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.

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.

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.

Assessing the effect of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes.

Longitudinal changes in brain structure and lifestyle can affect sleep phenotypes. However, the influence of the interaction between longitudinal changes in brain structure and lifestyle on sleep phenotypes remains unclear. Genome-wide association study dataset of longitudinal changes in brain structure was obtained from published study. Phenotypic data of lifestyles and sleep phenotypes were obtained from UK Biobank cohort. Using genotype data from UK Biobank, we calculated polygenetic risk scores of longitudinal changes in brain structure phenotypes. Linear/logistic regression analysis was conducted to evaluate interactions between longitudinal changes in brain structure and lifestyles on sleep duration, chronotype, insomnia, snoring and daytime dozing. Multiple lifestyle × longitudinal changes in brain structure interactions were detected for 5 sleep phenotypes, such as physical activity×caudate_age2 for daytime dozing (OR = 1.0389, P = 8.84 × 10-3) in total samples, coffee intake×cerebellar white matter volume_age2 for daytime dozing (OR = 0.9652, P = 1.13 × 10-4) in females. Besides, we found 4 overlapping interactions in different sleep phenotypes. We conducted sex stratification analysis and identified one overlapping interaction between female and male. Our results support the moderate effects of interaction between lifestyle and longitudinal changes in brain structure on sleep phenotypes, and deepen our understanding of the pathogenesis of sleep disorders.

Assessing the interaction effects of brain structure longitudinal changes and life environmental factors on depression and anxiety.

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.

Exome-wide screening identifies novel rare risk variants for major depression disorder.

Despite thousands of common genetic loci of major depression disorders (MDD) have been identified by GWAS to date, a large proportion of genetic variation predisposing to MDD remains unaccounted for. By utilizing the newly released UK Biobank 200,643 exome dataset, we conducted an exome-wide association study to identify rare risk variants contributing to MDD. After quality control, 120,033 participants with MDD polygenic risk scores (PRS) values were included. The individuals with lower 30% quantile of the PRS value were filtered for case and control selecting. Then the cases were set as the individuals with upper 10% quantile of the PHQ depression score and lower 10% quantile were set as controls. Finally, 1612 cases and 1612 controls were included in this study. The variants were annotated by ANNOVRA software. After exclusions, 34,761 qualifying variants, including 148 frameshift variant, 335 non-frameshift variant, 33,758 nonsynonymous, 91 start-loss, 393 stop-gain, 36 stop-loss variants were imported into the SKAT R-package to perform single variants, gene-based burden and robust burden tests with minor allele frequency (MAF) < 0.01. Single variant association testing identified one variant, rs4057749 (P = 5.39 × 10-9), within OR8B4 gene at an exome-wide significance level. The gene-based burden test of the exonic variants identified genome-wide significant associations in OR8B4 (PSKAT = 6.23 × 10-5, PSKAT Robust = 4.49 × 10-5), TRAPPC11 (PSKAT = 0.014, PSKAT Robust = 0.015), SBK3 (PSKAT = 0.020, PSKAT Robust = 0.025) and TNRC6B (PSKAT = 0.026, PSKAT Robust = 0.036). We identified multiple novel rare risk variants contributing to MDD in the individuals with lower PRS of MDD. The findings can help to broaden the genetic insights of the MDD pathogenesis.

Treatment Resistance in Schizophrenia Is Associated with Attention Deficit/Hyperactivity Disorder and Gut Microbiota: A Genetic Correlation and Mendelian Randomization Study.

