OSGIN1 regulates PM2.5-induced fibrosis via mediating autophagy in an in vitro model of COPD.

Fine particulate matter (PM2.5) has been identified as a significant contributing factor to the exacerbation of chronic obstructive pulmonary disease (COPD). It has been observed that PM2.5 may induce lung fibrosis in COPD, although the precise molecular mechanism behind this remains unclear. In a previous study, we demonstrated that PM2.5 upregulates oxidative stress induced growth inhibitor 1 (OSGIN1), which in turn leads to injury in airway epithelial cells, thereby, suggesting a potential link between PM2.5 exposure and COPD. Based on this, we hypothesized that OSGIN1 plays a role in PM2.5-induced fibrosis in COPD. Human bronchial epithelial cells (HBEs) were treated with cigarette smoke extract (CSE) to construct an in vitro model of COPD. Our findings revealed that PM2.5 increased fibrosis indicators and upregulated OSGIN1 in CSE-stimulated HBEs (CSE-HBEs), and knockdown of OSGIN1 reduced the expression of fibrosis indicators. Through the use of microRNA target prediction software and the Gene Expression Omnibus database, we predicted miRNAs that targeted OSGIN1 in COPD. Subsequently, real-time polymerase chain reaction and western blot analysis confirmed that PM2.5 modulated miR-654-5p to regulate OSGIN1 in CSE-HBEs. Western blot demonstrated that OSGIN1 induced autophagy, thereby exacerbating fibrosis in CSE-HBEs. In summary, our results suggest that PM2.5 upregulates OSGIN1 through inhibiting miR-654-5p, leading to increased autophagy and fibrosis in CSE-HBEs.

RB1 Mutations Induce Smoking-Related Bladder Cancer by Modulating the Cytochrome P450 Pathway.

Cigarette smoking causes multiple cancers by directly influencing mutation burden of driver mutations. However, the mechanism between somatic mutation caused by cigarette smoking and bladder tumorigenesis remains elusive. Smoking-related mutation profile of bladder cancer was characterized by The Cancer Genome Atlas cohort. Integraticve OncoGenomics database was utilized to detect the smoking-related driver genes, and its biological mechanism predictions were interpreted based on bulk transcriptome and single-cell transcriptome, as well as cell experiments. Cigarette smoking was associated with an increased tumor mutational burden under 65 years old (p = 0.031), and generated specific mutational signatures in smokers. RB1 was identified as a differentially mutated driver gene between smokers and nonsmokers, and the mutation rate of RB1 increased twofold after smoking (p = 0.008). RB1 mutations and the 4-aminobiphenyl interference could significantly decrease the RB1 expression level and thus promote the proliferation, invasion, and migration ability of bladder cancer cells. Enrichment analysis and real-time quantitative PCR (RT-qPCR) data showed that RB1 mutations inhibited cytochrome P450 pathway by reducing expression levels of UGT1A6 and AKR1C2. In addition, we also observed that the component of immunological cells was regulated by RB1 mutations through the stronger cell-to-cell interactions between epithelial scissor+ cells and immune cells in smokers. This study highlighted that RB1 mutations could drive smoking-related bladder tumorigenesis through inhibiting cytochrome P450 pathway and regulating tumor immune microenvironment.

Polygenic prediction of human longevity on the supposition of pervasive pleiotropy.

The highly polygenic nature of human longevity renders pleiotropy an indispensable feature of its genetic architecture. Leveraging the genetic correlation between aging-related traits (ARTs), we aimed to model the additive variance in lifespan as a function of the cumulative liability from pleiotropic segregating variants. We tracked allele frequency changes as a function of viability across different age bins and prioritized 34 variants with an immediate implication on lipid metabolism, body mass index (BMI), and cognitive performance, among other traits, revealed by PheWAS analysis in the UK Biobank. Given the highly complex and non-linear interactions between the genetic determinants of longevity, we reasoned that a composite polygenic score would approximate a substantial portion of the variance in lifespan and developed the integrated longevity genetic scores (iLGSs) for distinguishing exceptional survival. We showed that coefficients derived from our ensemble model could potentially reveal an interesting pattern of genomic pleiotropy specific to lifespan. We assessed the predictive performance of our model for distinguishing the enrichment of exceptional longevity among long-lived individuals in two replication cohorts (the Scripps Wellderly cohort and the Medical Genome Reference Bank (MRGB)) and showed that the median lifespan in the highest decile of our composite prognostic index is up to 4.8 years longer. Finally, using the proteomic correlates of iLGS, we identified protein markers associated with exceptional longevity irrespective of chronological age and prioritized drugs with repurposing potentials for gerotherapeutics. Together, our approach demonstrates a promising framework for polygenic modeling of additive liability conferred by ARTs in defining exceptional longevity and assisting the identification of individuals at a higher risk of mortality for targeted lifestyle modifications earlier in life. Furthermore, the proteomic signature associated with iLGS highlights the functional pathway upstream of the PI3K-Akt that can be effectively targeted to slow down aging and extend lifespan.

