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Antimicrobial proteins possess a broad spectrum of bactericidal activity and play an important role in shaping the composition of gut microbiota, which is related to multiple diseases such as metabolic syndrome. However, it is incompletely known for the regulation of defensin expression in the gut Paneth cells. Here, we found that FABP4 in the Paneth cells of gut epithelial cells and organoids can downregulate the expression of defensins. FABP4fl/flpvillinCreT mice were highly resistance to Salmonella Typhimurium (S.T) infection and had increased bactericidal ability to pathogens. The FABP4-mediated downregulation of defensins is through degrading PPARγ after K48 ubiquitination. We also demonstrate that high-fat diet (HFD)-mediated downregulation of defensins is through inducing a robust FABP4 in Paneth cells. Firmicutes/Bacteroidetes (F/B) ratio in FABP4fl/flpvillinCreT mice is lower than control mice, which is opposite to that in mice fed HFD, indicating that FABP4 in the Paneth cells could reprogram gut microbiota. Interestingly, FABP4-mediated downregulation of defensins in Paneth cells not only happens in mice but also in human. A better understanding of the regulation of defensins, especially HFD-mediated downregulation of defensin in Paneth cells will provide insights into factor(s) underlying modern diseases.Abbreviations: FABP4: Fatty acid binding protein 4; S. T: Salmonella Typhimurium; HFD: High-fat diet; Defa: α-defensin; 930 HD5: Human α-defensin 5; HD6: Human α-defensin 6; F/B: Firmicutes/Bacteroidetes; SFB: Segmental filamentous bacteria; AMPs: Antimicrobial peptides; PPARγ: Peroxisome proliferator-activated receptor γ; P-PPAR: Phosphorylated PPAR; Dhx15: DEAD-box helicase 15; 935 EGF: Epidermal growth factor; ENR: Noggin and R-spondin 1; CFU: Colony forming unit; Lyz1: Lysozyme 1; Saa1: Serum amyoid A 1; Pla2g2a: Phospholipase A2, group IIA; MMP-7: Matrix metalloproteinase; AU-PAGE: Acid-urea polyacrylamide gel electrophoresis; PA: Palmitic 940 acid; GPR40: G-protein-coupled receptor; GF: Germ-free; EGF: Epidermal growth factor; LP: Lamina propria; KO: Knock out; WT: Wild-type.

Abstract Background Identifying and projecting the epidemiological burden of gastric cancer (GC) can optimize the control strategies, especially in high-burden areas. Methods We collected incidence, deaths, disability-adjusted life-years (DALYs), age-standardized incidence rate (ASIR), age-standardized mortality rate (ASMR), age-standardized DALY rate (ASDR) of GC from 1990 to 2019 in China, Japan, South Korea, and Mongolia from the Global Burden of Disease Study 2019. The average annual percentage change (AAPC) was calculated to quantify the temporal trends, and the projection was estimated by applying the Bayesian age-period-cohort model. Results In China, the ASIR of GC declined slightly from 37.56/100000 in 1990 to 30.64/100000 in 2019 (AAPC of − 0.41), while the declines of ASMR and ASDR were pronounced (AAPC of − 1.68 and − 1.98, respectively), which were weaker than Japan and South Korea. Although the age-standardized rates of gastric cancer in most countries have declined overall in the past 30 years, the downward trend in the last 4 years has become flattened. Smoking remained one main contributor to DALYs of GC in China, Japan, South Korea, and Mongolia, with more than 24%. The contribution from high-sodium diet was similar between men and women, and kept relatively stable over the three decades. The predicted ASMRs among the four East Asian countries continued to decline until 2030, but the absolute deaths would still increase significantly, especially in South Korea and Mongolia. Conclusions Although the age-standardized rates of GC in most countries have declined, the absolute burden of GC in the world, especially in China and Mongolia, is on the rise gradually. Low socio-demographic index and aging along with Helicobacter pylori infection, smoking, and high-salt diet were the main risk factors of GC occurrence and should be paid more attention.

BackgroundUnderstanding the spatiotemporal trends in disease burden of edentulism is critical to reducing disease burden of edentulism and deploying medical resources. We assessed the changing patterns of disease burden of edentulism at global, regional, and national levels from 1990 to 2019.MethodsData on incident cases, prevalent cases, disability-adjusted life years (DALYs), and age-standardized rates (ASRs) of edentulism were extracted from the Global Burden of Disease 2019 Study. We calculated the estimated annual percentage change (EAPC) to quantify spatiotemporal trends in the ASRs of edentulism.ResultsIn 2019, the number of prevalent cases and DALYs of edentulism were 35.2 and 9.6 million, and the ASPR and ASDR were 43.12/1,000 and 1.18/1,000, with EAPCs of −0.18 [95% confidence interval (CI): −0.28, −0.09] and −0.16[95% CI: −0.26, −0.07] from 1990 to 2019, respectively. Females and the elderly had a higher burden of edentulism. Although the ASPR, ASDR, and ASIR in the high SDI, high–middle SDI, and middle SDI regions showed a decreasing or stable trend, the absolute disease burdens of edentulism in these regions were still high. Although the absolute disease burdens of low SDI and low–middle SDI were low, their ASPR and ASDR showed an upward trend. In countries with high initial disease burden or high SDI, ASPR, ASDR, and ASIR showed stable or declining trends.ConclusionThe absolute disease burden due to edentulism was increasing in many countries and regions. Countries should reduce the disease burden caused by edentulism by adopting measures including the prevention and treatment of dental caries and periodontal disease.

BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by recurrent nasal polyp (NP) growth following surgical removal, but the mechanisms are still not clear. This study aimed to investigate the expression of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptor on NP and the role it plays in eosinophil inflammation and polyp recurrence.MethodsForty-one CRSwNPs patients and seventeen controls were enrolled in this study. mRNA was extracted from nasal tissues and evaluated for expression of CRTH2. Immunofluorescence staining was performed to confirm the distribution and expression of CRTH2 protein. CRTH2 expression on peripheral blood eosinophils was quantified by flow cytometry. The eosinophil count and clinical implications were also evaluated and their correlations with CRTH2 expression were analyzed.ResultsNasal polyps displayed increased expression of CRTH2 in mRNA level compared with control samples, with the highest expression observed in recurrent NP. Immunofluorescence confirmed over-expression of CRTH2 in recurrent NP and this was independent of the concurrent presence of asthma. CRTH2 expression was positively correlated with tissue eosinophil number (Spearman’s ρ=0.69, P

Autoimmune thyroid disease (AITD), the most common autoimmune disease, includes Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). Currently, the pathogenesis of AITD is not fully understood. Our study aimed to examine the presence of macrophage polarization imbalance in AITD patients, to investigate whether high iodine can cause macrophage polarization imbalance, and to investigate the role of key genes of metabolic reprogramming in macrophage polarization imbalance caused by high iodine. We synergistically used various research strategies such as systems biology, clinical studies, cell culture and mouse disease models. Gene set enrichment analysis (GSEA) revealed that M1 macrophage hyperpolarization was involved in the pathogenesis of AITD. In vitro and in vivo experiments showed that high iodine can affect the polarization of M1 or M2 macrophages and their related cytokines. Robust rank aggregation (RRA) method revealed that hexokinase 3 (HK3) was the most aberrantly expressed metabolic gene in autoimmune diseases. In vitro and in vivo studies revealed HK3 could mediate macrophage polarization induced by high iodine. In summary, hyperpolarization of M1-type macrophages is closely related to the pathogenesis of AITD. High iodine can increase HK3 expression in macrophages and promote macrophage polarization towards M1. Targeting HK3 can inhibit M1 polarization induced by high iodine.