INTRODUCTION: Observational studies highlight associations of common diseases with individual schizophrenia symptoms. However, it is unclear whether these diseases are associated with individual treatment-resistant schizophrenia (TRS). We aimed to explore the genetic associations between common immune diseases, metabolic diseases, psychiatric disorders, gut microbiota and TRS. METHODS: Genome-wide association study (GWAS) summary data of European participants (n = ∼456,327) included TRS, 11 psychiatric disorders, 23 immune and metabolic diseases, body mass index, height, and 211 gut microbiota. In this genetic correlation and two-sample Mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with common immune diseases, metabolic diseases, psychiatric disorders, and gut microbiota with TRS. RESULTS: LDSC revealed candidate associations between attention deficit/hyperactivity disorder (ADHD), schizophrenia, intestinal infectious diseases, obesity and TRS (genetic correlation range, 0.230-0.702; p < 0.05). Two-sample MR analyses suggested that ADHD was positively associated with TRS (estimate [SE] = 0.204 [0.073], p = 0.005), a finding that remained stable across statistical models. Besides, schizophrenia and genus Barnesiella levels were causally associated with TRS but not consistent across MR approaches. CONCLUSION: This study reports genetic correlations between ADHD, schizophrenia, intestinal infectious diseases, obesity and TRS. The study also found that genus Barnesiella was associated with TRS. These findings may have clinical implications, highlighting the possible strategy for TRS prevention.

Maternal smoking around birth may lower the protective effects of breastfeeding on anxiety, depression and neuroticism in adult offspring: a UK biobank study.

We aim to explore the combined effects of the smoking and breastfeeding on offspring mental health outcomes. We used data from UK biobank (N = 342,846) to evaluate joint effect of breastfeeding and maternal smoke during pregnancy (MSDP) on seven adult offspring mental health outcomes (self-reported depression, depression score, self-reported anxiety, anxiety score, neuroticism score, self-harm, suicide). We stratified individuals to MSDP group and non-MSDP group as well as breastfeeding group and non-breastfeeding group. Multiple linear regression and logistic regressions analysis were performed between independent variables (MSDP or breastfeeding) and dependent variables separately (seven mental health outcomes) in each stratum. Effect estimates were expressed as ß values and OR values. Sex, age, 10 principle components of population structure, smoking, alcohol use, and Townsend deprivation index were examined as covariates. At MSDP grouping level, coefficients (odds ratio [OR]) for association of breastfed as a baby with self-reported anxiety (category variable) were 0.87 (95%CI, (0.82-0.93), P = 1.74 × 10-5) in the MSDP group and 0.83 (95%CI, (0.79-0.87), P = 2.76 × 10-17) in the non-MSDP group. At breastfeeding grouping level, OR for association of MSDP and self-reported anxiety were 1.15 (95%CI, (1.10-1.20), P = 5.36 × 10-11) in breastfeeding group and 1.12(95%CI, (1.06-1.20), P = 2.02 × 10-4) in non-breastfeeding group. At MSDP grouping level, negatively associations were found for breastfeeding and anxiety score (continuable variable) in MSDP group (-0.04 SD change per SD change in MSDP, 95% CI, (- 0.06, - 0.02), P = 2.42 × 10-3) and non-MSDP group (-0.06 SD change per SD change in MSDP, 95%CI, (- 0.07, - 0.04), P = 1.70 × 10-11). At breastfeeding grouping level, positive association was found for MSDP and anxiety score in the breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.06-0.09), P = 1.49 × 10-20) and non-breastfeeding group (0.07 SD change per SD change in MSDP, 95%CI, (0.05-0.09), P = 7.19 × 10-8). Compared with non-MSDP group, the protective effect (reflected by coefficients) of breastfeeding on anxiety in the MSDP decreased. Our preliminary study found MSDP may lower the protective effect of breastfeeding on the adult offspring anxiety, depression and neuroticism, providing useful recommendations for health care service via quitting smoking during pregnancy and encouraging prolonged breastfeeding.

A CpG-Oligodeoxynucleotide Suppresses Th2/Th17 Inflammation by Inhibiting IL-33/ST2 Signaling in Mice from a Model of Adoptive Dendritic Cell Transfer of Smoke-Induced Asthma.

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.

Association between gut microbiota and longevity: a genetic correlation and mendelian randomization study.

