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Background Depression has been linked to an increased risk of cardiovascular and respiratory diseases; however, its impact on cardiac and lung function remains unclear, especially when accounting for potential gene–environment interactions. Methods We developed a novel polygenic and gene–environment interaction risk score (PGIRS) integrating the major genetic effect and gene–environment interaction effect of depression-associated loci. The single nucleotide polymorphisms (SNPs) demonstrating major genetic effect or environmental interaction effect were obtained from genome-wide SNP association and SNP-environment interaction analyses of depression. We then calculated the depression PGIRS for non-depressed individuals, using smoking and alcohol consumption as environmental factors. Using linear regression analysis, we assessed the associations of PGIRS and conventional polygenic risk score (PRS) with lung function (N  = 42 886) and cardiac function (N  = 1791) in the subjects with or without exposing to smoking and alcohol drinking. Results We detected significant associations of depression PGIRS with cardiac and lung function, contrary to conventional depression PRS. Among smokers, forced vital capacity exhibited a negative association with PGIRS (β  = −0.037, FDR = 1.00 × 10−8), contrasting with no significant association with PRS (β  = −0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (β  = 0.088, FDR = 0.010), whereas no such association was found with PRS (β  = 0.040, FDR = 0.265). Notably, in individuals who both smoked and drank, forced expiratory volume in 1-second demonstrated a negative association with PGIRS (β  = −0.042, FDR = 6.30 × 10−9), but not with PRS (β  = −0.003, FDR = 0.857). Conclusions Our findings underscore the profound impact of depression on cardiac and lung function, highlighting the enhanced efficacy of considering gene–environment interactions in PRS-based studies. [ABSTRACT FROM AUTHOR]

The connection between the gut microbiota and brain structure changes is still unclear. We conducted a Mendelian randomization (MR) study to examine the bidirectional causality between the gut microbiota (211 taxa, including 131 genera, 35 families, 20 orders, 16 classes and 9 phyla; N = 18,340 individuals) and age-independent/dependent longitudinal changes in brain structure across the lifespan (N = 15,640 individuals aged 4~99 years). We identified causal associations between the gut microbiota and age-independent/dependent longitudinal changes in brain structure, such as family Peptostreptococcaceae with age-independent longitudinal changes of cortical gray matter (GM) volume and genus Faecalibacterium with age-independent average cortical thickness and cortical GM volume. Taking age-independent longitudinal changes in brain structure across the lifespan as exposures, there were causal relationships between the surface area and genus Lachnospiraceae. Our findings may serve as fundamentals for further research on the genetic mechanisms and biological treatment of complex traits and diseases associated with the gut microbiota and the brain structure change rate. [ABSTRACT FROM AUTHOR]

Grain size control is an important aspect to manipulate the microstructure and high temperature stability of ceramic fibers. In the present work, phase competition mechanism was proposed to regulate the grain size of ZrO2/CaZrO3 composite fibers. Calcium precursor with different molar ratio of Ca/Zr was introduced to the zirconia system not only for phase stabilization of ZrO2 but also for phase competition between solid‐solution CaxZr1‐xO2‐x and new phase CaZrO3. Effects of Ca/Zr molar ratio on the thermal pyrolysis, crystallization, solid reaction of precursor fibers were fully explored. The change of grain size of fibers with various Ca/Zr molar ratio was characterized and discussed. Furthermore, the near‐infrared reflectivity and high‐temperature stability of fibrous membranes were also presented. The results indicated that ZrO2/CaZrO3 fibrous membrane has promising applications in high‐temperature for the excellent thermal stability and high near infrared (NIR) reflectivity. [ABSTRACT FROM AUTHOR]

Tobacco smoke exposure is a major environmental risk factor that facilitates the development and progression of asthma. Our previous study showed that CpG oligodeoxynucleotide (CpG-ODN) inhibits thymic stromal lymphopoietin (TSLP)-dendritic cells (DCs) to reduce Th2/Th17-related inflammatory response in smoke-related asthma. However, the mechanism underlying CpG-ODN -downregulated TSLP remains unclear. A combined house dust mite (HDM)/cigarette smoke extract (CSE) model was used to assess the effects of CpG-ODN on airway inflammation, Th2/Th17 immune response, and amount of IL-33/ST2 and TSLP in mice with smoke-related asthma induced by adoptive transfer of bone-marrow-derived dendritic cells (BMDCs) and in the cultured human bronchial epithelium (HBE) cells administered anti-ST2, HDM, and/or CSE. In vivo, compared to the HDM alone model, the combined HDM/CSE model had aggravated inflammatory responses, while CpG-ODN attenuated airway inflammation, airway collagen deposition, and goblet cell hyperplasia and reduced the levels of IL-33/ST2, TSLP, and Th2/Th17-cytokines in the combined model. In vitro, IL-33/ST2 pathway activation promoted TSLP production in HBE cells, which could be inhibited by CpG-ODN. CpG-ODN administration alleviated Th2/Th17 inflammatory response, decreased the infiltration of inflammatory cells into the airway, and improved the remodeling of smoke-related asthma. The underlying mechanism may be that CpG-ODN inhibits the TSLP-DCs pathway by downregulating the IL-33/ST2 axis. [ABSTRACT FROM AUTHOR]