Abstract Background Tetrapyrroles play indispensable roles in various biological processes. In higher plants, glutamate 1-semialdehyde 2,1-aminomutase (GSAM) converts glutamate 1-semialdehyde (GSA) to 5-aminolevulinic acid (ALA), which is the rate-limiting step of tetrapyrrole biosynthesis. Up to now, GSAM genes have been successively identified from many species. Besides, it was found that GSAM could form a dimeric protein with itself by x-ray crystallography. However, no mutant of GSAM has been identified in monocotyledonous plants, and no experiment on interaction of GSAM protein with itself has been reported so far. Result We isolated a yellow leaf mutant, ys53, in rice (Oryza sativa). The mutant showed decreased photosynthetic pigment contents, suppressed chloroplast development, and reduced photosynthetic capacity. In consequence, its major agronomic traits were significantly affected. Map-based cloning revealed that the candidate gene was LOC_Os08g41990 encoding GSAM protein. In ys53 mutant, a single nucleotide substitution in this gene caused an amino acid change in the encoded protein, so its ALA-synthesis ability was significantly reduced and GSA was massively accumulated. Complementation assays suggested the mutant phenotype of ys53 could be rescued by introducing wild-type OsGSAM gene, confirming that the point mutation in OsGSAM is the cause of the mutant phenotype. OsGSAM is mainly expressed in green tissues, and its encoded protein is localized to chloroplast. qRT-PCR analysis indicated that the mutation of OsGSAM not only affected the expressions of tetrapyrrole biosynthetic genes, but also influenced those of photosynthetic genes in rice. In addition, the yeast two-hybrid experiment showed that OsGSAM protein could interact with itself, which could largely depend on the two specific regions containing the 81th–160th and the 321th–400th amino acid residues at its N- and C-terminals, respectively. Conclusions We successfully characterized rice GSAM gene by a yellow leaf mutant and map-based cloning approach. Meanwhile, we verified that OsGSAM protein could interact with itself mainly by means of the two specific regions of amino acid residues at its N- and C-terminals, respectively.

As the ornamental plants and traditional medicines, Rhododendron przewalskii, R. anthopogonoides, R. thymifolium, and R. capitatum are widely distributed in western China. In this paper, the essential oils from these four species were extracted by supercritical extraction and the components were analyzed using headspace solid phase microextraction combined with gas chromatography-mass spectrometry (HS-SPME-GC-MS), the antibacterial, acaricidal and anti-inflammatory activities were investigated. Results showed that R. thymifolium (RTEO) contained the highest yield of 0.99% with 246 compounds, followed by R. capitatum (RCEO, 0.81%) with 290 chemicals, R. anthopogonoides (RAEO, 0.57%) with 302 compounds and R. przewalskii (RPEO, 0.30%) with 294 components. They also exhibited the safety at given doses and have the anti-inflammatory in vitro and in vivo tests via inhibiting the cytokines productions, the acaricidal and antibacterial activities also were found. 4-Hydroxy-3-methylacetophenone from RPEO, α-pinene and β-pinene from RAEO, β-farnesene and germacrone from RTEO, and benzylacetone from RCEO, as main and active components, inhibited the NO content in RAW 264.7 cells induced by LPS. These results indicated that four essential oils have certain medicinal value and laid the foundation for the development of these species as raw materials for the pharmaceutical and perfume industries.

BackgroundFront-line nurses have played a critical role during the coronavirus disease 2019 (COVID-19) pandemic. A number of qualitative studies reported front-line nurses' experiences and needs in caring for patients with COVID-19. However, the application of evidence from a single qualitative study to guide clinical practice has limitations. This study aimed to explore front-line nurses' experiences and needs during the COVID-19 pandemic through a qualitative meta-synthesis.MethodsSeven databases were searched from 1 December 2019 to 20 January 2022, including PubMed, Web of Science, Cochrane COVID-19 study register, CINAHL, PsycINFO, MedRxiv, and bioRxiv. The quality of included studies was appraised using the Critical Appraisal Skills Program (CASP) qualitative research appraisal tool. Meta-synthesis was used to synthesize the data from included studies.ResultsA total of 70 studies were included, and five synthesized findings were developed: (1) Although nurses actively devoted themselves to fighting against COVID-19, considering their professional responsibility and historical previous experience with mankind, they were not invulnerable; (2) There were various difficulties and challenges in caring for patients with COVID-19, including fear related to providing patients with care, shortage of protective equipment and manpower, and negative attitude of family members; (3) Facing difficulties and challenges, nurses could only partly cope by using mixed means to overcome those, including media, learning, gaining skills, responding together, and organizational assistance; (4) To better respond to the COVID-19 pandemic, nurses' needs should be paid attention to. Counseling, training, information, resources, and investment are pivotal; (5) Despite the hardships, nurses became stronger and gained gratitude, positivity, mental peace, and confidence.ConclusionsThis study reveals that the psychological experiences of front-line nurses varied, and they faced a variety of challenges. Although nurses had some coping strategies, they still needed multifaceted support to meet the challenges.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/, PROSPERO: CRD42021255468.

BackgroundUrinary tract infections (UTIs) are one of the most common infections worldwide, but little is known about their global scale and long-term trends. We aimed to estimate the spatiotemporal patterns of UTIs' burden along with its attributable risk factors at a global level, as well as the variations of the burdens according to socio-demographic status, regions, nations, sexes, and ages, which may be helpful in guiding targeted prevention and treatment programs.MethodsData from the Global Burden of Disease Study 2019 were analyzed to depict the incidence, mortality, and disability-adjusted life years (DALYs) of UTIs in 204 countries and territories from 1990 to 2019 by socio-demographic status, nations, region, sex, and age.ResultsGlobally, 404.61 million cases, 236,790 deaths, and 520,200 DALYs were estimated in 2019. In particular, 2.4 times growth in deaths from 1990 to 2019 was observed, along with an increasing age-standardized mortality rate (ASMR) from 2.77/100,000 to 3.13/100,000. Age-standardized incidence rate (ASIR) was consistently pronounced in regions with higher socio-demographic index (SDI), which presented remarkable upward trends in ASMR and age-standardized DALY rate (ASDR). In contrast, countries with a low SDI or high baseline burden achieved a notable decline in burden rates over the past three decades. Although the ASIR was 3.6-fold higher in females than males, there was no sex-based difference in ASMR and ASDR. The burden rate typically increased with age, and the annual increasing trend was more obvious for people over 60 years, especially in higher SDI regions.ConclusionsThe burden of UTIs showed variations according to socio-demographic status, nation, region, sex, and age in the last three decades. The overall increasing burden intimates that proper prevention and treatment efforts should be strengthened, especially in high-income regions and aging societies.

BackgroundLead exposure is an important risk factor for stroke. However, the latest global spatiotemporal patterns of lead exposure-related stroke burden were unclear. In this study, we assessed this topic.MethodsThe data were obtained from the Global Burden of Disease Study (2019). The estimated annual percentage change (EAPC) was estimated to evaluate the temporal trends of the age-standardized mortality and disability-adjusted life years (DALYs) rates (ASMR and ASDR) of stroke attributable to lead exposure.ResultsIn 2019, the numbers of global stroke deaths and DALYs attributable to lead exposure were 305.27 and 6738.78 thousand, respectively. The corresponding ASMR and ASDR were highest in males, the elderly population, low and middle-income countries, and the intracerebral hemorrhage subtype. From 1990 to 2019, the ASMR and ASDR of global stroke attributable to lead exposure decreased [ASMR: EAPC = −1.34, 95% confidence interval (CI): (−1.57, −1.10); ASDR: EAPC = −1.74, 95% CI: (−1.95, −1.52)], especially in females, the high-income countries, and the subarachnoid hemorrhage subtype.ConclusionThis study emphasizes the importance of continued implementation of lead exposure prevention strategies and improved high-efficiency treatment and stroke acute health care, especially in low and middle-income countries.

