This study was aimed at determining the molecular characteristics of Yersinia pestis in the natural plague foci around Qinghai Lake through single nucleotide polymorphism technology,to lay a foundation for molecular epidemiological and source-tracing analysis of Y.pestis in this area.Using the whole genome sequencing technology,we obtained the whole genome sequences of 84 representative Y.pestis strains.Using the sequences of Y.pestis and Yersinia pseudotuberculosis IP32953 from the NCBI database as references,we compared and analyzed the 2 298 SNP loci of these strains.From 1957 to 2020,84 representative strains of Y.pestis from the natural plague foci around Qinghai Lake were divided into two clades:1.IN2 and 3.ANT1.The 1.IN2 clade was the characteristic population of Y.pestis throughout all epidemic years in this area.Additionally,analysis of the SNP distribution and hosts in the region indicated that the 1.IN2 clade was located in five counties except Wulan,whereas the 3.ANT1 clade was isolated from Himalayan marmot and dog in two counties.In conclusion,the population structure of SNP of Y.pestis in the natural plague foci around Qinghai Lake is relatively simple,and SNP analysis of Y.pestis provided a scientific basis for tracing plague epidemic sources and formulating plague prevention and control measures in this area.

This study was aimed at determining the molecular characteristics of Yersinia pestis in the natural plague foci around Qinghai Lake through single nucleotide polymorphism technology,to lay a foundation for molecular epidemiological and source-tracing analysis of Y.pestis in this area.Using the whole genome sequencing technology,we obtained the whole genome sequences of 84 representative Y.pestis strains.Using the sequences of Y.pestis and Yersinia pseudotuberculosis IP32953 from the NCBI database as references,we compared and analyzed the 2 298 SNP loci of these strains.From 1957 to 2020,84 representative strains of Y.pestis from the natural plague foci around Qinghai Lake were divided into two clades:1.IN2 and 3.ANT1.The 1.IN2 clade was the characteristic population of Y.pestis throughout all epidemic years in this area.Additionally,analysis of the SNP distribution and hosts in the region indicated that the 1.IN2 clade was located in five counties except Wulan,whereas the 3.ANT1 clade was isolated from Himalayan marmot and dog in two counties.In conclusion,the population structure of SNP of Y.pestis in the natural plague foci around Qinghai Lake is relatively simple,and SNP analysis of Y.pestis provided a scientific basis for tracing plague epidemic sources and formulating plague prevention and control measures in this area.

Objectives:To analyze the risk factors of atrial fibrillation in patients with non-obstructive hypertrophic cardiomyopathy(NOHCM)and explore the relationship between left ventricular/atrial volume and atrial fibrillation.Methods:Consecutive NOHCM patients admitted at Fuwai Hospital from January 2023 to January 2024 with complete clinical data,satisfactory echocardiography imaging data were included in this analysis,patients were divided into atrial fibrillation group(n=28)and non-atrial fibrillation group(n=57).Left-sided volumetric and functional parameters were measured by one-beat real-time full-volume three-dimensional echocardiography,including left ventricular end-diastolic volume(LVEDV),left ventricular end-systolic volume(LVESV),left ventricular ejection fraction(LVEF),left atrial volume(LAV).The left ventricular end-diastolic volume(LVEDVi)index,left ventricular end-systolic volume index(LVESVi)and left atrial volume index(LAVi)were calculated.Other echocardiographic parameters including interventricular septum(IVSmax)thickness,left ventricular posterior wall thickness(LVPW),and left atrial diameter(LAD)were routinely measured.Mitral valve forward flow spectrum,tissue Doppler,tricuspid regurgitation velocity,and left atrial size were used to evaluate the left ventricular diastolic function of patients,and diastolic dysfunction was classified into grade I,II,and III.Multivariate logistic regression was used to analyze the influencing factors of atrial fibrillation in patients with non-obstructive hypertrophic cardiomyopathy Results:Compared with the non-atrial fibrillation group,LVEDV([143.8±26.7]ml vs.[117.1±21.9]ml)and LVEDVi([79.4±11.9]ml/m2 vs.[64.2±10.6]ml/m2)were smaller in atrial fibrillation group(both P<0.001).Compared with the non-atrial fibrillation group,LAD([40.2±4.7]mm vs.[48.6±4.8]mm)and LAVi([37.3±8.9]ml/m2 vs.[64.4±17.1]ml/m2)were lager in atrial fibrillation group(both P<0.001).Compared with the non-atrial fibrillation group,the proportion of NYHA functional classification≥Ⅲ was higher(15.8%vs.50.0%,P<0.001),LVEF was lower([61.5±5.5]%vs.[57.6±5.0]%,P=0.002),and proportion of severe diastolic dysfunction was higher in atrial fibrillation group(P<0.001).Logistic regression analysis showed that the factors associated with atrial fibrillation in NOHCM patients were LVEDVi(OR=0.744,95%CI:0.575-0.962,P=0.024)and LAVi(OR=1.602,95%CI:1.032-2.486,P=0.036).Conclusions:LVEDVi and LAVi are related factors for atrial fibrillation in patients with non-obstructive hypertrophic cardiomyopathy.LVEDVi is negatively,while LAVi is positively associated with the occurrence of atrial fibrillation in NOHCM patients.