Disrupted brain structures and several life environmental factors have been shown to influence depression and anxiety, but their interactions with anxiety and depression remain elusive. Genome‐wide association study datasets of 15 brain structure longitudinal changes (N = 15,640) were obtained from the published study. Genotype and phenotype‐related data of depression, anxiety, and life environmental factors (including smoking, alcohol drinking, coffee intake, maternal smoking, physical activity, vitamin D, insomnia, sleep duration, and family satisfaction) were collected from UK Biobank. We calculated the polygenic risk scores (PRS) of 15 brain structure changes and then conducted linear regression analyses to explore the interactions of brain structure changes and life environmental factors on depression and anxiety using 15 brain structure change‐related PRS, life environmental factors and interactions of them as instrumental variables, and depression score or anxiety score as outcomes. Sex stratification in all analyses was performed to reveal sex‐specific differences in the interactions. We found 14 shared interactions related to both depression and anxiety in total sample, such as alcohol drinking × cerebellum white matter 3 (WM; beta = −.003, p =.018 for depression; beta = −003, p =.008 for anxiety) and maternal smoking × nucleus accumbens 2 (beta =.088, p =.002 for depression; beta =.070, p =.008 for anxiety). We also observed sex‐specific differences in the interactions, for instance, alcohol drinking × cerebellum WM 3 was negatively associated with depression and anxiety in males (beta = −.004, p =.020 for depression; beta = −.005, p =.002 for anxiety). Our study results reveal the important interactions between brain structure changes and several life environmental factors on depression and anxiety, which may help to explore the pathogenesis of depression and anxiety. [ABSTRACT FROM AUTHOR]

Habitual coffee consumption is an addictive behavior with unknown genetic variations and has raised public health issues about its potential health-related outcomes. We performed exome-wide association studies to identify rare risk variants contributing to habitual coffee consumption utilizing the newly released UK Biobank exome dataset (n = 200,643). A total of 34,761 qualifying variants were imported into SKAT to conduct gene-based burden and robust tests with minor allele frequency <0.01, adjusting the polygenic risk scores (PRS) of coffee intake to exclude the effect of common coffee-related polygenic risk. The gene-based burden and robust test of the exonic variants found seven exome-wide significant associations, such as OR2G2 (PSKAT = 1.88 × 10−9, PSKAT-Robust = 2.91 × 10−17), VEZT1 (PSKAT = 3.72 × 10−7, PSKAT-Robust = 1.41 × 10−7), and IRGC (PSKAT = 2.92 × 10−5, PSKAT-Robust = 1.07 × 10−7). These candidate genes were verified in the GWAS summary data of coffee intake, such as rs12737801 (p = 0.002) in OR2G2, and rs34439296 (p = 0.008) in IRGC. This study could help to extend genetic insights into the pathogenesis of coffee addiction, and may point to molecular mechanisms underlying health effects of habitual coffee consumption. [ABSTRACT FROM AUTHOR]

Although previous genome-wide association studies (GWASs) on post-traumatic stress disorder (PTSD) have identified multiple risk loci, how these loci confer risk of PTSD remains unclear. Through the FUSION pipeline, we integrated two human brain proteome reference datasets (ROS/MAP and Banner) with the PTSD GWAS dataset, respectively, to conduct a proteome-wide association study (PWAS) analysis. Then two transcriptome reference weights (Rnaseq and Splicing) were applied to a transcriptome-wide association study (TWAS) analysis. Finally, the PWAS and TWAS results were investigated through brain imaging analysis. In the PWAS analysis, 8 and 13 candidate genes were identified in the ROS/MAP and Banner reference weight groups, respectively. Examples included ADK (pPWAS-ROS/MAP = 3.00 × 10−5) and C3orf18 (pPWAS-Banner = 7.07 × 10−31). Moreover, the TWAS also detected multiple candidate genes associated with PTSD in two different reference weight groups, including RIMS2 (pTWAS-Splicing = 3.84 × 10−2), CHMP1A (pTWAS-Rnaseq = 5.09 × 10−4), and SIRT5 (pTWAS-Splicing = 4.81 × 10−3). Further comparison of the PWAS and TWAS results in different populations detected the overlapping genes: MADD (pPWAS-Banner = 4.90 × 10−2, pTWAS-Splicing = 1.23 × 10−2) in the total population and GLO1(pPWAS-Banner = 4.89 × 10−3, pTWAS-Rnaseq = 1.41 × 10−3) in females. Brain imaging analysis revealed several different brain imaging phenotypes associated with MADD and GLO1 genes. Our study identified multiple candidate genes associated with PTSD in the proteome and transcriptome levels, which may provide new clues to the pathogenesis of PTSD. [ABSTRACT FROM AUTHOR]

Ferrimagnetic nano‐crystal glass‐ceramics and glass fibers were prepared based on the ferrosilicate glass system of SiO2–Fe2O3–B2O3–Al2O3 using large amount of pyrite slag (PS) and small quantities of pure chemicals. Two different fabrication methods were employed, eg, annealing and fiber‐drawing method, without performing any nucleation and crystallization heat treatments. The influence of PS content on the magnetite spontaneous crystallization is investigated by the X‐ray diffraction, FTIR, SEM, and TEM. The X‐ray diffraction patterns show the presence of nanometric magnetite crystals in glass matrix. The ferrimagnetic glass fibers with a diameter of about 20 μm were one‐step drawn. The magnetic hysteresis loops of the glass‐ceramic and glass fiber samples were analyzed using a vibrating sample magnetometer (VSM). Electromagnetic parameters of samples were also examined. [ABSTRACT FROM AUTHOR]

