Ternary Passivation for Enhanced Carrier Transport and Recombination Suppression in Highly Efficient Sn-Based Perovskite Solar Cells.

The exploration of nontoxic Sn-based perovskites as a viable alternative to their toxic Pb-based counterparts has garnered increased attention. However, the power conversion efficiency of Sn-based perovskite solar cells lags significantly behind their Pb-based counterparts. This study presents a ternary passivation strategy aimed at enhancing device performance, employing [6,6]-phenyl-C61-butyric-acid-methyl-ester (PCBM), poly(3-hexylthiophene) (P3HT), and indene C60 bisadduct (ICBA). These components play crucial roles in managing energy levels and enhancing carrier transportation, respectively. The results reveal that the introduction of the ternary system leads to improvements in carrier collection and transportation, accompanied by a suppression of the recombination process. Ultimately, the champion device achieves a remarkable performance with an efficiency of 14.64%. Notably, the device also exhibits robust operational and long-term stored stability.

Exploring molecular mechanisms underlying changes in lipid fingerprinting of salmon (Salmo salar) during air frying integrating machine learning-guided REIMS and lipidomics analysis.

Lipid oxidation in air-fried seafood poses a risk to human health. However, the effect of a prooxidant environment on lipid oxidation in seafood at different air frying (AF) temperatures remains unknown. An integrated machine learning (ML) - guided REIMS and lipidomics method was applied to explore lipid profiles, lipid oxidation, and lipid metabolic pathways of salmons under different AF temperatures (140, 160, 180, and 200 °C). A significant difference in the lipidomic fingerprinting of air-dried salmon at different temperatures was shown by the main ML methods (neural networks, support vector machines, ensemble learning, and naïve bayes). In total, 773 differential expression metabolites (DEMs) were identified, including glycerophospholipids (GPs), glycerides (GLs), and sphingolipids. A total of 34 DEMs with p values <0.05 and variable importance of projection values >1.0 were analyzed, belonging to linoleic acid metabolism, GL metabolism, and GP metabolism pathways. Correlation network analysis revealed that some characteristic DEMs (phosphatidylcholine, lyso-phosphatidylcholine, triglycerides, fatty acids, and phosphatidylethanolamine) were highly correlated with lipid oxidation. In addition, variations of volatile compounds, color values, texture characteristics, and thiobarbituric acid-reactive substance values were analyzed to corroborate the oxidation characteristics.

History of childhood maltreatment associated with hospitalization or death due to COVID-19: a cohort study.

BACKGROUND: Childhood maltreatment (CM) has been indicated in adverse health outcomes across the lifespan, including severe infection-related outcomes. Yet, data are scarce on the potential role of CM in severe COVID-19-related outcomes as well as on mechanisms underlying this association. METHODS: We included 151,427 individuals in the UK Biobank who responded to questions on the history of CM in 2016 and 2017 and were alive on January 31, 2020. Binomial logistic regression models were performed to estimate the association between a history of CM and severe COVID-19 outcomes (i.e. hospitalization or death due to COVID-19), as well as COVID-19 diagnosis and vaccination as secondary outcomes. We then explored the potential mediating roles of socio-economic status, lifestyle and pre-pandemic comorbidities, and the effect modification by polygenic risk score for severe COVID-19 outcomes. RESULTS: The mean age of the study population at the start of the pandemic was 67.7 (SD = 7.72) years, and 56.5% were female. We found the number of CM types was associated with the risk of severe COVID-19 outcomes in a graded manner (pfor trend < 0.01). Compared to individuals with no history of CM, individuals exposed to any CM were more likely to be hospitalized or die due to COVID-19 (odds ratio [OR] = 1.54 [95%CI 1.31-1.81]), particularly after physical neglect (2.04 [1.57-2.62]). Largely comparable risk patterns were observed across groups of high vs. low genetic risks for severe COVID-19 outcomes (pfor difference > 0.05). Mediation analysis revealed that 50.9% of the association between CM and severe COVID-19 outcomes was explained by suboptimal socio-economic status, lifestyle, and pre-pandemic diagnosis of psychiatric disorders or other chronic medical conditions. In contrast, any CM exposure was only weakly associated with COVID-19 diagnosis (1.06 [1.01-1.12]) while significantly associated with not being vaccinated for COVID-19 (1.21 [1.13-1.29]). CONCLUSIONS: Our results add to the growing knowledge base indicating the role of childhood maltreatment in negative health outcomes across the lifespan, including severe COVID-19-related outcomes. The identified factors underlying this association represent potential intervention targets for mitigating the harmful effects of childhood maltreatment in COVID-19 and similar future pandemics.

