Corrigendum: Intratumor tertiary lymphatic structure evaluation predicts the prognosis and immunotherapy response of patients with colorectal cancer.

[This corrects the article DOI: 10.3389/fimmu.2024.1302903.].

An atlas of causal association between micronutrients and osteoarthritis.

OBJECTIVE: This study examines the causal relationships between serum micronutrients and site-specific osteoarthritis (OA) using Mendelian Randomization (MR). METHODS: This study performed a two-sample MR analysis to explore causal links between 21 micronutrients and 11 OA outcomes. These outcomes encompass overall OA, seven site-specific manifestations, and three joint replacement subtypes. Sensitivity analyses using MR methods, such as the weighted median, MR-Egger, and MR-PRESSO, assessed potential horizontal pleiotropy and heterogeneity. Genome-wide association summary statistical data were utilized for both exposure and outcome data, including up to 826,690 participants with 177,517 OA cases. All data was sourced from Genome-wide association studies datasets from 2009 to 2023. RESULTS: In the analysis of associations between 21 micronutrients and 11 OA outcomes, 15 showed Bonferroni-corrected significance (P < 0.000216), without significant heterogeneity or horizontal pleiotropy. Key findings include strong links between gamma-tocopherol and spine OA (OR = 1.70), and folate with hand OA in finger joints (OR = 1.15). For joint replacements, calcium showed a notable association with a reduced likelihood of total knee replacement (TKR) (OR = 0.52) and total joint replacement (TJR) (OR = 0.56). Serum iron was significantly associated with an increased risk of total hip replacement (THR) (OR = 1.23), while folate indicated a protective effect (OR = 0.95). Various sex-specific associations were also uncovered. CONCLUSION: These findings underscore the critical role of micronutrients in osteoarthritis, providing valuable insights for preventive care and potential enhancement of treatment outcomes.

Micronutrient-Associated Single Nucleotide Polymorphism and Mental Health: A Mendelian Randomization Study.

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.

The anti-tumor effect of extracellular vesicles derived from cytokine-activated CD8+ T cells.

Extracellular vesicles (EVs) are the nano-sized membrane particles secreted by various cell types, which are involved in many important cellular processes. Recently, EVs originating from immune cells, such as dendritic cells, chimeric antigen receptor T cells (CAR-T) and natural killer cells, have attracted much attention because of their known direct and indirect antitumor activity. Here, we report the EVs released by cytokine-activated CD8 + T cells (caCD8) and its cytotoxicity against cancer cells. CaCD8 cells can release EVs following stimulation of CD8+ T cells with an anti-CD3 antibody and a cytokines cocktail ex vivo. The isolated vesicles have typical EV characteristics, such as an oval shape and a size distribution between 30-200 nm, as well as CD81 expression. Notably, caCD8-EVs displayed cytotoxicity against various cancer cells in vitro. Furthermore, mechanism analysis demonstrates that caCD8-EVs not only contain typical cytotoxic proteins (i.e., granzyme B and perforin), but also significantly enrich IFNγ compared to caCD8 cells. The EVs-derived IFNγ participates in EVs-induced apoptosis in cancer cells. Therefore, our data reveal an antitumor effects of EVs secreted from caCD8 cells and the potential role of the EVs-derived IFNγ.

A genome-wide association study identifies candidate genes for sleep disturbances in depressed individuals.

OBJECTIVE: This study aimed to identify candidate loci and genes related to sleep disturbances in depressed individuals and clarify the co-occurrence of sleep disturbances and depression from the genetic perspective. METHODS: The study subjects (including 58,256 self-reported depressed individuals and 6,576 participants with PHQ-9 score ≥ 10, respectively) were collected from the UK Biobank, which were determined based on the Patient Health Questionnaire (PHQ-9) and self-reported depression status, respectively. Sleep related traits included chronotype, insomnia, snoring and daytime dozing. Genome-wide association studies (GWASs) of sleep related traits in depressed individuals were conducted by PLINK 2.0 adjusting age, sex, Townsend deprivation index and 10 principal components as covariates. The CAUSALdb database was used to explore the mental traits associated with the candidate genes identified by the GWAS. RESULTS: GWAS detected 15 loci significantly associated with chronotype in the subjects with self-reported depression, such as rs12736689 at RNASEL (P = 1.00 × 10- 09), rs509476 at RGS16 (P = 1.58 × 10- 09) and rs1006751 at RFX4 (P = 1.54 × 10- 08). 9 candidate loci were identified in the subjects with PHQ-9 ≥ 10, of which 2 loci were associated with insomnia such as rs115379847 at EVC2 (P = 3.50 × 10- 08), and 7 loci were associated with daytime dozing, such as rs140876133 at SMYD3 (P = 3.88 × 10- 08) and rs139156969 at ROBO2 (P = 3.58 × 10- 08). Multiple identified genes, such as RNASEL, RGS16, RFX4 and ROBO2 were reported to be associated with chronotype, depression or cognition in previous studies. CONCLUSION: Our study identified several candidate genes related to sleep disturbances in depressed individuals, which provided new clues for understanding the biological mechanism underlying the co-occurrence of depression and sleep disorders.