Understanding the spatio-temporal patterns of the disease burden attributable to ambient PM2.5 across the world is essential for the prevention of related diseases, as well as ambient PM2.5 control. Following the framework and methodology of the Global Burden of Disease Study (GBD) in 2019, the global, regional, and national data on ambient PM2.5-attributable death and disability-adjusted life years (DALYs), and the age-standardized rates of mortality (ASMR) and disability-adjusted life years (ASDR) were summarized based on age, gender, year, location and specific diseases. We calculated the average annual percentage change (AAPC) to depict the secular trends of ASMR and ASDR from 1990 to 2019. In 2019, the global ambient PM2.5-related deaths and DALYs were 4,140,970 and 118.2 million, respectively, with 1,702,150 deaths and 47.5 million DALYs for females and 2,438,820 deaths and 70.7 million DALYs for male. In the 13 level-three causes, ischemic heart disease, stroke, chronic obstructive and pulmonary disease (COPD) were the leading three causes of deaths and DALYs attributable to ambient PM2.5. The number of global deaths and DALYs attributable to ambient PM2.5 has increased by 102.3% and 67.7% from 1990 to 2019, respectively. However, ASMR and ASDR showed little change. In the 13 level-three diseases, ischemic heart disease, stroke, COPD, diabetes mellitus, and lung cancer were the top five contributors to the increase of global deaths or DALYs, among which diabetes mellitus had the fastest increase of ASMR and ASDR, with AAPC of 1.5 (95% CI: 1.43, 1.58) and 2.21 (95% CI: 2.15, 2.27), respectively. The population attributable fractions (PAF) of causes in ASMR or ASDR varied significantly across regions, of which PAF of COPD, stroke and lung cancer were the top three. Regarding the GBD region, high PAF mainly occurred in North Africa and Middle East, South Asia, and East Asia. The age-specific PAFs of ischemic heart disease and stroke deaths and DALYs due to ambient PM2.5 were negatively correlated with age. ASMR and ASDR of overall PM2.5 related-burden showed an inverted “V/U” relationship with the socio-demographic index (SDI). The AAPC of ASMR and ASDR of the overall causes showed a strong negative correlation with SDI in 2019, especially at the SDI larger than 0.5. The deaths and DALYs attributable to ambient PM2.5 continued to increase under the context of population growth and aging. Decision-makers should consider controlling the PM2.5 emission when developing the economy.

ABSTRACT In clinical practice, carbapenems and tigecycline are considered significant options for treating infections caused by multidrug-resistant Klebsiella spp. The continual evolution of resistance mechanisms to carbapenems and tigecycline is shattering the present condition. Meanwhile, convergence of the two resistance mechanisms in a single strain has been reported repeatedly, posing a significant threat to public health and safety. In this study, two carbapenem- and tigecycline-resistant Klebsiella species were obtained from patients and investigated using antimicrobial susceptibility testing, conjugation assay, whole-genome sequencing, and bioinformatics analysis. In Klebsiella variicola FK2020ZBJ35, an untransferable multidrug IncFIB(Mar)/IncHI1B-like plasmid carrying tmexCD2-toprJ2, blaIMP-4, and blaNDM-1 was discovered, as was a similar plasmid carrying tmexCD1-toprJ1 and blaIMP-4 in Klebsiella quasipneumoniae 2019SCSN059. Genetic context analysis found that two distinct tmexCD-toprJ variants were detected in comparable mobile units with genetic array int-int-hp-hp-tnfxB-tmexCD-toprJ and integrated into separate genetic locations. blaIMP-4 and blaNDM-1 were carried by an integron In1377 and a truncated Tn3000, respectively. These findings revealed that the carbapenem and tigecycline resistance genes carried by the two strains were located on mobile elements and might potentially transmit horizontally to additional strains. Furthermore, our findings showed that IncFIB(Mar)/IncHI1B-like plasmids represent a significant reservoir of essential resistance genes that warrants continued monitoring. IMPORTANCE Tigecycline is an essential antibiotic that is used to treat infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP). The emergence of high-level tigecycline-resistant CRKP poses a serious hazard to human health. This work screened two tigecycline-resistant CRKP strains from clinical patients and found a type of plasmid that encoded carbapenemase and TmexCD-ToprJ in Klebsiella. Importantly, one plasmid cocarried tmexCD-toprJ, blaNDM-1, and blaIMP-4, hinting that this plasmid could be a critical vector for superbug development. Furthermore, we discovered that the carbapenem and tigecycline resistance genes are located in mobile units by genetic structure analysis. Our research tracks the formation of clinically super-resistant Gram-negative bacteria.

Abstract Background Selection of high-risk subjects for endoscopic screening of esophageal squamous cell carcinoma (ESCC) lacks individual predictive tools based on environmental risk factors. Methods We performed a large population-based case-control study of 1418 ESCC cases and 1992 controls in a high-risk area of China. Information on potential risk factors was collected via face-to-face interview using an electronic structured questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models, and predictive nomograms were established accordingly. A weighted analysis was further conducted to introduce age into predictive nomograms due to frequency matching study design. Results Most cases were usually exposed to 4 to 6 risk factors, but most controls were usually exposed to 3 to 5 risk factors. The AUCs of male and female predictive nomograms were 0.75 (95%CI: 0.72, 0.77) and 0.76 (95%CI: 0.73, 0.79), respectively. The weighted analysis adding age in the predictive model improved the AUC in both men and women (0.81 (95%CI: 0.79, 0.84) and 0.88 (95%CI: 0.85, 0.90), respectively). Conclusions An easy-to-use preclinical predictive tool is provided to select candidate population with high ESCC risk for endoscopic screening. Its usefulness needs to be further evaluated in future screening practice.

Abstract Background Nearly half of the cases of esophageal cancer in the world were in China, but the corresponding burden in China has not been estimated for the past decades or for the near future. Methods Data on the incidence, mortality, and disability‐adjusted life years (DALYs) rates owing to esophageal cancer in China from 1990 to 2017 were extracted from the Global Burden of Disease Study 2017. To reflect the trend in the disease burden, we calculated the estimated annual percentage change (EAPC) in the age‐standardized rates of these three outcomes in China from 1990 to 2017. Results The age‐standardized incidence rate (ASIR) for esophageal cancer decreased from 19.38/100,000 in 1990 to 12.23/100,000 in 2017, with an EAPC of −2.53 (95%CI: −2.90, −2.16), but the number of cases of esophageal cancer increased from 164,473 to 234,624. The age‐standardized rates of esophageal cancer in females were always lower than they were in males during the study period, and there was a downward trend that was more pronounced among females than males. The most common risk factors for males were smoking and alcohol consumption, while the most common risk factors for females were a diet low in fruits and a high body mass index (BMI). New cases of, and deaths from esophageal cancer are predicted to increase by about 1.5 times in the coming 25 years. Conclusion Although the age‐standardized burden of esophageal cancer has been declining, the number of new cases of, and deaths from esophageal cancer have increased in China over the past 30 years, and they will continue to increase in the near future. Hence, national policies should be adopted to promote the prevention and management of known risk factors for it, especially smoking and excessive caloric intake.

