Search

Abstract 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.

Abstract 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.

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.

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.

Fine particulate matter (PM2.5) is known to enhance DNA damage levels and is involved in respiratory diseases. Exosomes can carry noncoding RNAs, especially long noncoding RNAs (lncRNAs), as regulators of DNA damage, which participate in diseases. However, their role in PM2.5-induced childhood asthma remains unclear. We performed RNA-seq to profile aberrantly expressed exosomal lncRNAs derived from PM2.5-treated human bronchial epithelial (HBE) cell models. The role of exosomal lncRNAs in childhood asthma was determined in a case–control study. The intercellular communication mechanisms of exosomal lncRNA on DNA damage were determined in vitro. Exosomes secreted by PM2.5-treated HBE cells (PM2.5-Exos) could increase the DNA damage levels of recipient HBE cells and promote the expression levels of airway remodeling-related markers in sensitive human bronchial smooth muscle cells (HBSMCs). LncRNA PM2.5-associated exosomal transcript (PAET) was highly expressed in PM2.5-Exos and was associated with PM2.5 exposure in childhood asthma. Mechanistically, exosomal lncRNA PAET promoted methyltransferase-like 3 (METTL3) accumulation by increasing its stability, which stimulated N6-methyladenosine (m6A) modification of cytochrome c oxidase subunit 4I1 (COX4I1), and COX4I1 levels were decreased in a mechanism dependent on the m6A “reader” YTH domain family 3 (YTHDF3). COX4I1 deficiency subsequently disrupted oxidative phosphorylation (OXPHOS), resulting in attenuated adenosine triphosphate (ATP) production and accumulation of reactive oxygen species (ROS), which increased DNA damage levels. This comprehensive study extends the understanding of PM2.5-induced childhood asthma via DNA damage and identifies exosomal lncRNA PAET as a potential target for childhood asthma.

Abstract Background Alternative splicing (AS)‐related single nucleotide polymorphisms (SNPs) are associated with risk of cancers, but the potential mechanism has not been fully elucidated. Methods Two‐stage case–control studies comprising 1630 cases and 2504 controls were conducted to investigate the association between the AS‐SNPs and bladder cancer susceptibility. A series of assays were used to evaluate the functional effect of AS‐SNPs on bladder cancer risk. Results We observed that SNP rs558814 A>G located in lncRNA BCLET (Bladder Cancer Low‐Expressed Transcript, ENSG00000245498) can decrease the risk of bladder cancer (odds ratio [OR] = 0.84, 95% confidence interval [CI] = 0.76–0.92, p = 3.26 × 10−4). Additionally, the G allele of rs558814 had transcriptional regulatory effects and facilitated the expression of BCLET transcripts, including BCLET‐long and BCLET‐short. We also found decreased BCLET expression in bladder cancer tissues and cells, and BCLET transcript upregulation substantially inhibited tumor growth of both bladder cancer cells and xenograft models. Mechanistically, BCLET recognized and regulated AS of MSANTD2 to participate in bladder carcinogenesis, preferentially promoting the production of MSANTD2‐004. Conclusions SNP rs558814 was associated with the expression of BCLET, which mainly increased the expression of MSANTD2‐004 through AS of MSANTD2.

Abstract Phycobilisomes (PBS) are the major light harvesting complexes of photosynthesis in the cyanobacteria and red algae. CpcL-PBS is a type of small PBS in cyanobacteria that transfers energy directly to photosystem I without the core structure. Here we report the cryo-EM structure of the CpcL-PBS from the cyanobacterium Synechocystis sp. PCC 6803 at 2.6-Å resolution. The structure shows the CpcD domain of ferredoxin: NADP+ oxidoreductase is located at the distal end of CpcL-PBS, responsible for its attachment to PBS. With the evidence of ultrafast transient absorption and fluorescence spectroscopy, the roles of individual bilins in energy transfer are revealed. The bilin 1Iβ82 2 located near photosystem I has an enhanced planarity and is the red-bilin responsible for the direct energy transfer to photosystem I.

Abstract Since the identification of the first case of pneumonia of unknown cause in 2019, the COVID‐19 pandemic has spread the globe for over 3 years. As the most populous country in the world, China's disease prevention policies and response plans concern the health of the country's 1.4 billion people and beyond. During the course of the pandemic, scientific research has been accumulated and given evidence‐based support to the official guidance of COVID‐19 management. The National Health Commission of China have compiled, published, and updated a total of 10 versions of the “Diagnosis and Treatment Protocol for COVID‐19 Patients” to better inform clinical practitioners and staff to effectively screen, diagnose, manage, treat, and care for cases of severe acute respiratory syndrome coronavirus 2 infection. This paper compares and summarizes each version of the protocol in terms of etiology and epidemiology, clinical manifestation and diagnosis, treatment and nursing, disease control and management, presenting detailed changes, additions, deletions, and refinement of the protocols.

This study took the Meijiang River Basin, China, as an example, to simulate the resilience interactions of three key subsystems of land, water and biodiversity from 2000 to 2015, using a spatially explicit model. Twelve environmental variables were selected from natural, landscape pattern and socioeconomic dimensions to detect the dominant factors of system resilience interactions using a geographic detector model. We found that the resilience of water yield, soil retention and biodiversity were mainly influenced by landscape pattern factors. Additionally, terrain is a main driver of soil retention resilience, precipitation plays a critical role influencing water yield resilience variations and biodiversity resilience variations remain stable influenced by landscape pattern. Larger synergy and loss occurred between water yield resilience and biodiversity resilience compared with other pairs of resilience, while greater tradeoffs occurred between soil retention resilience and biodiversity resilience. The interactions among landscape pattern, precipitation, terrain and GDP were the main driving forces of land and water resilience interactions. The interactions of landscape pattern and terrain were the main driving forces of land and biodiversity resilience interactions. The interactions of landscape pattern, precipitation and GDP were the main driving forces of water and biodiversity resilience interactions. Our study implied that improving habitat connectivity could maximize benefits. HIGHLIGHTS The resilience interactions of land, water and biodiversity are simulated using a spatially explicit model in the Meijiang River Basin, China.; Natural, landscape pattern and socioeconomic variables are selected to detect the dominant factors of system resilience interactions.; The embedded resilience interaction mechanisms for making adaptive strategies for sustainable watershed management are evaluated.;

A rare case of bacteremia caused by Escherichia albertii, in a 50-year-old male with liver cirrhosis was reported. Clear, colorless, and circular colonies were recovered on blood agar after 24 h of aerobic incubation at 37 °C. The isolate was identified as E. albertii using MALDI-TOF/MS and confirmed by the diagnostic triplex-PCR targeting clpX, lysP, and mdh genes. The administration of piperacillin/tazobactam intravenously (4.5g every 8 hours) for 3 days was effective. This study suggested that specific strains of E. albertii have been implicated in causing extraintestinal infections in humans, similar to extraintestinal pathogenic E. coli (ExPEC). However, a comprehensive understanding of the underlying pathogenic mechanisms requires further exploration.

