrix induced by hemarthrosis upregulates serological type II collagen (COL II), which activates CD4+ T cells. Systemic application of a COL II antibody blocks the activation. Furthermore, bulk RNAseq and single-cell qPCR analysis revealed that the cartilage Akt pathway is inhibited by blood treatment. Intra-articular application of Akt activator blocks the cartilage degeneration and thus protects against the liver impairment in mouse and pig models. Taken together, our study revealed a pathological joint-liver axis mediated by matrikine-activated CD4+ T cells, which refreshes the organ-crosstalk axis and provides a new treatment target for hemarthrosis-related disease. Intra-articular bleeding induces cartilage degradation through down-reulation of cartilage Akt pathway. During this process, the soluble COL II released from the damaged cartilage can activate peripheral CD4+ T cells, differention into Th17 cells and secretion of IL-17, which consequently induces liver impairment. Intra-articular application of sc79 (inhibitor of Akt pathway) can prevent the cartilage damage as well as its peripheral influences.

Halogen-Atom Transfer Enabled Catalytic Enantioselective Coupling to Chiral Trifluoromethylated Alkynes via Dual Nickel and Photocatalysis.

With halogen-atom transfer as an effective tool, a novel catalytic enantioselective protocol to generate chiral trifluoromethylated alkynes has been established by a cooperative photoredox and nickel catalysis system, providing a straightforward and modular route to access this type of product in good yields and enantioselectivities. The halogen-atom transfer process is essential for the reaction and this novel strategy offers another promising way to utilize alkyl halides with highly negative reduction potentials. It firstly expands nickel-catalyzed asymmetric reductive cross-couplings of organohalides from the traditional single-electron transfer to halogen-atom transfer.

Oligogenic basis of premature ovarian insufficiency: an observational study.

BACKGROUND: The etiology of premature ovarian insufficiency, that is, the loss of ovarian activity before 40 years of age, is complex. Studies suggest that genetic factors are involved in 20-25% of cases. The aim of this study was to explore the oligogenic basis of premature ovarian insufficiency. RESULTS: Whole-exome sequencing of 93 patients with POI and whole-genome sequencing of 465 controls were performed. In the gene-burden analysis, multiple genetic variants, including those associated with DNA damage repair and meiosis, were more common in participants with premature ovarian insufficiency than in controls. The ORVAL-platform analysis confirmed the pathogenicity of the RAD52 and MSH6 combination. CONCLUSIONS: The results of this study indicate that oligogenic inheritance is an important cause of premature ovarian insufficiency and provide insights into the biological mechanisms underlying premature ovarian insufficiency.

Effects of Installing Different Types of Cooling Fins on the Cold Side of a Thermoelectric Power Generation Device on the Thermal Efficiency and Exergy Efficiency of Power Cable Surface Waste Heat Recovery.

This study investigates the thermal efficiency and exergy efficiency of a thermoelectric power generation device for recovering power cable surface waste heat. Numerical simulations are conducted to analyze the impact of different types of cooling fins on the system's performance. The results demonstrate that the installation of cooling fins improves heat transfer efficiency and enhances the thermoelectric power generation device's output power. Among the various fin designs, the system equipped with cooling fins with 17 teeth exhibits the highest performance. These findings highlight the importance of fin design in optimizing the system's thermal efficiency and exergy efficiency. This study provides valuable insights for the development and improvement of thermoelectric power generation systems for power cable surface waste heat recovery applications.

Public Attitudes About the Use of Gene Therapy in Mainland China.

