Per- and polyfluoroalkyl substances (PFASs) in bivalve molluscs from Shandong Province, China: Occurrence, distribution, and implications for human consumption.

We examined the occurrence and levels of 19 legacy and emerging per- and polyfluoroalkyl substances (PFASs) in 7 species of marine bivalve molluscs collected from four coastal cities of Shandong Province, China. Perfluorooctanoic acid (PFOA) was the most prevalent component, accounting for 68.1 % of total PFASs. The total PFASs in bivalve molluscs ranged from 0.86 to 6.55 ng/g wet weight, with the highest concentration found in Meretrix meretrix L. The concentration of total PFASs in bivalve molluscs showed the following trend: clams > scallops > oysters > mussels. Estimation on the human intake of PFASs from consumption of bivalve molluscs resulted in hazard ratios (HR) ranging from 0.12 to 6.40. Five of the seven species had HR >1, indicating high exposure risks associated with PFASs. Therefore, the occurrence of PFASs in marine biota is particularly concerning and further investigations on the sources of PFASs in Shandong are warranted.

Mercury supply limits methylmercury production in paddy soils.

The neurotoxic methylmercury (MeHg) is a product of inorganic mercury (IHg) after microbial transformation. Yet it remains unclear whether microbial activity or IHg supply dominates Hg methylation in paddies, hotspots of MeHg formation. Here, we quantified the response of MeHg production to changes in microbial activity and Hg supply using 63 paddy soils under the common scenario of straw amendment, a globally prevalent agricultural practice. We demonstrate that the IHg supply is the limiting factor for Hg methylation in paddies. This is because IHg supply is generally low in soils and can largely be facilitated (by 336-747 %) by straw amendment. The generally high activities of sulfate-reducing bacteria (SRB) do not limit Hg methylation, even though SRB have been validated as the predominant microbial Hg methylators in paddies in this study. These findings caution against the mobilization of legacy Hg triggered by human activities and climate change, resulting in increased MeHg production and the subsequent flux of this potent neurotoxin to our dining tables.

Soil Geobacteraceae are the key predictors of neurotoxic methylmercury bioaccumulation in rice.

Contamination of rice by the potent neurotoxin methylmercury (MeHg) originates from microbe-mediated Hg methylation in soils. However, the high diversity of Hg methylating microorganisms in soils hinders the prediction of MeHg formation and challenges the mitigation of MeHg bioaccumulation via regulating soil microbiomes. Here we explored the roles of various cropland microbial communities in MeHg formation in the potentials leading to MeHg accumulation in rice and reveal that Geobacteraceae are the key predictors of MeHg bioaccumulation in paddy soil systems. We characterized Hg methylating microorganisms from 67 cropland ecosystems across 3,600 latitudinal kilometres. The simulations of a rice-paddy biogeochemical model show that MeHg accumulation in rice is 1.3-1.7-fold more sensitive to changes in the relative abundance of Geobacteraceae compared to Hg input, which is recognized as the primary parameter in controlling MeHg exposure. These findings open up a window to predict MeHg formation and accumulation in human food webs, enabling more efficient mitigation of risks to human health through regulations of key soil microbiomes.

Metabolic coupling between soil aerobic methanotrophs and denitrifiers in rice paddy fields.

Paddy fields are hotspots of microbial denitrification, which is typically linked to the oxidation of electron donors such as methane (CH4) under anoxic and hypoxic conditions. While several anaerobic methanotrophs can facilitate denitrification intracellularly, whether and how aerobic CH4 oxidation couples with denitrification in hypoxic paddy fields remains virtually unknown. Here we combine a ~3300 km field study across main rice-producing areas of China and 13CH4-DNA-stable isotope probing (SIP) experiments to investigate the role of soil aerobic CH4 oxidation in supporting denitrification. Our results reveal positive relationships between CH4 oxidation and denitrification activities and genes across various climatic regions. Microcosm experiments confirm that CH4 and methanotroph addition promote gene expression involved in denitrification and increase nitrous oxide emissions. Moreover, 13CH4-DNA-SIP analyses identify over 70 phylotypes harboring genes associated with denitrification and assimilating 13C, which are mostly belonged to Rubrivivax, Magnetospirillum, and Bradyrhizobium. Combined analyses of 13C-metagenome-assembled genomes and 13C-metabolomics highlight the importance of intermediates such as acetate, propionate and lactate, released during aerobic CH4 oxidation, for the coupling of CH4 oxidation with denitrification. Our work identifies key microbial taxa and pathways driving coupled aerobic CH4 oxidation and denitrification, with important implications for nitrogen management and greenhouse gas regulation in agroecosystems.