Abstract Identification of cancer‐associated variants, especially those in functional regions of long noncoding RNAs (lncRNAs), has become an essential task in tumor etiology. However, the genetic function of lncRNA variants involved in bladder cancer susceptibility remains poorly understood. Herein, it is identified that the rs62483508 G > A variant in microRNA response elements (MREs) of lncRNA Bladder cancer Cell Cytoplasm‐Enriched abundant transcript 4 (BCCE4) is significantly associated with decreased bladder cancer risk (odds ratio = 0.84, P = 7.33 × 10−8) in the Chinese population (3603 cases and 4986 controls) but not in the European population. The protective genetic effect of the rs62483508 A allele is found in smokers or cigarette smoke‐related carcinogen 4‐aminobiphenyl (4‐ABP) exposure. Subsequent biological experiments reveal that the A allele of rs62483508 disrupts the binding affinity of miR‐328‐3p to facilitate USP18 from miRNA‐mediated degradation and thus specifically attenuates the downstream PD‐L1/PD‐1 interaction. LncRNA BCCE4 is also enriched in exosomes from bladder cancer plasma, tissues, and cells. This comprehensive study clarifies the genetic mechanism of lncRNA BCCE4 in bladder cancer susceptibility and its role in the regulation of the immune response in tumorigenesis. The findings provide a valuable predictor of bladder cancer risk that can facilitate diagnosis and prevention.

Background: Environmental pollutant measurement is essential for accurate health risk assessment. However, the detection of humans’ internal exposure to pollutants is cost-intensive and consumes time and energy. Polygenic risk scores (PRSs) have been widely applied in genetic studies of complex trait diseases. It is important to construct a genetically relevant environmental surrogate for pollutant exposure and to explore its utility for disease prediction and risk assessment. Objectives: This study enrolled 714 individuals with complete genomic data and exposomic data on 22 plasma-persistent organic pollutants (POPs). Methods: We first conducted 22 POP genome-wide association studies (GWAS) and constructed the corresponding environmental pollutant-based PRS (EpPRS) by clumping and P value thresholding (C + T), lassosum, and PRS-CS methods. The best-fit EpPRS was chosen by its regression R2. An adverse outcome pathway (AOP) framework was developed to assess the effects of contaminants on candidate diseases. Furthermore, Mendelian randomization (MR) analysis was performed to explore the causal association between POPs and cancer risk. Results: The C + T method produced the best-performing EpPRSs for 7 PCBs and 4 PBDEs. EpPRSs replicated the correlations of environmental exposure measurements based on consistent patterns. The diagnostic performance of type 2 diabetes mellitus (T2DM) PRS was improved by the combined model of T2DM-EpPRS of PCB126/BDE153. Finally, the AKT1-mediated AOP framework illustrated that PCB126 and BDE153 may increase the risk of T2DM by decreasing AKT1 phosphorylation through the cGMP-PKG pathway and promoting abnormal glucose homeostasis. MR analysis showed that digestive system tumors, such as colorectal cancer and biliary tract cancer, are more sensitive to POP exposure. Conclusions: EpPRSs can serve as a proxy for assessing pollutant internal exposure. The application of the EpPRS to disease risk assessment can reveal the toxic pathway and mode of action linking exposure and disease in detail, providing a basis for the development of environmental pollutant control strategies.

Abstract Background The genetic architectures of colorectal cancer are distinct across different populations. To date, the majority of polygenic risk scores (PRSs) are derived from European (EUR) populations, which limits their accurate extrapolation to other populations. Here, we aimed to generate a PRS by incorporating East Asian (EAS) and EUR ancestry groups and validate its utility for colorectal cancer risk assessment among different populations. Methods A large-scale colorectal cancer genome-wide association study (GWAS), harboring 35,145 cases and 288,934 controls from EAS and EUR populations, was used for the EAS-EUR GWAS meta-analysis and the construction of candidate EAS-EUR PRSs via different approaches. The performance of each PRS was then validated in external GWAS datasets of EAS (727 cases and 1452 controls) and EUR (1289 cases and 1284 controls) ancestries, respectively. The optimal PRS was further tested using the UK Biobank longitudinal cohort of 355,543 individuals and ultimately applied to stratify individual risk attached by healthy lifestyle. Results In the meta-analysis across EAS and EUR populations, we identified 48 independent variants beyond genome-wide significance (P < 5 × 10−8) at previously reported loci. Among 26 candidate EAS-EUR PRSs, the PRS-CSx approach-derived PRS (defined as PRSCSx) that harbored genome-wide variants achieved the optimal discriminatory ability in both validation datasets, as well as better performance in the EAS population compared to the PRS derived from known variants. Using the UK Biobank cohort, we further validated a significant dose-response effect of PRSCSx on incident colorectal cancer, in which the risk was 2.11- and 3.88-fold higher in individuals with intermediate and high PRSCSx than in the low score subgroup (P trend = 8.15 × 10−53). Notably, the detrimental effect of being at a high genetic risk could be largely attenuated by adherence to a favorable lifestyle, with a 0.53% reduction in 5-year absolute risk. Conclusions In summary, we systemically constructed an EAS-EUR PRS to effectively stratify colorectal cancer risk, which highlighted its clinical implication among diverse ancestries. Importantly, these findings also supported that a healthy lifestyle could reduce the genetic impact on incident colorectal cancer.

Tumor development is closely associated with a complex tumor microenvironment, which is composed of tumor cells, blood vessels, tumor stromal cells, infiltrating immune cells, and associated effector molecules. T helper type 17 (Th17) cells, which are a subset of CD4+ T cells and are renowned for their ability to combat bacterial and fungal infections and mediate inflammatory responses, exhibit context-dependent effector functions. Within the tumor microenvironment, different molecular signals regulate the proliferation, differentiation, metabolic reprogramming, and phenotypic conversion of Th17 cells. Consequently, Th17 cells exert dual effects on tumor progression and can promote or inhibit tumor growth. This review aimed to investigate the impact of various alterations in the tumor microenvironment on the antitumor and protumor effects of Th17 cells to provide valuable clues for the exploration of additional tumor immunotherapy strategies.

Fine particulate matter (PM2.5) exposure correlates with airway obstruction, but the mechanism remains to be fully elucidated. We aim to investigate the role of exosomal circular RNAs (circRNAs)-mediated communication between airway epithelial cells and airway smooth muscle cells in PM2.5-induced airway obstruction. RNA sequencing revealed that acute PM2.5 exposure altered the expression profiles of 2904 exosomal circRNAs. Among them, exosomal hsa_circ_0029069 (spliced from CLIP1, thus termed circCLIP1 hereafter) with a loop structure was upregulated by PM2.5 exposure and mainly encapsulated in exosomes. Then, the biological functions and the underlying mechanisms were explored by Western blot, RNA immunoprecipitation and RNA pull-down, etc. Phenotypically, exosomal circCLIP1 entered recipient cells, inducing mucus secretion in recipient HBE cells and contractility of sensitive HBSMCs. Mechanistically, circCLIP1 was upregulated by METTL3-mediated N6-methyladenine (m6A) modification in PM2.5-treated producer HBE cells and exosomes, then enhancing the expression of SEPT10 in recipient HBE cells and sensitive HBSMCs. Our study revealed that exosomal circCLIP1 played a critical role in PM2.5-induced airway obstruction and provided a new potential biomarker for the assessment of PM2.5-related adverse effects.