Importance: In addition to technical barriers, public attitudes about the use of gene therapy have an important association with the clinical implementation of gene therapy. Objective: To investigate the factors associated with public acceptance of gene therapy among individuals in China. Design, Setting, and Participants: This cross-sectional study used data from a survey conducted among 21 880 individuals in mainland China from June 20 to August 31, 2022. Main Outcomes and Measures: Stepwise linear regression was used to analyze factors associated with public acceptance of gene therapy in 5 key areas: basic personal information (gender, region, age, and educational level), family situation (marital status, children, and cousins), economic status (assets, debts, and insurance coverage), health knowledge (health literacy score and media use), and physical health status (chronic illness, cancer, European Quality of Life 5-Dimension 5-Level version [EQ-5D-5L] score, and Brief Illness Perception Questionnaire [BIPQ] score). Acceptance scores were calculated based on a visual analog scale (range, 0-100, with higher scores indicating higher acceptance of gene therapy). Further subgroup analysis was carried out in different age subgroups and populations with or without chronic diseases. Results: A total of 21 880 participants (mean [SD] age, 39.4 [18.9] years; 10 947 female participants [50.0%]; 10 933 male participants [50.0%]) were analyzed in this study. The mean (SD) acceptance score of gene therapy in the survey was 60.56 (27.60). Compared with people aged 60 years or older, those aged 12 to 18 years had higher acceptance of gene therapy (ß = 1.48 [95% CI, 0.09-2.88]), while groups aged 19 to 30 years (ß = -3.43 [95% CI, -4.80 to -2.07]), 31 to 44 years (ß = -1.44 [95% CI, -2.76 to -0.12]), and 45 to 59 years (ß = -2.05 [95% CI, -3.27 to -0.83]) had lower acceptance. Compared with people living in Eastern China, those in Central China had lower acceptance of gene therapy (ß = -1.58 [95% CI, -2.54 to -0.62]), while those in Western China had higher acceptance (ß = 0.92 [95% CI, 0.09-1.76]). Higher educational level (undergraduate or above vs junior high or below) was associated with higher acceptance of gene therapy (ß = 1.56 [95% CI, 0.49-2.63]). Number of properties owned was also associated with higher acceptance of gene therapy (2 vs 0: ß = 2.38 [95% CI, 1.04-3.72]; ≥3 vs 0: ß = 4.66 [95% CI, 2.92-6.39]). Diagnosis of chronic disease was associated with lower acceptance of gene therapy (ß = -17.86 [95% CI, -20.49 to -15.24]), while diagnosis of cancer was associated with higher acceptance (ß = 6.99 [95% CI, 1.84-12.14]). Higher BIPQ score (ß = 0.40 [95% CI, 0.34-0.45]), higher health literacy score (ß = 0.70 [95% CI, 0.62-0.78]), and media use (ß = 0.49 [95% CI, 0.41-0.57]) were all associated with high acceptance of gene therapy, while a higher EQ-5D-5L score was associated with lower acceptance (ß = -0.29 [95% CI, -0.47 to -0.11]). For older people, being in debt, not having health insurance, and the EQ-5D-5L score were uniquely relevant factors. For people with chronic disease, having an undergraduate degree or higher, a diagnosis of cancer, and the BIPQ score were uniquely relevant factors. Conclusions and Relevance: These results suggest that basic personal information, economic status, health knowledge, and physical health status were the main factors associated with the acceptance of gene therapy. Improving the health literacy of the population and promoting trust in gene therapy may be effective ways to increase the acceptance of gene therapy. Poorer economic levels and worse disease states may reduce the public's willingness to accept gene therapy.

Optimal Strategies of Quantum Metrology with a Strict Hierarchy.

One of the main quests in quantum metrology is to attain the ultimate precision limit with given resources, where the resources are not only of the number of queries, but more importantly of the allowed strategies. With the same number of queries, the restrictions on the strategies constrain the achievable precision. In this Letter, we establish a systematic framework to identify the ultimate precision limit of different families of strategies, including the parallel, the sequential, and the indefinite-causal-order strategies, and provide an efficient algorithm that determines an optimal strategy within the family of strategies under consideration. With our framework, we show there exists a strict hierarchy of the precision limits for different families of strategies.

Train-induced vibration attenuation measurements and prediction from ground soil to building column.

