BACKGROUND: Bile acids (BAs) facilitate the progression of gastric intestinal metaplasia (GIM). Long non-coding RNAs (lncRNAs) dysregulation was observed along with the initiation of gastric cancer. However, how lncRNAs function in GIM remains unclear. This study aimed to explore the role and mechanism of lncRNA PVT1 in GIM, and provide a potential therapeutic target for GIM treatment. METHODS: We employed RNA sequencing (RNA-seq) to screen dysregulated lncRNAs in gastric epithelial cells after BA treatment. Bioinformatics analysis was conducted to reveal the regulatory mechanism. PVT1 expression was detected in 21 paired biopsies obtained under endoscopy. Overexpressed and knockdown cell models were established to explore gene functions in GIM. Molecular interactions were validated by dual-luciferase reporter assay, RNA immunoprecipitation (RIP), and chromatin immunoprecipitation (Ch-IP). The levels of relative molecular expression were detected in GIM tissues. RESULTS: We confirmed that lncRNA PVT1 was upregulated in BA-induced GIM model. PVT1 promoted the expression of intestinal markers such as CDX2 , KLF4 , and HNF4α . Bioinformatics analysis revealed that miR-34b-5p was a putative target of PVT1 . miR-34b-5p mimics increased CDX2 , KLF4 , and HNF4α levels. Restoration of miR-34b-5p decreased the pro-metaplastic effect of PVT1 . The interactions between PVT1 , miR-34b-5p, and the downstream target HNF4α were validated. Moreover, HNF4α could transcriptionally activated PVT1 , sustaining the GIM phenotype. Finally, the activation of the PVT1 /miR-34b-5p/ HNF4α loop was detected in GIM tissues. CONCLUSIONS BAs facilitate GIM partially via a PVT1/miR-34b-5p/HNF4α positive feedback loop. PVT1 may become a novel target for blocking the continuous development of GIM and preventing the initiation of gastric cancer in patients with bile reflux.
Humans ; RNA, Long Noncoding/metabolism* ; MicroRNAs/metabolism* ; Hepatocyte Nuclear Factor 4/genetics* ; Bile Acids and Salts ; Kruppel-Like Factor 4 ; Metaplasia/metabolism*

Objective To investigate the causal relationship between serum total bile acid (TBA) levels and gastric cancer (GC) using regression discontinuity design (RDD). Methods A total of 1244 GC patients and 1333 healthy controls were included in the study. Demographic characteristics, gallbladder disease history, tumor markers, and serum TBA levels were collected from both groups. Logistic regression was used to construct a risk prediction model to estimate the risk of GC. RDD was employed with serum TBA as the grouping variable and the individual risk of developing GC as the outcome variable. Results The predictive factors in the GC risk prediction model included age, sex, body mass index(BMI), serum TBA, carcinoembryoniv antigen(CEA), alpha fetoprotein(AFP), carbohydrate antigen 199(CA199), and CA125. Serum TBA was identified as an independent risk factor for GC (OR=1.054, 95% CI: 1.030 to 1.079). RDD analysis indicated that when serum TBA levels reached 8 μmol/L, the probability of developing GC increased sharply by 23.7%. The breakpoint remained statistically significant following validity and robustness assessments. Conclusion The study demonstrates a positive causal relationship between serum TBA levels and GC, when the serum TBA level reaches 8 μmol/L, the risk of an individual developing GC increases sharply.
Humans ; Stomach Neoplasms/etiology* ; Male ; Female ; Middle Aged ; Bile Acids and Salts/blood* ; Aged ; Adult ; Risk Factors ; Case-Control Studies ; Biomarkers, Tumor/blood* ; Logistic Models