Deforestation impacts soil biodiversity and ecosystem services worldwide.

Deforestation poses a global threat to biodiversity and its capacity to deliver ecosystem services. Yet, the impacts of deforestation on soil biodiversity and its associated ecosystem services remain virtually unknown. We generated a global dataset including 696 paired-site observations to investigate how native forest conversion to other land uses affects soil properties, biodiversity, and functions associated with the delivery of multiple ecosystem services. The conversion of native forests to plantations, grasslands, and croplands resulted in higher bacterial diversity and more homogeneous fungal communities dominated by pathogens and with a lower abundance of symbionts. Such conversions also resulted in significant reductions in carbon storage, nutrient cycling, and soil functional rates related to organic matter decomposition. Responses of the microbial community to deforestation, including bacterial and fungal diversity and fungal guilds, were predominantly regulated by changes in soil pH and total phosphorus. Moreover, we found that soil fungal diversity and functioning in warmer and wetter native forests is especially vulnerable to deforestation. Our work highlights that the loss of native forests to managed ecosystems poses a major global threat to the biodiversity and functioning of soils and their capacity to deliver ecosystem services.

Different Valence States of Copper Ion Delivery against Triple-Negative Breast Cancer.

Different valence states of copper (Cu) ions are involved in complicated redox reactions in vivo, which are closely related to tumor proliferation and death pathways, such as cuproptosis and chemodynamic therapy (CDT). Cu ion mediated Fenton-like reagents induced tumor cell death which presents compelling attention for the CDT of tumors. However, the superiority of different valence states of Cu ions in the antitumor effect is unknown. In this study, we investigated different valence states of Cu ions in modulating tumor cell death by Cu-chelated cyanine dye against triple-negative breast cancer. The cuprous ion (Cu+) and copper ion (Cu2+) were chelated with four nitrogen atoms of dipicolylethylenediamine-modified cyanine for the construction of Cu+ and Cu2+ chelated cyanine dyes (denoted as CC1 and CC2, respectively). Upon 660 nm laser irradiation, the CC1 or CC2 can generate reactive oxygen species, which could disrupt the cyanine structure, achieving the rapid release of Cu ions and initiating the Fenton-like reaction for CDT. Compared with Cu2+-based Fenton-like reagent, the CC1 with Cu+ exhibited a better therapeutic outcome for the tumor due to there being no need for a reduction by glutathione and a shorter route to generate more hydroxyl radicals. Our findings suggest the precision delivery of Cu+ could achieve highly efficient antitumor therapy.

Accuracy of radiomics in the diagnosis and preoperative high-risk assessment of endometrial cancer: a systematic review and meta-analysis.

Background: With the increasing use of radiomics in cancer diagnosis and treatment, it has been applied by some researchers to the preoperative risk assessment of endometrial cancer (EC) patients. However, comprehensive and systematic evidence is needed to assess its clinical value. Therefore, this study aims to investigate the application value of radiomics in the diagnosis and treatment of EC. Methods: Pubmed, Cochrane, Embase, and Web of Science databases were retrieved up to March 2023. Preoperative risk assessment of EC included high-grade EC, lymph node metastasis, deep myometrial invasion status, and lymphovascular space invasion status. The quality of the included studies was appraised utilizing the RQS scale. Results: A total of 33 primary studies were included in our systematic review, with an average RQS score of 7 (range: 5-12). ML models based on radiomics for the diagnosis of malignant lesions predominantly employed logistic regression. In the validation set, the pooled c-index of the ML models based on radiomics and clinical features for the preoperative diagnosis of endometrial malignancy, high-grade tumors, lymph node metastasis, lymphovascular space invasion, and deep myometrial invasion was 0.900 (95%CI: 0.871-0.929), 0.901 (95%CI: 0.877-0.926), 0.906 (95%CI: 0.882-0.929), 0.795 (95%CI: 0.693-0.897), and 0.819 (95%CI: 0.705-0.933), respectively. Conclusions: Radiomics shows excellent accuracy in detecting endometrial malignancies and in identifying preoperative risk. However, the methodological diversity of radiomics results in significant heterogeneity among studies. Therefore, future research should establish guidelines for radiomics studies based on different imaging sources. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=364320 identifier CRD42022364320.