The investigation of the influence of soil-structure coupling on the vibration propagation pattern is the key to ensuring the reliability of the prediction of train-induced building vibration. This study selects different metro depots with over-track buildings as the research objects based on the existing engineering examples. It analyzes the general laws of vibration propagation from the ground soil to the building columns. The study provides valuable references for predicting vibration and designing vibration isolation measures for over-track buildings. Additionally, this study proposes a vibration prediction method for over-track buildings above metro depots based on the back propagation (BP) neural network model in machine learning. This model considers the soil-structure coupling loss in a data-driven manner based on the rich data samples, which avoids the problems of complex numerical simulation calculations and parameter uncertainties to some extent. This prediction method has a good balance of efficiency and convenience and also meets the accuracy requirements. It was judged to be a promising prediction method for the preliminary design stage of the over-track buildings above metro depots.

Enantioselective C(sp3)-C(sp3) Reductive Cross-Electrophile Coupling of Unactivated Alkyl Halides with α-Chloroboronates via Dual Nickel/Photoredox Catalysis.

Substantial advances in enantioconvergent C(sp3)-C(sp3) bond formations have been made with nickel-catalyzed cross-coupling of racemic alkyl electrophiles with organometallic reagents or nickel-hydride-catalyzed hydrocarbonation of alkenes. Herein, we report an unprecedented enantioselective C(sp3)-C(sp3) reductive cross-coupling by the direct utilization of two different alkyl halides with dual nickel/photoredox catalysis system. This highly selective coupling of racemic α-chloroboronates and unactivated alkyl iodides furnishes chiral secondary alkyl boronic esters, which serve as useful and important intermediates in the realm of organic synthesis and enable a desirable protocol to fast construction of enantioenriched complex molecules.

Deoxygenative Haloboration and Enantioselective Chloroboration of Carbonyls.

Deoxygenative difunctionalization of carbonyls affords a straightforward and effective route to construct geminal dual functionalized motifs. However, the research in this field is very challenging due to the strong bond dissociation energies of the C-O double bond or the subsequently formed C-O bond. Herein, we report a highly efficient deoxygenative haloboration of aldehydes to generate secondary α-haloboronates. Meanwhile, the difficult-to-obtain tertiary α-haloboronates can be also readily prepared via the same strategy with ketones. Furthermore, enantioselective chloroboration of carbonyls was successfully achieved to give chiral secondary or tertiary α-chloroboronates, the important intermediates to access enantioenrich multisubstituted stereocenters. These versatile products can be surprisingly attained through this simple and mild process with remarkable substrate scope expansion and functional group tolerance. Additionally, these reactions can proceed well on large scales, giving more practical values in the application.

Modular and Fast Synthesis of Versatile Secondary α,α-Dialkyl Boronates via Deoxygenative Alkylboration of Aldehydes.

Secondary α,α-dialkyl boronates are widely used due to their great versatility. Herein we report an unprecedented deoxygenative alkylboration of aldehydes, a facile method to access this type of products. A sequence of difunctionalization can be obtained smoothly from the readily available aldehydes in only two steps. This difunctionalization of aldehydes rather than conventional alkenes also opens new possibilities within the field.

Noise annoyance and vibration perception assessment on passengers during train operation in Guangzhou Metro.

With the development of urban rail transit, taking the metro train has become one of the main modes of transportation, and passengers have an increasing demand for the comfort of taking the metro trains. This paper mainly discusses the impact of noise and vibration caused by metro train on passengers. All 13 metro lines in Guangzhou, China, were selected to conduct the questionnaire survey on the subjective perception of 601 respondents. At the same time, noise and vibration measurements were carried out in the train. The results show that the distribution of noise and vibrations along the metro lines is not uniform, and 50.6% of the interviewees are disturbed by noise. Wheel-rail squeal was found to be the most annoying and disturbing noise source. Three dose-response relationships for noise, vertical vibration, and horizontal vibration are proposed, respectively. The proposed dose-response relationship can be applied to the evaluation of noise annoyance or vibration perception in an environment similar to metro lines. Once the noise or vibration level of a metro line is obtained, the noise disturbance or vibration perception can be estimated. As for the dose-response relationship of vibration perception, people's sensitivity to vibration is much lower than that to noise. Horizontal vibrations are more acceptable to passengers, while vertical vibrations are more disturbing to passengers. The results are helpful to predict the noise annoyance and vibration perception of train passengers between metro stations, and to achieve the purpose of designing effective noise and vibration reduction measures.