Genetic variants reduced POPs-related colorectal cancer risk via altering miRNA binding affinity and m6A modification.

Exposure to persistent organic pollutants (POPs) may contribute to colorectal cancer risk, but the underlying mechanisms of crucial POPs exposure remain unclear. Hence, we systematically investigated the associations among POPs exposure, genetics and epigenetics and their effects on colorectal cancer. A case-control study was conducted in the Chinese population for detecting POPs levels. We measured the concentrations of 24 POPs in the plasma using gas chromatography-tandem mass spectrometry (GC-MS/MS) and evaluated the clinical significance of POPs by calculating the area under the receiver operating characteristic curve (AUC). To assess the associations between candidate genetic variants and colorectal cancer risk, unconditional logistic regression was used. Compared with healthy control individuals, individuals with colorectal cancer exhibited higher concentrations of the majority of POPs. Exposure to PCB153 was positively associated with colorectal cancer risk, and PCB153 demonstrated superior accuracy (AUC=0.72) for predicting colorectal cancer compared to other analytes. On PCB153-related genes, the rs67734009 C allele was significantly associated with reduced colorectal cancer risk and lower plasma levels of PCB153. Moreover, rs67734009 exhibited an expression quantitative trait locus (eQTL) effect on ESR1, of which the expression level was negatively related to PCB153 concentration. Mechanistically, the risk allele of rs67734009 increased ESR1 expression via miR-3492 binding and m6A modification. Collectively, this study sheds light on potential genetic and epigenetic mechanisms linking PCB153 exposure and colorectal cancer risk, thereby providing insight into the accurate protection against POPs exposure.

piRNA PROPER Suppresses DUSP1 Translation by Targeting N6-Methyladenosine-Mediated RNA Circularization to Promote Oncogenesis of Prostate Cancer.

Genetic and epigenetic alterations occur in many physiological and pathological processes. The existing knowledge regarding the association of PIWI-interacting RNAs (piRNAs) and their genetic variants on risk and progression of prostate cancer (PCa) is limited. In this study, three genome-wide association study datasets are combined, including 85,707 PCa cases and 166,247 controls, to uncover genetic variants in piRNAs. Functional investigations involved manipulating piRNA expression in cellular and mouse models to study its oncogenetic role in PCa. A specific genetic variant, rs17201241 is identified, associated with increased expression of PROPER (piRNA overexpressed in prostate cancer) in tumors and are located within the gene, conferring an increased risk and malignant progression of PCa. Mechanistically, PROPER coupled with YTHDF2 to recognize N6-methyladenosine (m6A) and facilitated RNA-binding protein interactions between EIF2S3 at 5'-untranslated region (UTR) and YTHDF2/YBX3 at 3'-UTR to promote DUSP1 circularization. This m6A-dependent mRNA-looping pattern enhanced DUSP1 degradation and inhibited DUSP1 translation, ultimately reducing DUSP1 expression and promoting PCa metastasis via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PROPER expression using antagoPROPER effectively suppressed xenograft growth, suggesting its potential as a therapeutic target. Thus, targeting piRNA PROPER-mediated genetic and epigenetic fine control is a promising strategy for the concurrent prevention and treatment of PCa.

Rare genetic coding variants associated with age-related episodic memory decline implicate distinct memory pathologies in the hippocampus.

Background: Approximately 40% of people aged 65 or older experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes. Methods: We investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom MD simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline. Results: In addition to the common polygenic risk of Alzheimer's Disease (AD), we identified and replicated rare variant association in ITSN1 and CRHR2 . Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis. Discussion: Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogeneous memory pathologies mediated by rare coding variants.

Colonization of bacterial and viral respiratory pathogens among healthcare workers in China during COVID-19 pandemic.

