Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals.

Admixture has played a prominent role in shaping patterns of human genomic variation, including gene flow with now-extinct hominins like Neanderthals and Denisovans. Here, we describe a novel probabilistic method called IBDmix to identify introgressed hominin sequences, which, unlike existing approaches, does not use a modern reference population. We applied IBDmix to 2,504 individuals from geographically diverse populations to identify and analyze Neanderthal sequences segregating in modern humans. Strikingly, we find that African individuals carry a stronger signal of Neanderthal ancestry than previously thought. We show that this can be explained by genuine Neanderthal ancestry due to migrations back to Africa, predominately from ancestral Europeans, and gene flow into Neanderthals from an early dispersing group of humans out of Africa. Our results refine our understanding of Neanderthal ancestry in African and non-African populations and demonstrate that remnants of Neanderthal genomes survive in every modern human population studied to date.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

Blockade of OX40/OX40L signaling using anti-OX40L alleviates murine lupus nephritis.

Genetic variants of the OX40 ligand (OX40L) locus are associated with the risk of systemic lupus erythematosus (SLE), it is unclear how the OX40L blockade delays the lupus phenotype. Therefore, we examined the effects of an anti-OX40L antibody in MRL/Lpr mice. Next, we investigated the effect of anti-OX40L on immunosuppression in keyhole limpet hemocyanin-immunized C57BL/6J mice. In vitro treatment of anti-OX40L in CD4+ T and B220+ B cells was used to explore the role of OX40L in the pathogenesis of SLE. Anti-OX40L alleviated murine lupus nephritis, accompanied by decreased production of anti-dsDNA and proteinuria, as well as lower frequencies of splenic T helper (Th) 1 and T-follicular helper cells (Tfh). In keyhole limpet hemocyanin-immunized mice, decreased levels of immunoglobulins and plasmablasts were observed in the anti-OX40L group. Anti-OX40L reduced the number and area of germinal centers. Compared with the control IgG group, anti-OX40L downregulated CD4+ T-cell differentiation into Th1 and Tfh cells and upregulated CD4+ T-cell differentiation into regulatory T cells in vitro. Furthermore, anti-OX40L inhibited toll-like receptor 7-mediated differentiation of antibody-secreting cells and antibody production through the regulation of the SPIB-BLIMP1-XBP1 axis in B cells. These results suggest that OX40L is a promising therapeutic target for SLE.

A high-resolution haplotype-resolved Reference panel constructed from the China Kadoorie Biobank Study.

Precision medicine depends on high-accuracy individual-level genotype data. However, the whole-genome sequencing (WGS) is still not suitable for gigantic studies due to budget constraints. It is particularly important to construct highly accurate haplotype reference panel for genotype imputation. In this study, we used 10 000 samples with medium-depth WGS to construct a reference panel that we named the CKB reference panel. By imputing microarray datasets, it showed that the CKB panel outperformed compared panels in terms of both the number of well-imputed variants and imputation accuracy. In addition, we have completed the imputation of 100 706 microarrays with the CKB panel, and the after-imputed data is the hitherto largest whole genome data of the Chinese population. Furthermore, in the GWAS analysis of real phenotype height, the number of tested SNPs tripled and the number of significant SNPs doubled after imputation. Finally, we developed an online server for offering free genotype imputation service based on the CKB reference panel (https://db.cngb.org/imputation/). We believe that the CKB panel is of great value for imputing microarray or low-coverage genotype data of Chinese population, and potentially mixed populations. The imputation-completed 100 706 microarray data are enormous and precious resources of population genetic studies for complex traits and diseases.

Mars' emitted energy and seasonal energy imbalance.

SignificanceThe radiant energy budget is a fundamental metric for planets. Based on the observations from multiple missions, we provide a global picture of Mars' emitted power. Furthermore, we estimate the radiant energy budget of Mars, which suggests that there are energy imbalances at the time scale of Mars' seasons. Such energy imbalances provide a new perspective to understanding the generating mechanism of dust storms. Mars' radiant energy budget is assumed to be balanced at all time scales in current models and theories, but our analyses show that the energy budget is not balanced, at least at the time scale of Mars' seasons. Therefore, current theories and models should be revisited with the newly revealed energy characteristics.

Development and evaluation of a polygenic risk score for lung cancer in never-smoking women: A large-scale prospective Chinese cohort study.