BACKGROUND: High temperatures are known to be associated with an increased risk of self-harm, but the influence of demographic changes and country-level indicators on the burden of heat-related self-harm remains unclear. This study examined the key factors driving changes in self-harm mortality linked to high temperatures and explored their impact at the country level. METHODS: This is an ecological study that analyzes data from the 2021 Global Burden of Disease (GBD) study, the World Bank, and the Climate Research Unit (CRU) were analyzed. Decomposition analyses were used to identify key factors driving changes in high temperature-related self-harm mortality between 1990 and 2021. A panel data model assessed the impact of national indicators on heat-related self-harm mortality. RESULTS: In 2021, 14,885 deaths globally were attributed to heat-related self-harm, a 41.94% increase from 1990, with low-middle SDI regions accounting for 47.84% of these deaths. While the global death rate from heat-related self-harm declined slightly over this period, South Asia and low-middle SDI regions contributed most to the decline. However, population aging exacerbated mortality rates. Demographic and meteorological factors were also linked to heat-related self-harm. CONCLUSION The global decline in heat-related self-harm mortality is largely driven by reductions in females, low-middle SDI regions, and South Asia. However, population aging and growth in these regions have added to the mortality burden, slowing the overall decline. Factors such as population density are also associated with heat-related self-harm. Targeted measures are needed to mitigate heat-induced self-harm more effectively in future.
Humans ; Self-Injurious Behavior/etiology* ; Hot Temperature/adverse effects* ; Global Health/statistics & numerical data* ; Female ; Male ; Adult ; Middle Aged ; Aged ; Young Adult ; Adolescent

Objective To study the protective effect of lipoxin A4(LXA4)against sepsis-induced acute kidney in-jury(SAKI)in rats and its effect on the expression of toll-like receptor 4(TLR4),myeloid differentiation factor88(MyD88),nuclear factor kappa B(NF-κB)in the kidney.Methods Forty male specific pathogen-free C57BL/6J mice were randomly divided into SAKI group,SAKI+LXA4 group,sham procedure group,sham procedure+LXA4 group.The mice in SAKI group and SAKI+LXA4 group were given cecum ligation and puncture(CLP)to establish SAKI animal models.The mice in SAKI+LXA4 group and sham procedure+LXA4 group were given LXA4(40 ng/kg)with intraperitoneal injection 30 mins after CLP.All mice were sacrificed at the 24th hour after CLP to collect serum,urine and kidney tissues.The enzyme linked immunosorbent assay(ELISA)was used to test the serum creat-inine(Scr),blood urea nitrogen(Bun),interleukin-1 β(IL-1β),IL-6,tumor necrosis factor-α(TNF-α)and urine neutrophil gelatinase-associated lipocalin(NGAL),kidney injury molecule 1(KIM-1)levels of mice.The pathologi-cal changes were examined through hematoxylin-eosin(HE)staining and Periodic Acid-Schiff(PAS)staining.And the mRNA levels of TLR4,MyD88,NF-κB p65 were detected through real-time PCR(RT-PCR);the expression lev-els of TLR4,MyD88,NF-κB p65,phospho-NF-KB p65(p-NF-KB p65)were detected through immunohistochemistry(IHC)and Western blot assay.Results ELISA showed that the values of Scr,Bun,IL-1 β,IL-6,TNF-α,NGAL,KIM-1 in SAKI group were higher than those in SAKI+LXA4 group(P＜0.05),and there were no significant differences in Scr,Bun,IL-1 β,IL-6,TNF-α,NGAL,KIM-1 between sham procedure group and sham procedure+LXA4 group.HE and PAS staining showed that SAKI group had severer pathological changes than SAKI+LXA4 group in the kidney structure(P＜0.05),while pathological structures of the kidney were normal in sham proce-dure group and sham procedure+LXA4 group.RT-PCR showed that the mRNA levels of TLR4,MyD88,N F-κB p65 in SAKI group,SAKI+LXA4 group were higher than sham procedure group and sham procedure+LXA4 group(P＜0.05);the mRNA levels of TLR4,MyD88,NF-κB p65 in SAKI group were higher than SAKI+LXA4 group(P＜0.05);The results of IHC,Western blot assay were as follows:The expression levels of TLR4,MyD88,NF-κB p65,p-NF-κB p65 in SAKI group,SAKI+LXA4 group were higher than sham procedure group and sham procedure+LXA4 group(P＜0.05);the expression levels of TLR4,MyD88,NF-κB p65,p-NF-κB p65 in SAKI group were higher than SAKI+LXA4 group(P＜0.05).Conclusion TLR4/MyD88/NF-KB pathway plays an important role in the occurrence and development of SAKI,and LXA4 may reduce SAKI by inhibiting TLR4/MyD88/NF-κB sig-naling pathway.