Intratumor tertiary lymphatic structure evaluation predicts the prognosis and immunotherapy response of patients with colorectal cancer.

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.

Mendelian randomization study of the relationship between blood and urine biomarkers and schizophrenia in the UK Biobank cohort.

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.

People with schizophrenia experience periods of time during which they misperceive reality. Some people with schizophrenia do not respond well to the usual drugs that are used to relieve their symptoms. This type of schizophrenia is known as treatment-resistant schizophrenia (TRS). We looked at differences in the genes (inherited characteristics), blood and urine of a group of people in the UK with schizophrenia to see if people with TRS have particular characteristics that would enable them to be distinguished from patients with schizophrenia who tend to respond to usual treatment. We found several differences in the blood that could be used to predict which people might get TRS, including some that were specific to men or women. These discoveries are important because they can help doctors identify people who are more likely to develop TRS earlier, enabling them to avoid using treatments that might not work well for them.

Enhanced polygenic risk score incorporating gene-environment interaction suggests the association of major depressive disorder with cardiac and lung function.

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 (ß = -0.037, FDR = 1.00 × 10-8), contrasting with no significant association with PRS (ß = -0.002, FDR = 0.943). In drinkers, we observed a positive association between cardiac index with PGIRS (ß = 0.088, FDR = 0.010), whereas no such association was found with PRS (ß = 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 (ß = -0.042, FDR = 6.30 × 10-9), but not with PRS (ß = -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.

Effects of immunogenic cell death-inducing chemotherapeutics on the immune cell activation and tertiary lymphoid structure formation in melanoma.

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 (TRM) 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.

Immune checkpoint ligands expressed on mature high endothelial venules predict poor prognosis of NSCLC: have a relationship with CD8+ T lymphocytes infiltration.

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 ICLtotal 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 ICLtotal score > 1 represent a weak CD8+ T cell infiltration and a high ICLtotal 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.

Long-term ambient air pollution and the risk of musculoskeletal diseases: A prospective cohort study.

Evidence of the associations of air pollution and musculoskeletal diseases is inconsistent. This study aimed to examine the associations between air pollutants and the risk of incident musculoskeletal diseases, such as degenerative joint diseases (n = 38,850) and inflammatory arthropathies (n = 20,108). An air pollution score was constructed to assess the combined effect of PM2.5, PM2.5-10, NO2, and NOX. Cox proportional hazard model was applied to assess the relationships between air pollutants and the incidence of each musculoskeletal disease. The air pollution scores exhibited the modest association with an increased risk of osteoporosis (HR = 1.006, 95% CI: 1.002-1.011). Among the individual air pollutants, PM2.5 and PM2.5-10 exhibited the most significant effect on elevated risk of musculoskeletal diseases, such as PM2.5 on osteoporosis (HR = 1.064, 95% CI: 1.020-1.110), PM2.5-10 on inflammatory arthropathies (HR = 1.059, 95% CI: 1.037-1.081). Females were found to have a higher risk of incident musculoskeletal diseases when exposed to air pollutants. Individuals with extreme BMI or lower socioeconomic status had a higher risk of developing musculoskeletal diseases. Our findings reveal that long-term exposure to ambient air pollutants may contribute to an increased risk of musculoskeletal diseases.

Associations of classical HLA alleles with depression and anxiety.