A Novel Method for Accurate Quantification of Split Glomerular Filtration Rate Using Combination of Tc-99m-DTPA Renal Dynamic Imaging and Its Plasma Clearance.

PURPOSE: To precisely quantify split glomerular filtration rate by Tc-99m-DTPA renal dynamic imaging and plasma clearance in order to increase its consistency among doctors. METHODS: Tc-99m-DTPA renal dynamic imaging was performed according to the conventional radionuclide renal dynamic imaging by five double-blinded doctors independently and automatically calculated split GFR, namely, gGFR. Moreover, the conventional radionuclide renal dynamic imaging was assessed to only outline the kidney, blank background, and automatically calculated split GFR, gGFR'. The total GFR value of patients, tGFR, was obtained by the double-plasma method. According to the formula, Precise GFR (pGFR) = gGFR'/(gGFR' + gGFR') × tGFR. The precise GFR value of the divided kidney, pGFR, was calculated. The Kendall's W test was used to compare the consistency of gGFR and pGFR drawn by five physicians. RESULTS: According to Kendall's W consistency test, Kendall's coefficient of concordance was 0.834, p = 0.0001 using conventional method. The same five doctors used blank background again and the same standard Gates method to draw the kidneys, which automatically calculated gGFR'. Using input formula, the pGFR was calculated and Kendall's W consistency test (Kendall's coefficient of concordance = 0.956, p = 0.0001). CONCLUSION: The combination of Tc-99m-DTPA renal dynamic imaging combined with the double-plasma method could achieve accurate split GFR, and because of the omission of influence factors, the consistency of pGFR obtained by different doctors using this method was significantly higher than that of conventional Tc-99m-DTPA renal dynamic imaging.

A Novel Cleavage Pattern of Complement C5 Induced by Chlamydia trachomatis Infection via the Chlamydial Protease CPAF.

Urogenital Chlamydia trachomatis infection is one of the most common bacterial sexually transmitted diseases globally. Untreated C. trachomatis infections can ascend to the upper genital tract and establish a series of severe complications. Previous studies using C3-/- and C5-/- mice models demonstrated that C3-independent activation of C5 occurred during C. trachomatis infection. However, the mechanism of how chlamydial infection activates C5 in the absence of C3 has yet to be elucidated. To delineate interactions between C5 and chlamydial infection, cleavage products in a co-incubation system containing purified human C5 and C. trachomatis-HeLa229 cell lysates were analyzed, and a novel cleavage pattern of C5 activation induced by C. trachomatis infection was identified. C5 was cleaved efficiently at the previously unidentified site K970, but was cleaved poorly at site R751. C5b was modified to C5bCt, which later formed C5bCt-9, which had enhanced lytic ability compared with C5b-9. The chlamydial serine protease CPAF contributed to C3-independent C5 activation during C. trachomatis infection. Nafamostat mesylate, a serine protease inhibitor with a good safety profile, had a strong inhibitory effect on C5 activation induced by chlamydial infection. These discoveries reveal the mechanism of C3-independent C5 activation induced by chlamydial infection, and furthermore provide a potential therapeutic target and drug for preventing tubal fibrosis caused by chlamydial infection.

Nafamostat mesylate inhibits chlamydial intracellular growth in cell culture and reduces chlamydial infection in the mouse genital tract.