The lithium storage performance and bioimaging of metal sulfides are restricted by their intrinsic poor conductivity, large volumetric expansion and toxicity. Here we report a new strategy to solve these problems by coating pyrrhotite (Fe1−xS) (FS) nanoparticles with N-doped hard carbon ultrathin film (N-HCUF). The porous nanocomposites with multilevel structures have been synthesized by using petrochemical waste water (PWW) as the organic ligands of iron metal-organic frameworks (Fe-MOFs) precursor and the sources of sulfur, nitrogen and carbon. We have clarified the formation mechanism and the influences of wash and calcination temperature on the structural composition, electrochemical and luminescence properties of the nanocomposites. As a novel anode for lithium ion batteries (LIBs), the FS/N-HCUF-700S exhibits high initial discharge capacity of 1542.08 mAh g−1 at a current density of 0.1 A g−1 and the discharge specific capacity becomes stable at 632.16 mAh g−1 after 200 cycles; Meanwhile, the Li+ storage mechanism in the as-prepared samples has also been investigated. More importantly, FS/N-HCUF-700S exhibits strong yellow-fluorescent emission at 614 nm, which is particularly important for bioimaging. Last, the removal efficiency of chemical oxygen demand of PWW is up to 80.7% during the synthesis process. [ABSTRACT FROM AUTHOR]

The Ce3+-, Ho3+-, and Sm3+- single and co-doped oxyfluoride silicate glasses for light emitting diodes are studied. These glasses were prepared by melt quenching method and their optical and structural properties were investigated by absorption spectra, photoluminescence spectra, Commission International de I'Eclairage chromaticity coordinates, X-ray diffraction, and Fourier transform infrared spectra. It is found that the introduction of Al2O3 in glass composition can improve the emissions of Ho3+ and Sm3+. While the presence of B2O3 has the adverse effect and can suppress the emissions of Ho3+ and Sm3+. With substituting Na2O for CaO in the glass compositions, CaF2 crystals can be formed during the melt quenching process. We find the formation of CaF2 crystals can change the emission behavior of Ho3+ and Sm3+ ions. White light emissions can be achieved in the glasses and the luminescence colors can be tuned by varying the concentrations of the doped rare-earth ions and the composition of glass matrix. The Ce3+-, Ho3+-, and Sm3+-doped oxyfluoride silicate glasses presented here demonstrate promising applications in the fields of light emitting diodes. [ABSTRACT FROM AUTHOR]

Using polypyrrole (PPy) nanotubes as the substrate, the layered molybdenum disulfide (MoS) nanosheets were wrapped on PPy nanotubes to form MoS/PPy nanocomposites by a hydrothermal reaction. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images showed that MoS nanosheets coated uniformly on the surface of PPy nanotubes owing to the electrostatic force. The specific capacitance of the MoS/PPy nanocomposites was high up to 307.5 F g, much higher than that of the pure PPy with specific capacitance of 106.3 F g and MoS with specific capacitance of 138.5 F g at a current density of 1.0 A g in 1 M KCl electrolyte. And the special structure of MoS/PPy nanocomposites electrode reduces the deformation during the charge-discharge process and thus improves the rate stability and electrochemical cycling stability of the electrode significantly. The specific capacitance retains 96.47 % after 1000 charge-discharge processes which provides potential as supercapacitors. [ABSTRACT FROM AUTHOR]

We have developed hollow MnO/C composite by using impregnation method and followed by heat treatment. One dimensional hollow MnO nanotubes are dispersed inside the partially graphited carbon matrix. As an anode for Li-ion batteries, the well-designed hollow MnO/C composite deliver a reversible capacity of 680.7 mAh g at 0.2 A g after 190 cycles. After 180 cycles at varied current densities from 0.2 to 2 A g, this anode still delivered a high discharge capacity of 476.9 mAh g and nearly 100 % coulombic efficiency. We also have experimentally realized a maximal discharge specific energy of 425 Wh kg. The well-designed hollow hybrid structure assists in overcoming the issues associated with using manganese oxide in Li-ion batteries, such as poor electric conductivity, volumetric expansion and structural instability during the electrochemical process. Such hollow MnO/C composite could be used as a class of electrode materials for developing high performance Li-ion batteries. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that vitamin D (VD) was associated with psychiatric diseases, but efforts to elucidate the functional relevance of VD with depression and anxiety from genetic perspective have been limited. Based on the UK Biobank cohort, we first calculated polygenic risk score (PRS) for VD from genome-wide association study (GWAS) data of VD. Linear and logistic regression analysis were conducted to evaluate the associations of VD traits with depression and anxiety traits, respectively. Then, using individual genotype and phenotype data from the UK Biobank, genome-wide environment interaction studies (GWEIS) were performed to identify the potential effects of gene × VD interactions on the risks of depression and anxiety traits. In the UK Biobank cohort, we observed significant associations of blood VD level with depression and anxiety traits, as well as significant associations of VD PRS and depression and anxiety traits. GWEIS identified multiple candidate loci, such as rs114086183 (p = 4.11 × 10−8, LRRTM4) for self-reported depression status and rs149760119 (p = 3.88 × 10−8, GNB5) for self-reported anxiety status. Our study results suggested that VD was negatively associated with depression and anxiety. GWEIS identified multiple candidate genes interacting with VD, providing novel clues for understanding the biological mechanism potential associations between VD and psychiatric disorders. [ABSTRACT FROM AUTHOR]