Background: Healthcare settings may amplify transmission of respiratory pathogens, however empirical evidence is lacking. We aimed to describe the spectrum and distribution of respiratory pathogens among healthcare workers in eastern China. Methods: Healthcare workers were recruited from October 2020 to November 2021 in Jiangsu province. Participants were interviewed regarding demographic and hospital-based protective measures. Thirty-seven common respiratory pathogens were tested using real-time PCR/RT-PCR (Probe qPCR). The role of demographic and hospital-based protective measures on pathogens colonization using multivariable logistic regression models. Results: Among 316 enrolled healthcare workers, a total of 21 pathogens were detected. In total, 212 (67.1%) healthcare workers had at least one respiratory pathogen; 195 (61.7%) and 70 (22.2%) with a bacterial and viral pathogen. The most commonly detected pathogen was streptococcus pneumoniae (47.5%) followed by Haemophilus influenzae (21.2%). One hundred and five (33.2%) healthcare workers with copathogens had at least two respiratory pathogens. Both bacterial and viral colonization were more common in 2020 compared to 2021. A decreased risk of colonization was seen in participants with infection prevention and control training and suitable hand hygiene. Conclusions: Colonization of respiratory pathogens in healthcare workers from eastern China was high. Differential risk was impacted only by hospital-based protective measures and not demographic factors.

Distinctive multicellular immunosuppressive hubs confer different intervention strategies for left- and right-sided colon cancers.

Primary colon cancers arising from the left and right sides exhibit distinct clinical and molecular characteristics. Sidedness-associated heterogeneity relies intricately on the oncogenic properties of cancer cells and multicellular interactions in tumor microenvironments. Here, combining transcriptomic profiling of 426,863 single cells from 105 colon cancer patients and validation with spatial transcriptomics and large-scale histological analysis, we capture common transcriptional heterogeneity patterns between left- and right-sided malignant epithelia through delineating two side-specific expression meta-programs. The proliferation stemness meta-program is notably enriched in left-sided malignant epithelia that colocalize with Mph-PLTP cells, activated regulatory T cells (Tregs), and exhausted CD8-LAYN cells, constituting the glucose metabolism reprogramming niche. The immune secretory (IS) meta-program exhibits specific enrichment in right-sided malignant epithelia, especially in smoking patients with right-sided colon cancer. The IShigh malignant epithelia spatially localize in hypoxic regions and facilitate immune evasion through attenuating Mph-SPP1 cell antigen presentation and recruiting innate-like cytotoxicity-reduced CD8-CD161 cells.

Genetic variants in C1GALT1 are associated with gastric cancer risk by influencing immune infiltration.

Core 1 synthase glycoprotein-N-acetylgalactosamine 3-ß-galactosyltransferase 1 (C1GALT1) is known to play a critical role in the development of gastric cancer, but few studies have elucidated associations between genetic variants in C1GALT1 and gastric cancer risk. By using the genome-wide association study data from the database of Genotype and Phenotype (dbGAP), we evaluated such associations with a multivariable logistic regression model and identified that the rs35999583 G>C in C1GALT1 was associated with gastric cancer risk (odds ratio, 0.83; 95% confidence interval [CI], 0.75-0.92; P = 3.95 × 10 -4). C1GALT1 mRNA expression levels were significantly higher in gastric tumor tissues than in normal tissues, and gastric cancer patients with higher C1GALT1 mRNA levels had worse overall survival rates (hazards ratio, 1.33; 95% CI, 1.05-1.68; P log-rank = 1.90 × 10 -2). Furthermore, we found that C1GALT1 copy number differed in various immune cells and that C1GALT1 mRNA expression levels were positively correlated with the infiltrating levels of CD4 + T cells and macrophages. These results suggest that genetic variants of C1GALT1 may play an important role in gastric cancer risk and provide a new insight for C1GALT1 into a promising predictor of gastric cancer susceptibility and immune status.

Expression profiling and bioinformatics analysis of serum exosomal circular RNAs in lymph node metastasis of papillary thyroid carcinoma.

Most papillary thyroid carcinoma (PTC) patients have a good prognosis, but lymph node metastasis (LNM) is the most common progressive manifestation and often leads to a poor-prognosis. However, few studies focused on the underlying mechanisms of LNM. This study aimed to identity the potential role of exosomal circRNAs that contribute to LNM in PTC. We found that 9000 aberrantly expressed exosomal circRNAs in PTC patients with LNM, including 684 observably upregulation and 2193 notably downregulation. Functional enrichment analyses indicated that these aberrantly expressed circRNAs were mainly enriched in a variety of molecules and signaling pathways related to the progression and LNM of PTC. Bioinformatics analysis screened 14 circRNA-miRNA-mRNA networks associated with LNM-related signaling pathways in PTC. Moreover, circTACC2-miR-7-EGFR and circBIRC6-miR-24-3p-BCL2L11 axes were verified for potential involvement in PTC with LNM. Additionally, 4 upregulated circRNAs-related hub genes and 8 hub genes associated with downregulated circRNAs were screened, some of which were involved in LNM of PTC through verification. Collectively, our data provided a novel framework for in-depth investigation of the function of dysregulated exosomal circRNAs and their potential biomarkers in PTC patients with LNM.

