Background Kurtosis reflecting noise's temporal structure is an effective metric for evaluating noise-induced hearing loss (NIHL), and its threshold is still unclear. Objective To explore the energy range of kurtosis and the threshold of NIHL induced by kurtosis in this energy rangeMethods Using cross-sectional design, 4631 noise-exposed workers in manufacturing industry were selected. The hearing loss and noise exposure data of each worker were collected. Logistic regression model was used to establish the dose-response relationship between noise exposure and hearing loss and estimate the range of energy effects. Restricted cubic spline model was utilized to analyze the dose-response relationship curves of kurtosis to noise-induced hearing loss (NIHI) and high-frequency noise-induced hearing loss (HFNIHL) under different 8 h equivalent sound levels (L_{EX,8 h}), as well as to estimate the kurtosis effect threshold. Results The logistic regression model analysis showed that the prevalence of NIHI and HFNIHL increased significantly with increase of L_{EX,8 h} for steady noise; when L_{EX,8 h} of non-steady noise was 80-100 dB(A), the risk of hearing loss increased with an increase in kurtosis (P<0.05). The restricted cubic spline model showed that when L_{EX,8 h} of non-steady noise was 0-80 dB(A) or >100 dB(A), there was no significant relationship between kurtosis and NIHI or HFNIHL. When L_{EX,8 h} was 80-100 dB(A), there was a significant nonlinear dose-response relationship between kurtosis and NIHL or HFNIHL (P <0.001), and kurtosis > 28.08 exerted effect in elevating NIHI or HFNIHL. Conclusion The effect threshold of kurtosis on NIHL is 28.08 when non-steady noise levels are in the range of 80-100 dB(A). The effect threshold of kurtosis needs further verification.

T7 RNA polymerase (T7 RNAP) is one of the simplest known RNA polymerases. Its unique structural features make it a critical model for studying the mechanisms of RNA synthesis. This review systematically examines the static crystal structure of T7 RNAP, beginning with an in-depth examination of its characteristic “thumb”, “palm”, and “finger” domains, which form the classic “right-hand-like” architecture. By detailing these structural elements, this review establishes a foundation for understanding the overall organization of T7 RNAP. This review systematically maps the functional roles of secondary structural elements and their subdomains in transcriptional catalysis, progressively elucidating the fundamental relationships between structure and function. Further, the intrinsic flexibility of T7 RNAP and its applications in research are also discussed. Additionally, the review presents the structural diagrams of the enzyme at different stages of the transcription process, and through these diagrams, it provides a detailed description of the complete transcription process of T7 RNAP. By integrating structural dynamics and kinetics analyses, the review constructs a comprehensive framework that bridges static structure to dynamic processes. Despite its advantages, T7 RNAP has a notable limitation: it generates double-stranded RNA (dsRNA) as a byproduct. The presence of dsRNA not only compromises the purity of mRNA products but also elicits nonspecific immune responses, which pose significant challenges for biotechnological and therapeutic applications. The review provides a detailed exploration of the mechanisms underlying dsRNA formation during T7 RNAP catalysis, reviews current strategies to mitigate this issue, and highlights recent progress in the field. A key focus is the semi-rational design of T7 RNAP mutants engineered to minimize dsRNA generation and enhance catalytic performance. Beyond its role in transcription, T7 RNAP exhibits rapid development and extensive application in fields, including gene editing, biosensing, and mRNA vaccines. This review systematically examines the structure-function relationships of T7 RNAP, elucidates the mechanisms of dsRNA formation, and discusses engineering strategies to optimize its performance. It further explores the engineering optimization and functional expansion of T7 RNAP. Furthermore, this review also addresses the pressing issues that currently need resolution, discusses the major challenges in the practical application of T7 RNAP, and provides an outlook on potential future research directions. In summary, this review provides a comprehensive analysis of T7 RNAP, ranging from its structural architecture to cutting-edge applications. We systematically examine: (1) the characteristic right-hand domains (thumb, palm, fingers) that define its minimalistic structure; (2) the structure-function relationships underlying transcriptional catalysis; and (3) the dynamic transitions during the complete transcription cycle. While highlighting T7 RNAP’s versatility in gene editing, biosensing, and mRNA vaccine production, we critically address its major limitation—dsRNA byproduct formation—and evaluate engineering solutions including semi-rationally designed mutants. By synthesizing current knowledge and identifying key challenges, this work aims to provide novel insights for the development and application of T7 RNAP and to foster further thought and progress in related fields.