The proportion of lung cancer in never smokers is rising, especially among Asian women, but there is no effective early detection tool. Here, we developed a polygenic risk score (PRS), which may help to identify the population with higher risk of lung cancer in never-smoking women. We first performed a large GWAS meta-analysis (8595 cases and 8275 controls) to systematically identify the susceptibility loci for lung cancer in never-smoking Asian women and then generated a PRS using GWAS datasets. Furthermore, we evaluated the utility and effectiveness of PRS in an independent Chinese prospective cohort comprising 55 266 individuals. The GWAS meta-analysis identified eight known loci and a novel locus (5q11.2) at the genome-wide statistical significance level of P < 5 × 10-8 . Based on the summary statistics of GWAS, we derived a polygenic risk score including 21 variants (PRS-21) for lung cancer in never-smoking women. Furthermore, PRS-21 had a hazard ratio (HR) per SD of 1.29 (95% CI = 1.18-1.41) in the prospective cohort. Compared with participants who had a low genetic risk, those with an intermediate (HR = 1.32, 95% CI: 1.00-1.72) and high (HR = 2.09, 95% CI: 1.56-2.80) genetic risk had a significantly higher risk of incident lung cancer. The addition of PRS-21 to the conventional risk model yielded a modest significant improvement in AUC (0.697 to 0.711) and net reclassification improvement (24.2%). The GWAS-derived PRS-21 significantly improves the risk stratification and prediction accuracy for incident lung cancer in never-smoking Asian women, demonstrating the potential for identification of high-risk individuals and early screening.

Infectious pathogens and risk of esophageal, gastric and duodenal cancers and ulcers in China: A case-cohort study.

Infection by certain pathogens is associated with cancer development. We conducted a case-cohort study of ~2500 incident cases of esophageal, gastric and duodenal cancer, and gastric and duodenal ulcer and a randomly selected subcohort of ~2000 individuals within the China Kadoorie Biobank study of >0.5 million adults. We used a bead-based multiplex serology assay to measure antibodies against 19 pathogens (total 43 antigens) in baseline plasma samples. Associations between pathogens and antigen-specific antibodies with risks of site-specific cancers and ulcers were assessed using Cox regression fitted using the Prentice pseudo-partial likelihood. Seroprevalence varied for different pathogens, from 0.7% for Hepatitis C virus (HCV) to 99.8% for Epstein-Barr virus (EBV) in the subcohort. Compared to participants seronegative for the corresponding pathogen, Helicobacter pylori seropositivity was associated with a higher risk of non-cardia (adjusted hazard ratio [HR] 2.73 [95% CI: 2.09-3.58]) and cardia (1.67 [1.18-2.38]) gastric cancer and duodenal ulcer (2.71 [1.79-4.08]). HCV was associated with a higher risk of duodenal cancer (6.23 [1.52-25.62]) and Hepatitis B virus was associated with higher risk of duodenal ulcer (1.46 [1.04-2.05]). There were some associations of antibodies again some herpesviruses and human papillomaviruses with risks of gastrointestinal cancers and ulcers but these should be interpreted with caution. This first study of multiple pathogens with risk of gastrointestinal cancers and ulcers demonstrated that several pathogens are associated with risks of gastrointestinal cancers and ulcers. This will inform future investigations into the role of infection in the etiology of these diseases.

Associations of diabetes, circulating protein biomarkers, and risk of pancreatic cancer.

BACKGROUND: Type 2 diabetes (T2D) is associated with higher risk of pancreatic cancer (PC), but the underlying mechanisms are not fully understood. METHODS: We conducted a case-subcohort study involving 610 PC cases and 623 subcohort participants with 92 protein biomarkers measured in baseline plasma samples. Genetically-instrumented T2D was derived using 86 single-nucleotide polymorphisms (SNPs), including insulin resistance (IR) SNPs. RESULTS: In observational analyses of 623 subcohort participants (mean age, 52 years; 61% women), T2D was positively associated with 13 proteins (SD difference: IL6: 0.52 [0.23-0.81]; IL10: 0.41 [0.12-0.70]), of which 8 were nominally associated with incident PC. The 8 proteins potentially mediated 36.9% (18.7-75.0%) of the association between T2D and PC. In MR, no associations were observed for genetically-determined T2D with proteins, but there were positive associations of genetically-determined IR with IL6 and IL10 (SD difference: 1.23 [0.05-2.41] and 1.28 [0.31-2.24]). In two-sample MR, fasting insulin was associated with both IL6 and PC, but no association was observed between IL6 and PC. CONCLUSIONS: Proteomics were likely to explain the association between T2D and PC, but were not causal mediators. Elevated fasting insulin driven by insulin resistance might explain the associations of T2D, proteomics, and PC.