Comprehensive lipidomics study of basa catfish and sole fish using ultra-performance liquid chromatography Q-extractive orbitrap mass spectrometry for fish authenticity.

The authenticity of fish products has become a widespread issue in markets due to substitution and false labeling. Lipidomics combined with chemometrics enables the fraudulence identification of food through the analysis of a large amount of data. This study utilized ultra-high-performance liquid chromatography (UHPLC)-QE Orbitrap MS technology to comprehensively analyze the lipidomics of commercially available basa catfish and sole fish. In positive and negative ion modes, a total of 779 lipid molecules from 21 lipid subclasses were detected, with phospholipid molecules being the most abundant, followed by glycerides molecules. Significant differences in the lipidome fingerprinting between the two fish species were observed. A total of 165 lipid molecules were screened out as discriminative features to distinguish between basa catfish and sole fish, such as TAG(16:0/16:0/18:1), PC(14:0/22:3), and TAG(16:1/18:1/18:1), etc. This study could provide valuable insights into authenticating aquatic products through comprehensive lipidomics analysis, contributing to quality control and consumer protection in the food industry.

Design, synthesis, and in vivo and in vitro biological screening of pseudolaric acid B derivatives as potential anti-tumor agents.

Pseudolaric Acid B (PAB), a natural product with remarkable anti-tumor activity, is a starting point for new anticancer therapeutics. We designed and synthesized 27 PAB derivatives and evaluated their anti-proliferative activities against four cancer cell lines: MCF-7, HCT-116, HepG2, and A549. Compared with unmodified PAB, the PAB derivatives showed stronger anti-proliferative activity. The ability of compound D3 (IC50 = 0.21 µM) to inhibit HCT-116 cells was approximately 5.3 times that of PAB (IC50 = 1.11 µM) and the antiproliferative action was unrelated to cytotoxicity (SI=20.38), indicating its superior safety profile (PAB; SI=0.95). Compound D3 effectively suppressed the EdU-positive rate and reduced colony formation, arrested HCT-116 cells in the S and G2/M phases and induced apoptosis. In vivo experiments further demonstrated low toxicity of compound D3 while suppressing tumor growth in mice. In summary, given its strong anti-proliferative effect and relative safety, further development of compound D3 is warranted.

Loosely Bounded Exciton with Enhanced Delocalization Capability Boosting Efficiency of Organic Solar Cells.

In organic solar cells (OSCs), electron acceptors have undergone multiple updates, from the initial fullerene derivatives, to the later acceptor-donor-acceptor type non-fullerene acceptors (NFAs), and now to Y-series NFAs, based on which efficiencies have reached over 19%. However, the key property responsible for further improved efficiency from molecular structure design is remained unclear. Herein, the material properties are comprehensively scanned by selecting PC71BM, IT-4F, and L8-BO as the representatives for different development stages of acceptors. For comparison, asymmetric acceptor of BTP-H5 with desired loosely bounded excitons is designed and synthesized. It's identified that the reduction of intrinsically exciton binding energy (Eb) and the enhancement of exciton delocalization capability act as the key roles in boosting the performance. Notably, 100 meV reduction in Eb has been observed from PC71BM to BTP-H5, correspondingly, electron-hole pair distance of BTP-H5 is almost two times over PC71BM. As a result, efficiency is improved from 40% of S-Q limit for PC71BM-based OSC to 60% for BTP-H5-based one, which achieves an efficiency of 19.07%, among the highest values for binary OSCs. This work reveals the confirmed function of exciton delocalization capability quantitatively in pushing the efficiency of OSCs, thus providing an enlightenment for future molecular design.

Self-assembly of a ruthenium-based cGAS-STING photoactivator for carrier-free cancer immunotherapy.

The cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway promotes antitumor immune responses by sensing cytosolic DNA fragments leaked from nucleus and mitochondria. Herein, we designed a highly charged ruthenium photosensitizer (Ru1) with a ß-carboline alkaloid derivative as the ligand for photo-activating of the cGAS-STING pathway. Due to the formation of multiple non-covalent intermolecular interactions, Ru1 can self-assemble into carrier-free nanoparticles (NPs). By incorporating the triphenylphosphine substituents, Ru1 can target and photo-damage mitochondrial DNA (mtDNA) to cause the cytoplasmic DNA leakage to activate the cGAS-STING pathway. Finally, Ru1 NPs show potent antitumor effects and elicit intense immune responses in vivo. In conclusion, we report the first self-assembling mtDNA-targeted photosensitizer, which can effectively activate the cGAS-STING pathway, thus providing innovations for the design of new photo-immunotherapeutic agents.

Deciphering the Atomic-Scale Structural Origin for Photoluminescence Quenching in Tin-Lead Alloyed Perovskite Nanocrystals.

The development of tin-lead alloyed halide perovskite nanocrystals (PNCs) is highly desirable for creating ultrastable, eco-friendly optoelectronic applications. However, the current incorporation of tin into the lead matrix results in severe photoluminescence (PL) quenching. To date, the precise atomic-scale structural origins of this quenching are still unknown, representing a significant barrier to fully realizing the potential of these materials. Here, we uncover the distinctive defect-related microstructures responsible for PL quenching using atomic-resolution scanning transmission electron microscopy and theoretical calculations. Our findings reveal an increase in point defects and Ruddlesden-Popper (RP) planar faults with increasing tin content. Notably, the point defects include a spectrum of vacancies and previously overlooked antisite defects with bromide vacancies and cation antisite defects emerging as the primary contributors to deep-level defects. Furthermore, the RP planar faults exhibit not only the typical rock-salt stacking pattern found in pure Pb-based PNCs but also previously undocumented microstructures rich in bromide vacancies and deep-level cation antisite defects. Direct strain imaging uncovers severe lattice distortion and significant inhomogeneous strain distributions caused by point defect aggregation, potentially breaking the local force balance and driving RP planar fault formation via lattice slippage. Our work illuminates the nature and evolution of defects in tin-lead alloyed halide perovskite nanocrystals and their profound impact on PL quenching, providing insights that support future material strategies in the development of less toxic tin-lead alloyed perovskite nanocrystals.

Comparative evaluating laser ionization and iKnife coupled with rapid evaporative ionization mass spectrometry and machine learning for geographical authentication of Larimichthys crocea.

Larimichthys crocea (LYC) holds significant economic value as a marine fish species. However, inaccuracies in labeling its origin can adversely affect consumer interests. Herein, a laser assisted rapid evaporative ionization mass spectrometry (LA-REIMS) and machine learning (ML) was developed for geographical authentication. When compared to iKnife, the LA demonstrated to be superior owing to reduced thermal damage to sample tissue, enhanced automation, and ease of use. Analysis of LYC from six distinct geographical origins across China revealed a total of 798 ions, which were then subjected to six classifiers to establish ML models. Following hyperparameter optimization and feature engineering, the Chi2(15%)-KNN model exhibited the highest training and testing accuracy, achieving 98.4 ± 0.9% and 98.5 ± 1.4%, respectively. This LA-REIMS/ML methodology offers a rapid, accurate, and intelligent solution for tracing the origin of LYC, thereby providing valuable technical support for the establishment of traceability systems in the aquatic product industry.

Rational Construction of a 3D Self-Supported Electrode Based on ZIF-67 and Amorphous NiCoP for an Enhanced Oxygen Evolution Reaction.

The development of efficient and Earth-abundant electrocatalysts for the oxygen evolution reaction (OER) is an urgent requirement in the field of electrochemical water splitting. The electrocatalytic performance of the OER can be greatly enhanced by the synergistic combination of zeolite imidazolate frameworks (ZIFs) and transition-metal phosphides, both of which individually exhibit promising capabilities in this regard. In this study, a novel amorphous NiCoP deposited on ZIF-67 sheets supported on Ni foam (labeled as NiCoP/ZIF-67/NF) as an OER electrocatalytic material was successfully synthesized using a simple, secure, and time-efficient two-step strategy. The experimental results demonstrate that NiCoP/ZIF-67/NF possesses a large active surface area with abundant active sites. Also, the synergistic effect and interaction between NiCoP and ZIF-67, as well as between Ni and Co within NiCoP, effectively enhance its electrochemical performance under alkaline conditions. Consequently, NiCoP/ZIF-67/NF exhibits outstanding catalytic activity for OER with an overpotential (η) of 175 mV at a current density of 10 mA cm-2 and a long-term stability over 40 h at 20 mA cm-2 in a 1.0 M KOH electrolyte. The corresponding analyses suggest that the real active sites responsible for the OER are identified as NiOOH and CoOOH species within the structure of NiCoP/ZIF-67/NF. Additionally, the catalytic function and stability of ZIF-67 toward the OER under alkaline conditions were also briefly discussed. This work provides a novel catalytic material for the OER along with a facile strategy to fabricate superior, efficient, and noble metal-free catalysts suitable for energy-related applications.