Abstract Background Early diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. We aimed to develop a serum multi-protein signature for the early detection of ESCC. Methods We selected 70 healthy controls, 30 precancerous patients, 60 stage I patients, 70 stage II patients and 70 stage III/IV ESCC patients from a completed ESCC case-control study in a high-risk area of China. Olink Multiplex Oncology II targeted proteomics panel was used to simultaneously detect the levels of 92 cancer-related proteins in serum using proximity extension assay. Results We found that 10 upregulated and 13 downregulated protein biomarkers in serum could distinguish the early-stage ESCC from healthy controls, which were validated by the significant dose-response relationships with ESCC pathological progression. Applying least absolute shrinkage and selection operator (LASSO) regression and backward elimination algorithm, ANXA1 (annexin A1), hK8 (kallikrein-8), hK14 (kallikrein-14), VIM (vimentin), and RSPO3 (R-spondin-3) were kept in the final model to discriminate early ESCC cases from healthy controls with an area under curve (AUC) of 0.936 (95% confidence interval: 0.899 ~ 0.973). The average accuracy rates of the five-protein classifier were 0.861 and 0.825 in training and test data by five-fold cross-validation. Conclusions Our study suggested that a combination of ANXA1, hK8, hK14, VIM and RSPO3 serum proteins could be considered as a potential tool for screening and early diagnosis of ESCC, especially with the establishment of a three-level hierarchical screening strategy for ESCC control.

Objective To investigate the clinical effect of high intensity focused ultrasound (HIFU) ablation combined with gonadotropin-releasing hormone agonist (GnRH-a) and levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of adenomyosis patients who failed to respond to drug therapies. Study design A total of 47 patients with adenomyosis who had failed to respond to drug therapies and had no fertility desires were treated with HIFU combined with GnRH-a and LNG-IUS. The score of dysmenorrhea and menstrual volume were measured at pre and 6-, 12-, 18-, 24-month post-HIFU. Results All patients completed HIFU ablation without major postoperative complications. Compared with the symptom scores before the HIFU treatment, the score of dysmenorrhea and menstrual volume decreased significantly at 6, 12, 18 and 24 months after HIFU treatment (p 0.05). The clinical success rate was 100%, 100%, 95.7% and 93.6% respectively at 6, 12, 18 and 24 months after the combined treatment. Conclusion The combined therapeutic regimen of HIFU, GnRH-a and LNS-IUS is safe and effective, which can be an alternative treatment option for patients with adenomyosis who failed to respond to drug therapies to avoid adenomyomectomy or hysterectomy.

Abstract Wilson’s disease (WD) is an autosomal recessive inherited disorder of chronic copper toxicosis with high mortality and disability. Recent evidence suggests a correlation between dysbiosis in gut microbiome and multiple diseases such as genetic and metabolic disease. However, the impact of intestinal microbiota polymorphism in WD have not been fully elaborated and need to be explore for seeking some microbiota benefit for WD patients. In this study, the 16S rRNA sequencing was performed on fecal samples from 14 patients with WD and was compared to the results from 16 healthy individuals. The diversity and composition of the gut microbiome in the WD group were significantly lower than those in healthy individuals. The WD group presented unique richness of Gemellaceae, Pseudomonadaceae and Spirochaetaceae at family level, which were hardly detected in healthy controls. The WD group had a markedly lower abundance of Actinobacteria, Firmicutes and Verrucomicrobia, and a higher abundance of Bacteroidetes, Proteobacteria, Cyanobacteria and Fusobacteria than that in healthy individuals. The Firmicutes to Bacteroidetes ratio in the WD group was significantly lower than that of healthy control. In addition, the functional profile of the gut microbiome from WD patients showed a lower abundance of bacterial groups involved in the host immune and metabolism associated systems pathways such as transcription factors and ABC-type transporters, compared to healthy individuals. These results implied dysbiosis of gut microbiota may be influenced by the host metabolic disorders of WD, which may provide a new understanding of the pathogenesis and new possible therapeutic targets for WD.

BackgroundUnderstanding the epidemiological characteristics of various cancers can optimize the prevention and control strategies in the national cancer control plan. This study aimed to report the burden differences, pattern trend, and potential risk factors of all neoplasm types in China in recent 30 years, and further compared with top economies in the world.MethodsThe disability-adjusted life-years (DALYs) and age-standardized DALY rate (ASDR) of all neoplasms with the attributable risk factors from 1990 to 2019 in China, Japan, European Union, USA, and the world were extracted from the Global Burden of Disease Study 2019. The temporal trend analysis was estimated using the joinpoint regression model.ResultsIn 2019, about 251.4 million DALYs worldwide were caused by all neoplasms, and nearly 26.9% (67.5 million DALYs) occurred in China with the ASDR in 2019 of 342.09/10 000, which was higher than European Union (334.25/10 000), USA (322.94/10 000), and Japan (250.36/10 000). Although the cancer burden of the colorectum, non-Hodgkin lymphoma, oral cavity, ovary, and kidney in China was lower than in Japan, European Union and USA, the corresponding ASDR gradually increased in China over the past 30 years, but declined in the three developed areas. Around 46.29% of overall neoplasms DALYs in China in 2019 were attributed to 22 identified risk factors, and the specific risk attributable-fraction for several neoplasm types varied greatly in these regions.ConclusionThe ASDR of cancers of the lung, colorectum, pancreas, non-Hodgkin lymphoma, oral cavity, ovary, kidney, and chronic lymphoid leukemia increased in China compared to 30 years ago. With the population aging and the social transformation in China, the increasing burden of neoplasms and the changing spectrum of neoplasms suggest that effective comprehensive prevention and treatment measures should be adopted to reduce the burden, including public health education, strict tobacco-control policy, healthier lifestyles, along with expanding vaccination programs and early cancer screening.

The nutrition and active compounds from plants are very important to regulate the immunity of the body by improving the oxidant and inflammatory response. In this article, we aimed to investigate the nutritional profile and the phytochemical compositions of Adonis coerulea; the functional characteristics and its possible mechanism were studied. Results showed that the aerial parts of Adonis coerulea (ACAP) contained the abundant of proteins (16.15%) and the minerals (31.02.09 mg/100 g dried ACAP); promisingly, the content of essential amino acids (8.25%) and fatty acids (13,220.45 mg/100 g) also were obtained to regulate the immunity and prevent some chronic diseases. The methanol extract of ACAP played the anti-inflammatory activity via peroxisome proliferators-activated receptor (PPAR)-γ-mediated nuclear factor kappa B (NF-κB) pathway. Among the 18 identified compounds, linolenic acid from fatty acids and licochalcone A were active compounds by inhibiting nitric oxide (NO) production of RAW264.7 cells induced by lipopolysaccharide (LPS). The alleviation of inflammatory response results in the decrease of oxidative stress; ACAP showed the antioxidant activity by attenuating antioxidant enzymes, improving mitochondrial membrane potential and reactive oxygen species. These results highlight the potential of A. coerulea as a source of active ingredients in pharmaceutical industries.

Advancement of novel sequencing technologies facilitates modern life science and medicine unprecedentedly. Exploring complete genome sequences of bacteria by long-read sequencing technology is significant for microbial genomics research. However, third-generation long-read sequencing technologies are available with limited choices, which generate technological barrier to scientific research. Recently, a novel QitanTech nanopore long-read sequencing technology has emerged in China, but the potential application and performance were unexplored. Herein, we comprehensively evaluated the feasibility of the emerging sequencing technology in assembling complete genomes of MDR pathogens. The results showed that 500 Mbp QitanTech nanopore sequencing data could be generated within 8 h in one flow cell with the standard library preparation method. The mean read length, longest read length, and mean read-level accuracy of QitanTech sequencing data were 6,041 bp, 57,037 bp, and 81.50% (LAST)/81.40% (Minimap2), respectively. Two routine assembly strategies including long-read assembly and hybrid assembly enable the achievement of complete bacterial genomes. The accuracy of assembled draft bacterial genomes with QitanTech long-read data could be improved up to 99.9% dramatically by polishing using accurate short-read data. Furthermore, the assembled bacterial genomes cover accurate structures of complex resistance plasmids harboring critical resistance genes such as tet(X), tmexCD-toprJ, and blaVIM–2, even the complex fusion MDR plasmid generated from homologous recombination. In conclusion, QitanTech nanopore sequencing, as a nanopore long-read sequencing technology launched in China, could be a good option for investigation of complex bacterial genomes. More potential applications based on this novel platform warrant investigations.