Immune dysregulation has been widely observed in patients with psychiatric disorders. This study aims to examine the association between HLA alleles and depression and anxiety. Using data from the UK Biobank, we performed regression analyses to assess the association of 359 HLA alleles with depression and anxiety, as determined by Patient Health Questionnaire (PHQ) score (n = 120,033), self-reported depression (n = 121,685), general anxiety disorder (GAD-7) score (n = 120,590), and self-reported anxiety (n = 108,310). Subsequently, we conducted gene environmental interaction study (GEIS) to evaluate the potential effects of interactions between HLA alleles and environmental factors on the risk of depression and anxiety. Sex stratification was implemented in all analysis. Our study identified two significant HLA alleles associated with self-reported depression, including HLA-C*07:01 (ß = -0.015, p = 5.54 × 10-5 ) and HLA-B*08:01 (ß = -0.015, p = 7.78 × 10-5 ). Additionally, we identified four significant HLA alleles associated with anxiety score, such as HLA-DRB1*07:01 (ß = 0.084, p = 9.28 × 10-5 ) and HLA-B*57:01 (ß = 0.139, p = 1.22 × 10-4 ). GEIS revealed that certain HLA alleles interacted with environmental factors to influence mental health outcomes. For instance, HLA-A*02:07 × cigarette smoking was associated with depression score (ß = 0.976, p = 1.88 × 10-6 ). Moreover, sex stratification analysis revealed significant sex-based differences in the interaction effects of certain HLA alleles with environmental factors. Our findings indicate the considerable impact of HLA alleles on the risks of depression and anxiety, providing valuable insights into the functional relevance of immune dysfunction in these conditions.

Interplay of IL-33 and IL-35 Modulates Th2/Th17 Responses in Cigarette Smoke Exposure HDM-Induced Asthma.

Cigarette smoke (CS) facilitates adverse effects on the airway inflammation and treatment of asthma. Here, we investigated the mechanisms by which CS exacerbates asthma. The roles of IL-33 and IL-35 in asthma development were examined by treatment with IL-33 knockout (IL-33 KO) or transfection of adenovirus encoding IL-35 (Ad-IL-35) in a murine model of cigarette smoke-exposure asthma. Furthermore, the involvement of IL-33 and IL-35 in regulating DCs and Th2/Th17 cells was examined in a coculture system of DCs with CD4+ T cells. Additionally, we observed the effect of CpG-ODNs on the balance of IL-33 and IL-35. We show that CS and house dust mite (HDM) exposure induced IL-33 and suppressed IL-35 levels in cigarette smoke-exposure asthma in vivo and in vitro. Treatment with IL-33 KO or Ad-IL-35 significantly attenuated airway hyperreactivity, goblet hyperplasia, airway remodelling, and eosinophil and neutrophil infiltration in the lung tissues from asthmatic mice. Furthermore, we demonstrated reciprocal regulation between CS and HDM-modulated IL-33 and IL-35. Mechanistically, IL-33 KO (or anti-ST2) and Ad-IL-35 attenuated Th2- and Th17-associated inflammation by downregulating TSLP-DC signalling. Finally, administration of CpG-ODNs suppressed the expression of IL-33/ST2 and elevated the levels of IL-35, which is mainly derived from CD4+Foxp+ Tregs, to alleviate Th2- and Th17-associated inflammation by inhibiting the activation of BMDCs. Taken together, the IL-33/ST2 pathway drives the DC-Th2 and Th17 responses of cigarette smoke-exposure asthma, while IL-35 has the opposite effect. CpG-ODNs represent a potential therapeutic strategy for modulating the balance of IL-33 and IL-35 to suppress allergic airway inflammation.

Identification of novel rare variants for anxiety: an exome-wide association study in the UK Biobank.