Prevalence of Liver Steatosis and Fibrosis in the General Population and Various High-Risk Populations: A Nationwide Study With 5.7 Million Adults in China.

BACKGROUND & AIMS: This study aimed to estimate the prevalence of liver steatosis and fibrosis in the general population and populations with potential risk factors in China, so as to inform policies for the screening and management of fatty liver disease and liver fibrosis in general and high-risk populations. METHODS: This cross-sectional, population-based, nationwide study was based on the database of the largest health check-up chain in China. Adults from 30 provinces who underwent a check-up between 2017 and 2022 were included. Steatosis and fibrosis were assessed and graded by transient elastography. Overall and stratified prevalence was estimated among the general population and various subpopulations with demographic, cardiovascular, and chronic liver disease risk factors. A mixed effect regression model was used to examine predictors independently associated with steatosis and fibrosis. RESULTS: In 5,757,335 participants, the prevalence of steatosis, severe steatosis, advanced fibrosis, and cirrhosis was 44.39%, 10.57%, 2.85%, and 0.87%, respectively. Participants who were male, with obesity, diabetes, hypertension, dyslipidemia, metabolic syndrome, or elevated alanine aminotransferase or aspartate aminotransferase had a significantly higher prevalence of all grades of steatosis and fibrosis, and those with fatty liver, decreased albumin or platelet count, and hepatitis B virus infection also had a significantly higher prevalence of fibrosis than their healthy counterparts. Most cardiovascular and chronic liver disease risk factors were independent predictors for steatosis and fibrosis, except for dyslipidemia for fibrosis. CONCLUSIONS: A substantial burden of liver steatosis and fibrosis was found in China. Our study provides evidence for shaping future pathways for screening and risk stratification of liver steatosis and fibrosis in the general population. The findings of this study highlight that fatty liver and liver fibrosis should be included in disease management programs as targets for screening and regular monitoring in high-risk populations, especially in those with diabetes.

Long-Term Exposure to Fine Particulate Matter and Incidence of Esophageal Cancer: A Prospective Study of 0.5 Million Chinese Adults.

BACKGROUND & AIMS: Evidence is sparse and inconclusive on the association between long-term fine (≤2.5 µm) particulate matter (PM2.5) exposure and esophageal cancer. We aimed to assess the association of PM2.5 with esophageal cancer risk and compared the esophageal cancer risk attributable to PM2.5 exposure and other established risk factors. METHODS: This study included 510,125 participants without esophageal cancer at baseline from China Kadoorie Biobank. A high-resolution (1 × 1 km) satellite-based model was used to estimate PM2.5 exposure during the study period. Hazard ratios (HR) and 95% CIs of PM2.5 with esophageal cancer incidence were estimated using Cox proportional hazard model. Population attributable fractions for PM2.5 and other established risk factors were estimated. RESULTS: There was a linear concentration-response relationship between long-term PM2.5 exposure and esophageal cancer. For each 10-µg/m3 increase in PM2.5, the HR was 1.16 (95% CI, 1.04-1.30) for esophageal cancer incidence. Compared with the first quarter of PM2.5 exposure, participants in the highest quarter had a 1.32-fold higher risk for esophageal cancer, with an HR of 1.32 (95% CI, 1.01-1.72). The population attributable risk because of annual average PM2.5 concentration ≥35 µg/m3 was 23.3% (95% CI, 6.6%-40.0%), higher than the risks attributable to lifestyle risk factors. CONCLUSIONS: This large prospective cohort study of Chinese adults found that long-term exposure to PM2.5 was associated with an elevated risk of esophageal cancer. With stringent air pollution mitigation measures in China, a large reduction in the esophageal cancer disease burden can be expected.

Classical swine fever virus NS5A protein activates autophagy via the PP2A-DAPK3-Beclin 1 axis.

