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Causal mediation analysis has gained increasing attention in recent years. This article guides empirical researchers through the concepts and challenges of causal mediation analysis. I first clarify the difference between traditional and causal mediation analysis and highlight the importance of adjusting for the treatment-by-mediator interaction and confounders of the treatment-mediator, treatment-outcome, and mediator-outcome relationships. I then introduce the definition of causal mediation effects under the potential outcomes framework and different methods for the identification and estimation of the effects. After that, I highlight the importance of conducting a sensitivity analysis to assess the sensitivity of analysis results to potential unmeasured confounding. I also list various statistical software that can conduct causal mediation analysis and sensitivity analysis and provide suggestions for writing a causal mediation analysis paper. Finally, I briefly introduce some extensions that I made with my colleagues, including power analysis, multisite causal mediation analysis, causal moderated mediation analysis, and relaxing the assumption of no post-treatment confounding.

In the field of disparities research, there has been growing interest in developing a counterfactual-based decomposition analysis to identify underlying mediating mechanisms that help reduce disparities in populations. Despite rapid development in the area, most prior studies have been limited to regression-based methods, undermining the possibility of addressing complex models with multiple mediators and/or heterogeneous effects. We propose a novel estimation method that effectively addresses complex models. Moreover, we develop a sensitivity analysis for possible violations of an identification assumption. The proposed method and sensitivity analysis are demonstrated with data from the Midlife Development in the US study to investigate the degree to which disparities in cardiovascular health at the intersection of race and gender would be reduced if the distributions of education and perceived discrimination were the same across intersectional groups.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimers disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.

Mechanical properties are the key guidance for controlling the product quality of steel and optimizing its process. In this work, four machine learning (ML) algorithms (XGBoost, SVR, BP, and RBF) are used to establish a correlation model between chemical composition, process parameters, and mechanical properties for performance optimization. The ML model showing high prediction accuracy is selected to analyze the importance of the model parameters. The XGBoost model has the highest prediction accuracy, with both yield strength (YS) and elongation-to-failure (EL) achieving a prediction accuracy of over 0.9 on the test set. Subsequently, the (YS) and (EL) of typical steel grades SPHC and Q235B are optimized by combining the high-precision XGBoost model and NSGA-II multi-objective optimization strategy. A comprehensive mechanical performance evaluation index (CP and EV) was proposed to screen the optimal Pareto frontiers, and two types of steel with excellent performance were successfully selected.

Abstract This article explores the criteria used to ascertain whether or not, and how, ancient Chinese bronze bells might form sets of musical instruments, thus clarifying their original intended use by ancient musicians. The focus is on ten bells unearthed from Changsha city in Hunan province in China, which date to the twelfth century BCE. A range of diverse relationships between these bells provide valuable insights that can be explored. Debate is ongoing among music historians regarding the nature of the bells. Some argue that the ten bells do not constitute a set of musical instruments because their designs and acoustic properties lack sufficient similarity and correlation. Conversely, another group of historians suggests that nine of the ten bells could indeed be seen as a set, but with the tenth bell being an outlier due to its distinct design. The third group of historians contends that the ten bells should be considered a musical set because of their organized sequence of consecutive semi-tones, while the design differences of the bells are less significant and can be overlooked if we focus on their musical functions. In this study, we scrutinize the assumptions made by these music historians, including their definitions of design similarity and the sequence of progressive pitches. Further previously overlooked criteria, such as the geographical proximity of these ten bells and others found in neighboring areas, and the incremental changes in the bell sizes, are also considered. Through the use of these criteria we aim to explore a wide range of relationships between ancient Chinese bells and to reassess what other new evidence the bells may offer to the study of ancient Chinese musical concepts. The concept of the chromatic scale discovered by ancient Chinese musicians was embodied on the casting of bronze bells.