Labile carbon inputs boost microbial contribution to legacy mercury reduction and emissions from industry-polluted soils.

Soils is a crucial reservoir influencing mercury (Hg) emissions and soil-air exchange dynamics, partially modulated by microbial reducers aiding Hg reduction. Yet, the extent to which microbial engagements contribute to soil Hg volatilization remains largely unknown. Here, we characterized Hg-reducing bacterial communities in natural and anthropogenically perturbed soil environments and quantified their contribution to soil Hg(0) volatilization. Our results revealed distinct Hg-reducing bacterial compositions alongside elevated mercuric reductase (merA) gene abundance and diversity in soils adjacent to chemical factories compared to less-impacted ecosystems. Notably, solely industry-impacted soils exhibited increased merA gene abundance along Hg gradients, indicating microbial adaption to Hg selective pressure through quantitative changes in Hg reductase and genetic diversity. Microcosm studies demonstrated that glucose inputs boosted microbial involvement and induced 2-8 fold increments in cumulative Hg(0) volatilization in industry-impacted soils. Microbially-mediated Hg reduction contributed to 41.6% of soil Hg(0) volatilization in industry-impacted soils under 25% water-holding capacity and glucose input conditions over a 21-day incubation period. Alcaligenaceae, Moraxellaceae, Nitrosomonadaceae and Shewanellaceae were identified as potential contributors to Hg(0) volatilization in the soil. Collectively, our study provides novel insights into microbially-mediated Hg reduction and soil-air exchange processes, with important implications for risk assessment and management of industrial Hg-contaminated soils.

Deciphering microbiomes dozens of meters under our feet and their edaphoclimatic and spatial drivers.

Microbes inhabiting deep soil layers are known to be different from their counterpart in topsoil yet remain under investigation in terms of their structure, function, and how their diversity is shaped. The microbiome of deep soils (>1 m) is expected to be relatively stable and highly independent from climatic conditions. Much less is known, however, on how these microbial communities vary along climate gradients. Here, we used amplicon sequencing to investigate bacteria, archaea, and fungi along fifteen 18-m depth profiles at 20-50-cm intervals across contrasting aridity conditions in semi-arid forest ecosystems of China's Loess Plateau. Our results showed that bacterial and fungal α diversity and bacterial and archaeal community similarity declined dramatically in topsoil and remained relatively stable in deep soil. Nevertheless, deep soil microbiome still showed the functional potential of N cycling, plant-derived organic matter degradation, resource exchange, and water coordination. The deep soil microbiome had closer taxa-taxa and bacteria-fungi associations and more influence of dispersal limitation than topsoil microbiome. Geographic distance was more influential in deep soil bacteria and archaea than in topsoil. We further showed that aridity was negatively correlated with deep-soil archaeal and fungal richness, archaeal community similarity, relative abundance of plant saprotroph, and bacteria-fungi associations, but increased the relative abundance of aerobic ammonia oxidation, manganese oxidation, and arbuscular mycorrhizal in the deep soils. Root depth, complexity, soil volumetric moisture, and clay play bridging roles in the indirect effects of aridity on microbes in deep soils. Our work indicates that, even microbial communities and nutrient cycling in deep soil are susceptible to changes in water availability, with consequences for understanding the sustainability of dryland ecosystems and the whole-soil in response to aridification. Moreover, we propose that neglecting soil depth may underestimate the role of soil moisture in dryland ecosystems under future climate scenarios.

Differential response of Hg-methylating and MeHg-demethylating microbiomes to dissolved organic matter components in eutrophic lake water.