Among ornamental plants, the colour of the petals is an important feature. However, the reason for the colour differences of Rhododendron liliiflorum remains unclear. To reveal the differences in the colour of R. liliiflorum, high-efficiency liquid chromatographic collar (UPLC–MS/MS) technology was used to study the yellow and white parts of R. liliiflorum. A total of 1187 metabolites were identified in R. liliiflorum petals, including 339 flavonoid metabolites. Seventy-eight types of flavonoids in these metabolites were found in the yellow and white parts of R. liliiflorum petals, along with 11 other significantly enriched substances. Combining gene expression-related data with differential metabolite data demonstrated effects of enrichment in the flavanonols (fustin), flavonols (epiafzelechin and afzelechin), and flavanones (pinocembrin) of flavonoid biosynthesis; glyccitin, 6″-O-malonylgenistin, and 6-hydroxydaidzein of isoflavonoid biosynthesis; and anthocyanin biosynthesis of malvidin-3-O-galactoside (primulin), delphinidin-3-O-rutinoside, cyanidin-3-O-glucoside (kuromanin), and cyanidin-3-O-rutinoside (keracyanin), which are potentially the contributing factors responsible for the differences in petal colour in R. liliiflorum. This study establishes a connection between the differential metabolites underlying the color differences in the petals of R. liliiflorum and the gene expression in R. liliiflorum. This will provide a foundation for subsequent research on the regulation of flower color in R. liliiflorum and have profound implications for horticultural applications of R. liliiflorum.

Objective To evaluate the outcomes of Ilizarov ankle arthrodesis in the treatment of end‐stage varus ankle osteoarthritis (OA). Methods This was a retrospective study of 63 patients with varus ankle OA who underwent Ilizarov ankle arthrodesis between June 2013 and December 2018. There were 24 males and 39 females with an average age of 56.57 ± 4.45 years (range, 47–64 years). Thirty‐six cases were affected on the left side, and 27 were affected on the right side. The patients' mean body mass index (BMI) was 25.18 ± 2.93 kg/m2. According to the modified Takakura staging criteria, there were 18 cases of stage 3b (28.57%) and 45 cases of stage 4 (71.43%). Nine patients were primary (14.29%), 48 were traumatic (76.19%), and six were caused by rheumatoid OA (9.52%). Functional assessments were performed according to the American Orthopedic Foot and Ankle Society (AOFAS) ankle‐hindfoot score, Ankle Osteoarthritis Scale (AOS), and visual analogue scale (VAS). The tibial anterior surface angle (TAS), coronal plane tibial‐talar angle (CPT), talar tilt angle (TT), deformity angle (DA), and tibial lateral surface angle (TLS) were assessed on X‐ray films. Results The average operation time was 147.84 ± 13.67 min (range, 135–168 min). The average follow‐up time was 34.24 ± 8.72 months (range, 24–61 months). Bony fusion was achieved in all ankles, and the fusion time was 12.43 ± 1.99 weeks on average. The average AOFAS score at the final follow‐up increased from 42.14 ± 8.66 to 80.90 ± 6.80. The average VAS score and AOS pain and disability scores at the final follow‐up decreased from 7.29 ± 1.27 to 2.24 ± 0.94, from 67.94 ± 7.68 to 27.92 ± 5.82, and from 71.64 ± 9.37 to 41.32 ± 8.99, respectively. The average TAS, CPT, and TLS at the final follow‐up increased from 77.76° ± 4.44° to 89.81° ± 1.25°, from 69.04° ± 3.73° to 90.43° ± 1.80°, and from 82.14° ± 3.77° to 88.67° ± 2.50°, respectively. The average TT and DA at the final follow‐up decreased from 8.76° ± 4.30° to 2.05° ± 1.28° and from 20.95° ± 3.73° to 1.57° ± 0.93°, respectively. Three patients developed superficial pin tract infections, all settled with local dressing and antibiotic treatment. Two patients were found to have subtalar arthritis and underwent conservative treatment. Conclusion Ankle arthrodesis using the Ilizarov technique is efficient in treating end‐stage varus ankle OA.

Abstract Background The association between vitamin E and cancer risk has been widely investigated by observational studies, but the findings remain inconclusive. Here, we aimed to evaluate the causal effect of circulating vitamin E on the risk of ten common cancers, including bladder, breast, colorectal, esophagus, lung, oral and pharynx, ovarian, pancreatic, prostate, and kidney cancer. Methods A Mendelian randomization (MR) analytic framework was applied to data from a cancer-specific genome-wide association study (GWAS) comprising a total of 297,699 cancer cases and 304,736 controls of European ancestry. Three genetic instrumental variables associated with circulating vitamin E were selected. Summary statistic-based methods of inverse variance weighting (IVW) and likelihood-based approach, as well as the individual genotyping-based method of genetic risk score (GRS) were used. Multivariable IVW analysis was further performed to control for potential confounding effects. Furthermore, the UK Biobank cohort was used as external validation, supporting 355,543 European participants (incident cases ranged from 437 for ovarian cancer to 4882 for prostate cancer) for GRS-based estimation of circulating vitamin E, accompanied by a one-sample MR analysis of dietary vitamin E intake underlying the time-to-event analytic framework. Results Specific to cancer GWAS, we found that circulating vitamin E was significantly associated with increased bladder cancer risk (odds ratios [OR]IVW = 6.23, P IVW = 3.05×10-3) but decreased breast cancer risk (ORIVW = 0.68, P IVW = 8.19×10-3); however, the significance of breast cancer was dampened (P multivariable IVW > 0.05) in the subsequent multivariable MR analysis. In the validation stage of the UK Biobank cohort, we did not replicate convincing causal effects of genetically predicted circulating vitamin E concentrations and dietary vitamin E intake on the risk of ten cancers. Conclusions This large-scale population study upon data from cancer-specific GWAS and a longitudinal biobank cohort indicates plausible non-causal associations between circulating vitamin E and ten common cancers in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.

Diabetes has become a global public health problem. Diabetic foot is one of the most severe complications of diabetes, which often places a heavy economic burden on patients and seriously affects their quality of life. The current conventional treatment for the diabetic foot can only relieve the symptoms or delay the progression of the disease but cannot repair damaged blood vessels and nerves. An increasing number of studies have shown that mesenchymal stem cells (MSCs) can promote angiogenesis and re-epithelialization, participate in immune regulation, reduce inflammation, and finally repair diabetic foot ulcer (DFU), rendering it an effective means of treating diabetic foot disease. Currently, stem cells used in the treatment of diabetic foot are divided into two categories: autologous and allogeneic. They are mainly derived from the bone marrow, umbilical cord, adipose tissue, and placenta. MSCs from different sources have similar characteristics and subtle differences. Mastering their features to better select and use MSCs is the premise of improving the therapeutic effect of DFU. This article reviews the types and characteristics of MSCs and their molecular mechanisms and functions in treating DFU to provide innovative ideas for using MSCs to treat diabetic foot and promote wound healing.