Objective To investigate the effects of the Pingan qushi prescription on traditional Chinese medicine syndrome,adverse events,and compliance in young and middle-aged hypertensive patients.Methods One hundred thirty-two young and middle-aged patients with hypertension were selected and randomly divided into two groups.After elimination,64 cases were included in each group.For 2 months,the control group was treated with irbesartan tablets,and the observation group underwent the Pingan qushi prescription based on the control group.The blood pressure,curative effect,traditional Chinese medicine syndrome score,safety,adverse events,and prognosis-related indicators were compared between the two groups.Results The total effective rate of the observation group(96.88%,92.19%)was higher than that of the control group(82.52%,78.13%),and the difference was statistically significant(P = 0.005,P = 0.025).After 1 and 2 months of treatment,the blood pressure,syndrome scores,ALD,PRA,AngⅡ,and ET-1 in the observation group were lower than those in the control group,and the differences were statistically significant(all P<0.05).There was no sig-nificant difference in the incidence of adverse reactions between the two groups(P>0.05).There was no statistically significant difference(P>0.05)in the incidence of adverse events during treatment between the observation group(1.56%)and control group(10.94%).Conclusion The treatment of young and middle-aged community patients with hypertension undergoing the Pingan qushi pre-scription can further improve patients'symptoms,increase blood pressure control,promote prognosis improvement.

Objective To explore the therapeutic efficacy of the Fuyang Tongluo therapy combined with conventional western medicine in elderly patients with heart failure due to coronary heart disease.Methods In this single-blind randomized controlled trial,96 elderly patients with coronary heart disease and heart failure were randomly divided into three groups,each consisting of 32 individuals.Control group A was treated with conventional western medicine(atorvastatin combined with metoprolol),control group B with Fuyang Tongluo therapy,and the observation group with Fuyang Tongluo therapy and conventional western medicine.The three groups were compared in terms of therapeutic efficacy and traditional Chinese medicine symptom points as well as blood interleukin(IL)-23 and IL-17 levels,left ventricular end-systolic diameter(LVESD),left ventricular end-diastolic diameter(LVEDD),and left ventricular ejection fraction(LVEF)values before and after treatment.Results The total clinical efficacy rate in the observation group was 93.75%,which was significantly higher than those in control groups A(68.75%)and B(65.63%)(P<0.05).After 4 and 8 weeks of treatment,the primary and minor symptom scores,total symptom scores,LVESD,LVEDD,and IL-23 and IL-17 levels in the observation group were significantly lower than those in control groups A and B(P<0.05).Conclusion The combination of the Fuyang Tongluo therapy with conventional western medicine exhibited good therapeutic efficacy in elderly patients with coronary heart disease and heart failure.These effects were achieved by inhibiting excessive expression of the inflammatory axis factors IL-23 and IL-17 and promoting the recovery of cardiac function.

OBJECTIVE To observe the efficacy and safety of ticagrelor combined with Compound xueshuantong capsules in the treatment of unstable angina pectoris. METHODS Totally 120 patients with unstable angina pectoris with deficiency of Qi and Yin combined admitted to Sanmenxia Hospital of Traditional Chinese Medicine from January 2021 to December 2022 were randomly divided into clopidogrel group （group A）， ticagrelor group （group B） and combined medication group （group C）， with 40 patients in each group. In addition to conventional treatment， group A was given clopidogrel orally； group B was given ticagrelor orally； group C was given ticagrelor and Compound xueshuantong capsule orally. After 12 weeks of treatment， the clinical efficacy， frequency of angina attacks， coagulation function indicators， cardiac function indicators， traditional Chinese medicine syndrome efficacy， and the incidence of adverse cardiovascular events and bleeding incidence were evaluated in the 3 groups. RESULTS The total effective rates of group A， group B and group C were 77.5%， 85.0% and 90.0%， respectively. The incidence of adverse cardiovascular events and bleeding events were 7.5%， 7.5% and 5.0% in the respective groups， with no statistically significant difference （P＞0.05）. The frequency of angina attacks， duration of angina attacks and duration of dyspnea were significantly reduced or shortened in all 3 groups after treatment compared to before treatment （P＜0.05）. The frequency of angina attacks in group C was significantly lower than that in groups A and B after treatment （P＜0.05）. The levels of fibrinogen （FBG） and D-dimer in all 3 groups were significantly lower after treatment compared to before treatment （P＜0.05）； group A had significantly higher levels of FBG and D-dimer compared to group B and C （P＜0.05）. The left ventricular end-diastolic diameter and left ventricular end-systolic diameter in all three groups were significantly shorter after treatment， and the left ventricular ejection fraction was significantly higher compared to before treatment （P＜0.05）， but there were no statistically significant differences among those groups （P＞0.05）. The total effective rates of traditional Chinese medicine syndrome efficacy in groups A， B and C were 67.5%， 80.0% and 87.5%， respectively， with group C being significantly higher than group A （P＜0.05）. CONCLUSIONS In addition to conventional treatment， ticagrelor combined with Compound xueguantong capsules can more significantly reduce the frequency of angina attacks in patients with unstable angina pectoris， reduce the levels of FBG and D- dimer， improve traditional Chinese medicine syndrome efficacy， and do not increase the risk of bleeding.