Biomimetic bone-periosteum scaffold for spatiotemporal regulated innervated bone regeneration and therapy of osteosarcoma.

The complexity of repairing large segment defects and eradicating residual tumor cell puts the osteosarcoma clinical management challenging. Current biomaterial design often overlooks the crucial role of precisely regulating innervation in bone regeneration. Here, we develop a Germanium Selenium (GeSe) co-doped polylactic acid (PLA) nanofiber membrane-coated tricalcium phosphate bioceramic scaffold (TCP-PLA/GeSe) that mimics the bone-periosteum structure. This biomimetic scaffold offers a dual functionality, combining piezoelectric and photothermal conversion capabilities while remaining biodegradable. When subjected to ultrasound irradiation, the US-electric stimulation of TCP-PLA/GeSe enables spatiotemporal control of neurogenic differentiation. This feature supports early innervation during bone formation, promoting early neurogenic differentiation of Schwann cells (SCs) by increasing intracellular Ca2+ and subsequently activating the PI3K-Akt and Ras signaling pathways. The biomimetic scaffold also demonstrates exceptional osteogenic differentiation potential under ultrasound irradiation. In rabbit model of large segment bone defects, the TCP-PLA/GeSe demonstrates promoted osteogenesis and nerve fibre ingrowth. The combined attributes of high photothermal conversion capacity and the sustained release of anti-tumor selenium from the TCP-PLA/GeSe enable the synergistic eradication of osteosarcoma both in vitro and in vivo. This strategy provides new insights on designing advanced biomaterials of repairing large segment bone defect and osteosarcoma.

Integration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment.

The development of an effective survival prediction tool is key for reducing colorectal cancer mortality. Here, we apply a three-stage study to devise a polygenic prognostic score (PPS) for stratifying colorectal cancer overall survival. Leveraging two cohorts of 3703 patients, we first perform a genome-wide survival association analysis to develop eight candidate PPSs. Further using an independent cohort with 470 patients, we identify the 287 variants-derived PPS (i.e., PPS287) achieving an optimal prediction performance [hazard ratio (HR) per SD = 1.99, P = 1.76 × 10-8], accompanied by additional tests in two external cohorts, with HRs per SD of 1.90 (P = 3.21 × 10-14; 543 patients) and 1.80 (P = 1.11 × 10-9; 713 patients). Notably, the detrimental impact of pathologic characteristics and genetic risk could be attenuated by a healthy lifestyle, yielding a 7.62% improvement in the 5-year overall survival rate. Therefore, our findings demonstrate the integrated contribution of pathologic characteristics, germline variants, and lifestyle exposure to the prognosis of colorectal cancer patients.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Simultaneous Rapid Detection of Multiple Physicochemical Properties of Jet Fuel Using Near-Infrared Spectroscopy.

Jet fuel is the primary fuel used in the aviation industry, and its quality has a direct impact on the safety and operational efficiency of aircraft. The accurate quantitative detection and analysis of various physicochemical property indicators are important for improving and ensuring the quality of jet fuel in the domestic market. This study used near-infrared (NIR) spectroscopy to establish a suitable model for the simultaneous and rapid detection of multiple physicochemical properties in jet fuel. Using more than 40 different sources of jet fuel, a rapid detection model was established by optimizing the spectral processing methods. The measurement models were separately built using the partial least-squares (PLS) and orthogonal PLS algorithms, and the model parameters were optimized. The results show that after the Savitzky-Golay second derivative preprocessing, the PLS model built using the feature spectra selected by the uninformative variable elimination wavelength algorithm achieved the best measurement performance. Compared with the PLS model without preprocessing, the range of the resulting accuracy improvement was at least 15.01%. Under the optimal model parameters, the calibration set regression coefficient (Rc2) of the 11 jet fuel property index models ranged from 0.9102 to 0.9763, with the root-mean-square error of calibration values up to 0.8468 °C (for flash points). The regression coefficient (Rp2) of the validation set ranged from 0.8239 to 0.9557, with the root-mean-square error of prediction values up to 1.1354 °C (for flash points). The ratios of prediction to deviation (RPD) values were all in the range of 1.9-3.0, indicating high accuracy and reliability of the model. The rapid NIR analysis method established in this study enables the simultaneous and rapid detection of multiple physicochemical properties of jet fuel, thereby providing effective technical support for ensuring the quality of jet fuel in the market.