Summary: Background: Polygenic risk score (PRS) has been demonstrated to be effective in identifying individuals at high risk of developing cancer, but its prognostic value remains unclear. Methods: We constructed site-specific PRSs by aggregating the risk effect of independent variants derived from previous genome-wide association studies (GWASs) across 17 cancer types. The Cox proportional hazards model was used to evaluate the association of each PRS with cancer survival, leveraging data from two prospective European cohorts, namely the UK Biobank involving 19,628 incident cases and The Cancer Genome Atlas involving 7079 prevalent cases. The combined PRS (CPRS), determined by merging site-specific PRSs, was further used to assess the prognostic effect of PRS on overall cancer in a sex-specific manner. Findings: We discovered that the cancer risk-related PRS was associated with neither overall survival (OS) nor cancer-specific survival (CSS) of each site-specific cancer with an underlying false discovery rate (FDR) P > 0.05, as evidenced by consistent findings from the two cohorts. Furthermore, the fixed-effect meta-analysis of the two cohorts provided no evidence to support for an association between CPRS and overall cancer survival in both males [OS: hazard ratio (HR)meta = 1.00, Pmeta = 0.760; CSS: HRmeta = 1.01, Pmeta = 0.447] and females (OS: HRmeta = 0.97, Pmeta = 0.067; CSS: HRmeta = 0.96, Pmeta = 0.054). Similar results were observed across multiple sensitivity analyses. Interpretation: Our findings indicate that the risk-specific PRS might not be a clinically useful tool in cancer prognosis prediction and further studies focusing on the development of polygenic prognostic score are warranted. Funding: This project was funded by the National Natural Science Foundation of China (82173601 and 82073631), and Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

Objective To explore the role of blood glucose, blood lipids, and androgen receptor gene (CAG)n genotype in the pathogenesis of osteoporosis in Chinese Han men and to provide theoretical value for screening people susceptible to osteoporosis. Methods Patients who visited the First Affiliated Hospital of Chengdu Medical College from February 2021 to October 2021 were selected as research subjects to measure bone density by double-energy X-ray, osteoporosis patients as osteoporosis group (40 patients), and non-osteoporosis patients as the control group (40 patients). The STR method detected the repeat times of the androgen receptor gene (CAG)n in the two groups. The repeat times ≤22 were the SS genotype, and >22 were the LL genotype. Meanwhile, the patient’s age, body mass index (BMI), blood glucose, blood lipids, calcium, phosphorus, and alkaline phosphatase examined on day one after admission were collected, and the statistical analysis was performed using SPSS 26.0. Results The results of the univariate analysis showed that there was no significant difference in age, calcium, phosphorus, alkaline phosphatase, and glycosylated hemoglobin between the two groups (P > 0.05). There were significant differences in average blood glucose, total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, and genotype frequency (P < 0.05). The multivariate logistic regression analysis results showed significant differences in total cholesterol and genotype frequency between the two groups (P < 0.05). Conclusion Androgen receptor LL genotype and elevated total cholesterol may be the risk factors for osteoporosis in older men of Han nationality.

Abstract Background Exosomes have emerged as vital biomarkers of multiple cancers and contain abundant circular RNAs (circRNAs). However, the potential for exosomal circRNAs to be used in diagnostics and their molecular mechanism of action in colorectal cancer (CRC) remain unclear. Methods CRC-specific exosomal circRNAs were identified by RNA sequencing, exoRBase database and a tissue microarray. The diagnostic performance of plasma exosomal circRNAs was evaluated among cancer-free controls, precancer individuals, CRC patients, and patients with other types of cancer. The corresponding biological functions were mainly assessed using circRNA pull-down, proteomic analysis, and RNA immunoprecipitation assay underlying cellular and mouse models. Results CircLPAR1 was encapsulated in exosomes with high stability and detectability, and its expression in plasma exosomes was remarkably decreased during CRC development but recovered after surgery. Exosomal circLPAR1 showed cancer specificity in CRC diagnosis and increased the diagnostic performance to an area under the receiver operating characteristic curve of 0.875, as determined by analysing its performance in combination with common clinical biomarkers CEA and CA19–9. Additionally, circLPAR1 was downregulated in CRC tissues and was associated with overall survival. Mechanistically, exosomal circLPAR1 was internalized by CRC cells, and it suppressed tumor growth, likely because exosomal circLPAR1 directly bound with eIF3h specifically suppressed the METTL3-eIF3h interaction, decreasing the translation of oncogene BRD4. Conclusions This comprehensive study highlights plasma exosomal circLPAR1 as a promising predictor in CRC diagnosis and describes its biological regulation of colorectal tumorigenesis. This study provides a new perspective on early diagnosis in the clinic and pathogenesis in disease development.

Abstract Background Few studies focus on the treatment of femoral head fracture combined with posterior hip dislocation, and the safe interval time between injury and hip reduction remains controversial. The purpose of this study was to evaluate and compare the outcome of early and delayed hip reduction in the surgical treatment of femoral head fracture combined with posterior hip dislocation. Methods A total of 71 patients were evaluated in this retrospective study. Based on the time to hip reduction, they were divided into early group (within 6 h after injury) and delayed group (between 6 and 12 h after injury). The two groups were compared in reference to hospital day, fracture healing time, the occurrence of complications and final functional outcome. The Thompson-Epstein criteria, modified Merle D’Aubigné and Postel scores, visual analog scale (VAS) and Medical Outcomes Short Form 12-item questionnaire score (SF-12) were used for final functional evaluation. Results The mean hospital stay and fracture healing time in the early group were significantly lower than those in the delayed group. The incidence of infection, post-traumatic osteoarthritis, and avascular necrosis of the femoral head (ANFH) in the delayed group were higher than that in the early group. The early group had better functional outcomes in terms of Thompson-Epstein criteria, modified Merle D’Aubigné and Postel scores and physical component scale (PCS) than the delayed group. Conclusions For the treatment of femoral head fracture combined with posterior hip dislocation, the early and prompt hip reduction can effectively facilitate the fracture healing and patient rehabilitation, and obtain a better functional outcome.

Abstract Background Streptococcus pneumoniae (S. pneumoniae) is the common cause of community-acquired pneumonia (CAP) and is also found in the upper respiratory tract of healthy people. Hence, the study aimed to compare the serotypes, virulence/pili genes, and antibiotic susceptibility of S. pneumoniae from healthy asymptomatic participants and CAP patients. Methods Streptococcus pneumoniae were retrospectively collected from health asymptomatic participants and CAP patients in Sichuan, China. The serotypes were tested by multiplex polymerase chain reaction (PCR) or Quellung reaction. Antibiotic susceptibility testing was performed using the broth microdilution method. The molecular epidemiology of S. pneumoniae was analyzed by multilocus sequence typing (MLST). Additionally, the presence of virulence/pili genes were detected using PCR. Results A total of 83 pneumococcal isolates were collected in the current study. Of these, 52 and 31 isolates were from healthy asymptomatic participants and CAP patients, respectively. Most of S. pneumoniae were resistant to erythromycin (ERY), clindamycin (CLI), tetracycline (TET) and trimethoprim-sulfamethoxazole (SXT). 90.4% isolates were classified as multidrug resistant (MDR). The predominant serotypes were 3, 19F and 19A in the CAP carriers, whereas 3, 6 and 19F were the main serotypes among the asymptomatic carriers. The overall coverage rates of pneumococcal conjugate vaccine (PCV) 10 and PCV13 serotypes were 34.9% and 66.3%, respectively. The predominant sequence types (STs) were ST271, ST320, and ST3397. There were significant differences in some resistance and virulence characteristics between CAP patients and asymptomatic carriers. Additionally, clonal complex (CC) 271 strains had higher percentage in resistance to cefuroxime (CXM) and cefotaxime (CEF), meropenem (MER) and cefepime (CFP), which mainly carried the rlrA and sipA genes. Conclusions High coverage rate of PCV13 and high prevalence of MDR indicated the necessity to expand immunization with PCV13 and rationally use the antibiotics in Sichuan, China. Importantly, long-term surveillance should be conducted to assess effectiveness brought by vaccines. Our findings may supply new guidance for developing new pneumococcal vaccines.