Dietary habits have considerable impact on brain development and mental health. Despite long-standing interest in the association of dietary habits with mental health, few population-based studies of dietary habits have assessed depression and fluid intelligence. Our aim is to investigate the association of dietary habits with depression and fluid intelligence. In total, 814 independent loci were utilized to calculate the individual polygenic risk score (PRS) for 143 dietary habit-related traits. The individual genotype data were obtained from the UK Biobank cohort. Regression analyses were then conducted to evaluate the association of dietary habits with depression and fluid intelligence, respectively. PLINK 2.0 was utilized to detect the single nucleotide polymorphism (SNP) × dietary habit interaction effect on the risks of depression and fluid intelligence. We detected 22 common dietary habit-related traits shared by depression and fluid intelligence, such as red wine glasses per month, and overall alcohol intake. For interaction analysis, we detected that OLFM1 interacted with champagne/white wine in depression, while SYNPO2 interacted with coffee type in fluid intelligence. Our study results provide novel useful information for understanding how eating habits affect the fluid intelligence and depression. [ABSTRACT FROM AUTHOR]

Purpose: Previous studies have demonstrated the link between micronutrients and mental health. However, it remains uncertain whether this connection is causal. We aim to investigate the potential causal effects of micronutrients on mental health based on linkage disequilibrium score (LDSC) regression and Mendelian randomization (MR) analysis., Methods: Utilizing publicly available genome-wide association study (GWAS) summary datasets, we performed LDSC and MR analysis to identify candidate micronutrients with potential causal effects on mental health. Single nucleotide polymorphisms (SNPs) significantly linked with candidate micronutrients with a genome-wide significance level ( p < 5 × 10 -8 ) were selected as instrumental variables (IVs). To estimate the causal effect of candidate micronutrients on mental health, we employed inverse variance weighted (IVW) regression. Additionally, two sensitivity analyses, MR-Egger and weighted median, were performed to validate our results., Results: We found evidence supporting significant causal associations between micronutrients and mental health. LDSC detected several candidate micronutrients, including serum iron (genetic correlation = -0.134, p = 0.032) and vitamin C (genetic correlation = -0.335, p < 0.001) for attention-deficit/hyperactivity disorder (ADHD), iron-binding capacity (genetic correlation = 0.210, p = 0.037) for Alzheimer's disease (AD), and vitamin B12 (genetic correlation = -0.178, p = 0.044) for major depressive disorder (MDD). Further MR analysis suggested a potential causal relationship between vitamin B12 and MDD (b = -0.139, p = 0.009). There was no significant heterogeneity or pleiotropy, indicating the validity of the findings., Conclusion: In this study, we identified underlying causal relationships between micronutrients and mental health. Notably, more research is necessary to clarify the underlying biological mechanisms by which micronutrients affect mental health.

Background: The identification of suitable biomarkers is of crucial clinical importance for the early diagnosis of treatment-resistant schizophrenia (TRS). This study aims to comprehensively analyze the association between TRS and blood and urine biomarkers., Methods: Candidate TRS-related single nucleotide polymorphisms (SNPs) were obtained from a recent genome-wide association study. The UK Biobank cohort, comprising 376,807 subjects with blood and urine biomarker testing data, was used to calculate the polygenic risk score (PRS) for TRS. Pearson correlation analyses were performed to evaluate the correlation between TRS PRS and each of the biomarkers, using calculated TRS PRS as the instrumental variables. Bidirectional two-sample Mendelian randomization (MR) was used to assess potential causal associations between candidate biomarkers with TRS., Results: Here we identify a significant association between TRS PRS and phosphate (r = 0.007, P = 1.96 × 10 -4 ). Sex subgroup analyses identify seven and three candidate biomarkers associated with TRS PRS in male and female participants, respectively. For example, total protein and phosphate for males, creatinine and phosphate for females. Bidirectional two-sample MR analyses indicate that TRS is negatively associated with cholesterol (estimate = -0.363, P  = 0.008). Conversely, TRS is positively associated with total protein (estimate = 0.137, P  = 0.027), mean corpuscular volume (estimate = 0.032, P  = 2.25 × 10 -5 ), and mean corpuscular hemoglobin (estimate = 0.018, P  = 0.007)., Conclusions: Our findings provide insights into the roles of blood and urine biomarkers in the early detection and treatment of TRS., (© 2024. The Author(s).)

Background: Immune checkpoint therapy, involving the programmed cell death 1 (PD-1) monoclonal antibody, has revolutionized the treatment of cancer. Tertiary lymphatic structure (TLS) serves as an immune indicator to predict the efficacy of PD-1 antibody therapy. However, there is no clear result whether the distribution, quantity, and maturity of TLS can be effective indicators for predicting the clinical efficacy of anti-PD1 immunotherapy in patients with colorectal cancer (CRC)., Methods: Fifty-seven patients who underwent surgical resection and thirty-nine patients who received anti-PD-1 immunotherapy were enrolled in this retrospective study. Immunohistochemical staining and multiple fluorescence immunohistochemistry were used to evaluate the mismatch repair (MMR) subtypes and TLS distribution, quantity, and maturity, respectively., Results: A comprehensive patient score system was built based on TLS quantity and maturity. We found that the proportion of patients with score >1 was much higher in the deficient mismatch repair(dMMR) group than in the proficient mismatch repair(pMMR) group, and this difference was mainly due to intratumoral TLS. Patient score, based on the TLS evaluation of whole tumor, peritumor, or intratumor, was used to evaluate the efficacy of anti-PD1 immunotherapy. Based only on the intratumor TLS evaluation, the proportion of patients with a score >1 was higher in the response (PR + CR) group than in the non-response (PD) group. Multivariate analysis revealed that patient scores were positively correlated with the clinical efficacy of immunotherapy. Further analysis of immune-related progression-free survival was performed in patients with CRC who received anti-PD-1 immunotherapy. Patients with score >1 based on the intratumor TLS evaluation had significantly better survival., Conclusions: These results suggest that the patient score based on intratumor TLS evaluation may be a good immune predictive indicator for PD-1 antibody therapy in patients with CRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Feng, Zhang, Zhou, Han, Du, Wang, Yang, Zhang, Yu, Wei, Hao, Ren and Zhao.)