Humans ; Bile Reflux/complications* ; Cross-Sectional Studies ; Risk Factors ; Gastric Mucosa

Arabidopsis thaliana is an important and long-established model species for plant molec-ular biology,genetics,epigenetics,and genomics.However,the latest version of reference genome still contains a significant number of missing segments.Here,we reported a high-quality and almost complete Col-0 genome assembly with two gaps(named Col-XJTU)by combining the Oxford Nanopore Technologies ultra-long reads,Pacific Biosciences high-fidelity long reads,and Hi-C data.The total genome assembly size is 133,725,193 bp,introducing 14.6 Mb of novel sequences compared to the TAIR1 0.1 reference genome.All five chromosomes of the Col-XJTU assembly are highly accurate with consensus quality(QV)scores＞60(ranging from 62 to 68),which are higher than those of the TAIR10.1 reference(ranging from 45 to 52).We completely resolved chro-mosome(Chr)3 and Chr5 in a telomere-to-telomere manner.Chr4 was completely resolved except the nucleolar organizing regions,which comprise long repetitive DNA fragments.The Chr1 cen-tromere(CEN1),reportedly around 9 Mb in length,is particularly challenging to assemble due to the presence of tens of thousands of CEN180 satellite repeats.Using the cutting-edge sequencing data and novel computational approaches,we assembled a 3.8-Mb-long CEN1 and a 3.5-Mb-long CEN2.We also investigated the structure and epigenetics of centromeres.Four clusters of CEN180 monomers were detected,and the centromere-specific histone H3-like protein(CENH3)exhibited a strong preference for CEN 180 Cluster 3.Moreover,we observed hypomethylation patterns in CENH3-enriched regions.We believe that this high-quality genome assembly,Col-XJTU,would serve as a valuable reference to better understand the global pattern of centromeric polymorphisms,as well as the genetic and epigenetic features in plants.

Complex structural variants(CSVs)are genomic alterations that have more than two breakpoints and are considered as the simultaneous occurrence of simple structural variants.How-ever,detecting the compounded mutational signals of CSVs is challenging through a commonly used model-match strategy.As a result,there has been limited progress for CSV discovery com-pared with simple structural variants.Here,we systematically analyzed the multi-breakpoint con-nection feature of CSVs,and proposed Mako,utilizing a bottom-up guided model-free strategy,to detect CSVs from paired-end short-read sequencing.Specifically,we implemented a graph-based pattern growth approach,where the graph depicts potential breakpoint connections,and pattern growth enables CSV detection without pre-defined models.Comprehensive evaluations on both simulated and real datasets revealed that Mako outperformed other algorithms.Notably,validation rates of CSVs on real data based on experimental and computational validations as well as manual inspections are around 70％,where the medians of experimental and computational breakpoint shift are 13 bp and 26 bp,respectively.Moreover,the Mako CSV subgraph effectively characterized the breakpoint connections of a CSV event and uncovered a total of 15 CSV types,including two novel types of adjacent segment swap and tandem dispersed duplication.Further analysis of these CSVs also revealed the impact of sequence homology on the formation of CSVs.Mako is publicly available at https://github.com/xjtu-omics/Mako.