Inflation persistence (or inertia) has been a problem in many developing countries and due to the relationship between inflation and economic growth, much research has been conducted on the literature to study closely these macroeconomic variables in developing countries (Brick, 2010; Gokal and Hanif, 2004). This paper however made use of a superior method known as quantile autoregressive model proposed by Koenker and Xiao (2006) to estimate the persistence of inflation, the dynamic behavior and examine how diverse shocks may perhaps affect the rate of inflation within different quantiles. The data employed in this study is the monthly year-on-year Ghana inflation rate from January 2000 to July 2019. The result shows that Ghana inflation rates exhibits low persistence at both lower and higher quantiles and a mean reversion behavior across quantiles. Also, we observe that Ghana inflation rate is globally stationary as well as portraying non-stationary behavior in about 10% of the sampled observations. Evidently, the results again reveal that Ghana inflation rate has irregular characteristics at different quantiles in its conditional distribution. Also, there is a bidirectional relationship between Ghana overall inflation rate and its components (food and non-food inflation).

Abstract Background Gastric adenocarcinoma of the fundic gland type (GA-FG) has been added to the 2019 edition of the World Health Organization’s list of digestive system-associated cancers. This lesion differentiates toward the fundic gland and mostly involves chief cell-predominant differentiation with low-grade cytology. Clinicians and pathologists are still unaware of this rare disease; consequently, some cases are incorrectly diagnosed. This study aimed to investigate the clinicopathological features of GA-FG using retrospective analyses of endoscopic and pathological findings. Materials and methods Samples were collected from patients diagnosed with GA-FG. The clinical courses of all patients were monitored prospectively and reviewed retrospectively. Available clinical information, endoscopic features, pathological appearance, and follow-up data were assessed. Immunohistochemistry [mucin (MUC) 2, MUC5, MUC6, P53, CDX2, Ki67, SYN, CD56, CGA, β-catenin, and pepsinogen-I] was examined using Envision two-step method. Results Eight cases of endoscopic submucosal dissection (ESD) were obtained from our institution. Patient age ranged from 48 to 80 years (mean, 65 years). Some patients were on acid-suppressing medication. Most lesions were located in the upper third (n = 7) and one was in the middle third of the stomach. Six lesions were of the superficial flat type, whereas two were of the superficial elevated type. Narrow-band imaging using magnifying endoscopy showed irregular microvascular patterns (MVPs) in four cases and regular MVPs in the remaining cases. All lesions were primarily solitary and ~ 6 mm in diameter (largest, 12 mm). The main body of the tumors were localized in the mucosal layer, of which six cases invade into the submucosal layer. Well-formed glands of chief cells were predominant. Tumor cells were positive for pepsinogen-I, MUC6, SYN, and CD56. Lymphatic and vascular infiltration and metastatic and recurrent disease were not observed in any case. Conclusion GA-FG, a well-differentiated adenocarcinoma with mild atypia, can be completely removed using ESD, with a favorable prognosis in patients.

Patients whose disease is diagnosed in its early stages have better outcomes. In this study, the authors develop a non invasive blood test based on circulating tumor DNA methylation that can potentially detect cancer occurrence even in asymptomatic patients.

Abstract Background Calvin cycle plays a crucial role in carbon fixation which provides the precursors of organic macromolecules for plant growth and development. Currently, no gene involved in Calvin cycle has been identified in monocotyledonous plants through mutant or/and map-based cloning approach. Results Here, we isolated a low-tillering mutant, c6635, in rice (Oryza sativa). The mutant displayed light green leaves and intensely declined pigment contents and photosynthetic capacity at early growth stage. Moreover, its individual plant showed a much smaller size, and most individuals produced only two tillers. At mature stage, its productive panicles, grain number and seed setting rate were significantly decreased, which lead to a sharp reduction of the grain yield. We confirmed that a single nucleotide mutation in LOC_Os04g16680 gene encoding sedoheptulose 1,7-bisphosphatase (SBPase) involved in Calvin cycle was responsible for the mutant phenotype of c6635 through map-based cloning, MutMap analysis and complementation experiments. Sequence analysis suggested that the point mutation caused an amino acid change from Gly-364 to Asp at the C-terminal of SBPase. In addition, OsSBPase gene was mainly expressed in leaf, and the encoded protein was located in chloroplast. The mutation of OsSBPase could significantly affect expression levels of some key genes involved in Calvin cycle. Conclusions We successfully identified a SBPase gene in monocotyledonous plants. Meanwhile, we demonstrated that a single nucleotide substitution at the 3′-end of this gene severely affects plant growth and grain yield, implying that the Gly-364 at the C-terminal of SBPase could play an important role in SBPase function in rice.

Abstract Background Neuroendocrine tumors (NETs) can secrete bioactive amines in the bloodstream, resulting in the carcinoid syndrome characterized by diarrhea and flushing. The frequency of occurrence of primary cardiac neuroendocrine neoplasms is lesser than that of metastases, and hence, metastases must be adequately ruled out before diagnosis. Cardiac tumors, both primary and metastatic, mainly result in heart-related symptoms, such as heart failure and acquired valvular dysfunction. Here, we report a unique case of a primary left ventricular neuroendocrine tumor presenting with diarrhea. Case presentation A 51-year-old female complaining of intermittent diarrhea for 2 years was admitted to our hospital. Enhancement of total abdominal computed tomography scan, echocardiography, and magnetic resonance imaging indicated a mass in the left ventricle. The indexes of myocardial enzymes were normal. Histologically, round cells with well-differentiated neuroendocrine morphology were arranged in typical pseudo-glandular, trabecular, ribbon-like, and solid nest patterns. Immunohistochemically, the tumor cells were positive for cytokeratin, chromogranin, synaptophysin, and CD56. However, they were negative for caudal type homeobox 2, S100, paired box gene 8, thyroid transcription factor 1, and CD20, which ruled out the origin of gastrointestinal, pancreatic, lung, and Merkel cell carcinomas. The symptoms of diarrhea disappeared after the operation. The patient was asymptomatic at the 9-month follow-up. Conclusion Cardiac neuroendocrine tumors with diarrhea are considerably rare and related clinical research is limited. We presented a case and reviewed related articles to improve the identification, diagnosis, and management of patients with cardiac neuroendocrine tumors. The site of origin of a neuroendocrine tumor is clinically vital, and identification of an occult primary tumor using imaging modalities is necessary. Immunohistochemistry is well-suited to indicate the origin of the tumor. Regular follow-up is necessary for both poorly differentiated and well-differentiated cardiac neuroendocrine tumors. It is suggested to detect some neuroendocrinal markers for patients with unexplained reasons of diarrhea.

Introduction Oral health and genetic factors can independently influence the risk of developing esophageal squamous cell carcinoma (ESCC). Objectives The primary objective of this study was to investigate the interactive effects of oral health and genetic factors on ESCC risk. Methods This was a matched case-control study with 927 ESCC patients and 1701 matched controls. We selected 101 candidate single nucleotide polymorphisms (SNPs) from 59 genes that were associated with ESCC. Oral health was assessed based on tooth-brushing frequency, tooth loss, and age at the time of first tooth loss. An unconditional logistic regression model was employed in which SNP–oral health interactions were assessed as risk factors for ESCC, after adjusting for age and sex. A genetic risk score (GRS) analysis was conducted. Results The association between GRS and ESCC and the synergistic effect of GRS and oral health on ESCC were examined. Daily frequency of tooth-brushing was found to interact with 5 SNPs, rs3765524, rs753724, rs994771, rs3781264, and rs11187842, to increase the risk of ESCC. In particular, individuals with genotype TT of rs3765524 who brushed their teeth less than twice a day had a 5.13-times higher risk of ESCC than those with genotype CC who brushed their teeth at least twice a day. Furthermore, tooth loss interacted with two SNPs: rs1159918 from ADH1B and rs3813867 from CYP2E1. Conclusion Oral health may interact with genetic factors increasing ESCC risk, which provides new insights into the relationship between ESCC and gene–lifestyle interactions which can be used for disease prevention.