IMPORTANCE: Autophagy is a conserved degradation process that maintains cellular homeostasis and regulates native and adaptive immunity. Viruses have evolved diverse strategies to inhibit or activate autophagy for their benefit. The paper reveals that CSFV NS5A mediates the dissociation of PP2A from Beclin 1 and the association of PP2A with DAPK3 by interaction with PPP2R1A and DAPK3, PP2A dephosphorylates DAPK3 to activate its protein kinase activity, and activated DAPK3 phosphorylates Beclin 1 to trigger autophagy, indicating that NS5A activates autophagy via the PP2A-DAPK3-Beclin 1 axis. These data highlight a novel mechanism by which CSFV activates autophagy to favor its replication, thereby contributing to the development of antiviral strategies.

Reproductive factors and risk of lung cancer among 300,000 Chinese female never-smokers: evidence from the China Kadoorie Biobank study.

BACKGROUND: Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. METHODS: The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004-2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. RESULTS: During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02-1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78-0.95) for > 12 months compared with those who breastfed for 7-12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. CONCLUSION: Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

A radiomics signature derived from CT imaging to predict MSI status and immunotherapy outcomes in gastric cancer: a multi-cohort study.

BACKGROUND: Accurate microsatellite instability (MSI) testing is essential for identifying gastric cancer (GC) patients eligible for immunotherapy. We aimed to develop and validate a CT-based radiomics signature to predict MSI and immunotherapy outcomes in GC. METHODS: This retrospective multicohort study included a total of 457 GC patients from two independent medical centers in China and The Cancer Imaging Archive (TCIA) databases. The primary cohort (n = 201, center 1, 2017-2022), was used for signature development via Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression analysis. Two independent immunotherapy cohorts, one from center 1 (n = 184, 2018-2021) and another from center 2 (n = 43, 2020-2021), were utilized to assess the signature's association with immunotherapy response and survival. Diagnostic efficiency was evaluated using the area under the receiver operating characteristic curve (AUC), and survival outcomes were analyzed via the Kaplan-Meier method. The TCIA cohort (n = 29) was included to evaluate the immune infiltration landscape of the radiomics signature subgroups using both CT images and mRNA sequencing data. RESULTS: Nine radiomics features were identified for signature development, exhibiting excellent discriminative performance in both the training (AUC: 0.851, 95%CI: 0.782, 0.919) and validation cohorts (AUC: 0.816, 95%CI: 0.706, 0.926). The radscore, calculated using the signature, demonstrated strong predictive abilities for objective response in immunotherapy cohorts (AUC: 0.734, 95%CI: 0.662, 0.806; AUC: 0.724, 95%CI: 0.572, 0.877). Additionally, the radscore showed a significant association with PFS and OS, with GC patients with a low radscore experiencing a significant survival benefit from immunotherapy. Immune infiltration analysis revealed significantly higher levels of CD8 + T cells, activated CD4 + B cells, and TNFRSF18 expression in the low radscore group, while the high radscore group exhibited higher levels of T cells regulatory and HHLA2 expression. CONCLUSION: This study developed a robust radiomics signature with the potential to serve as a non-invasive biomarker for GC's MSI status and immunotherapy response, demonstrating notable links to post-immunotherapy PFS and OS. Additionally, distinct immune profiles were observed between low and high radscore groups, highlighting their potential clinical implications.

Association of sex hormones with non-alcoholic fatty liver disease: An observational and Mendelian randomization study.

BACKGROUND AND AIMS: Sex-specific associations of sex hormone-binding globulin (SHBG) and bioavailable testosterone (BAT) with NAFLD remain indeterminate. We aimed to explore observational and genetically determined relationships between each hormone and NAFLD. METHODS: We included 187 395 men and 170 193 women from the UK Biobank. Linear and nonlinear Cox regression models and Mendelian randomization (MR) analysis were used to test the associations. RESULTS: During 12.49 years of follow-up, 2209 male and 1886 female NAFLD cases were documented. Elevated SHBG levels were linearly associated with a lower risk of NAFLD in women (HR (95% CI), .71 (.63, .79)), but not in men (a "U" shape, pnon-linear < .001). Higher BAT levels were associated with a lower NAFLD risk in men (HR (95% CI), .81 (.71, .93)) but a higher risk in women (HR (95% CI): 1.25 (1.15, 1.36)). Genetically determined SHBG and BAT levels were linearly associated with NAFLD risk in women (OR (95% CI): .57 (.38, .87) and 2.21 (1.41, 3.26) respectively); in men, an "L-shaped" MR association between SHBG levels and NAFLD risk was found (pnon-linear = .016). The bidirectional MR analysis further revealed the effect of NAFLD on SHBG and BAT levels in both sexes. CONCLUSIONS: Consistently, linear associations of lower SHBG and higher BAT levels with increased NAFLD risk were both conventionally and genetically found in women, while in men, SHBG acts in a nonlinear manner. In addition, NAFLD may affect SHBG and BAT levels.