13C metabolic flux analysis (13C-MFA) has emerged as a forceful tool for quantifying in vivo metabolic pathway activity of different biological systems. This technology plays an important role in understanding intracellular metabolism and revealing patho-physiology mechanism. Recently, it has evolved into a method family with great diversity in experiments, analytics, and mathematics. In this review, we classify and characterize the various branch of 13C-MFA from a unified perspective of mathematical modeling. By linking different parts in the model to each step of its workflow, the specific technologies of 13C-MFA are put into discussion, including the isotope labeling model (ILM), isotope pattern measuring technique, optimization algorithm and statistical method. Its application in physiological research in neural cell has also been reviewed.

ObjectiveTo describe the demographic characteristics, risk factors, and bacterial resistance of fracture-related infection (FRI) of the long bones of the extremities.Materials and MethodsThis single-center study retrospectively evaluated patients with FRI of the long bones of the extremities at West China Hospital between January 2012 and December 2017, and analyzed the demographic characteristics, risk factors, distribution of pathogenic bacteria, and bacterial drug resistance.ResultsAmong 9,900 patients, 535 patients (5.4%) were diagnosed with FRI. The most common site of FRI was tibiofibular (298, 55.7%), with 424 cases (79.2%) of open fractures, and 282 cases (52.7%) due to traffic injuries. The 41–50 years age group had the highest incidence of FRI with 157 (29.3%) cases. Overall, 546 strains of 52 types of bacteria were detected in FRI patients, with 105 strains of multidrug-resistant (MDR) bacteria. Methicillin-resistant Staphylococcus aureus (48, 8.8%) and extended-spectrum-β-lactamase Escherichia coli (32, 5.8%) accounted for the largest proportion. Multivariate logistic regression analysis showed that sex (odds ratio [OR] 1.813; 95% confidence interval [CI], 1.071∼3.070; P = 0.027) and fracture type (OR 3.128; 95% CI, 1.683∼5.815; P < 0.001) were independent risk factors for monomicrobial infection (MI). Female sex (OR 4.190; 95% CI, 1.212∼14.486; P = 0.024) was an independent risk factor for polymicrobial infection (PI).ConclusionThis study clarified the infection rates, changes in the bacterial spectrum, and drug resistance characteristics, and risk factors of FRI of the long bones of the extremities in the largest trauma center in southwest China.

Abstract Small non-coding RNAs (ncRNAs) are vital regulators of biological activities, and aberrant levels of small ncRNAs are commonly found in precancerous lesions and cancer. PIWI-interacting RNAs (piRNAs) are a novel type of small ncRNA initially discovered in germ cells that have a specific length (24–31 nucleotides), bind to PIWI proteins, and show 2′-O-methyl modification at the 3′-end. Numerous studies have revealed that piRNAs can play important roles in tumorigenesis via multiple biological regulatory mechanisms, including silencing transcriptional and posttranscriptional gene processes and accelerating multiprotein interactions. piRNAs are emerging players in the malignant transformation of normal cells and participate in the regulation of cancer hallmarks. Most of the specific cancer hallmarks regulated by piRNAs are involved in sustaining proliferative signaling, resistance to cell death or apoptosis, and activation of invasion and metastasis. Additionally, piRNAs have been used as biomarkers for cancer diagnosis and prognosis and have great potential for clinical utility. However, research on the underlying mechanisms of piRNAs in cancer is limited. Here, we systematically reviewed recent advances in the biogenesis and biological functions of piRNAs and relevant bioinformatics databases with the aim of providing insights into cancer diagnosis and clinical applications. We also focused on some cancer hallmarks rarely reported to be related to piRNAs, which can promote in-depth research of piRNAs in molecular biology and facilitate their clinical translation into cancer treatment.

Rhododendron liliiflorum H. Lév., with white outer edges and yellow inner edges of petals, is an ornamental flower that originated in China. In this study, we analysed the white (W) and yellow (Y) parts of R. liliiflorum flowers by RNA sequencing. Then, unigene assembly, unigene annotation, and classification of Eukaryotic Orthologous Groups (KOGs) were performed. Gene ontology (GO) classification and pathway enrichment analysis for unigenes were also conducted. A total of 219,221 transcripts and 180,677 unigenes of R. liliiflorum were obtained from 48.52 Gb of clean reads. Differentially expressed gene (DEG) analysis indicated that 2310 unigenes were upregulated and 3062 were downregulated in W vs. Y. Thirty-six of these DEGs were involved in the flavonoid biosynthesis pathway. Pathway enrichment analysis showed that DEGs were significantly enriched in phenylpropanoid, flavonoid, and isoflavone biosynthesis. The expression of dihydroflavonol-4-reductase (DFR) and chalcone synthase (CHS) may affect differences in R. liliiflorum flower colour. The findings on flavonoid biosynthesis and other related genes in this study will provide guidance for exploring the mechanism of flower colour formation in Rhododendron.

Osteoclasts and osteoblasts play a major role in bone tissue homeostasis. The homeostasis and integrity of bone tissue are maintained by ensuring a balance between osteoclastic and osteogenic activities. The remodeling of bone tissue is a continuous ongoing process. Osteoclasts mainly play a role in bone resorption, whereas osteoblasts are mainly involved in bone remodeling processes, such as bone cell formation, mineralization, and secretion. These cell types balance and restrict each other to maintain bone tissue metabolism. Bone tissue is very sensitive to mechanical stress stimulation. Unloading and loading of mechanical stress are closely related to the differentiation and formation of osteoclasts and bone resorption function as well as the differentiation and formation of osteoblasts and bone formation function. Consequently, mechanical stress exerts an important influence on the bone microenvironment and bone metabolism. This review focuses on the effects of different forms of mechanical stress stimulation (including gravity, continuously compressive pressure, tensile strain, and fluid shear stress) on osteoclast and osteoblast function and expression mechanism. This article highlights the involvement of osteoclasts and osteoblasts in activating different mechanical transduction pathways and reports changings in their differentiation, formation, and functional mechanism induced by the application of different types of mechanical stress to bone tissue. This review could provide new ideas for further microscopic studies of bone health, disease, and tissue damage reconstruction.