Background: An insufficient number of intratumoral CD8 + T lymphocytes is a major barrier to antitumor immunity and immunotherapy. High endothelial venules (HEVs) are the major sites through which lymphocytes enter tumors; however, the molecular mechanism through which HEVs mediate CD8 + T lymphocyte infiltration remains poorly understood., Methods: Forty-two patients with stage IIIA lung adenocarcinoma, who underwent surgery, were recruited. Multiplex immunohistochemical staining was conducted on tumor tissues to detect the immune checkpoint ligands (ICLs) expressed in the HEVs, blood vessels, and lymphatics. A new ICL score model was constructed to evaluate ligand expression. The relationship between ICL score, tumor-infiltrating CD8 + T cell frequency, and survival of patients was investigated., Results: Mature HEVs, but not blood vessels or lymphatics, mediated CD8 + T cell infiltration. However, the ICLs expressed on mature HEVs could negatively regulate CD8 + T cell entry into tertiary lymphoid structures (TLSs). In addition, according to the results obtained using our ICL total score model, the expression of ICLs on HEVs was observed to be a predictor of both CD8 + T cell infiltration and survival, in which a high ICL total score > 1 represent a weak CD8 + T cell infiltration and a high ICL total score > 2 predicts poor survival., Conclusion: Using the ICL score model, we discovered that ICLs expressed on HEVs are indicative of CD8 + T cell subset infiltration in TLSs, as well as of patient survival with lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Luo, Shi, Liu, Wang, Wang, Yang, Sun, Hui, Wei, Ren and Zhao.)

Background: The infiltration and activation of immune cells in the tumor microenvironment (TIME) affect the prognosis of patients with cancer. Tertiary lymphoid structure (TLS) formation favors tumour- infiltrating-lymphocyte (TIL) recruitment and is regarded as an important indicator of good prognosis associated with immunotherapy in patients with tumors. Chemotherapy is currently one of the most commonly used clinical treatment methods. However, there have been no clear report to explore the effects of different types of chemotherapy on TLS formation in the TIME. This study examined the effects of immunogenic cell death (ICD)-inducing chemotherapeutics on immune cells, high-endothelial venules (HEV), and TLSs in mouse melanomas., Methods: Doxorubicin (an ICD inducer), gemcitabine (non-ICD inducer), and a combination of the two drugs was delivered intra-peritoneally to B16F1-loaded C57BL/6 mice. The infiltration of immune cells into tumor tissues was evaluated using flow cytometry. HEV and TLS formation was assessed using immunohistochemistry and multiple fluorescent immunohistochemical staining., Results: Doxorubicin alone, gemcitabine alone, and the two-drug combination all slowed tumor growth, with the combined treatment demonstrating a more pronounced effect. Compared with the control group, the doxorubicin group showed a higher infiltration of CD8 + T cells and tissue-resident memory T cells (T RM ) and an increase in the secretion of interferon-γ, granzyme B, and perforin in CD8 + T subsets and activation of B cells and dendritic cells. Doxorubicin alone and in combination with gemcitabine decreased regulatory T cells in the TIME. Moreover, doxorubicin treatment promoted the formation of HEV and TLS. Doxorubicin treatment also upregulated the expression of programmed cell death protein (PD)-1 in CD8 + T cells and programmed cell death protein ligand (PD-L)1 in tumor cells., Conclusions: These results indicate that doxorubicin with an ICD reaction promotes TLS formation and increases PD-1/PD-L1 expression in tumor tissues. The results demonstrate the development of a therapeutic avenue using combined immune checkpoint therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Zhao, Zhang, Wang, Yu, Dong, Yang, Zhang, Sun, Hao and Ren.)

Background: Mental disorders are largely socially determined, yet the combined impact of multidimensional social factors on the two most common mental disorders, depression and anxiety, remains unclear., Methods: We constructed a polysocial risk score (PsRS), a multidimensional social risk indicator including components from three domains: socioeconomic status, neighborhood and living environment and psychosocial factors. Supported by the UK Biobank cohort, we randomly divided 110 332 participants into the discovery cohort (60%; n = 66 200) and the replication cohort (40%; n = 44 134). We tested the associations between 13 single social factors with Patient Health Questionnaire (PHQ) score, Generalized Anxiety Disorder Scale (GAD) score and self-reported depression and anxiety. The significant social factors were used to calculate PsRS for each mental disorder by considering weights from the multivariable linear model. Generalized linear models were applied to explore the association between PsRS and depression and anxiety. Genome-wide environmental interaction study (GWEIS) was further performed to test the effect of interactions between PsRS and SNPs on the risk of mental phenotypes., Results: In the discovery cohort, PsRS was positively associated with PHQ score (β = 0.37; 95% CI = 0.35-0.38), GAD score (β = 0.27; 95% CI = 0.25-0.28), risk of self-reported depression (OR = 1.29; 95% CI = 1.28-1.31) and anxiety (OR = 1.19; 95% CI = 1.19-1.23). Similar results were observed in the replication cohort. Emotional stress, lack of social support and low household income were significantly associated with the development of depression and anxiety. GWEIS identified multiple candidate loci for PHQ score, such as rs149137169 (ST18) (P discovery  = 1.08 × 10 -8 , P replication  = 3.25 × 10 -6 ) and rs3759812 (MYO9A) (P discovery  = 3.87 × 10 -9 , P replication  = 6.21 × 10 -5 ). Additionally, seven loci were detected for GAD score, such as rs114006170 (TMPRSS11D) (P discovery  = 1.14 × 10 -9 , P replication  = 7.36 × 10 -5 ) and rs77927903 (PIP4K2A) (P discovery  = 2.40 × 10 -9 , P replication  = 0.002)., Conclusions: Our findings reveal the positive effects of multidimensional social factors on the risk of depression and anxiety. It is important to address key social disadvantage in mental health promotion and treatment., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2023 by the Journal of Global Health. All rights reserved.)