T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain as a promising immune checkpoint target for the treatment of SLE.

Immune checkpoints (ICs) play a pivotal role in orchestrating immune regulation, crucial for the maintenance of immune tolerance and prevention of autoimmune diseases. One noteworthy example among these immune regulators is T cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT). The TIGIT pathway's inhibition or the absence of TIGIT has been linked to the hyperactivation and excessive proliferation of T cells, rendering individuals more susceptible to autoimmune diseases and exacerbating inflammatory responses. Conversely, the activation of TIGIT has exhibited promising outcomes in ameliorating autoimmune disorders, as observed in murine models of systemic lupus erythematosus (SLE). Consequently, a judicious exploration of the co-inhibitory axis appears warranted for the effective management of pathogenic immune responses in SLE. In light of compelling evidence, this review undertakes a comprehensive examination of TIGIT's characteristics within the context of autoimmunity, offering insights into its potential as a therapeutic target for SLE.

Has the UK Campaign to End Loneliness Reduced Loneliness and Improved Mental Health in Older Age? A Difference-in-Differences Design.

OBJECTIVE: To estimate the impact of the UK nationwide campaign to End loneliness on loneliness and mental health outcomes among older people in England. DESIGN: Quasi-experimental design, namely, a difference-in-differences approach. SETTING: Local authorities across England. PARTICIPANTS: Older adults aged 65 and over participating in waves 4-8 (2008-2017) of the English Longitudinal Study of Aging (ELSA) and waves 1-9 (2009-2019) of the UK Household Longitudinal Study (UKHLS). MAIN OUTCOME MEASURES: Loneliness was measured through the UCLA Loneliness scale. A social isolation scale with components of household composition, social contact and participation was constructed. Mental health was measured by The Centre for Epidemiological Studies of Depression (CES-D) score, the General Health Questionnaire (GHQ-12) score, and the Short-Form-12 Mental Component Summary (SF-12 MCS) score. RESULTS: There was no evidence of change in loneliness scores over the study period. Difference-in-differences estimates suggest that explicitly developed and implemented antiloneliness strategies led to no change in loneliness scores (estimate = 0.044, SE = 0.085), social isolation caseness (estimate = 0.038, SE = 0.020) or levels of depressive symptoms (estimate = 0.130, SE = 0.165). Heterogeneity analyses indicate that antiloneliness strategies produced little impact on loneliness or mental health overall, despite small reductions in loneliness and increases in social engagement among well-educated and higher-income older adults. The results were robust to various sensitivity and robustness analyses. CONCLUSIONS: Antiloneliness strategies implemented by local authorities have not generated a significant change in loneliness or mental health in older adults in England. Generating changes in loneliness in the older population might require longer periods of exposure, larger scope of intervention or more targeted strategies.

Prevalent lightning sferics at 600 megahertz near Jupiter's poles.

Lightning has been detected on Jupiter by all visiting spacecraft through night-side optical imaging and whistler (lightning-generated radio waves) signatures1-6. Jovian lightning is thought to be generated in the mixed-phase (liquid-ice) region of convective water clouds through a charge-separation process between condensed liquid water and water-ice particles, similar to that of terrestrial (cloud-to-cloud) lightning7-9. Unlike terrestrial lightning, which emits broadly over the radio spectrum up to gigahertz frequencies10,11, lightning on Jupiter has been detected only at kilohertz frequencies, despite a search for signals in the megahertz range 12 . Strong ionospheric attenuation or a lightning discharge much slower than that on Earth have been suggested as possible explanations for this discrepancy13,14. Here we report observations of Jovian lightning sferics (broadband electromagnetic impulses) at 600 megahertz from the Microwave Radiometer 15 onboard the Juno spacecraft. These detections imply that Jovian lightning discharges are not distinct from terrestrial lightning, as previously thought. In the first eight orbits of Juno, we detected 377 lightning sferics from pole to pole. We found lightning to be prevalent in the polar regions, absent near the equator, and most frequent in the northern hemisphere, at latitudes higher than 40 degrees north. Because the distribution of lightning is a proxy for moist convective activity, which is thought to be an important source of outward energy transport from the interior of the planet16,17, increased convection towards the poles could indicate an outward internal heat flux that is preferentially weighted towards the poles9,16,18. The distribution of moist convection is important for understanding the composition, general circulation and energy transport on Jupiter.