BACKGROUND: Rare variants are believed to play a substantial role in the genetic architecture of mental disorders, particularly in coding regions. However, limited evidence supports the impact of rare variants on anxiety. METHODS: Using whole-exome sequencing data from 200,643 participants in the UK Biobank, we investigated the contribution of rare variants to anxiety. Firstly, we computed genetic risk score (GRS) of anxiety utilizing genotype data and summary data from a genome-wide association study (GWAS) on anxiety disorder. Subsequently, we identified individuals within the lowest 50% GRS, a subgroup more likely to carry pathogenic rare variants. Within this subgroup, we classified individuals with the highest 10% 7-item Generalized Anxiety Disorder scale (GAD-7) score as cases (N = 1869), and those with the lowest 10% GAD-7 score were designated as controls (N = 1869). Finally, we conducted gene-based burden tests and single-variant association analyses to assess the relationship between rare variants and anxiety. RESULTS: Totally, 47,800 variants with MAF ≤0.01 were annotated as non-benign coding variants, consisting of 42,698 nonsynonymous SNVs, 489 nonframeshift substitution, 236 frameshift substitution, 617 stop-gain and 40 stop-loss variants. After variation aggregation, 5066 genes were included in gene-based association analysis. Totally, 11 candidate genes were detected in burden test, such as RNF123 (PBonferroni adjusted = 3.40 × 10-6), MOAP1(PBonferroni adjusted = 4.35 × 10-4), CCDC110 (PBonferroni adjusted = 5.83 × 10-4). Single-variant test detected 9 rare variants, such as rs35726701(RNF123)(PBonferroni adjusted = 3.16 × 10-10) and rs16942615(CAMTA2) (PBonferroni adjusted = 4.04 × 10-4). Notably, RNF123, CCDC110, DNAH2, and CSKMT gene were identified in both tests. CONCLUSIONS: Our study identified novel candidate genes for anxiety in protein-coding regions, revealing the contribution of rare variants to anxiety.

A multidimensional social risk atlas of depression and anxiety: An observational and genome-wide environmental interaction study.

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 (ß = 0.37; 95% CI = 0.35-0.38), GAD score (ß = 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) (Pdiscovery = 1.08 × 10-8, Preplication = 3.25 × 10-6) and rs3759812 (MYO9A) (Pdiscovery = 3.87 × 10-9, Preplication = 6.21 × 10-5). Additionally, seven loci were detected for GAD score, such as rs114006170 (TMPRSS11D) (Pdiscovery = 1.14 × 10-9, Preplication = 7.36 × 10-5) and rs77927903 (PIP4K2A) (Pdiscovery = 2.40 × 10-9, Preplication = 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.

Insight into the Causal Relationship between Gut Microbiota and Back Pain: A Two Sample Bidirectional Mendelian Randomization Study.

Observational studies have shown that alterations in gut microbiota composition are associated with low back pain. However, it remains unclear whether the association is causal. To reveal the causal association between gut microbiota and low back pain, a two-sample bidirectional Mendelian randomization (MR) analysis is performed. The inverse variance weighted regression (IVW) is performed as the principal MR analysis. MR-Egger and Weighted Median is further conducted as complementary analysis to validate the robustness of the results. Finally, a reverse MR analysis is performed to evaluate the possibility of reverse causation. The inverse variance weighted (IVW) method suggests that Peptostreptococcaceae (odds ratio [OR] 1.056, 95% confidence interval [CI] [1.015-1.098], P IVW = 0.010), and Lactobacillaceae (OR 1.070, 95% CI [1.026-1.115], P IVW = 0.003) are positively associated with back pain. The Ruminococcaceae (OR 0.923, 95% CI [0.849-0.997], P IVW = 0.033), Butyricicoccus (OR 0.920, 95% CI [0.868 - 0.972], P IVW = 0.002), and Lachnospiraceae (OR 0.948, 95% CI [0.903-0.994], P IVW = 0.022) are negatively associated with back pain. In this study, underlying causal relationships are identified among gut microbiota and low back pain. Notably, further research is needed on the biological mechanisms by which gut microbiota influences low back pain.

Single-cell transcriptomics reveals tumor-infiltrating B cell function after neoadjuvant pembrolizumab and chemotherapy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most pervasive lung cancer subtype. Recent studies have shown that immune checkpoint inhibitors achieved favorable clinical benefits in resectable NSCLC; however, the associated mechanism remains unclear. The role of T cells in antitumor immunity has received considerable attention, while the antitumor effects of tumor-infiltrating B cells (TIBs) in NSCLC remain poorly understood. Here, we conducted a single-cell RNA-seq analysis of immune cells isolated from 12 patients with IIIA NSCLC to investigate B cell subtypes and their functions following neoadjuvant chemoimmunotherapy. We confirmed the simultaneous existence of the four B cell subtypes. Among them, memory B cells were found to be associated with a positive therapeutic effect to neoadjuvant chemoimmunotherapy. Furthermore, we found that G Protein-Coupled Receptor 183 (GPR183) was most prevalent in memory B cells and associated with a positive therapeutic response. Multiplex immunofluorescence and flow cytometry experiments in an additional cohort of 22 treatment-naïve and 30 IIIA/IIIB NSCLC patients treated with neoadjuvant chemoimmunotherapy verified these findings. Overall, our analysis revealed the functions of TIBs and their potential effect on clinical treatment in NSCLC.