Objective To construct a diagnostic model for phlegm-dampness syndrome in hypertension based on multimodal feature fusion.Methods Clinical text information(physiological/lifestyle data,symptoms,pulse characteristics)and tongue image data were collected from 261 hypertension patients.For clinical text data,statistical analyses,including ANOVA,Mann-Whitney U test,and Chi-square test,were performed to identify significant features(P<0.05),which were incorporated into a clinical text-based diagnosis model(CTDM)using a multilayer perceptron algorithm.For tongue images,a tongue image-based diagnosis model(TIDM)was constructed based on channel attention mechanisms and residual networks.A multimodal diagnostic model(MDM)was built by fusing clinical text and tongue image features using a feature concatenation method.The diagnostic performance of each model was evaluated using five-fold cross-validation with the area under the receiver operating characteristic curve(AUC),accuracy,specificity,and sensitivity.Results Seven clinical text features,including physiological/lifestyle factors(disease duration,body mass index),symptoms(chest tightness,loss of appetite,excessive phlegm),and pulse characteristics(slippery pulse,damp pulse),were identified as risk factors for phlegm-dampness syndrome in hypertension.The AUC of the CTDM was 0.831±0.021,the AUC of the TIDM was 0.878±0.035,and the MDM achieved an AUC of 0.972±0.015.Conclusion The multimodal diagnostic model that integrates clinical text and tongue image features demonstrates high diagnostic accuracy and provides valuable guidance for AI-assisted diagnosis of phlegm-dampness syndrome in hypertension.

Objective To investigate the clinical efficacy and safety of facilitated percutaneous coronary intervention(PCI)with half-dose recombinant staphylokinase(r-SAK)in patients with ST-segment elevation myocardial infarction(STEMI)who are expected to undergo PCI within 120 minutes.Methods From October 2021 to August 2022,a total of 200 STEMI patients in eight centers were included and randomly assigned in a 1﹕1 ratio to either r-SAK group or control group.Patients received loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive an intravenous bolus of either 5 mg r-SAK or normal saline prior to PCI.The outcomes were set as ST-segment resolution(STR)at 60-90 minutes after PCI,the proportion and transition of pathological Q waves on the 5th day after PCI,and the proportion of high-sensitivity cardiac troponin T(hs-cTnT)peaking within 12 hours of onset.The safety outcome was major bleeding events defined as Bleeding Academic Research Consortium(BARC)≥type 3 bleeding during hospitalization.Results Compared with the control group,the r-SAK group had a higher proportion of STR≥70%within 60-90 minutes after PCI(58.3%vs.40.3%,P=0.009);a lower proportion of pathological Q waves(59.1%vs.74.1%,P=0.040);a lower rate of Q wave progression(14.8%vs.43.2%,P＜0.001);a higher rate of Q wave disappearance(12.5%vs.3.7%,P=0.027);and a higher proportion of hs-cTnT peaking within 12 hours of symptom onset[31/40(77.5%)vs.17/33(51.5%),P=0.027].Regarding the safety outcome,no significant difference in BARC≥type 3 bleeding was found between the two groups during hospitalization(P＞0.05).Conclusions For STEMI patients who were expected to undergo primary PCI within 120 minutes of symptom onset,the facilitated PCI with half-dose r-SAK significantly increased the proportion of STR≥70%at 60-90 minutes after PCI,reduced the formation of pathological Q waves,and shortened the time to peak hs-cTnT,without increasing the risk of bleeding,which should be an alternative reperfusion strategy worthy of further study.