Methylmercury (MeHg) production in aquatic ecosystems is a global concern because of its neurotoxic effect. Dissolved organic matter (DOM) plays a crucial role in biogeochemical cycling of Hg. However, owing to its complex composition, the effects of DOM on net MeHg production have not been fully understood. Here, the Hg isotope tracer technique combined with different DOM treatments was employed to explore the influences of DOM with divergent compositions on Hg methylation/demethylation and its microbial mechanisms in eutrophic lake waters. Our results showed that algae-derived DOM treatments enhanced MeHg concentrations by 1.42-1.53 times compared with terrestrial-derived DOM. Algae-derived DOM had largely increased the methylation rate constants by approximately 1-2 orders of magnitude compared to terrestrial-derived DOM, but its effects on demethylation rate constants were less pronounced, resulting in the enhancement of net MeHg formation. The abundance of hgcA and merB genes suggested that Hg-methylating and MeHg-demethylating microbiomes responded differently to DOM treatments. Specific DOM components (e.g., aromatic proteins and soluble microbial byproducts) were positively correlated with both methylation rate constants and the abundance of Hg-methylating microbiomes. Our results highlight that the DOM composition influences the Hg methylation and MeHg demethylation differently and should be incorporated into future Hg risk assessments in aquatic ecosystems.

Advances in the study of ELABELA in renal physiological functions and related diseases.

ELABELA (ELA), also known as Toddler or Apela, is a novel endogenous ligand of the angiotensin receptor AT1-related receptor protein (APJ). ELA is highly expressed in human embryonic, cardiac, and renal tissues and involves various biological functions, such as embryonic development, blood circulation regulation, and maintaining body fluid homeostasis. ELA is also closely related to the occurrence and development of acute kidney injury, hypertensive kidney damage, diabetic nephropathy, renal tumors, and other diseases. Understanding the physiological role of ELA and its mechanism of action in kidney-related diseases would provide new targets and directions for the clinical treatment of kidney diseases.

Phase Change Material-Embedded Multifunctional Janus Nanofiber Dressing with Directional Moisture Transport, Controlled Release of Anti-Inflammatory Drugs, and Synergistic Antibacterial Properties.

Wound healing is a systematic and complex process that involves various intrinsic and extrinsic factors affecting different stages of wound repair. Therefore, multifunctional wound dressings that can modulate these factors to promote wound healing are in high demand. In this work, a multifunctional Janus electrospinning nanofiber dressing with antibacterial and anti-inflammatory properties, controlled release of drugs, and unidirectional water transport was prepared by depositing coaxial nanofibers on a hydrophilic poly(ε-caprolactone)@polydopamine-ε-polyl-lysine (PCL@PDA-ε-PL) nanofiber membrane. The coaxial nanofiber was loaded with the phase change material lauric acid (LA) in the shell layer and anti-inflammatory ibuprofen (IBU) in the core layer. Among them, LA with a melting point of 43 °C served as a phase change material to control the release of IBU. The phase transition of LA was induced by near-infrared (NIR) irradiation that triggered the photothermal properties of PDA. Moreover, the Janus nanofiber dressing exhibited synergistic antimicrobial properties for Escherichia coli and Staphylococcus aureus due to the photothermal properties of PDA and antibacterial ε-PL. The prepared Janus nanofiber dressing also exhibited anti-inflammatory activity and biocompatibility. In addition, the Janus nanofiber dressing had asymmetric wettability that enabled directional water transport, thereby draining excessive wound exudate. The water vapor transmission test indicated that the Janus nanofiber dressing had good air permeability. Finally, skin wound healing evaluation in rats confirmed its efficacy in promoting wound healing. Therefore, this strategy of designing and manufacturing a multifunctional Janus nanofiber dressing had great potential in wound healing applications.

Assessing microbial degradation potential of methylmercury in different types of paddy soil through short-term incubation.