Novel PEI/Zein core-shell composite as mixed-mode stationary phase for high performance liquid chromatography.

Based on the adhesion of polyethyleneimine (PEI), a novel PEI/zein co-modified core-shell stationary phase (PEI/Zein@SiO2) was prepared by doping zein to form a composite modification layer. The stationary phase achieved effective separation of nucleosides, bases and antibiotics in hydrophilic interaction mode on account of the hydrophilic groups of composite coating. With the hydrophobicity of zein, the flavones could be separated in reversed-phase mode. In short, the separation and analysis of hydrophilic/hydrophobic compounds were accomplished excellently by the PEI/Zein@SiO2 column with mixed double mode. The prepared chromatographic stationary phase not only avoided the dissolution of zein, but also covered the strong adsorption of some analytes caused by silica hydroxyl groups on the surface of silica spheres. The morphological structure and specific surface area of the material were reflected by various characterization techniques. Hydrophilic/hydrophobic compounds were used as tested analytes to research separation performance and retention mechanisms of PEI/Zein@SiO2 column. The stability and reproducibility of the PEI/Zein@SiO2 stationary phase were satisfied. Therefore, the modification of zein could improve the separation selectivity of stationary phase effectively for complex samples, which had the potential to be one of the significant potential application materials in stationary phase packing.

An efficient ratiometric fluorescence and colorimetric dual-mode probe for convenient determination of nitrite in real samples and E. coli.

Developing an effective and convenient nitrite detection method is indispensable in food safety, environmental monitoring, clinical diagnosis of diseases, and many other areas. Herein, a dicyanoisophorone derivative, TMN-NH2 with large Stokes shift and near-infrared (NIR) emission, was proposed as a ratiometric fluorescence and colorimetric dual-mode probe for the rapid determination of NO2- in acidic media, showing excellent selectivity and high sensitivity. The sensing mechanism is based on the diazotization of TMN-NH2 with NO2- and subsequent diazonium salt hydrolysis to form a hydroxyl-substituted product (TMN-OH). Under the optimized conditions of reaction and detection, a new quantitative analysis method based on TMN-NH2 was established for NO2- detection, exhibiting good linear relationships to NO2- in the range of 0.5 to 15 µM with practical detection limits of 26.6 nM and 17.6 nM for the colorimetric and fluorescent readout, respectively. The quantitative detection of NO2- in real samples demonstrated satisfactory recoveries and repeatability. Moreover, TMN-NH2 was successfully applied for monitoring NO2- in Escherichia coli by confocal fluorescence imaging.

Suppression of excitatory synaptic transmission in the centrolateral amygdala via presynaptic histamine H3 heteroreceptors.

The central histaminergic system has a pivotal role in emotional regulation and psychiatric disorders, including anxiety, depression and schizophrenia. However, the effect of histamine on neuronal activity of the centrolateral amygdala (CeL), an essential node for fear and anxiety processing, remains unknown. Here, using immunostaining and whole-cell patch clamp recording combined with optogenetic manipulation of histaminergic terminals in CeL slices prepared from histidine decarboxylase (HDC)-Cre rats, we show that histamine selectively suppresses excitatory synaptic transmissions, including glutamatergic transmission from the basolateral amygdala, on both PKC-δ- and SOM-positive CeL neurons. The histamine-induced effect is mediated by H3 receptors expressed on VGLUT1-/VGLUT2-positive presynaptic terminals in CeL. Furthermore, optoactivation of histaminergic afferent terminals from the hypothalamic tuberomammillary nucleus (TMN) also significantly suppresses glutamatergic transmissions in CeL via H3 receptors. Histamine neither modulates inhibitory synaptic transmission by presynaptic H3 receptors nor directly excites CeL neurons by postsynaptic H1, H2 or H4 receptors. These results suggest that histaminergic afferent inputs and presynaptic H3 heteroreceptors may hold a critical position in balancing excitatory and inhibitory synaptic transmissions in CeL by selective modulation of glutamatergic drive, which may not only account for the pathophysiology of psychiatric disorders but also provide potential psychotherapeutic targets. KEY POINTS: Histamine selectively suppresses the excitatory, rather than inhibitory, synaptic transmissions on both PKC-δ- and SOM-positive neurons in the centrolateral amygdala (CeL). H3 receptors expressed on VGLUT1- or VGLUT2-positive afferent terminals mediate the suppression of histamine on glutamatergic synaptic transmission in CeL. Optogenetic activation of hypothalamic tuberomammillary nucleus (TMN)-CeL histaminergic projections inhibits glutamatergic transmission in CeL via H3 receptors.