Urogenital Chlamydia trachomatis (C. trachomatis) infection is one of the most common bacterial sexually transmitted diseases worldwide. Untreated C. trachomatis infections that ascend to the upper genital tract lead to a series of severe complications. To search for novel antichlamydial drugs, we evaluated the effect of nafamostat mesylate (NM), a synthetic serine protease inhibitor, on chlamydial infection. NM inhibited chlamydial intracellular growth and reduced both the inclusion size and number in cell culture. NM may mainly target the intracellular reticulate bodies for inhibition. NM was also effective in enhancing chlamydial clearance from mouse genital tract when NM was applied to mice via intravaginal inoculation. The vaginal NM did not significantly alter inflammatory cytokine responses in the mouse genital tract. Thus, we have demonstrated a novel role of NM in inhibiting the obligate intracellular bacterium Chlamydia.

Two-year monitoring of gaseous elementary mercury in a typical iron-steel plant in Yangtze River Delta, China: Characterization and estimation of its dynamic oxidation.

A two-year gaseous elementary mercury (GEM) measurement was implemented at an iron-steel plant in Yangtze River Delta, China, which provided an excellent opportunity to investigate their dynamic cycling. The hourly GEM concentrations ranged between 0.78 and 113.8 ng m-3, with a mean value of 3.83 ±â€¯2.53 ng m-3. Temporally, seasonal GEM contents decreased as winter ≈ spring > summer > autumn, while diurnal cycling was observed with a steady decrease at 14:00-17:00. GEM variations were found to be related to source emissions, meteorology and regional transportation. Three major oxidants (O3, Br and OH radicals) were used to evaluate GEM oxidation in the daytime, and the estimated GEM depletion rate was 70.8 ±â€¯52.5 molecule cm-3 s-1 (0.09 ±â€¯0.06 ng m-3 h-1). The GEM oxidized by Br radicals accounted for 83.4% of the total GEM oxidation rate, followed by O3 (13.8%). The estimated atmospheric lifetime of GEM was 22.9 to 345.2 days, which implies a major contribution of Br radicals to the GEM sink. These findings highlight the ability of iron-steel industry emissions and in-situ oxidation to affect daily local GEM cycling significantly.

Particulate mercury in ambient air in Shanghai, China: Size-specific distribution, gas-particle partitioning, and association with carbonaceous composition.

Mercury (Hg) has a complex atmospheric transformation cycle and acts as a global pollutant. Size-specific particle bound mercury (PBM) was implemented in different functional (industrial, urban and suburban) areas in Shanghai, China. The total concentration of 13-staged PBM (rang of 0.01-18.0 µm) varied of 99.0-611 pg/m3, with an average value of 318 ±â€¯144 pg/m3. The Gaoqiao petrochemical industry (GQPI) site showed the highest concentrations, whereas the suburban Shanghai Jiao Tong University (SJTU) displayed the lowest. The PBM in nucleation, accumulation and coarse modes were 7.63-96.7, 69.5-455, and 9.43-176 pg/m3, respectively, and the fractions of 0.56-1.00 and 0.32-0.56 µm were the two most abundant. Both OC and EC displayed unimodal distribution patterns (peak of 0.56-1.00 µm) at GQPI, while bimodal distributions were observed at urban and suburban sites. Statistically positive correlations between the overall PBM and the corresponding PM and carbonaceous compounds (r = 0.38-0.54, p < 0.01), indicating their similar origins and OC/EC enhanced gaseous mercury forming PBM. The gas-particle partition model predicted gaseous oxidized mercury (GOM) were 253 ±â€¯133, 237 ±â€¯122, and 257 ±â€¯144 pg/m3 for GQPI, SAES and SJTU, respectively. The particle proportions of divalent mercury in the fraction of 0.32-1.00 µm were substantial (>80%), but smaller (<50%) for nucleation and coarse modes. The fraction of 9.90-18.00 µm occupied nearly 50% of the overall dry deposition fluxes of mercury. These finding highlight the emissions from different mercury and OC/EC origins, caused different size-specific distributions of PBM, which further affect their gas-particle partitioning and dry deposition of mercury species.