Abstract Fine particulate matter less than 2.5 µm in diameter (PM2.5) is a major risk factor for acute asthma attacks in children. However, the biological mechanism underlying this association remains unclear. In the present study, PM2.5‐treated HBE cells‐secreted extracellular vesicles (PM2.5‐EVs) caused cytotoxicity in “horizontal” HBE cells and increased the contractility of “longitudinal” sensitive human bronchial smooth muscle cells (HBSMCs). RNA sequencing showed that let‐7i‐5p is significantly overexpressed in PM2.5‐EVs and asthmatic plasma; additionally, its level is correlated with PM2.5 exposure in children with asthma. The combination of EV‐packaged let‐7i‐5p and the traditional clinical biomarker IgE exhibits the best diagnostic performance (area under the curve [AUC] = 0.855, 95% CI = 0.786–0.923). Mechanistically, let‐7i‐5p is packaged into PM2.5‐EVs by interacting with ELAVL1 and internalized by both “horizontal” recipient HBE cells and “longitudinal” recipient‐sensitive HBSMCs, with subsequent activation of the MAPK signaling pathway via suppression of its target DUSP1. Furthermore, an injection of EV‐packaged let‐7i‐5p into PM2.5‐treated juvenile mice aggravated asthma symptoms. This comprehensive study deciphered the remodeling of the extracellular environment mediated by the secretion of let‐7i‐5p‐enriched EVs during PM2.5‐induced asthma attacks and identified plasma EV‐packaged let‐7i‐5p as a novel predictor of childhood asthma.

Background A precise map of the metabolic fluxome, the closest surrogate to the physiological phenotype, is becoming progressively more important in the metabolic engineering of photosynthetic organisms for biofuel and biomass production. For photosynthetic organisms, the state-of-the-art method for this purpose is instationary 13C fluxomics, which has arisen as a sibling of transcriptomics or proteomics. Instationary 13C data processing requires solving high-dimensional nonlinear differential equations and leads to large computational and time costs when its scope is expanded to a genome-scale metabolic network. Result Here, we present a parallelized method to model instationary 13C labeling data. The elementary metabolite unit (EMU) framework is reorganized to allow treating individual mass isotopomers and breaking up of their networks into strongly connected components (SCCs). A variable domain parallel algorithm is introduced to process ordinary differential equations in a parallel way. 15-fold acceleration is achieved for constant-step-size modeling and ~ fivefold acceleration for adaptive-step-size modeling. Conclusion This algorithm is universally applicable to isotope granules such as EMUs and cumomers and can substantially accelerate instationary 13C fluxomics modeling. It thus has great potential to be widely adopted in any instationary 13C fluxomics modeling.

Abstract Background Neonatal listeriosis is a rare but severe disease manifesting as septicemia and central nervous system (CNS) infections with a high fatality rate of around 20 to 30%. Whole genome sequencing (WGS) is a promising technique for pathogen identification and infection source tracing with its high resolution. Case presentation A case of neonatal sepsis with listeriosis was reported with positive blood culture for Listeria monocytogenes. The case was investigated to confirm the vertical transmission of the infection and identify the potential food source of the maternal L. monocytogenes infection using WGS. L. monocytogenes was isolated from the neonate’s blood sample the day after caesarean delivery and from the mother’s genital and pudenda swab samples 5 days and 13 days after caesarean delivery. WGS showed that the isolate from the neonate was identical to the genome type of the isolates from the mother, with only one of the 4 isolates from the mother differing by one single nucleotide polymorphism (SNP). By WGS, one L. monocytogenes isolate from a ready-to-eat (RTE) meat sample in the patients’ community market shared the same sequence type but was ruled out as the cause of infection, with 57 SNP differences to the strain causing the maternal-neonatal infection. The food isolate also carried a novel plasmid pLM1686 that harbored heavy metal resistance genes. After caesarean section, the mother was treated with a third generation cephalosporin which L. monocytogenes is naturally resistant to, which may explain why genital and pudenda swabs were still culture-positive for L. monocytogenes 13 days after delivery. Conclusions Genital swab culture for L. monocytogenes had been informative in the diagnosis of maternal listeriosis in this case. The high resolution of WGS confirmed the maternal-neonatal transmission of L. monocytogenes infection and ruled out the L. monocytogenes contaminated RTE meat from the local market as the direct source of the mother’s infection.

Abstract Background The topic that whether the injured deltoid ligament should be repaired when associated with ankle joint fractures is still discussed. The objective of this study was to compare the clinical effect of open reduction and internal fixation (ORIF) with deltoid ligament repair (DLR) or transarticular external fixation (TEF) in treating supination-external rotation type IV (SER IV) ankle fractures. Methods Between January 2012 and December 2015, 43 patients were diagnosed as SER IV ankle fractures, 20 underwent ORIF and transarticular external fixation (TEF) without DLR (group 1), 23 were treated with ORIF and DLR (group 2). The pre- and post-operative radiographic examination were performed, the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, the visual analog scale (VAS), the Medical Outcomes Short Form 36-item questionnaire score (SF-36), and the ankle range of motion (ROM) were used for functional evaluation. Results In both groups, the three scores improved significantly after surgery, but there was no significant difference between the two groups. At 6 weeks after surgery, patients in group 2 had better ankle ROM than group 1 (29.35 ± 2.033 vs. 40.35 ± 3.550, P

Objectives: To explore and understand the SARS-CoV-2 seroprevalence of convalescents, the association between antibody levels and demographic factors, and the seroepidemiology of convalescents of COVID-19 till March 2021.Methods: We recruited 517 voluntary COVID-19 convalescents in Sichuan Province and collected 1,707 serum samples till March 2021. Then we reported the seroprevalence and analyzed the associated factors.Results: Recent travel history was associated with IgM levels. Convalescents who had recent travel history were less likely to be IgM antibody negative [OR = 0.232, 95% CI: (0.128, 0.420)]. Asymptomatic cases had, approximately, twice the odds of being IgM antibody negative compared with symptomatic cases [OR = 2.583, 95% CI: (1.554, 4.293)]. Participants without symptoms were less likely to be IgG seronegative than those with symptoms [OR = 0.511, 95% CI: (0.293, 0.891)]. Convalescents aged 40–59 were less likely to be IgG seronegative than those aged below 20 [OR = 0.364, 95% CI: (0.138, 0.959)]. The duration of positive IgM antibodies persisted 365 days while the IgG persisted more than 399 days.Conclusions: Our findings suggested that recent travel history might be associated with the antibody levels of IgM, while age could be associated with the antibody levels of IgG. Infection type could be associated with both antibody levels of IgM and IgG that declined quicker in asymptomatic cases.

Dichlorodiphenyldichloroethylene (DDE) is the major and most stable toxic metabolite of dichlorodiphenyltrichloroethane (DDT), a well-known organochlorine pesticide banned worldwide in the 1980s. However, it remains easy to detect in humans, and internal levels vary widely among individuals. In the present study, a genome-wide association study (GWAS) (511 subjects) and two replications (812 and 1030 subjects) were performed in non-occupational populations in eastern China. An estimated dietary intake (EDI) of p, p′-DDT and p, p′-DDE was calculated by a food frequency questionnaire (FFQ) and the determination of 195 food and 85 drinking water samples. In addition, functional verifications of susceptible loci were performed by dual-luciferase reporter, immunoblotting and metabolic activity assays in vitro. p, p′-DDT and p, p′-DDE were measured using gas chromatography-tandem mass spectrometry (GC-MS/MS). A common loci rs3181842 (high linkage equilibrium with rs2279345) in CYP2B6 at 19p13.2 were found to be strongly associated with low serum levels of p, p′-DDE in this population in GWAS and were verified by two replications and combined analysis of 2353 subjects (P = 1.00 × 10-22). In addition, p, p′-DDE levels were significantly lower in subjects with the rs3181842 C allele than in those carrying the normal genotype, even in individuals with similar EDIs of p, p′-DDT. Furthermore, the rs3181842 C allele functionally led to low CYP2B6 expression and activity, resulting in a low metabolic capacity for the formation of p, p′-DDE from p, p′-DDT. The study highlighted that CYP2B6 variants were more relevant than environmental exposure to internal p, p′-DDE exposure, which is important information for DDT risk assessments.