Objective To investigate the inhibitory effects of Wumeiwan on oxidative stress injury of ulcerative colitis mice induced by dextran sulfate sodium(DSS)by regulating Kelch-like ECH related protein 1(Keap-1)-nuclear factor E2 related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling pathwayand.Methods Forty C57BL/6 mice were randomly divided into five groups:normal group,model group,positive control group,experimental-L,-H groups.UC mice model were induced by free access to 2％DSS water.Mice in normal and model group were orally administered with 0.9％NaCl,mice in positive control group were orally treated with Mesalazine solution(0.005 g·10 g-1·d-1),while mice in experimental groups were orally administered with Wumeiwan decoction at the dose of 0.13 and 0.26 g·10 g-1·d-1,respectively.All the drugs were administered for consecutive 7 days,1 times a day.The levels of disease activity index(DAI)and the colon length were scored.The levels of superoxide dismutase(SOD),catalase(CAT),cyclooxygenase-2(COX-2)and inducible nitric oxide synthase(iNOS)in colon tissue of mice were determined by real-time fluorescence quantitative polymerase chain reaction(qRT-PCR)method.The level of Keap-1,Nrf2,HO-1 proteins in colon tissue were determined by Western blot method.Results The levels of DAI of seventh day in normal group,positive control group,experimental-L,-H groups were 0、(2.62±0.33),(1.87±0.35),(1.87±0.35)and(1.58±0.35);the colon lengths were(8.16±0.47)、(5.98±0.24),(7.58±0.38),(7.33±0.24)and(7.48±0.51)cm;the SOD mRNA were 1.01±0.16、0.40±0.01,1.43±0.45,0.65±0.01 and 0.83±0.02;the CAT mRNA were 1.01±0.20、0.45±0.01,0.84±0.02,0.68±0.07 and 0.87±0.05;the COX-2 mRNA were 1.03±0.33、16.65±0.60,4.78±0.25,14.07±0.60 and 7.39±0.15;the iNOS mRNA were 1.04±0.40、20.71±0.66,8.09±0.93,15.44±0.68 and 11.66±0.06;the levels of Keap-1 were 1.22±0.16、1.10±0.05,1.18±0.05,1.94±0.08 and 1.17±0.08;the levels of Nrf2 were 1.12±0.16、0.76±0.15,0.65±0.13,0.70±0.16 and 0.82±0.18;the levels of HO-1 were 1.34±0.15、1.00±0.12,0.89±0.10,1.50±0.18 and 1.40±0.13,respectively.Significant difference was found between normal group and model group(P＜0.01,P＜0.05);significant difference was also found between the experimental-L,-H groups and model group(P＜0.01,P＜0.05).Conclusion Wumeiwan can inhibit oxidative stress in mice with UC,the mechanisms may be related to adjusted the expression of Keap-1-Nrf2/HO-1 signaling pathway protein in colon.