There is a strong link between irritable bowel syndrome and brain volumes, yet, to date, research examining the mediators of this association has been little. Based on the phenotypic data of 15 248 participants from the UK Biobank, a two-stage mediation analysis was performed to assess the association among brain volumes, anxiety, and irritable bowel syndrome. In the first stage, we identified the candidate mediating role of anxiety for irritable bowel syndrome associated with brain volumes using regression models. Then, we quantified the magnitude of the mediation effects by evaluating the average causal-mediated effect and proportion of mediation through performing mediation analyses in the R package in the second stage. In the first stage, we identified the partly mediating role of anxiety in the association between irritable bowel syndrome and the volume of thalamus ( P left = 1.16 × 10 -4 , P right = 2.41 × 10 -4 ), and grey matter ( P left = 3.22 × 10 -2 , P right = 1.18 × 10 -2 ) in the VIIIa cerebellum. In the second stage, we observed that the proportion of the total effect of irritable bowel syndrome on volume of thalamus mediated by anxiety was 14.3% for the left region ( β Average causal-mediated effect = -0.008, P Average causal-mediated effect = 0.004) and 14.6% for the right region ( β Average causal-mediated effect = -0.007, P Average causal-mediated effect = 0.006). Anxiety mediated 30.8% for the left region ( β Average causal-mediated effect = -0.013, P Average causal-mediated effect = 0.002) and 21.6% for the right region ( β Average causal-mediated effect = -0.010, P Average causal-mediated effect x= 0.018) of the total effect of irritable bowel syndrome on the volume of grey matter in the VIIIa cerebellum. Our study revealed the indirect mediating role of anxiety in the association between irritable bowel syndrome and brain volumes, promoting our understanding of the functional mechanisms of irritable bowel syndrome and its related psychosocial factors., Competing Interests: The authors declare that the publication of this paper has no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Vertigo is a leading symptom of various peripheral and central vestibular disorders. Although genome-wide association studies (GWASs) have identified multiple risk variants for vertigo, how these risk variants contribute to the risk of vertigo remains unknown. Discovery proteome-wide association study (PWAS) was first performed by integrating the protein quantitative trait loci from the dorsolateral prefrontal cortex (DLPFC) in the Banner Sun Health Research Institute dataset ( n = 152) and GWAS summary of vertigo ( n = 942 613), followed by replication PWAS using the protein quantitative trait loci from the DLPFC in Religious Orders Study or the Rush Memory and Aging Project dataset ( n = 376). Transcriptome-wide association studies (TWASs) were then performed by integrating the same GWAS datasets of vertigo ( n = 942 613) with mRNA expression reference from human fetal brain, and DLPFC. Chemical-related gene set enrichment analysis (GSEA) and Gene ontology/Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were finally conducted to further reveal the pathogenesis of vertigo. Permutation-based empirical P values were calculated in PWAS, TWAS, and GSEA. By integrating the GWAS of vertigo and two independent brain proteomes from human DLPFC, three genes were identified to genetically regulate protein abundance levels in vertigo, and were not previously implicated by GWAS, including MTERFD2 ( P Banner = 0.045, P ROSMAP = 0.031) , MGST1 ( P Banner = 0.014, P ROSMAP = 0.018), and RAB3B ( P Banner = 0.045, P ROSMAP = 0.035). Compared with TWAS results, we identified overlapping genes RAB3B ( P TWAS = 0.017) and MTERFD2 ( P TWAS = 0.003) that showed significant associations with vertigo at both proteome-wide and transcriptome-wide levels. Chemical-related GSEA identified multiple chemicals that might be associated with vertigo, such as nickel ( P = 0.007), glycidamide ( P = 0.005), and proanthocyanidins ( P = 0.015). Our study provides novel clues for understanding the biological mechanism of vertigo, and highlights several possible risks and therapeutic chemicals for vertigo., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Growing evidence supports that alterations in the gut microbiota play an essential role in the etiology of anxiety, depression, and other psychiatric disorders. However, the potential effect of oral microbiota on mental health has received little attention., Methods: Using the latest genome-wide association study (GWAS) summary data of the oral microbiome, polygenic risk scores (PRSs) of 285 salivary microbiomes and 309 tongue dorsum microbiomes were conducted. Logistic and linear regression models were applied to evaluate the relationship between salivary-tongue dorsum microbiome interactions with anxiety and depression. Two-sample Mendelian randomization (MR) was utilized to compute the causal effects between the oral microbiome, anxiety, and depression., Results: We observed significant salivary-tongue dorsum microbiome interactions related to anxiety and depression traits. Significantly, one common interaction was observed to be associated with both anxiety score and depression score, Centipeda periodontii SGB 224 × Granulicatella uSGB 3289 (P depressionscore = 1.41 × 10 -8 , P anxietyscore = 5.10 × 10 -8 ). Furthermore, we detected causal effects between the oral microbiome and anxiety and depression. Importantly, we identified one salivary microbiome associated with both anxiety and depression in both the UKB database and the Finngen public database, Eggerthia (P IVW - majordepression - UKB = 2.99 × 10 -6 , P IVW - Self - reportedanxiety/panicattacks - UKB = 3.06 × 10 -59 , P IVW - depression - Finngen = 3.16 × 10 , - 16 P IVW - anxiety - Finngen = 1.14 × 10 -115 )., Conclusion: This study systematically explored the relationship between the oral microbiome and anxiety and depression, which could help improve our understanding of disease pathogenesis and propose new diagnostic targets and early intervention strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Chen, Wen, Jia, Cheng, Liu, Zhang, Pan, Zhang, Zhang, Yang, Meng, Yao and Zhang.)