Two types of cyanobacterial phycobilisomes (PBS) are present: the hemidiscoidal PBS (CpcG-PBS) and the membrane-bound PBS (CpcL-PBS). Both types of PBS have ferredoxin:NADP+ oxidoreductase (FNR) attached to the termini of their rods through a CpcD domain. To date, the physiological significance of the attachment remains unknown. We constructed a mutant (dF338) which contains an FNR lacking the N-terminal CpcD domain in Synechococcus sp. PCC 7002. Isolated CpcG-PBS from dF338 did not contain FNR and the cell extracts of the mutant had a 35 kDa protein cross-reacting to anti-FNR antibodies. dF338 grows normally under photoautotrophic conditions, but little growth was observed under photoheterotrophic conditions. A cpcL (cpcG2) mutant grows extremely slowly under photoheterotrophic conditions while a cpcG (cpcG1) mutant, in which PBS rods could not attach to the cores of the CpcG-PBS, can grow photoheterotrophically, strongly suggesting that the attachment of FNR to CpcL-PBS is critical to photoheterotrophic growth. We show that electron transfer to the plastoquinone pool in dF338 and the cpcL mutant was impaired. We also provide evidence that trimeric photosystem I (PSI) and intact CpcL-PBS with a full-length FNR is critical to plastoquinone reduction. The presence of a NADPH-dehydrogenase (NDH)-CpcL-PBS-PSI trimer supercomplex and its roles are discussed.

The distribution of water resources is usually characterized by spatial heterogeneity, resulting in different water supply and demand pressures within the basin. Therefore, the analysis of water resources supply and demand balance and the mapping of water resources spatial flow can be an effective suggestion for the regional water resources allocation to relieve the regional water pressure. The uneven distribution of water resources in the Dongjiang River Basin is significant, and how to effectively allocate water resources in the Dongjiang River Basin has become a major focus of research. Based on the multi-source data of the Dongjiang River Basin from 2005 to 2020, this paper uses the SWAT model and water demand model to establish the spatial flow model of water resources supply and demand, and uses the subbasin-scale to explore the spatial distribution and flow of water resources supply and demand, obtaining the spatial scope and flow of water resources supply and beneficiary areas in the basin. The results show that (1) the water supply in the Dongjiang River Basin has been decreasing year by year, and the water demand has been increasing from 2005 to 2015, leading to an increase in the imbalance between supply and demand, and there is a significant reduction in industrial water use from 2015 to 2020, resulting in a reduction in the imbalance between water supply and demand; (2) the supply and demand pressure of water resources in the Dongjiang River Basin has obvious spatial heterogeneity, showing that the pressure of water use in the middle and upper reaches is small, while the pressure of water use in the lower reaches is large; (3) under the framework of spatial service flows of water resources supply and demand, this paper obtains three main beneficiary area ranges, which are Dongyuan County of Heyuan City, Yuancheng District of Heyuan City, and the main urban area of Shenzhen Dongguan Huizhou, and specifies the flow of service flows. This study can not only provide reasonable suggestions for water resources allocation in the Dongjiang River Basin but it also provides references for water resources management in other basins.

Abstract Background Extracellular communication within the tumor microenvironment plays a critical role in tumor progression. Although exosomes can package into long non-coding RNAs (lncRNAs) to mediate extracellular communication, the role of exosomal lncRNA PTENP1 in bladder cancer (BC) remains unclear. Method We detected PTENP1 expression between patients with BC and healthy controls; the expression occurred in tissues and exosomes from plasma. We assessed the diagnostic accuracy by the receiver operating characteristic curve (ROC) and the area under curve (AUC). Cell phenotypes and animal experiments were performed to determine the effect of exosomal PTENP1. Results PTENP1 was significantly reduced in BC tissues and in exosomes from plasma of patients with BC (P

Background: Fine particulate matter (PM2.5) is suspected to increase the risk of colorectal cancer, but the mechanism remains unknown. We aimed to investigate the association between PM2.5 exposure, genetic variants and colorectal cancer risk in the Prostate, Lung, Colon and Ovarian (PLCO) Cancer Screening trial. Methods: We included a prospective cohort of 139,534 cancer-free individuals from 10 United States research centers with over ten years of follow-up. We used a Cox regression model to assess the association between PM2.5 exposure and colorectal cancer incidence by calculating the hazard ratio (HR) and 95% confidence interval (CI) with adjustment for potential confounders. The polygenic risk score (PRS) and genome-wide interaction analysis (GWIA) were used to evaluate the multiplicative interaction between PM2.5 exposure and genetic variants in regard to colorectal cancer risk. Results: After a median of 10.43 years of follow-up, 1,666 participants had been diagnosed with colorectal cancer. PM2.5 exposure was significantly associated with an increased risk of colorectal cancer (HR = 1.27; 95% CI = 1.17–1.37 per 5 μg/m3 increase). Five independent susceptibility loci reached statistical significance at P

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD) in many developed and developing countries. Pyroptosis is a recently discovered form of programmed cell death (PCD). With progress in research on DKD, researchers have become increasingly interested in elucidating the role of pyroptosis in DKD pathogenesis. This review focuses on the three pathways of pyroptosis generation: the canonical inflammasome, non-canonical inflammasome, and caspase-3-mediated inflammasome pathways. The molecular and pathophysiological mechanisms of the pyroptosis-related inflammasome pathway in the development of DKD are summarized. Activation of the diabetes-mediated pyroptosis-related inflammasomes, such as nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), Toll-like receptor 4 (TLR4), caspase-1, interleukin (IL)-1β, and the IL-18 axis, plays an essential role in DKD lesions. By inhibiting activation of the TLR4 and NLRP3 inflammasomes, the production of caspase-1, IL-1β, and IL-18 is inhibited, thereby improving the pathological changes associated with DKD. Studies using high-glucose–induced cell models, high-fat diet/streptozotocin-induced DKD animal models, and human biopsies will help determine the spatial and temporal expression of DKD inflammatory components. Recent studies have confirmed the relationship between the pyroptosis-related inflammasome pathway and kidney disease. However, these studies are relatively superficial at present, and the mechanism needs further elucidation. Linking these findings with disease activity and prognosis would provide new ideas for DKD research.