BACKGROUND: Longevity is one of the most complex phenotypes, and its genetic basis remains unclear. This study aimed to explore the genetic correlation and potential causal association between gut microbiota and longevity. RESULTS: Linkage disequilibrium score (LDSC) regression analysis and a bi-directional two-sample Mendelian Randomization (MR) analysis were performed to analyze gut microbiota and longevity-related traits. LDSC analysis detected four candidate genetic correlations, including Veillonella (genetic correlation = 0.5578, P = 4.67 × 10- 2) and Roseburia (genetic correlation = 0.4491, P = 2.67 × 10- 2) for longevity, Collinsella (genetic correlation = 0.3144, P = 4.07 × 10- 2) for parental lifespan and Sporobacter (genetic correlation = 0.2092, P = 3.53 × 10- 2) for healthspan. Further MR analysis observed suggestive causation between Collinsella and parental longevity (father's age at death) (weighted median: b = 1.79 × 10- 3, P = 3.52 × 10- 2). Reverse MR analysis also detected several causal effects of longevity-related traits on gut microbiota, such as longevity and Sporobacter (IVW: b = 7.02 × 10- 1, P = 4.21 × 10- 25). Statistical insignificance of the heterogeneity test and pleiotropy test supported the validity of the MR study. CONCLUSION: Our study found evidence that gut microbiota is causally associated with longevity, or vice versa, providing novel clues for understanding the roles of gut microbiota in aging development.

An eQTL variant of ALDH1A2 is associated with Kashin-Beck disease in Chinese population.

INTRODUCTION: The aims of the study were to investigate the relationship between aldehyde dehydrogenase 1 family member A2 (ALDH1A2) and Kashin-Beck disease (KBD), explore the effects of the rs3204689 polymorphism and methylation status on the expression levels of ALDH1A2, and further clarify the pathogenesis of KBD. MATERIALS AND METHODS: The genotype of ALDH1A2 rs3204689 was detected by PCR-RFLP in 103 KBD patients and 109 healthy controls in the whole blood. The mRNA level of ALDH1A2 was measured by qRT-PCR, and the protein expression was detected using IHC staining and Western blotting. The MSP-PCR was used to identify the ALDH1A2 methylation level. RESULTS: There were significant differences in G/G, G/C, and C/C frequencies of ALDH1A2 rs3204689 between the KBD and control groups (χ2 = 7.113, P = 0.029); the minor allele G of ALDH1A2 was associated with the risk of KBD (χ2 = 5.984, P = 0.014). The mRNA and protein levels of ALDH1A2 were increased in the whole blood and cartilage of KBD patients compared with the controls (P = 0.049, P < 0.0001, P = 0.019). Meanwhile, a statistically significant difference was observed between G/G, G/C and C/C genotype on mRNA expression (P = 0.039). The methylation level of the ALDH1A2 gene promoter region showed no significant difference between the KBD and control groups (χ2 = 0.317, P = 0.573). CONCLUSION: Our case-control study indicates that the common variant rs3204689 near ALDH1A2 is associated with KBD in Chinese population. The risk allele G of rs3204689 is statistically linked to the high expression of ALDH1A2, which is up-regulated in the cartilage and whole blood of KBD patients. Our findings suggest a potential role of ALDH1A2 in the pathogenesis of KBD.

Crosstalk between CpG Methylation and Polymorphisms (CpG-SNPs) in the Promotor Region of DIO2 in Kashin-Beck Disease.

Objective This study was designed to determine the methylation profile of four CpGs and the genotypes of two CpG-SNPs located in promoter region of DIO2 in patients with Kashin-Beck disease (KBD). We also analyzed the interaction between the CpGs methylations and CpG-SNPs. Methods Whole blood specimens were collected from 16 KBD patients and 16 healthy subjects. Four CpGs and two CpG-SNPs in the promoter regions of DIO2 were detected using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The CpGs methylation levels were compared between samples from KBD patients and healthy subjects. The methylation levels were also analyzed in KBD patients with different CpG-SNP genotypes. Results The mRNA expression of DIO2 in whole blood of KBD patients was significnatly lower than in healthy controls (P <0.05). The methylation levels of DIO2-1_CpG_3 in KBD patients were significantly higher than those in healthy controls (P <0.05). The methylation levels of four CpGs were not significantly different between KBD patients and healthy controls. The methylation level of DIO2-1_CpG_3 in the promoter region of DIO2 in KBD patients with GA/AA genotype was significantly higher than that of KBD patients with GG genotype (P <0.05). Conclusion The methylation level of DIO2 increases in KBD patients. Similar trends exist in KBD carriers of variant genotypes of CpG-SNPs DIO2 rs955849187.