Dissecting the Association between Gut Microbiota and Brain Structure Change Rate: A Two-Sample Bidirectional Mendelian Randomization Study.

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.

Epigenetic analysis suggests aberrant cerebellum brain aging in old-aged adults with autism spectrum disorder and schizophrenia.

The aberrant aging hypothesis of schizophrenia (SCZ) and autism spectrum disorder (ASD) has been proposed, and the DNA methylation (DNAm) clock, which is a cumulative evaluation of DNAm levels at age-related CpGs, could serve as a biological aging indicator. This study evaluated epigenetic brain aging of ASD and SCZ using Horvath's epigenetic clock, based on two public genome-wide DNA methylation datasets of post-mortem brain samples (NASD = 222; NSCZ = 142). Total subjects were further divided into subgroups by gender and age. The epigenetic age acceleration (AgeAccel) for each sample was calculated as the residual value resulting from the regression model and compared between groups. Results showed DNAm age has a strong correlation with chronological age in both datasets across multiple brain regions (P < 0.05). When divided into equally sized age groups, the AgeAccel of the cerebellum (CB) region from people over 45 years of age was greater compared to the control sample (AgeAccel of ASD vs control: 5.069 vs -6.249; P < 0.001). And a decelerated epigenetic aging process was observed in the CB region of individuals with SCZ aged 50-70 years (AgeAccel of SCZ vs control: -3.171 vs 2.418; P < 0.05). However, our results showed no significant difference in AgeAccel between ASD and control groups, and between SCZ and control groups in the total and gender-specific groups (P > 0.05). This study's results revealed some evidence for aberrant epigenetic CB brain aging in old-aged patients with ASD and SCZ, indicating a different pattern of CB aging in older adults with these two diseases. However, further studies of larger ASD and SCZ cohorts are necessary to make definitive conclusions on this observation.

Mitochondria-wide association study observed significant interactions of mitochondrial respiratory and the inflammatory in the development of anxiety and depression.

The aim of this study was to investigate the possible interaction of mitochondrial dysfunction and inflammatory cytokines in the risk of anxiety and depression. We utilized the UK Biobank for the sample of this study. A mitochondria-wide association(MiWAS) and interaction analysis was performed to investigate the interaction effects of mitochondrial DNA (mtDNA)×C-reactive protein (CRP) on the risks of self-reported anxiety (N = 72,476), general anxiety disorder (GAD-7) scores (N = 80,853), self-reported depression (N = 80,778), Patient Health Questionnaire (PHQ-9) scores (N = 80,520) in total samples, females and males, respectively, adjusting for sex, age, Townsend deprivation index (TDI), education score, alcohol intake, smoking and 10 principal components. In all, 25 mtSNPs and 10 mtSNPs showed significant level of association with self-reported anxiety and GAD-7 score respectively. A total of seven significant mtDNA × CRP interactions were found for anxiety, such as m.3915G>A(MT-ND1) for self-reported anxiety in total subjects (P = 6.59 × 10-3), m.4561T>C(MT-ND2) (P = 3.04 × 10-3) for GAD-7 score in total subjects. For depression, MiWAS identified 17 significant mtSNPs for self-reported depression and 14 significant mtSNPs for PHQ-9 scores. 17 significant mtDNA associations (2 for self-reported depression and 15 for PHQ-9 score) was identified, such as m.14869G>A(MT-CYB; P = 2.22 × 10-3) associated with self-reported depression and m.4561T>C (MT-ND2; P value = 3.02 × 10-8) associated with PHQ-9 score in all subjects. In addition, 5 common mtDNA shared with anxiety and depression were found in MiWAS, and 4 common mtDNA variants were detected to interact with CRP for anxiety and depression, such as m.9899T>C(MT-CO3). Our study suggests the important interaction effects of mitochondrial function and CRP on the risks of anxiety and depression.