Objective The Laiwu Basin is a typical monocline fault basin in the central and southern regions of Shandong Province. It has a complex geological structure and an uneven distribution of groundwater resources within the region. Previous researchers have conducted a large number of hydrogeological and spring water protection studies, but no relevant research has been conducted on the relationship between the development laws of fissure karst and the distribution of karst groundwater. Methods In this study, karstification and groundwater enrichment characteristics were investigated in the Laiwu Basin through research methods of data collection, field geological surveys, hydrogeological drilling, and rock and mineral testing. Results Carbonate strata are concentrated in the southern part of the Laiwu Basin, with a monoclinal structure controlled by the geological structure, which is scattered sporadically in the northern and eastern regions. Karst development is affected by many factors, such as formation lithology, geological structure, groundwater dynamic conditions, and magma intrusion. The principal surface karst features are grikes and karst valleys. In addition, the principal underground karst features were dominated by dissolution fissures and holes at 400 m depth. Karst groundwater is primarily concentrated in multistage structural fault basins, hanging walls formed by water-blocking faults, groundwater pressure discharge areas, and karst development areas on the anticlinal flank of the mine. Conclusion The karst water cycle in the Laiwu Basin has a general regularity of monoclinic basins but is influenced by multiple factors, forming karst water systems of varying sizes that are relatively independent. Significant differences were observed in the development characteristics and water abundance patterns of karsts in different regions. Fault structures and geological water-blocking areas have relatively abundant karst water, whereas the shallow karst water has a strong runoff cycle. [ Significance ] This study provides scientific and technical support for the exploitation and utilization of groundwater resources in water-scarce mountainous areas of central and southern Shandong Province.

Carrot is a highly significant vegetable cultivated worldwide and possesses a unique aroma with abundant edible and medicinal values. However, it remains largely unknown whether jasmonic acid could regulate aroma formation in carrot. Here, an integrated analysis of the volatile metabolome and transcriptome of carrot roots exposed to different concentrations of methyl jasmonate (MeJA) was performed. The results revealed 1,227 volatile organic compounds and 972 differential accumulated metabolites, with terpenes representing the largest portion. MeJA treatment evidently increased the relative odor activity values as well as the accumulation of most volatile compounds. In addition, 4,787 differentially expressed genes were identified and subjected to function enrichment analysis, indicating a role of terpene biosynthesis and metabolism in response to MeJA application. A network consisting of 4,680 transcription factor-structural pairs that showed highly significant positive correlations was constructed, which may be utilized as genetic targets for examining terpene accumulation and aroma formation elicited by methyl jasmonate. The results from the present work substantially improved our understanding of MeJA-mediated aroma formation in carrot.

To explore the influence of the working face excavation rate on the rock deformation mechanism and seepage characteristics, deformation and seepage tests of sandstone under different loading and unloading stress paths, such as constant axial pressure unloading confining pressure and loading axial pressure unloading confining pressure, were carried out. Particle Flow Code in 3 Dimensions (PFC3D) and Python were used to realize fluid-solid coupling, and numerical simulation calculations were performed along the test path to analyze the influence of the unloading rate on the fine-scale deformation mechanism and permeability characteristics of sandstone, and the relationship between crack type and permeability was obtained. A sandstone fracture mechanics model is established to analyze the stress concentration degree at the end of the branch crack of the test path. The results show that the rate of confining pressure unloading is inversely proportional to the strain. Additionally, permeability correlates with the principal stress difference in an exponential manner. Interestingly, the sensitivity of permeability to stress shows an inverse trend with the unloading rate of confining pressure. Furthermore, there exists a linear relationship between permeability and the number of cracks. During the unloading process, tensile cracks predominate, and the propagation of shear cracks lags behind that of tensile cracks. The proportion of tensile cracks decreases with the increase of the unloading rate when the axial pressure is unchanged but increases when axial pressure is added, resulting in axial compression deformation and expansion deformation along the unloading direction. These research outcomes offer theoretical insights for the prudent selection of mining rates, and they hold significant implications for mitigating water inrush disasters in deep mining operations.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with a global prevalence of 25%. Patients with NAFLD are more likely to suffer from advanced liver disease, cardiovascular disease, or type II diabetes. However, unfortunately, there is still a shortage of FDA-approved therapeutic agents for NAFLD. Lian-Mei-Yin (LMY) is a traditional Chinese medicine formula used for decades to treat liver disorders. It has recently been applied to type II diabetes which is closely related to insulin resistance. Given that NAFLD is another disease involved in insulin resistance, we hypothesize that LMY might be a promising formula for NAFLD therapy. Herein, we verify that the LMY formula effectively reduces hepatic steatosis in diet-induced zebrafish and NAFLD model mice in a time- and dose-dependent manner. Mechanistically, LMY suppresses Yap1-mediated Foxm1 activation, which is crucial for the occurrence and development of NAFLD. Consequently, lipogenesis is ameliorated by LMY administration. In summary, the LMY formula alleviates diet-induced NAFLD in zebrafish and mice by inhibiting Yap1/Foxm1 signaling-mediated NAFLD pathology.