Background: T-2 toxin is recognized as one of the high-risk environmental factors for etiology and pathogenesis of Kashin-Beck disease (KBD). Previous evidence indicates decreased serum fluorine level in KBD patients. However, whether fluoride could regulate carboxylesterase 1 (CES1)-mediated T-2 toxin hydrolysis and alter its chondrocyte toxicity remains largely unknown., Methods: In this study, in vitro hydrolytic kinetics were explored using recombinant human CES1. HPLC-MS/MS was used to quantitative determination of hydrolytic metabolites of T-2 toxin. HepG2 cells were treated with different concentration of sodium fluoride (NaF). qRT-PCR and western blot analysis were used to compare the mRNA and protein expression levels of CES1. C28/I2 cells were treated with T-2 toxin, HT-2 toxin, and neosolaniol (NEO), and then cell viability was determined by MTT assay, cell apoptosis was determined by Annexin V-FITC/PI, Hoechst 33258 staining, and cleaved caspase-3, and cell cycle was monitored by flow cytometry assay, CKD4 and CDK6., Results: We identified that recombinant human CES1 was involved in T-2 toxin hydrolysis to generate HT-2 toxin, but not NEO, and NaF repressed the formation of HT-2 toxin. Both mRNA and protein expression of CES1 were significantly down-regulated in a dose-dependent manner after NaF treatment in HepG2 cells. Moreover, we evaluated the chondrocyte toxicity of T-2 toxin and its hydrolytic metabolites. Results showed that T-2 toxin induced strongest cell apoptosis, followed by HT-2 toxin and NEO. The decreased the proportion of cells in G0/G1 phase was observed with the descending order of T-2 toxin, HT-2 toxin, and NEO., Conclusions: This study reveals that CES1 is responsible for the hydrolysis of T-2 toxin, and that fluoride impairs CES1-mediated T-2 toxin detoxification to increase its chondrocyte toxicity. This study provides novel insight into understanding the relationship between fluoride and T-2 toxin in the etiology of KBD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jia, Shi, Cheng, Cheng, Liu, Meng, Yang, Chu, Wen, Zhang and Guo.)

Background: Despite cumulative evidence showing obesity is associated with changes in sleep quality and quantity, the study about the relationships between sleep and body composition is scarce, and whether the relationship is causal remains unknown. In this study, we examined whether there are causal associations between sleep and body composition., Methods: First, we estimated genetic correlations between sleep-related phenotypes and body composition using the linkage disequilibrium score regression (LDSC). Mendelian randomization (MR) analysis was then conducted to test 2-way causal relationships on phenotypes with significant genetic associations. Finally, Bayesian colocalization (COLOC) analysis was performed to calculate the posterior probability of causal variation and identify the common genes to verify the results of MR., Results: For the LDSC analysis, we observed some significant genetic correlations (rG), such as snoring and right leg fat mass (rG = 0.376, P = 7.21 × 10-80). For the MR analysis, we identified some significant causal relationships, such as snoring is the causal risk factor for whole-body fat-free mass (Pweighted median = 1.28 × 10-6, PMR-PRESSO = 1.35 × 10-7), dozing is the causal risk factor for right leg fat mass (Pweighted median = 9.22 × 10-4, PMR-PRESSO = 9.55 × 10-4), and right arm fat mass (Pweighted median = 1.11 × 10-40, PMR-PRESSO = 4.93 × 10-55) is the causal risk factor for snoring. For the COLOC analysis, we identified rs143384 mapping on GDF5 and 6 overlapped single nucleotide polymorphisms (eg, rs1421085, rs11642015) mapping on FTO., Conclusion: Our study identified the causal relationships between sleep-related phenotypes and body composition. These findings may give insights into the mechanism of sleep disturbances and provide novel therapeutic targets., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Depression is a debilitating mental disorder that often coexists with anxiety. The genetic mechanisms of depression and anxiety have considerable overlap, and studying depression in non-anxiety samples could help to discover novel gene. We assess the genetic variation of depression in non-anxiety samples, using genome-wide association studies (GWAS) and linkage disequilibrium score regression (LDSC)., Methods: The GWAS of depression score and self-reported depression were conducted using the UK Biobank samples, comprising 99,178 non-anxiety participants with anxiety score <5 and 86,503 non-anxiety participants without self-reported anxiety, respectively. Replication analysis was then performed using two large-scale GWAS summary data of depression from Psychiatric Genomics Consortium (PGC). LDSC was finally used to evaluate genetic correlations with 855 health-related traits based on the primary GWAS., Results: Two genome-wide significant loci for non-anxiety depression were identified: rs139702470 ( p  = 1.54 × 10 -8 , OR = 0.29) locate in PIEZO2 , and rs6046722 ( p  = 2.52 × 10 -8 , OR = 1.09) locate in CFAP61. These associated genes were replicated in two GWAS of depression from PGC, such as rs1040582 ( p replication GWAS1  = 0.02, p replication GWAS2  = 2.71 × 10 -3 ) in CFAP61 , and rs11661122 ( p replication GWAS1  = 8.16 × 10 -3 , p replication GWAS2  = 8.08 × 10 -3 ) in PIEZO2. LDSC identified 19 traits genetically associated with non-anxiety depression ( p  < 0.001), such as marital separation/divorce ( rg  = 0.45, SE = 0.15)., Conclusions: Our findings provide novel clues for understanding of the complex genetic architecture of depression.