Dissecting the association between psychiatric disorders and neurological proteins: a genetic correlation and two-sample bidirectional Mendelian randomization study.

OBJECTIVES: The role of neurological proteins in the development of bipolar disorder (BD) and schizophrenia (SCZ) remains elusive now. The current study aims to explore the potential genetic correlations of plasma neurological proteins with BD and SCZ. METHODS: By using the latest genome-wide association study (GWAS) summary data of BD and SCZ (including 41,917 BD cases, 11,260 SCZ cases, and 396,091 controls) derived from the Psychiatric GWAS Consortium website (PGC) and a recently released GWAS of neurological proteins (including 750 individuals), we performed a linkage disequilibrium score regression (LDSC) analysis to detect the potential genetic correlations between the two common psychiatric disorders and each of the 92 neurological proteins. Two-sample Mendelian randomisation (MR) analysis was then applied to assess the bidirectional causal relationship between the neurological proteins identified by LDSC, BD and SCZ. RESULTS: LDSC analysis identified one neurological protein, NEP, which shows suggestive genetic correlation signals for both BD (coefficient = -0.165, p value = 0.035) and SCZ (coefficient = -0.235, p value = 0.020). However, those association did not remain significant after strict Bonferroni correction. Two sample MR analysis found that there was an association between genetically predicted level of NEP protein, BD (odd ratio [OR] = 0.87, p value = 1.61 × 10-6) and SCZ (OR = 0.90, p value = 4.04 × 10-6). However, in the opposite direction, there is no genetically predicted association between BD, SCZ, and NEP protein level. CONCLUSION: This study provided novel clues for understanding the genetic effects of neurological proteins on BD and SCZ.

Effects of methylation of deiodinase 3 gene on gene expression and severity of Kashin-Beck disease.

Kashin-Beck disease (KBD) is a complex endemic osteoarthropathy, which mainly occurs in the northeast to southwest China. Iodothyronine deiodinases 3 (DIO3) is one of the selenoproteins, which is closely related to bone metabolism and unclear to KBD. This study aims to investigate the role and associated mechanisms of methylation and expression of DIO3 with disease severity in patients with KBD. We performed a bioinformatics analysis first to identify the biological mechanisms involved in selenoproteins. The methylation status of the DIO3 gene and DIO3 gene expression, as well as DIO3-related regulatory genes in patients with KBD, were analyzed. We found that 15 CpG sites of six selenoproteins were hypomethylated with 5-azacytidine treatment. DIO3 hypermethylation was associated with an increased risk of KBD and may lead to downregulation of DIO3 gene expression as well as be an indicator of the severity of KBD, which may provide a new insight for gene-environment correlations and interactions in etiology and pathogenesis of KBD.

Highly Enantiospecific Borylation for Chiral α-Amino Tertiary Boronic Esters.

Herein we report a highly efficient and enantiospecific borylation method to synthesize a wide range of enantiopure (>99 % ee) α-amino tertiary boronic esters. The configurationally stable α-N-Boc substituted tertiary organolithium species and pinacolborane (HBpin) underwent enantiospecific borylation at -78 °C with the formation of a new stereogenic C-B bond. This reaction has a broad scope, enabling the synthesis of various α-amino tertiary boronic esters in excellent yields and, importantly, with universally excellent enantiospecificity (>99 % es) and complete retention of configuration.

Hormesis of glyceollin I, an induced phytoalexin from soybean, on budding yeast chronological lifespan extension.

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.

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.

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.

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.