Hypertrophic scar is a fibrous hyperplastic disorder that arises from skin injuries. The current therapeutic modalities are constrained by the dense and rigid scar tissue which impedes effective drug delivery. Additionally, insufficient autophagic activity in fibroblasts hinders their apoptosis, leading to excessive matrix deposition. Here, we developed an active microneedle (MN) system to overcome these challenges by integrating micromotor-driven drug delivery with autophagy regulation to remodel the scar microenvironment. Specifically, sodium bicarbonate and citric acid were introduced into the MNs as a built-in engine to generate CO₂ bubbles, thereby enabling enhanced lateral and vertical drug diffusion into dense scar tissue. The system concurrently encapsulated curcumin (Cur), an autophagy activator, and triamcinolone acetonide (TA), synergistically inducing fibroblast apoptosis by upregulating autophagic activity. In vitro studies demonstrated that active MNs achieved efficient drug penetration within isolated scar tissue. The rabbit hypertrophic scar model revealed that TA-Cur MNs significantly reduced the scar elevation index, suppressed collagen I and transforming growth factor-β1 (TGF-β1) expression, and elevated LC3 protein levels. These findings highlight the potential of the active MN system as an efficacious platform for autonomous augmented drug delivery and autophagy-targeted therapy in fibrotic disorder treatments.

Objectives:To analyze the risk factors of atrial fibrillation in patients with non-obstructive hypertrophic cardiomyopathy(NOHCM)and explore the relationship between left ventricular/atrial volume and atrial fibrillation.Methods:Consecutive NOHCM patients admitted at Fuwai Hospital from January 2023 to January 2024 with complete clinical data,satisfactory echocardiography imaging data were included in this analysis,patients were divided into atrial fibrillation group(n=28)and non-atrial fibrillation group(n=57).Left-sided volumetric and functional parameters were measured by one-beat real-time full-volume three-dimensional echocardiography,including left ventricular end-diastolic volume(LVEDV),left ventricular end-systolic volume(LVESV),left ventricular ejection fraction(LVEF),left atrial volume(LAV).The left ventricular end-diastolic volume(LVEDVi)index,left ventricular end-systolic volume index(LVESVi)and left atrial volume index(LAVi)were calculated.Other echocardiographic parameters including interventricular septum(IVSmax)thickness,left ventricular posterior wall thickness(LVPW),and left atrial diameter(LAD)were routinely measured.Mitral valve forward flow spectrum,tissue Doppler,tricuspid regurgitation velocity,and left atrial size were used to evaluate the left ventricular diastolic function of patients,and diastolic dysfunction was classified into grade I,II,and III.Multivariate logistic regression was used to analyze the influencing factors of atrial fibrillation in patients with non-obstructive hypertrophic cardiomyopathy Results:Compared with the non-atrial fibrillation group,LVEDV([143.8±26.7]ml vs.[117.1±21.9]ml)and LVEDVi([79.4±11.9]ml/m2 vs.[64.2±10.6]ml/m2)were smaller in atrial fibrillation group(both P<0.001).Compared with the non-atrial fibrillation group,LAD([40.2±4.7]mm vs.[48.6±4.8]mm)and LAVi([37.3±8.9]ml/m2 vs.[64.4±17.1]ml/m2)were lager in atrial fibrillation group(both P<0.001).Compared with the non-atrial fibrillation group,the proportion of NYHA functional classification≥Ⅲ was higher(15.8%vs.50.0%,P<0.001),LVEF was lower([61.5±5.5]%vs.[57.6±5.0]%,P=0.002),and proportion of severe diastolic dysfunction was higher in atrial fibrillation group(P<0.001).Logistic regression analysis showed that the factors associated with atrial fibrillation in NOHCM patients were LVEDVi(OR=0.744,95%CI:0.575-0.962,P=0.024)and LAVi(OR=1.602,95%CI:1.032-2.486,P=0.036).Conclusions:LVEDVi and LAVi are related factors for atrial fibrillation in patients with non-obstructive hypertrophic cardiomyopathy.LVEDVi is negatively,while LAVi is positively associated with the occurrence of atrial fibrillation in NOHCM patients.