Objective:To investigate the surgical situations and perioperative outcome of pancreaticoduodenectomy in Jiangsu Province and the influencing factors for postoperative 90-day mortality.Methods:The retrospective case-control study was conducted. The clinicopathological data of 2 886 patients who underwent pancreaticoduodenectomy in 21 large tertiary hospitals of Jiangsu Quality Control Center for Pancreatic Diseases, including The First Affiliated Hospital of Nanjing Medical University, from March 2021 to December 2022 were collected. There were 1 732 males and 1 154 females, aged 65(57,71)years. Under the framework of the Jiangsu Provincial Pancreatic Disease Quality Control Project, the Jiangsu Quality Control Center for Pancreatic Diseases adopted a multi-center registration research method to establish a provincial electronic database for pancrea-ticoduodenectomy. Observation indicators: (1) clinical characteristics; (2) intraoperative and post-operative conditions; (3) influencing factors for 90-day mortality after pancreaticoduodenectomy. Measurement data with skewed distribution were represented as M( Q1, Q3) or M(IQR), and comparison between groups was conducted using the Mann-Whitney U test. Count data were expressed as absolute numbers or constituent ratio, and comparison between groups was conducted using the chi-square test, continuity correction chi-square test and Fisher exact probability. Maximal Youden index method was used to determine the cutoff value of continuous variables. Univariate analysis was performed using the corresponding statistical methods based on data types. Multivariate analysis was performed using the Logistic multiple regression model. Results:(1) Clinical characteristics. Of the 2 886 patients who underwent pancreaticoduodenectomy, there were 1 175 and 1 711 cases in 2021 and 2022, respectively. Of the 21 hospitals, 8 hospitals had an average annual surgical volume of <36 cases for pancreaticoduodenectomy, 10 hospitals had an average annual surgical volume of 36-119 cases, and 3 hospitals had an average annual surgical volume of ≥120 cases. There were 2 584 cases performed pancreaticoduodenectomy in thirteen hospitals with an average annual surgical volume of ≥36 cases, accounting for 89.536%(2 584/2 886)of the total cases. There were 1 357 cases performed pancrea-ticoduodenectomy in three hospitals with an average annual surgical volume of ≥120 cases, accounting for 47.020%(1 357/2 886) of the total cases. (2) Intraoperative and postoperative conditions. Of the 2 886 patients, the surgical approach was open surgery in 2 397 cases, minimally invasive surgery in 488 cases, and it is unknown in 1 case. The pylorus was preserved in 871 cases, not preserved in 1 952 cases, and it is unknown in 63 cases. Combined organ resection was performed in 305 cases (including vascular resection in 209 cases), not combined organ resection in 2 579 cases, and it is unknown in 2 cases. The operation time of 2 885 patients was 290(115)minutes, the volume of intra-operative blood loss of 2 882 patients was 240(250)mL, and the intraoperative blood transfusion rate of 2 880 patients was 27.153%(782/2 880). Of the 2 886 patients, the invasive treatment rate was 11.342%(327/2 883), the unplanned Intensive Care Unit (ICU) treatment rate was 3.087%(89/2 883), the reoperation rate was 1.590%(45/2 830), the duration of postoperative hospital stay was 17(11)days, the hospitalization mortality rate was 0.798%(23/2 882), and the failure rate of rescue data in 2 083 cases with severe complications was 6.529%(19/291). There were 2 477 patients receiving postoperative 90-day follow-up, with the 90-day mortality of 2.705%(67/2477). The total incidence rate of complication in 2 886 patients was 58.997%(1 423/2 412). The incidence rate of severe complication was 13.970%(291/2 083). The comprehensive complication index was 8.7(22.6) in 2 078 patients. (3) Influencing factors for 90-day mortality after pancreaticoduodenectomy. Results of multivariate analysis showed that age ≥ 70 years, postoperative invasive treatment, and unplanned ICU treatment were independent risk factors for 90-day mortality after pancreaticoduodenectomy ( odds ratio=2.403, 2.609, 16.141, 95% confidence interval as 1.281-4.510, 1.298-5.244, 7.119-36.596, P<0.05). Average annual surgical volume ≥36 cases in the hospital was an independent protective factor for 90-day mortality after pancreaticoduodenectomy ( odds ratio=0.368, 95% confidence interval as 0.168-0.808, P<0.05). Conclusions:Pancreaticoduodenectomy in Jiangsu Province is highly con-centrated in some hospitals, with a high incidence of postoperative complications, and the risk of postoperative 90-day mortality is significant higher than that of hospitallization mortality. Age ≥ 70 years, postoperative invasive treatment, and unplanned ICU treatment are independent risk factors for 90-day motality after pancreaticoduodenectomy, and average annual surgical volume ≥36 cases in the hospital is an independent protective factor.

Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.

Background::Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants.Methods::A total of 3053 healthy Han Chinese adults (1922 women) aged 18-79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere-Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance.Results::All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction <0.05). The blood pressures, body mass index (BMI), and triglyceride levels were identified as major clinical determinants of carotid properties with adjustment of age and sex. Conclusions::The age- and sex-specific reference values of carotid properties measured by RF ultrasound for healthy Chinese adults were established. The blood pressures, BMI, and triglyceride levels should be considered for clinical application of corresponding reference values.

Dental age estimation is a crucial aspect and one of the ways to accomplish forensic age estimation,and imaging technology is an important technique for dental age estimation.In recent years,some studies have preliminarily confirmed the feasibility of magnetic resonance imaging(MRI)in evaluating dental development,providing a new perspective and possibility for the evaluation of den-tal development,suggesting that MRI is expected to be a safer and more accurate tool for dental age estimation.However,further research is essential to verify its accuracy and feasibility.This article re-views the current state,challenges and limitations of MRI in dental development and age estimation,offering reference for the research of dental age assessment based on MRI technology.

Objective To evaluate the application effect of broth microdilution(BMD)method in susceptibility testing of multidrug-resistant Mycobacterium tuberculosis(MDR-MTB).Methods The Roche's proportion method and BMD method were adopted in drug susceptibility testing on 108 MDR-MTB strains and 11 non-MDR-MTB strains in Hainan Province.Whole genome sequencing(WGS)was performed on strains with inconsistent results by the above two methods.Results The average time to acquire drug susceptibility testing results by Roche's propor-tional method and BMD method were 28.0 and 8.5 days,respectively.Roche's proportional method showed higher resistance rates to isoniazid(INH),rifampicin(RFP),ethambutol(EMB),kanamycin(KM),and capreomycin(CPM)than BMD method(all P＜0.001).BMD method showed higher resistance rates to protionamide(PTO)and para-aminosalicylic acid(PAS)than Roche's proportional method(both P＜0.001).Taking Roche's proportional method as the gold standard,the sensitivity and specificity of BMD method for testing drug resistance were 50.00％-100％and 95.69％-100％,respectively.Except EMB(87.39％)and INH(94.96％),the consistency rates of the BMD method in testing drug resistance of other drugs were all ≥95.00％.The overall consistency rate between Roche's proportional method and WGS was 76.19％(32/42),while the consistency rate between BMD method and WGS was 23.81％(10/42),difference was statistically significant(x2=23.048,P＜0.001).34 MTB strains showed inconsistent results by two drug susceptibility testing methods.Among the 26 MTB strains that were resis-tant in Roche's proportion method but sensitive in BMD method,22 strains(84.62％)had mutations in relevant re-sistance genes.Among the 11 MTB strains that were sensitive in Roche's proportion method but resistant in BMD method,5 strains(45.45％)had mutations in relevant resistance genes.Conclusion BMD method is an accurate and rapid MDR-MTB susceptibility testing method,but further improvement and optimization are still needed.Drug resistance is closely related to mutations in relevant resistance genes.