Identification of neutrophil extracellular trap-driven gastric cancer heterogeneity and C5AR1 as a therapeutic target.

Neutrophil extracellular traps (NETs) are implicated in gastric cancer (GC) growth, metastatic dissemination, cancer-associated thrombosis, etc. This work is conducted to elucidate the heterogeneity of NETs in GC. The transcriptome heterogeneity of NETs is investigated in TCGA-STAD via a consensus clustering algorithm, with subsequent external verification in the GSE88433 and GSE88437 cohorts. Clinical and molecular traits, the immune microenvironment, and drug response are characterized in the identified NET-based clusters. Based upon the feature genes of NETs, a classifier is built for estimating NET-based clusters via machine learning. Multiple experiments are utilized to verify the expressions and implications of the feature genes in GC. A novel NET-based classification system is proposed for reflecting the heterogeneity of NETs in GC. Two NET-based clusters have unique and heterogeneous clinical and molecular features, immune microenvironments, and responses to targeted therapy and immunotherapy. A logistic regression model reliably differentiates the NET-based clusters. The feature genes C5AR1, CSF1R, CSF2RB, CYBB, HCK, ITGB2, LILRB2, MNDA, MPEG1, PLEK, SRGN, and STAB1 are proven to be aberrantly expressed in GC cells. Specific knockdown of C5AR1 effectively hinders GC cell growth and elicits intracellular ROS accumulation. In addition, its suppression suppresses the aggressiveness and EMT phenotype of GC cells. In all, NETs are the main contributors to intratumoral heterogeneity and differential drug sensitivity in GC, and C5AR1 has been shown to trigger GC growth and metastatic spread. These findings collectively provide a theoretical basis for the use of anti-NETs in GC treatment.

Association of psychological distress and DNA methylation: A 5-year longitudinal population-based twin study.

AIM: To identify the psychological distress (PD)-associated 5'-cytosine-phosphate-guanine-3' sites (CpGs), and investigate the temporal relationship between dynamic changes in DNA methylation (DNAm) and PD. METHODS: This study included 1084 twins from the Chinese National Twin Register (CNTR). The CNTR conducted epidemiological investigations and blood withdrawal twice in 2013 and 2018. These included twins were used to perform epigenome-wide association studies (EWASs) and to validate the previously reported PD-associated CpGs selected from previous EWASs in PubMed, Embase, and the EWAS catalog. Next, a cross-lagged study was performed to examine the temporality between changes in DNAm and PD in 308 twins who completed both 2013 and 2018 surveys. RESULTS: The EWAS analysis of our study identified 25 CpGs. In the validation analysis, 741 CpGs from 29 previous EWASs on PD were selected for validation, and 101 CpGs were validated to be significant at a false discovery rate <0.05. The cross-lagged analysis found a unidirectional path from PD to DNAm at 14 CpGs, while no sites showed significance from DNAm to PD. CONCLUSIONS: This study identified and validated PD-related CpGs in a Chinese twin population, and suggested that PD may be the cause of changes in DNAm over time. The findings provide new insights into the molecular mechanisms underlying PD pathophysiology.

Gastric mucormycosis presenting as diffuse thickening of the gastric wall with enhancement.

We report the case of a 63-year-old woman who presented with abdominal distension and pain two months ago, which worsened after eating. An abdominal CT examination revealed uneven thickening of the gastric wall on the greater curvature side of the gastric body, with progressive obviously enhancement. She was then examined by an upper endoscopy, which showed mucosal swelling on the greater curvature side of the lower gastric body with exudation of necrotic materials. Biopsies of the lesion were taken and histological results revealed a large number of broad-based and non-septate hyphae, with positive expression of PAS (Periodic Acid-Schiff) and hexamine silver stains, The patient was treated with amphotericin B liposomal antifungal therapy and remained under surveillance for six months without evidence of disease progression by follow-up upper endoscopy.