The long non-coding RNA (lncRNA) H19 has been demonstrated to play a crucial role in carcinogenesis, including renal cell carcinoma (RCC). However, the impact of genetic variations in H19 gene on RCC has not been investigated before. In the present study, we sought to evaluate whether genetic polymorphisms in H19 are related to the susceptibility and mortality of RCC. We genotyped four widely studied polymorphisms in H19 and assessed their relationship with susceptibility and prognosis of RCC in a case-control study compromising 1,027 cases and 1,094 controls. The functionality of the important polymorphism was further investigated by real-time polymerase chain reaction and luciferase reporter assay. We found that H19 rs2839698 was significantly associated with risk and prognosis of RCC. Compared with the H19 rs2839698 CC genotype, the variant genotypes (CT/TT) were significantly associated with increased risk of RCC (P = 0.023, OR = 1.21; 95% CI = 1.03–1.45). Besides, patients with variant genotypes (CT/TT) were more likely to develop large tumor (P = 0.003, OR = 1.47; 95% CI = 1.16–1.85) and advanced disease (P = 0.010, OR = 1.59; 95% CI = 1.12–2.26); and had a significantly unfavorable overall survival than those with the rs2839698 CC genotype (CT/TT vs. CC: Log-rank P = 0.026, HR = 2.25, 95%CI = 1.07–4.75). Furthermore, the CT/TT genotypes were associated with significantly increased expression of H19 in renal tissue. The luciferase reporter assays revealed the potential effect of rs2839698 variant on the binding of microRNAs to H19. Our results suggest that the H19 rs2839698 variant may be a genetic predictor of susceptibility and mortality of RCC. The risk effects and the functional impact of the variant on H19 still need further validation.

Objective: The different incidence of colorectal cancer between the sexes suggests that sex hormones may be involved in the susceptibility to colorectal cancer. The association between sex hormones and genetic variants in hormone metabolic pathways and the colorectal cancer risk remains unclear. Methods: We detected sex hormone levels in plasma from colorectal cancer patients and controls in males by ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We evaluated the clinical significance of sex hormones on colorectal cancer diagnosis with the area under the receiver operating characteristic curve (AUC). The role of genetic variants in hormone metabolic pathways in the colorectal cancer risk was assessed by a logistic regression model. The biological functions were detected by luciferase reporter assays and cell behavior experiments. Results: We found that 2-methoxyestrone (2-MeO-E1) was highly expressed in cases (PFDR = 3.48 × 10−19). The expression of 2-MeO-E1 in plasma showed improved accuracy for predicting colorectal cancer (AUC = 0.88). In the 2-MeO-E1 metabolic pathway, rs165599 in COMT was significantly associated with an increased risk of colorectal cancer (P = 0.009). Mechanistically, we found that the rs165599 G allele could decrease the binding ability of miR-22-3p to the COMT 3′-UTR. Furthermore, knockdown of COMT inhibited cell proliferation, induced cell apoptosis and arrested the cell cycle in the G1 phase. Conclusion: This is the first study to show that 2-MeO-E1 and a genetic variant in COMT contribute to the susceptibility to colorectal cancer. These results shed light on the different incidence of colorectal cancer between the sexes. Keywords: Sex hormone, UPLC-MS/MS, Colorectal cancer, Genetic variants

Backgrounds: Genome-wide association studies (GWASs) have identified several gastric cancer (GC) susceptibility loci in Asians, but their effects on disease outcome are still unknown. This study aimed to investigate whether these GWAS-identified genetic variants could serve as robust prognostic biomarkers for GC. Methods: A multistage clinical cohort, including a total of 2432 GC patients in the Chinese population, was used to identify the association between GWAS-identified risk variants and overall survival of GC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed by Cox regression analysis, and the log-rank P was calculated by the log-rank test with the Kaplan-Meier method. Results: We found that rs2274223 A>G in PLCE1 was associated with increased GC survival in both training set (P = .011), which was independently replicated in validation set 1 (P = .045), but not in validation set 2. The area under the curve (AUC) from receiver-operator characteristic (ROC) curve showed this clinical relevance with onset age-dependence, especially in the subgroup of early-onset cases. Moreover, a significant improvement in overall survival prediction was identified when the rs2274223 genetic effect was included in the estimation; this result was also supported by the prognostic nomogram. In addition, patients with lower expression of PLCE1 showed benefits via longer survival, potentially due to the functional effect of rs2274223. Interpretation: This preliminary study suggests that a GWAS-identified genetic variant in PLCE1 may serve as a potential biomarker for GC survival. Additional replication with larger samples size is warranted to further investigation. Keywords: GWAS, Genetic variants, Gastric cancer, Survival

Abstract Background Emerging evidence has shown that dysregulation function of long non-coding RNAs (lncRNAs) implicated in gastric cancer (GC). However, the role of the differentially expressed lncRNAs in GC has not fully explained. Methods LncRNA expression profiles were determined by lncRNA microarray in five pairs of normal and GC tissues, further validated in another 75 paired tissues by quantitative real-time PCR (qRT-PCR). Overexpression of lncRNA MT1JP was conducted to assess the effect of MT1JP in vitro and in vivo. The biological functions were demonstrated by luciferase reporter assay, western blotting and rescue experiments. Results LncRNA MT1JP was significantly lower in GC tissues than adjacent normal tissues, and higher MT1JP was remarkably related to lymph node metastasis and advance stage. Besides, GC patients with higher MT1JP expression had a well survival. Functionally, overexpression of lncRNA MT1JP inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro, and inhibited tumor growth and metastasis in vivo. Functional analysis showed that lncRNA MT1JP regulated FBXW7 expression by competitively binding to miR-92a-3p. MiR-92a-3p and down-regulated FBXW7 reversed cell phenotypes caused by lncRNA MT1JP by rescue analysis. Conclusion MT1JP, a down-regulated lncRNA in GC, was associated with malignant tumor phenotypes and survival of GC. MT1JP regulated the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate FBXW7 expression. Our study provided new insight into the post-transcriptional regulation mechanism of lncRNA MT1JP, and suggested that MT1JP may act as a potential therapeutic target and prognosis biomarker for GC.

Abstract MicroRNAs (miRNAs), endogenous small noncoding RNAs (ncRNAs), play crucial roles in cancer development. Many studies have demonstrated that miRNAs can serve as diagnostic and therapeutic biomarkers for malignancies. Additionally, single nucleotide polymorphisms (SNPs) located in miRNA functional regions have been reported to be involved in cancer susceptibility. In this study, we investigated the associations between SNPs located in miRNA functional regions and colorectal cancer (CRC) susceptibility. We systematically screened all candidate miRNAs and their SNPs and then evaluated the relationships between the SNPs and CRC susceptibility in a Han Chinese population including 878 patients with CRC and 884 controls. Genotyping was performed by TaqMan assay. After comprehensively screening the miRNAs and SNPs, we elected to evaluate the association between SNP rs2682818 in miR‐618 and CRC susceptibility. We found that the AA and AC/AA genotypes of rs2682818 were associated with a decreased risk of CRC compared with the CC genotype (odds ratio (OR) = 0.54, 95% confidence interval (CI) = 0.37–0.79 for AA vs. CC in codominant model; OR = 0.82, 95% CI = 0.68–0.99 for AC/AA vs. CC in dominant model). However, we obtained no statically significant results in our subgroup analyses. SNP rs2682818 in miR‐618 has potential as a biomarker for individuals with high CRC susceptibility. Our findings need to be verified in studies including larger samples. Moreover, molecular functional studies of miR‐681 must be performed to confirm its relationship with CRC.