Purpose: Most previous genetic studies of sleep behaviors were conducted individually, without comprehensive consideration of the complexity of various sleep behaviors. Our aim is to identify the genetic architecture and potential biomarker of the sleep health score, which more powerfully represents overall sleep traits., Patients and Methods: We conducted a genome-wide association study (GWAS) of sleep health score (overall assessment of sleep duration, snoring, insomnia, chronotype, and daytime dozing) using 336,463 participants from the UK Biobank. Proteome-wide association study (PWAS) and transcriptome-wide association study (TWAS) were then performed to identify candidate genes at the protein and mRNA level, respectively. We finally used linkage disequilibrium score regression (LDSC) to estimate the genetic correlations between sleep health score and other functionally relevance traits., Results: GWAS identified multiple variants near known candidate genes associated with sleep health score, such as MEIS1, FBXL13, MED20 and SMAD5. HDHD2 ( P PWAS = 0.0146) and GFAP ( P PWAS = 0.0236) were identified associated with sleep health score by PWAS. TWAS identified ORC4 ( P TWAS = 0.0212) and ZNF732 ( P TWAS = 0.0349) considering mRNA expression level. LDSC found significant genetic correlations of sleep health score with 3 sleep behaviors (including insomnia, snoring, dozing), 4 psychiatry disorders (major depressive disorder, attention deficit/hyperactivity disorder, schizophrenia, autism spectrum disorder), and 9 plasma protein (such as Stabilin-1, Stromelysin-2, Cytochrome c) (all LDSC P LDSC < 0.05)., Conclusion: Our results advance the comprehensive understanding of the aetiology and genetic architecture of the sleep health score, refine the understanding of the relationship of sleep health score with other traits and diseases, and may serve as potential targets for future mechanistic studies of sleep phenotype., Competing Interests: All authors declare that they have no competing interest., (© 2022 Yao et al.)

Aims: Despite the interest in the association of gut microbiota with bone health, limited population-based studies of gut microbiota and bone mineral density (BMD) have been made. Our aim is to explore the possible association between gut microbiota and BMD., Methods: A total of 3,321 independent loci of gut microbiota were used to calculate the individual polygenic risk score (PRS) for 114 gut microbiota-related traits. The individual genotype data were obtained from UK Biobank cohort. Linear regressions were then conducted to evaluate the possible association of gut microbiota with L1-L4 BMD (n = 4,070), total BMD (n = 4,056), and femur total BMD (n = 4,054), respectively. PLINK 2.0 was used to detect the single-nucleotide polymorphism (SNP) × gut microbiota interaction effect on the risks of L1-L4 BMD, total BMD, and femur total BMD, respectively., Results: We detected five, three, and seven candidate gut microbiota-related traits for L1-L4 BMD, total BMD, and femur BMD, respectively, such as genus Dialister (p = 0.004) for L1-L4 BMD, and genus Eisenbergiella (p = 0.046) for total BMD. We also detected two common gut microbiota-related traits shared by L1-L4 BMD, total BMD, and femur total BMD, including genus Escherichia Shigella and genus Lactococcus . Interaction analysis of BMD detected several genes that interacted with gut microbiota, such as phospholipase D1 ( PLD1 ) and endomucin ( EMCN ) interacting with genus Dialister in total BMD, and COL12A1 and Discs Large MAGUK Scaffold Protein 2 ( DLG2 ) interacting with genus Lactococcus in femur BMD., Conclusion: Our results suggest associations between gut microbiota and BMD, which will be helpful to further explore the regulation mechanism and intervention gut microbiota of BMD. Cite this article: Bone Joint Res  2021;10(11):734-741.

Glyceollin I, an induced phytoalexin isolated from soybean, has been reported to have various bioactivities, including anti-bacterial, anti-nematode, anti-fungal, anti-estrogenic and anti-cancer, anti-oxidant, anti-inflammatory, insulin sensitivity enhancing, and attenuation of vascular contractions. Here we show that glyceollin I has hormesis and extends yeast life span at low (nM) doses in a calorie restriction (CR)-dependent manner, while it reduces life span and inhibits yeast cell proliferation at higher (μM) doses. In contrast, the other two isomers (glyceollin II and III) cannot extend yeast life span and only show life span reduction and antiproliferation at higher doses. Our results in anti-aging activity indicate that glyceollin I might be a promising calorie restriction mimetic candidate, and the high content of glyceollins could improve the bioactivity of soybean as functional food ingredients.