Intraperitoneally injected d11-11(12)-epoxyeicosatrienoic acid is rapidly incorporated and esterified within rat plasma and peripheral tissues but not the brain.

Epoxyeicosatrienoic acids (EpETrEs) are bioactive lipid mediators of arachidonic acid cytochrome P450 oxidation. In vivo, the free (unbound) form of EpETrEs regulate multiple processes including blood flow, angiogenesis and inflammation resolution. Free EpETrEs are thought to rapidly degrade via soluble epoxide hydrolase (sEH); yet, in many tissues, the majority of EpETrEs are esterified to complex lipids (e.g. phospholipids) suggesting that esterification may play a major role in regulating free, bioactive EpETrE levels. This hypothesis was tested by quantifying the metabolism of intraperitoneally injected free d11-11(12)-Epoxyeicosatrienoic acid (d11-11(12)-EpETrE) in male and female rats. Plasma and tissues (liver, adipose and brain) were obtained 3 to 4 min later and assayed for d11-11(12)-EpETrE and its sEH metabolite, d11-11,12-dihydroxyeicosatrienoic acid (d11-11,12-diHETrE) in both the free and esterified lipid fractions. In both males and females, the majority of injected tracer was recovered in liver followed by plasma and adipose. No tracer was detected in the brain, indicating that brain levels are maintained by endogenous synthesis from precursor fatty acids. In plasma, liver, and adipose, the majority (>54 %) of d11-11(12)-EpETrE was found esterified to phospholipids or neutral lipids (triglycerides and cholesteryl esters). sEH-derived d11-11,12-diHETrE was not detected in plasma or tissues, suggesting negligible conversion within the 3-4 min period post tracer injection. This study shows that esterification is the main pathway regulating free 11(12)-EpETrE levels in vivo.

Radiogenomic analysis for predicting lymph node metastasis and molecular annotation of radiomic features in pancreatic cancer.

BACKGROUND: To provide a preoperative prediction model for lymph node metastasis in pancreatic cancer patients and provide molecular information of key radiomic features. METHODS: Two cohorts comprising 151 and 54 pancreatic cancer patients were included in the analysis. Radiomic features from the tumor region of interests were extracted by using PyRadiomics software. We used a framework that incorporated 10 machine learning algorithms and generated 77 combinations to construct radiomics-based models for lymph node metastasis prediction. Weighted gene coexpression network analysis (WGCNA) was subsequently performed to determine the relationships between gene expression levels and radiomic features. Molecular pathways enrichment analysis was performed to uncover the underlying molecular features. RESULTS: Patients in the in-house cohort (mean age, 61.3 years ± 9.6 [SD]; 91 men [60%]) were separated into training (n = 105, 70%) and validation (n = 46, 30%) cohorts. A total of 1,239 features were extracted and subjected to machine learning algorithms. The 77 radiomic models showed moderate performance for predicting lymph node metastasis, and the combination of the StepGBM and Enet algorithms had the best performance in the training (AUC = 0.84, 95% CI = 0.77-0.91) and validation (AUC = 0.85, 95% CI = 0.73-0.98) cohorts. We determined that 15 features were core variables for lymph node metastasis. Proliferation-related processes may respond to the main molecular alterations underlying these features. CONCLUSIONS: Machine learning-based radiomics could predict the status of lymph node metastasis in pancreatic cancer, which is associated with proliferation-related alterations.

Fluorinated benzothiadiazole fluorescent probe based on ICT mechanism for highly selectivity and sensitive detection of fluoride ion.