Accurate identification of methanol and ethanol gasoline types and rapid detection of the alcohol content using effective chemical information.

Methanol and ethanol gasoline are two emerging clean energy sources with different characteristics. To achieve the qualitative identification and quantitative analysis of the alcohols present in methanol and ethanol gasoline, effective chemical information (ECI) models based on the characteristic spectral bands of the near-infrared (NIR) spectra of the methanol and ethanol molecules were developed using the partial least squares discriminant analysis (PLS-DA) and partial least squares (PLS) algorithms. The ECI model was further compared with models built from the full wavenumber (Full) spectra, variable importance in projection (VIP) spectra, and Monte Carlo uninformative variable elimination (MC-UVE) spectra to determine the predictive performance of ECI model. Among the various qualitative identification models, it was found that the ECI-PLS-DA model, which is built using the differences in molecular chemical information between methanol and ethanol, exhibited sensitivity, specificity and accuracy values of 100%. The ECI-PLS-DA model accurately identified methanol gasoline and ethanol gasoline with different contents. In the quantitative analysis model for methanol gasoline, the methanol gasoline and ethanol gasoline ECI-PLS models exhibited the smallest root mean squared error of predictions (RMSEP) of 0.18 and 0.21% (v/v), respectively, compared to the other models. Meanwhile, the F-test and T-test results revealed that the NIR method employing the ECI-PLS model showed no significant difference compared to the standard method. Compared with other spectral models examined herein, the ECI model demonstrated the highest recognition success and determination accuracy. This study therefore established a highly accurate and rapid determination model for the qualitative identification and quantitative analysis based on chemical structures. It is expected that this model could be extended to the NIR analysis of other physicochemical properties of fuel.

Single-cell and multi-omics analyses highlight cancer-associated fibroblasts-induced immune evasion and epithelial mesenchymal transition for smoking bladder cancer.

Tobacco carcinogens are recognized as critical hazard factors for bladder tumorigenesis, affecting the prognosis of patients through aromatic amines components. However, the specific function of tobacco carcinogens and systematic assessment models in the prognosis of bladder cancer remains poorly elucidated. We retrieved bladder cancer specific tobacco carcinogens-related genes from Comparative Toxicogenomic Database, our Nanjing Bladder Cancer cohort and TCGA database. Gene×Gene interaction method was utilized to establish a prognostic signature. Integrative assessment of immunogenomics, tumor microenvironments and single-cell RNA-sequencing were performed to illustrate the internal relations of key events from different levels. Finally, we comprehensively identified 33 essential tobacco carcinogens-related genes to construct a novel prognostic signature, and found that high-risk patients were characterized by significantly worse overall survival (HR=2.25; Plog-rank < 0.01). Single-cell RNA-sequencing and multi-omics analysis demonstrated that cancer-associated fibroblasts mediated the crosstalk between epithelial-mesenchymal transition progression and immune evasion. Moreover, an adverse outcome pathway framework was established to facilitate our understanding to the tobacco carcinogens-triggered bladder tumorigenesis. Our study systematically provided immune microenvironmental alternations for smoking-induced adverse survival outcomes in bladder cancer. These findings facilitated the integrative multi-omics insights into risk assessment and toxic mechanisms of tobacco carcinogens.

Diagnosis, Treatment, and Associated Factors Among Patients with HCV Infection - Jiangsu Province, China, 2004-2020.

What is already known on this topic?: The global efforts to address the hepatitis C virus (HCV) are progressing, but there are still significant gaps in the diagnosis and treatment of HCV, leading to an increasing number of deaths related to HCV. What is added by this report?: An extensive investigation was conducted to assess HCV RNA diagnosis, treatment uptake, and associated factors among individuals infected with HCV within Jiangsu Province. The study encompassed a large geographical area and utilized a substantial sample size. What are the implications for public health practice?: Implementing focused interventions to improve the timely diagnosis of HCV RNA and increase the uptake of HCV treatment could effectively reduce the future burden of HCV-related health problems, deaths, and healthcare expenses. This is essential for achieving the global target of eliminating hepatitis C.