Objective To investigate the factors influencing prognosis in patients with acute myocardial infarction complicated with cardiogenic shock undergoing primary percutaneous coronary intervention(PPCI).Methods Patients with acute myocardial infarction complicated with cardiogenic shock who underwent PPCI at our hospital between January 2015 and December 2019 were enrolled.Clinical baseline characteristics,coronary angiography and PCI-related parameters,and mechanical support information were collected.The patients were followed up for one year and divided into survival and death groups based on their survival status within one year.Differences in various factors between the two groups were compared.Results A total of 40 patients were enrolled,including 26 in the survival group and 14 in the death group.There were no differences in baseline data,diagnosis,risk factors,and comorbidities between the two groups.The survival group had a lower heart rate and higher blood pressure trend at admission compared to the death group.Myocardial enzymes were significantly lower in the survival group compared to the death group(median CK peak:496.00(198.25,2 830.00)U/L vs.3 040.00(405.75,5 626.53)U/L,P=0.003;median CK-MB peak:52.65(31.75,219.50)U/L vs.306.00(27.25,489.63)U/L,P=0.006).When comparing coronary angiography and PCI-related indicators between the two groups,the survival group had a higher rate of complete revascularization compared to the control group(53.85％vs.21.43％,P=0.048).The survival group had a higher proportion of extracorporeal membrane oxygenation(ECMO)combined with intra-aortic balloon pump(IABP)support compared to the control group[38.46％vs.7.14％,P=0.034].Conclusions Survival in patients with acute myocardial infarction complicated with cardiogenic shock undergoing PPCI is associated with lower level of myocardial enzymes,ECMO combined with IABP support and complete revascularization.

Objective To explore the role and underlying mechanism of type Ⅲ secretion system(T3SS)in regulating the internalization of Pseudomonas aeruginosa(PA)into pulmonary epithelial cells.Methods The human non-small cell lung cancer A549 cells were infected with or without PA strains,including wild-type PAO1(a standard experimental PA strain),△exsA(knockout of the critical activator for T3SS genes),△pscJ(T3SS secretion-defective strain)and PAO1-E(EGTA-induced high expression of T3SS genes).The A549 cells pretreated with ERK inhibitor U0126 or reactive oxygen species(ROS)inhibitor apocynin(APO)/N-acetyl-L-cysteine(NAC)were infected with PAO1 or PAO1-E strain.Thus,the experiment was grouped as follows:the mock-treated group,PAO1-or PAO1-E-infected group,inhibitor-treated group,and PAO1/PAO1-E plus inhibitor-treated group.Extracellular bacteria were killed by gentamicin,and the cell lysates were diluted and then plated on PA screening plates.Bacterial amounts were detected by counting colony-forming units(CFUs).The production of ROS was analyzed using fluorescent probe labeling and flow cytometry.The activation of the ERK pathway was detected by Western blotting.Results Compared with the PAO1-infected group,the intracellular bacteria and ROS level in △exsA-or△pscJ-infected cells were lower(P＜0.05,P＜0.01),so was the generation of ROS(P＜0.01);In contrast,those of the PAO1-E strain-infected cells displayed an opposite trend(P＜0.01).Compared with the PAO1-or PAO1-E-infected group,the cells pretreated with APO/NAC followed by PAO1 or PAO1-E infection showed reduced intracellular bacterial amounts(P＜0.01).Compared to the PAO1-infected A549 cells,the phosphorylation level of ERK was increased in the △exsA-or △pscJ-infected cells(P＜0.01),while that level was suppressed in the PAO1-E-treated cells(P＜0.01).Compared with the PAO1-infected group,the PAO1-infected cells pretreated with U0126 displayed reduced ERK activation,elevated ROS production,and increased intracellular counts of PAO1(P＜0.01).Conclusion T3SS-mediated inhibition of the ERK pathway promotes the production of ROS and the internalization of PA in lung epithelial cells.