Objective. Hashimoto’s thyroiditis (HT) is one of the most common clinical autoimmune diseases. Recent studies have found that HT pathogenesis is associated with macrophage polarization. Saikosaponin-d (SSd) is an active component in the Chinese medicine Bupleurum, which has anti-inflammatory and immunomodulatory effects. The purpose of this study was to verify the therapeutic effect of SSd on HT and to investigate the regulatory effect of SSd on macrophage polarization in HT. Methods. Network pharmacology analysis was used to predict the relevant targets and signaling pathways of SSd for HT treatment. The therapeutic effect of SSd on HT model mice and the effect on macrophage polarization were detected by animal experiment. Results. Network pharmacological analysis showed that SSd can alleviate HT against multiple targets such as IL-6 and IL-10 and can act on macrophage polarization-related signaling pathways such as MAPK and JAK-STAT signaling pathways. Animal experiments showed that SSd intervention attenuated the lymphocytic infiltration in thyroid tissues of HT mice (P=0.044); SSd intervention reduced serum TPOAb antibody level in HT mice (P

Background: Understanding the spatiotemporal trends of colorectal cancer (CRC) deaths caused by low physical activity (LPA) and high body mass index (BMI) is essential for the prevention and control of CRC. We assessed patterns of LPA and high BMI-induced CRC deaths from 1990 to 2019 at global, regional, and national levels.Methods: Data on CRC deaths due to LPA and high BMI was downloaded from the Global Burden of Disease 2019 Study. We calculated estimated annual percentage change (EAPC) to quantify spatiotemporal trends in the CRC age-standardized mortality rate (ASMR) due to LPA and high BMI.Results: In 2019, CRC deaths due to LPA and high BMI were estimated as 58.66 thousand and 85.88 thousand, and the corresponding ASMRs were 0.77/100,000 and 1.07/100,000, with EAPCs of−0.39 [95% confidence interval (CI):−0.49,−0.29] and 0.64[95% CI: 0.57, 0.71] from 1990 to 2019 respectively. Since 1990, the ASMR of CRC attributable to LPA and high BMI has been on the rise in many geographic regions, especially in low middle and middle sociodemographic index (SDI) regions. Thirteen countries had a significant downward trend in CRC ASMR attributed to LPA, with EAPCs < −1. And, only 4 countries had a significant downward trend in CRC ASMR attributable to high BMI, with EAPCs < −1. Countries with a higher baseline burden in 1990 and a higher SDI in 2019 had a faster decline in ASMR due to high BMI and LPA.Conclusions: The burden of CRC caused by LPA and high BMI is on the rise in many countries. Countries should adopt a series of measures to control the local prevalence of obesity and LPA in order to reduce disease burden, including CRC.

There are significant gender differences in the incidence and mortality of hepatocellular carcinoma (HCC). Compared with men, the incidence and mortality of HCC in women are relatively low. The estrogen signaling pathway, composed of estrogen and estrogen receptors, has been postulated to have a protective effect on the occurrence and development of HCC. There have been multiple studies that have supported anti-HCC effects of the estrogen signaling pathways, including direct and indirect pathways such as genomic pathways, rapid transduction pathways, non-coding RNA, tumor microenvironment, estrogen metabolites, and inhibition of hepatitis infection and replication. Based on the evidence of an anti-HCC effect of the estrogen signaling pathway, a number of strategies have been investigated to determine the potential therapeutic effect. These have included estrogen replacement therapy, targeting the estrogen receptor, key molecules, inflammatory mediators, and regulatory pathways of the estrogen signaling pathway. In this review, we have systematically summarized the latest developments in the complex functions and molecular mechanisms of the estrogen signaling pathway in liver cancer. Furthermore, we have highlighted the potential targets of treatment strategies based on the estrogen signaling pathway in the treatment of liver cancer and the principal obstacles currently encountered for future investigation.

Age-related changes in bone tissue have always been an important part of bone research, and age estimation is also of great significance in forensic work. In our study, FTIR and Raman microspectroscopy were combined to explore the structural and chronological age-related changes in the occipital bones of 40 male donors. The FTIR micro-ATR mode not only achieves the comparison of FTIR and Raman efficiency but also provides a new pattern for the joint detection of FTIR and Raman in hard tissue. Statistical analysis and PCA results revealed that the structure had little effect on the FTIR and Raman results. The FTIR and Raman mineral/matrix ratio, carbonate/phosphate ratio, crystallinity, and collagen maturity of the whole showed an increasing trend during maturation, and a significant correlation was found between FTIR and Raman by comparing four outcomes. Furthermore, the results indicated that the cutoff point of the change in the relative proportion of organic matrix and inorganic minerals in males was between 19 and 35 years old, and the changes in the relative proportion of organic matrix and inorganic minerals may play a key role in age estimation. Ultimately, we established age estimation regression models. The FTIR GA-PLS regression model has the best performance and is more suitable for our experiment (RMSECV = 10.405, RMSEP = 9.2654, R2CV = 0.814, and R2Pred = 0.828). Overall, FTIR and Raman combined with chemometrics are an ideal method to estimate chronological age based on age-dependent component changes in male occipital bones. Our experiment provides a proof of concept and potential experimental method for chronological age estimation.

Phytoplasmas are uncultivable, phloem-limited, phytopathogenic bacteria that represent a major threat to agriculture worldwide. Phytoplasma membrane proteins are in direct contact with hosts and presumably play a crucial role in phytoplasma spread within the plant as well as by the insect vector. Three highly abundant types of immunodominant membrane proteins (IDP) have been identified within the phytoplasmas: immunodominant membrane protein (Imp), immunodominant membrane protein A (IdpA), and antigenic membrane protein (Amp). Although recent results indicate that Amp is involved in host specificity by interacting with host proteins such as actin, little is known about the pathogenicity of IDP in plants. In this study, we identified an antigenic membrane protein (Amp) of rice orange leaf phytoplasma (ROLP), which interacts with the actin of its vector. In addition, we generated Amp-transgenic lines of rice and expressed Amp in tobacco leaves by the potato virus X (PVX) expression system. Our results showed that the Amp of ROLP can induce the accumulation of ROLP and PVX in rice and tobacco plants, respectively. Although several studies have reported interactions between major phytoplasma antigenic membrane protein (Amp) and insect vector proteins, this example demonstrates that Amp protein can not only interact with the actin protein of its insect vector but can also directly inhibit host defense responses to promote the infection. The function of ROLP Amp provides new insights into the phytoplasma-host interaction.

During 2013–2017, a total of 211 cases of listeriosis were reported by 64 sentinel hospitals in China to a national foodborne disease surveillance network. The average case-fatality rate was 31.2% for perinatal cases and 16.4% for nonperinatal cases. Sequence types 87 and 8 were the most prevalent types.