Objective: To evaluate the feasibility of dynamic contrast-enhanced MRI (DCE-MRI) in differentiating tumor deposits (TDs) from metastatic lymph nodes (MLNs) in rectal cancer. Materials and Methods: A retrospective analysis was conducted on 70 patients with rectal cancer, including 168 lesions (70 TDs and 98 MLNs confirmed by histopathology), who underwent pretreatment MRI and subsequent surgery between March 2019 and December 2022. The morphological characteristics of TDs and MLNs, along with quantitative parameters derived from DCE-MRI (K trans , kep, and v e) and DWI (ADCmin, ADCmax, and ADCmean), were analyzed and compared between the two groups.Multivariable binary logistic regression and receiver operating characteristic (ROC) curve analyses were performed to assess the diagnostic performance of significant individual quantitative parameters and combined parameters in distinguishing TDs from MLNs. Results: All morphological features, including size, shape, border, and signal intensity, as well as all DCE-MRI parameters showed significant differences between TDs and MLNs (all P < 0.05). However, ADC values did not demonstrate significant differences (all P > 0.05). Among the single quantitative parameters, v e had the highest diagnostic accuracy, with an area under the ROC curve (AUC) of 0.772 for distinguishing TDs from MLNs. A multivariable logistic regression model incorporating short axis, border, v e, and ADC mean improved diagnostic performance, achieving an AUC of 0.833 (P = 0.027). Conclusion The combination of morphological features, DCE-MRI parameters, and ADC values can effectively aid in the preoperative differentiation of TDs from MLNs in rectal cancer.