Excessive fluoride ion (F-) in the environment can affect health and even endanger life when ingested by the human body. However, most fluoride probes have the disadvantages of low sensitivity and long detection time. Herein, fluorescent probe 3a is successfully synthesized by linking two acetylenyltrimethylsilyl groups at both ends of the fluorinated benzothiadiazole core. After the addition of F- to 3a, the emission at 436 nm is significantly quenched and slightly blue-shifted. It is confirmed by electrospray ionization high-resolution mass spectrometry (ESI-HRMS) and density functional theory calculations (DFT) that these changes are due to the F- triggered Si-C bond cleavage and the subsequent inactivation of intramolecular charge transfer (ICT). The detection limit and response time of probe 3a for F- are 10-8 mol/L and 25 s, respectively. Importantly, fluorescent material 3a can be processed into portable test tools for the visual detection of fluoride ion.

Development and validation of an ultra-performance liquid chromatography tandem mass spectrometry for target determination of bioactive compounds in Dendrobium spp.

As a medicine-food homology herb, Dendrobium spp. has versatile applications in modern medicine and food industry. Herein, an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) based method was established for simultaneous quantification of six active components, including gigantol, erianin, naringenin, quercetin, rutin, and p-coumaric acid in Dendrobium spp., on the basis of optimized sample preparation, mass spectrometry conditions, and chromatography conditions. Sample extraction was carried out using methanol at a temperature of 60 °C, followed by separation on a T3 C18 column utilizing a gradient eluting program. The results demonstrated excellent linearity (r > 0.999) for the six active components within a specified concentration range. The average recovery rates ranged from 84.7 % to 106.9 %, and the precision (RSD) was within 7.4 %. The detection and quantification limits of this method ranged from 0.34 to 4.17 ng mL-1 and 1.12-13.91 ng mL-1, respectively. The established method demonstrates high accuracy and reliability and is applicable in practical sample detection. Different Dendrobium spp. exhibit specific variations in compound composition, with D. fimbriatum Hook. having a higher content of benzyl compounds and D. crystallinum. Rchb. f. having a higher content of flavonoids. This study provides experimental evidence for the quality and safety regulation of Dendrobium spp.

Revolutionizing food science with mass spectrometry imaging: A comprehensive review of applications and challenges.

Food science encounters increasing complexity and challenges, necessitating more efficient, accurate, and sensitive analytical techniques. Mass spectrometry imaging (MSI) emerges as a revolutionary tool, offering more molecular-level insights. This review delves into MSI's applications and challenges in food science. It introduces MSI principles and instruments such as matrix-assisted laser desorption/ionization, desorption electrospray ionization, secondary ion mass spectrometry, and laser ablation inductively coupled plasma mass spectrometry, highlighting their application in chemical composition analysis, variety identification, authenticity assessment, endogenous substance, exogenous contaminant and residue analysis, quality control, and process monitoring in food processing and food storage. Despite its potential, MSI faces hurdles such as the complexity and cost of instrumentation, complexity in sample preparation, limited analytical capabilities, and lack of standardization of MSI for food samples. While MSI has a wide range of applications in food analysis and can provide more comprehensive and accurate analytical results, challenges persist, demanding further research and solutions. The future development directions include miniaturization of imaging devices, high-resolution and high-speed MSI, multiomics and multimodal data fusion, as well as the application of data analysis and artificial intelligence. These findings and conclusions provide valuable references and insights for the field of food science and offer theoretical and methodological support for further research and practice in food science.

Distinct biological signature and modifiable risk factors underlie the comorbidity between major depressive disorder and cardiovascular disease.

Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Here we show that CVDs share most of their genetic risk factors with MDD. Multivariate genome-wide association analysis of shared genetic liability between MDD and atherosclerotic CVD revealed seven loci and distinct patterns of tissue and brain cell-type enrichments, suggesting the involvement of the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic and psychosocial or lifestyle risk factors. Our data indicated causal effects of genetic liability to MDD on CVD risk, but not from most CVDs to MDD, and showed that the causal effects were partly explained by metabolic and psychosocial or lifestyle factors. The distinct signature of MDD-atherosclerotic CVD comorbidity suggests an immunometabolic subtype of MDD that is more strongly associated with CVD than overall MDD. In summary, we identified biological mechanisms underlying MDD-CVD comorbidity and modifiable risk factors for prevention of CVD in individuals with MDD.