Background: We aimed to explore the relationship between lifestyle factors, cancer family history, and gastric cancer risk.Methods: We examined the association between lifestyle factors, cancer family history, and gastric cancer risk based on a population-based case-control study in Taixing, China, with 870 cases and 1928 controls. A lifestyle score was constructed considering body shape, smoking, alcohol drinking, tooth brushing habit, and food storage method. Unconditional logistic regression models were used to calculate odd ratios (ORs) and 95% confidence intervals (CIs).Results: Compared with participants with a lifestyle score of 0, subjects with a lifestyle score of 1 (OR 0.59, 95%CI 0.43–0.83), 2 (OR 0.42, 95%CI 0.30–0.59), 3 (OR 0.29, 95%CI 0.20–0.41), 4 (OR 0.20, 95%CI 0.13–0.32), or 5 (OR 0.10, 95%CI 0.04–0.22) had a lower risk of gastric cancer (P for trend < 0.001). Overall, 34% of gastric cancer cases (95%CI 27–41%) can be attributed to non-compliance with ≥3 healthy lifestyle. Family history of early-onset cancer is closely related to the occurrence of gastric cancer, with an OR ranging from 1.77 to 3.27. Regardless of family history, a good lifestyle is associated with a reduced risk of gastric cancer, with an OR value between 0.38 and 0.70.Conclusions: The early-onset cancer family history is closely related to the occurrence of gastric cancer and a good lifestyle is associated with a reduced risk of gastric cancer regardless of family history. Our results provide a basis for identifying and providing behavior guidance of high-risk groups of gastric cancer.

SNHG10 is a long non-coding RNA (lncRNA) found to be overexpressed in multiple human cancers including prostate cancer (PC). However, the underlying mechanisms of SNHG10 driving the progression of PC remains unclear. In this study, we investigated the role of SNHG10 in PC and found that SNHG10 expression was significantly increased in datasets extracted from The Cancer Genome Atlas. Increased expression of SNHG10 was related to advanced clinical parameters. Receiver operating curve analysis revealed the significant diagnostic ability of SNHG10 (AUC = 0.805). In addition, immune infiltration analysis, and GSEA showed that SNHG10 expression was correlated with oxidative phosphorylation and immune infiltrated cells. Finally, we determined that SNHG10 regulated cell proliferation, migration, and invasion of PC in vitro. In conclusion, our data demonstrated that SNHG10 was correlated with progression and immune infiltration, and could serve as a prognostic biomarker for PC.

BackgroundLong noncoding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Gastric adenocarcinoma-associated, positive CD44 regulator, long intergenic noncoding RNA (GAPLINC) is a recently identified lncRNA that can actively participate in the tumorigenesis of various cancers. Here, we investigated the functional roles and mechanism of GAPLINC in renal cell carcinoma (RCC) development.MethodsDifferentially expressed lncRNAs between RCC tissues and normal kidney tissues were detected by using a microarray technique. RNA sequencing was applied to explore the mRNA expression profile changes after GAPLINC silencing. After gain- and loss-of-function approaches were implemented, the effect of GAPLINC on RCC in vitro and in vivo was assessed by cell proliferation and migration assays. Moreover, rescue experiments and luciferase reporter assays were used to study the interactions between GAPLINC, miR-135b-5p and CSF1.ResultsGAPLINC was significantly upregulated in RCC tissues and cell lines and was associated with a poor prognosis in RCC patients. Knockdown of GAPLINC repressed RCC growth in vitro and in vivo, while overexpression of GAPLINC exhibited the opposite effect. Mechanistically, we found that GAPLINC upregulates oncogene CSF1 expression by acting as a sponge of miR-135b-5p.ConclusionTaken together, our results suggest that GAPLINC is a novel prognostic marker and molecular therapeutic target for RCC.

As an important agronomic trait in rice (Oryza sativa), moderate leaf rolling helps to maintain the erectness of leaves and minimize shadowing between leaves, leading to improved photosynthetic efficiency and grain yield. However, the molecular mechanisms underlying rice leaf rolling still need to be elucidated. Here, we isolated a rice mutant, rl89, showing adaxially rolled leaf phenotype due to decreased number and size of bulliform cells. We confirmed that the rl89 phenotypes were caused by a single nucleotide substitution in OsDRB2 (LOC_Os10g33970) gene encoding DOUBLE-STRANDED RNA-BINDING2. This gene was constitutively expressed, and its encoded protein was localized to both nucleus and cytoplasm. Yeast two-hybrid assay showed that OsDRB2 could interact with DICER-LIKE1 (DCL1) and OsDRB1-2 respectively. qRT-PCR analysis of 29 related genes suggested that defects of the OsDRB2-miR166-OsHBs pathway could play an important role in formation of the rolled leaf phenotype of rl89, in which OsDRB2 mutation reduced miR166 accumulation, resulting in elevated expressions of the class III homeodomain-leucine zipper genes (such as OsHB1, 3 and 5) involved in leaf polarity and/or morphology development. Moreover, OsDRB2 mutation also reduced accumulation of miR160, miR319, miR390, and miR396, which could cause the abnormal leaf development in rl89 by regulating expressions of their target genes related to leaf development.

Neoadjuvant chemotherapy (NAC) is the standard therapeutic regimen for locally advanced breast cancer. However, clinical physical examination and imaging results fail to accurately assess the treatment response, and postoperative pathological examination has a time lag in response to therapeutic effect which is not conducive to the timely adjustment of treatment strategies. A previous study has shown that miR-301a was associated with invasion and metastasis in breast cancer, and was found to be involved in endocrine therapy resistance; however, evidence regarding the correlation between miR-301a expression and NAC efficacy remains scarce. In this study, 101 patients with locally advanced breast cancer were included. All patients received anthracycline based chemotherapy. The expression level of miR-301a in pretreatment core needle biopsy tissues was determined by real-time polymerase chain reaction analysis. Relevant clinicopathological data were collected, and the correlation between miR-301a expression and NAC efficacy was assessed. Based on our data, miR-301a cannot be used to identify whether breast cancer benefits from NAC, and no correlation was observed between miR-301a expression and clinicopathological characteristics. In conclusion, miR-301a may not be a potential prognostic biomarker of NAC efficacy in breast cancer.

It has shown that schizophrenia (SCZ) is associated with a higher chance of myocardial infarction (MI) and increased mortality. However, the underlying mechanism is largely unknown. Here, we first constructed a literature-based genetic pathway linking SCZ and MI, and then we tested the expression levels of the genes involved in the pathway by a meta-analysis using nine gene expression datasets of MI. In addition, a literature-based data mining process was conducted to explore the connection between SCZ at different levels: small molecules, complex molecules, and functional classes. The genetic pathway revealed nine genes connecting SCZ and MI. Specifically, SCZ activates two promoters of MI (IL6 and CRP) and deactivates seven inhibitors of MI (ADIPOQ, SOD2, TXN, NGF, ADORA1, NOS1, and CTNNB1), suggesting that no protective role of SCZ in MI was detected. Meta-analysis showed that one promoter of MI (CRP) presented no significant increase, and six out of seven genetic inhibitors of MI demonstrated minor to moderately increased expression. Therefore, the elevation of CRP and inhibition of the six inhibitors of MI by SCZ could be critical pathways to promote MI. Nine other regulators of MI were influenced by SCZ, including two gene families (inflammatory cytokine and IL1 family), five small molecules (lipid peroxide, superoxide, ATP, ascorbic acid, melatonin, arachidonic acid), and two complexes (CaM kinase 2 and IL23). Our results suggested that SCZ promotes the development and progression of MI at different levels, including genes, small molecules, complex molecules, and functional classes.