ObjectiveTo investigate the influence of histone deacetylase 3 (HDAC3) on the occurrence, development of psoriasis-like inflammation in mice, and the relative immune mechanisms. MethodsHealthy C57BL/6 mice aged 6-8 weeks were selected and randomly divided into 3 groups: control group (Control), psoriasis model group (IMQ), and HDAC3 inhibitor RGFP966-treated psoriasis model group (IMQ+RGFP966). One day prior to the experiment, the back hair of the mice was shaved. After a one-day stabilization period, the mice in Control group was treated with an equal amount of vaseline, while the mice in IMQ group was treated with imiquimod (62.5 mg/d) applied topically on the back to establish a psoriasis-like inflammation model. The mice in IMQ+RGFP966 group received intervention with a high dose of the HDAC3-selective inhibitor RGFP966 (30 mg/kg) based on the psoriasis-like model. All groups were treated continuously for 5 d, during which psoriasis-like inflammation symptoms (scaling, erythema, skin thickness), body weight, and mental status were observed and recorded, with photographs taken for documentation. After euthanasia, hematoxylin-eosin (HE) staining was used to assess the effect of RGFP966 on the skin tissue structure of the mice, and skin thickness was measured. The mRNA and protein expression levels of HDAC3 in skin tissues were detected using reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot (WB), respectively. Flow cytometry was employed to analyze neutrophils in peripheral blood and lymph nodes, CD4⁺ T lymphocytes, CD8⁺ T lymphocytes in peripheral blood, and IL-17A secretion by peripheral blood CD4⁺ T lymphocytes. Additionally, spleen CD4⁺ T lymphocyte expression of HDAC3, CCR6, CCR8, and IL-17A secretion levels were analyzed. Immunohistochemistry was used to detect the localization and expression levels of HDAC3, IL-17A, and IL-10 in skin tissues. ResultsCompared with the Control group, the IMQ group exhibited significant psoriasis-like inflammation, characterized by erythema, scaling, and skin wrinkling. Compared with the IMQ group, RGFP966 exacerbated psoriasis-like inflammatory symptoms, leading to increased hyperkeratosis. The psoriasis area and severity index (PASI) skin symptom scores were higher in the IMQ group than those in the Control group, and the scores were further elevated in the IMQ+RGFP966 group compared to the IMQ group. Skin thickness measurements showed a trend of IMQ+RGFP966>IMQ>Control. The numbers of neutrophils in the blood and lymph nodes increased sequentially in the Control, IMQ, and IMQ+RGFP966 groups, with a similar trend observed for CD4⁺ and CD8⁺ T lymphocytes in the blood. In skin tissues, compared with the Control group, the mRNA and protein levels of HDAC3 decreased in the IMQ group, but RGFP966 did not further reduce these expressions. HDAC3 was primarily located in the nucleus. Compared with the Control group, the nuclear HDAC3 content decreased in the skin tissues of the IMQ group, and RGFP966 further reduced nuclear HDAC3. Compared with the Control and IMQ groups, RGFP966 treatment decreased HDAC3 expression in splenic CD4⁺ and CD8⁺ T cells. RGFP966 treatment increased the expression of CCR6 and CCR8 in splenic CD4⁺ T cells and enhanced IL-17A secretion by peripheral blood and splenic CD4⁺ T lymphocytes. Additionally, compared with the IMQ group, RGFP966 reduced IL-10 protein levels and upregulated IL-17A expression in skin tissues. ConclusionRGFP966 exacerbates psoriatic-like inflammatory responses by inhibiting HDAC3, increasing the secretion of the cytokine IL-17A, and upregulating the expression of chemokines CCR8 and CCR6.

OBJECTIVE: To investigate the susceptibility of venetoclax-resistant acute myeloid leukemia (AML) cell lines to ferroptosis and to uncover the underlying molecular mechanisms using transcriptomic and metabolomic analysis methods. METHODS: Venetoclax-resistant AML cell lines were constructed using a low-dose concentration escalation method. The sensitivity of cells to chemotherapeutic drugs was detected by CCK-8 assay. The susceptibility of drug-resistant cell lines to ferroptosis was assessed using transcriptomic and metabolomic analysis methods. The expression of cellular GPX4 and SLC7A11 protein was detected by Western blot, and cell death and lipid peroxidation levels were measured by flow cytometry. Depmap database and TCGA cohort were applied to explore the effect of ferroptosis-related genes expression on prognosis. RESULTS: Venetoclax-resistant cell lines exhibited sensitivity to ferroptosis inducers RSL3, APR246, and sorafenib. The ferroptosis inhibitor Fer-1 partially inhibited cell death induced by these inducers. Compared with the parental cells, significant changes in metabolites and gene expression levels related to ferroptosis were observed in the resistant cell lines. In particular, deregulated expression of SLC7A11 and GPX4 may play critical role in ferroptosis susceptibility. Besides, GPX4 was identified as more important for AML cell survival and higher GPX4 expression may predict shortened overall survival, NPM1 mutant and IDH1 R132 mutation positive patients may prone to possess higher GPX4 expression. CONCLUSION Venetoclax-resistant AML cell lines remain susceptible to ferroptosis, higher GPX4 expression maybe a critical marker for poor prognosis. Regulating the expression of ferroptosis-related genes and metabolites may enhance the efficacy of venetoclax and provide new treatment options for AML patients.
Humans ; Ferroptosis ; Leukemia, Myeloid, Acute/metabolism* ; Sulfonamides/pharmacology* ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology* ; Drug Resistance, Neoplasm ; Metabolomics ; Cell Line, Tumor ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Amino Acid Transport System y+/metabolism* ; Transcriptome