The neurotoxic methylmercury (MeHg) in paddy soils can accumulate in rice grains. Microbial demethylation is an important pathway of MeHg degradation in soil, but the effect of soil type on microbial degradation of MeHg remains unclear. Therefore, we investigated MeHg degradation in eight typical paddy soils and analyzed the associations between soil physiochemical properties and microbial degradation efficiencies of MeHg. Results showed that MeHg was significantly degraded in unsterilized paddy soils, and the microbial degradation efficiency ranged from 10.8% to 64.6% after a 30-day incubation. The high microbial degradation efficiency of MeHg was observed in the soils with high levels of clay content, whereas relatively low degradation efficiency was found in the red paddy soils. We identified that Paenibacillaceae was the most important microbial predictor of MeHg degradation and was positively correlated with the degradation efficiency in the soils. The abundances of these microbial taxa associated with MeHg degradation were positively correlated with clay content. In addition, Eh, pH, and SOC could influence microbial degradation of MeHg by regulating certain microbial communities. Our results indicate that soil type is crucial in driving MeHg degradation, which has important implications for the mitigation of MeHg pollution in various croplands.

Unveiling Fragmentation of Plastic Particles during Biodegradation of Polystyrene and Polyethylene Foams in Mealworms: Highly Sensitive Detection and Digestive Modeling Prediction.

It remains unknown whether plastic-biodegrading macroinvertebrates generate microplastics (MPs) and nanoplastics (NPs) during the biodegradation of plastics. In this study, we utilized highly sensitive particle analyzers and pyrolyzer-gas chromatography mass spectrometry (Py-GCMS) to investigate the possibility of generating MPs and NPs in frass during the biodegradation of polystyrene (PS) and low-density polyethylene (LDPE) foams by mealworms (Tenebrio molitor larvae). We also developed a digestive biofragmentation model to predict and unveil the fragmentation process of ingested plastics. The mealworms removed 77.3% of ingested PS and 71.1% of ingested PE over a 6-week test period. Biodegradation of both polymers was verified by the increase in the δ13C signature of residual plastics, changes in molecular weights, and the formation of new oxidative functional groups. MPs accumulated in the frass due to biofragmentation, with residual PS and PE exhibiting the maximum percentage by number at 2.75 and 7.27 µm, respectively. Nevertheless, NPs were not detected using a laser light scattering sizer with a detection limit of 10 nm and Py-GCMS analysis. The digestive biofragmentation model predicted that the ingested PS and PE were progressively size-reduced and rapidly biodegraded, indicating the shorter half-life the smaller plastic particles have. This study allayed concerns regarding the accumulation of NPs by plastic-degrading mealworms and provided critical insights into the factors controlling MP and NP generation during macroinvertebrate-mediated plastic biodegradation.

Multidimensional Drivers of Mercury Distribution in Global Surface Soils: Insights from a Global Standardized Field Survey.

Soil stores a large amount of mercury (Hg) that has adverse effects on human health and ecosystem safety. Significant uncertainties still exist in revealing environmental drivers of soil Hg accumulation and predicting global Hg distribution owing to the lack of field data from global standardized analyses. Here, we conducted a global standardized field survey and explored a holistic understanding of the multidimensional environmental drivers of Hg accumulation in global surface soils. Hg content in surface soils from our survey ranges from 3.8 to 618.2 µg kg-1 with an average of 74.0 µg kg-1 across the globe. Atmospheric Hg deposition, particularly vegetation-induced elemental Hg0 deposition, is the major source of surface soil Hg. Soil organic carbon serves as the major substrate for sequestering Hg in surface soils and is significantly influenced by agricultural management, litterfall, and elevation. For human activities, changing land-use could be a more important contributor than direct anthropogenic emissions. Our prediction of a new global Hg distribution highlights the hot spots (high Hg content) in East Asia, the Northern Hemispheric temperate/boreal regions, and tropical areas, while the cold spots (low Hg content) are in arid regions. The holistic understanding of multidimensional environmental drivers helps to predict the Hg distribution in global surface soils under a changing global environment.

Contrastive Learning with Prototype-Based Negative Mixing for Satellite Telemetry Anomaly Detection.