Abstract The relationship between risk of esophageal squamous cell carcinoma (ESCC) and adult height, changes in individual body mass index (BMI) and body shape is not established. We performed a large population‐based case‐control study, which enrolled a total of 1414 ESCC cases and 1989 controls in a high‐incidence area in China. Using face‐to‐face interview with a structured questionnaire, information on participants' heights, weights, and perceived body shapes at 20 years of age was collected. Additionally, data on weight and perceived body shape among the same participants 10 years prior to ascertainment were collected using the same method. Odd ratios (ORs) of ESCC risk in relation to BMI and body shape were estimated using unconditional logistic regression models. The adjusted results indicated that ESCC risk in adults rapidly rose as height increased, plateauing at 170 cm among men and 157 cm among women. Among participants who were underweight, normal weight, or thinner than body shape 4, body weight loss was associated with increased risk of ESCC, and body weight gain was associated with decreased incidence of ESCC (ORs ranging from 0.40 to 0.76). Notably, however, changes in body weight did not significantly affect ESCC risk among participants who were overweight, obese, or larger than body shape 3. Maintaining a fit body shape and a reasonable BMI is advisable and of vital importance to reduce the risk of ESCC, especially in high‐risk areas.

Laccase is a multi‐copper oxidase which oxidizes substrate at the type 1 copper site, simultaneously coupling the reduction of dioxygen to water at the trinuclear copper center. In this study, we used site‐directed mutagenesis to study the effect of axial bonds between the metal and amino acid residue side chains in lacTT. Our kinetic and spectral data showed that the replacement of the axial residue with non‐coordinating residues resulted in higher efficiency (kcat/Km) and a lower Cu2+ population at the type 1 copper site, while substitution with strongly coordinating residues resulted in lower efficiency and a higher Cu2+ population, as compared with the wild‐type. The redox potentials of mutants with hydrophobic axial residues (Ala and Phe) were higher than that of the wild‐type. In conclusion, these insights into the catalytic mechanism of laccase may be of use in protein engineering to fine‐tune its enzymatic properties for industrial application.

Molecular mechanisms and observational studies have found that diet-derived antioxidants are associated with digestive system cancers, whereas there is a lack of causal evidence from randomized clinical trials. In this study, we aimed to assess the causality of these associations through a Mendelian randomization (MR) study. Single nucleotide polymorphisms of diet-derived circulating antioxidants (i.e., α- and γ-tocopherol, ascorbate, retinol, β-carotene, lycopene, and urate), accessed by absolute levels and relative metabolite concentrations, were used as genetic instruments. Summary statistics for digestive system cancers were obtained from the UK Biobank and FinnGen studies. Two-sample MR analyses were performed in each of the two outcome databases, followed by a meta-analysis. The inverse-variance weighted MR was adopted as the primary analysis. Five additional MR methods (likelihood-based MR, MR-Egger, weighted median, penalized weighted median, and MR-PRESSO) and replicate MR analyses for outcomes from different sources were used as sensitivity analyses. Genetically determined antioxidants were not significantly associated with five digestive system cancers, after correcting for multiple tests. However, we found suggestive evidence that absolute ascorbate levels were negatively associated with colon cancer in UK Biobank—the odds ratio (OR) per unit increase in ascorbate was 0.774 (95% confidence interval [CI] 0.608–0.985, p = 0.037), which was consistent with the results in FinnGen, and the combined OR was 0.764 (95% CI 0.623–0.936, p = 0.010). Likewise, higher absolute retinol levels suggestively reduced the pancreatic cancer risk in FinnGen—the OR per 10% unit increase in ln-transformed retinol was 0.705 (95% CI 0.529–0.940, p = 0.017), which was consistent with the results in UK Biobank and the combined OR was 0.747 (95% CI, 0.584–0.955, p = 0.020). Sensitivity analyses verified the above suggestive evidence. Our findings suggest that higher levels of antioxidants are unlikely to be a causal protective factor for most digestive system cancers, except for the suggestive protective effects of ascorbate on colon cancer and of retinol on pancreatic cancer.

Recent studies have identified pleiotropic roles of methyltransferase-like 3 (METTL3) in tumor progression. However, the roles of METTL3 in esophageal squamous cell carcinoma (ESCC) are still unclear. Here, we investigated the function and mechanism of METTL3 in ESCC tumorigenesis. We reported that higher METTL3 expression was found in ESCC tissues and was markedly associated with depth of invasion and poor prognosis. Loss- and gain-of function studies showed that METTL3 promoted the migration and invasion of ESCC cells in vitro. Integrated methylated RNA immunoprecipitation sequencing (MeRIP-Seq) and RNA sequencing (RNA-Seq) analysis first demonstrated that glutaminase 2 (GLS2) was regulated by METTL3 via m6A modification. Our findings identified METTL3/GLS2 signaling as a potential therapeutic target in antimetastatic strategies against ESCC.

Liver cancer is associated with high mortality, particularly in patients infected with the hepatitis B virus. Treatment methods remain very limited. Here, we explored the effects of 17β-estradiol (E2) on apoptosis of various liver cell lines (LO2, HepG2, and HepG2.2.15 cells). Within a certain concentration range, 17β-estradiol induced oxidative stress and apoptosis of HepG2 cells, downregulated ERα-36 expression, and increased Akt and Foxo3a phosphorylation. p-Foxo3a became localized around the nucleus but did not enter the organelle. The levels of mRNAs encoding manganese superoxide dismutase (MnSOD) and catalase, to the promoters of which Foxo3a binds to trigger gene expression, were significantly reduced in HepG2 cells. 17β-estradiol had no obvious effects on LO2 or HepG2.2.15 cells. We speculate that 17β-estradiol may induce oxidative stress in HepG2 cells by increasing Foxo3a phosphorylation, thus promoting apoptosis. This may serve as a new treatment for hepatocellular carcinoma.

Abstract Horizontal gene transfer facilitates the spread of antibiotic resistance genes, which constitutes a global challenge. However, the evolutionary trajectory of the mobile colistin resistome in bacteria is largely unknown. To investigate the coevolution and fitness cost of the colistin resistance genes in wild strains, different assays to uncover the genomic dynamics of mcr‐1 and mcr‐3 in bacterial populations are utilized. Escherichia coli strains harboring both mcr‐1 and mcr‐3.1/3.5 are isolated and mcr genes are associated with diverse mobile elements. Under exposure to colistin, the mcr‐1‐bearing resistome is stably inherited during bacterial replication, but mcr‐3 is prone to be eliminated in populations of certain strains. In the absence of colistin, the persistence rates of the mcr‐1 and mcr‐3‐bearing subclones varies depending on the genomic background. The decay of the mcr‐bearing bacterial populations can be mediated by the elimination of mcr‐containing segments, large genomic deletions, and plasmid loss. Mobile elements, including plasmids and transposons, are double‐edged swords in the evolution of the resistome. The findings support the idea that antibiotic overuse accounts for global spread of multidrug‐resistant (MDR) bacteria. Therefore, stringent regulation of antibiotic prescription for humans and animals should be performed systematically to alleviate the threat of MDR bacteria.

Obstructive sleep apnea (OSA) is characterized by repetitive intermittent oxygen desaturation during sleep. Carbon monoxide poisoning (COP) is the second most common cause of death among non-medicinal poisonings, and oxygen therapy is the current standard of treatment for COP. We herein report a case of a 50-year-old woman diagnosed with severe OSA associated with COP. Both the OSA and COP gradually resolved by automatic continuous positive airway pressure (CPAP) therapy. New OSA symptoms appeared following the development of delayed encephalopathy after acute COP (DEACMP) 3 weeks later. Severe OSA was diagnosed 76 days after COP with an apnea–hypopnea index of 66 events/hour, and CPAP therapy was immediately administered. The patient’s DEACMP symptoms and OSA both improved with CPAP therapy (her apnea–hypopnea index decreased to 32.4 and 16.5 events/hour at 161 and 204 days after COP, respectively). To our knowledge, this is the first case report of OSA caused by COP based on the occurrence and disappearance of OSA symptoms and laboratory findings associated with the emergence and improvement of DEACMP.