Telemetry data are the most important basis for ground operators to assess the status of satellites in orbit, and telemetry data-based anomaly detection has become a key tool to improve the reliability and safety of spacecrafts. Recent research on anomaly detection focuses on constructing a normal profile of telemetry data using deep learning methods. However, these methods cannot effectively capture the complex correlations between the various dimensions of telemetry data, and thus cannot accurately model the normal profile of telemetry data, resulting in poor anomaly detection performance. This paper presents CLPNM-AD, contrastive learning with prototype-based negative mixing for correlation anomaly detection. The CLPNM-AD framework first employs an augmentation process with random feature corruption to generate augmented samples. Following that, a consistency strategy is employed to capture the prototype of samples, and then prototype-based negative mixing contrastive learning is used to build a normal profile. Finally, a prototype-based anomaly score function is proposed for anomaly decision-making. Experimental results on public datasets and datasets from the actual scientific satellite mission show that CLPNM-AD outperforms the baseline methods, achieves up to 11.5% improvement based on the standard F1 score and is more robust against noise.

Photoelectric Conversion and Device Stability of PM6:PY-IT Solar Cells Based on a Water Solution-Processed MoO3 Hole Transport Layer.

To enhance the power conversion efficiency (PCE) and stability of all-polymer solar cells (all-PSCs), a new precursor solution based on an in situ chemical reaction of nanomolybdenum powder (Mo), hydrogen peroxide (H2O2), and ammonia (NH3·H2O) was developed for preparing a MoO3 hole transport layer (HTL) for all-PSCs. The results showed that the PCE and stability of PM6:PY-IT solar cells based on the MoO3 HTL were better than those based on a PEDOT:PSS layer. To further understand the relationship between the HTL and the device performance, ultrafast photophysical processes of all-PSCs based on different HTLs were contrastively analyzed. Our research indicated that the micromorphology of active layers could be influenced by the interfacial layer material, consequently determining the photoelectric conversion process of all-PSCs. The MoO3-based all-PSCs had longer charge lifetime, higher charge mobility, and lower charge recombination characteristics compared with the devices based on the PEDOT:PSS layer during the operation time. As a result, the MoO3-based PM6:PY-IT solar cells achieved an initial PCE of 15.2%, and they still maintained more than 80% of their initial efficiency after 1000 h.

Plastispheres as hotspots of microbially-driven methylmercury production in paddy soils.

Microplastics (MPs) as emerging contaminants have accumulated extensively in agricultural ecosystems and are known to exert important effects on biogeochemical processes. However, how MPs in paddy soils influence the conversion of mercury (Hg) to neurotoxic methylmercury (MeHg) remains poorly understood. Here, we evaluated the effects of MPs on Hg methylation and associated microbial communities in microcosms using two typical paddy soils in China (i.e., yellow and red soils). Results showed that the addition of MPs significantly increased MeHg production in both soils, which could be related to higher Hg methylation potential in the plastisphere than in the bulk soil. We found significant divergences in the community composition of Hg methylators between the plastisphere and the bulk soil. In addition, the plastisphere had higher proportions of Geobacterales in the yellow soil and Methanomicrobia in the red soil compared with the bulk soil, respectively; and plastisphere also had more densely connected microbial groups between non-Hg methylators and Hg methylators. These microbiota in the plastisphere are different from those in the bulk soil, which could partially account for their distinct MeHg production ability. Our findings suggest plastisphere as a unique biotope for MeHg production and provide new insights into the environment risks of MP accumulation in agricultural soils.

Nontargeted Metabolomics Revealed Novel Association Between Serum Metabolites and Incident Acute Coronary Syndrome: A Mendelian Randomization Study.

Background This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations. Methods and Results We performed nontargeted metabolomics in a nested case-control study in the Dongfeng-Tongji cohort, including 500 incident ACS cases and 500 age- and sex-matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5-anhydro-d-glucitol (1,5-AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut-brain peptide cholecystokinin-8 rather than angiotensin by the angiotensin-converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted P=0.025), 1,5-AG is a marker of short-term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted P=0.025), and tetracosanoic acid is a very-long-chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted P=0.091). Similar associations of 1,5-AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors (P-trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (P<0.05), supported by its causal links with hypertension (P<0.05) and hypertriglyceridemia (P=0.077) in Mendelian randomization analysis. The association of 1,5-AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5-AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], P=0.036), yet the association was nonsignificant when further adjusting for fasting glucose. Conclusions These findings highlighted novel angiotensin-independent involvement of the angiotensin-converting enzyme in ACS cause, and the importance of glycemic excursions and very-long-chain saturated fatty acid metabolism.