ObjectiveTo explore the potential mechanisms by which Myristica fragrans prevents and treats atherosclerosis （AS）. MethodsThe major active components of Myristica fragrans and their shared targets with AS were obtained from databases. The shared targets were subjected to pathway enrichment analysis and PPI network construction using the ClusterProfile package and the STRING database. Molecular docking between key targets and major active components was performed using AutoDock. Gene expression data from early and late， as well as stable and unstable AS plaques， were used to validate changes of key targets and major pathways during AS progression. Western blot， flow cytometry， YO-PRO-1/PI staining， and TUNEL staining were applied to verify the main mechanisms. ResultsNine active components of Myristica fragrans interacted with 293 AS-related targets， among which eight components acted on an average of 57.0% of the shared targets. Gene ontology （GO） and Kyoto encyclopedia of genes and genomes （KEGG） enrichment analyses indicated that the anti-AS effects mainly involved oxidative stress， inflammation， lipid metabolism， fluid shear stress， and apoptosis pathways. PPI network revealed JUN， CASP3， MAPK3， and AKT1 as key targets mainly involved in regulating apoptosis. Molecular docking showed stable binding conformations and high affinities between major components and these targets. Integrated analysis of gene expression in early and late， as well as stable and unstable AS plaques， showed significant enrichment of leukocyte apoptosis pathways in late and unstable plaques. Cell experiments further confirmed that Myristica fragrans significantly reduced Cleaved-CASP3（P=0.04）and p-MAPK3（P=0.000 3）levels， increased p-AKT1（P=0.004）levels， and inhibited macrophage apoptosis. ConclusionMyristica fragrans potentially interferes with AS development by modulating pathways related to oxidative stress， inflammation， lipid metabolism， fluid shear stress， and apoptosis， with CASP3， MAPK3， and AKT1 serving as key targets mediating its anti-apoptotic and anti-AS effects.

Objective:To analyze the biological parameters of the anterior segment of age-related cataracts patients with or without zonular weakness with the new generation of sweep-source anterior optical coherence tomography (OCT) device CASIA2 to provide a basis for the diagnosis of zonular weakness.Methods:A case-control study was conducted.A total of 158 cases (186 eyes) of patients with age-related cataracts having zonular weakness as a zonular weakness group, and 80 cases (80 eyes) of cataract with age-related cataracts without zonular weakness as a normal zonule group were enroll from June 2022 to June 2023 at Beijing Tongren Hospital.All patients underwent routine preoperative ophthalmological examination including slit lamp microsopy, IOLMaster 700, ocular B-ultrasound and OCT.The anterior chamber depth (ACD), anterior chamber volume (ACV), lens thickness (LT), lens vault (LV), anterior chamber angle opening distance at 750 μm (AOD750), lens decentration and tilt, radius of curvature of the anterior lens surface (RAL), and radius of curvature of the posterior lens surface (RPL) of patients were measured with CASIA2 and compared between the two groups.The relationship between zonular weakness and anterior chamber parameters and lens parameters was evaluated by logistic regression analysis.This study followed the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Beijing Tongren Hospital (No.TRECKY2018-049), and all enrolled patients signed the informed consent form.Results:In the zonular weakness group, ACD, ACV, RAL, and AOD750 were (2.34±0.56)mm, (85.05±40.19)mm 3, 7.52 (7.13, 8.08)mm, and 0.27 (0.07, 0.30)mm, respectively, which were smaller than (3.13±0.38)mm, (127.75±38.15)mm 3, 9.28(8.51, 9.76)mm, and 0.52 (0.31, 0.65)mm in the normal zonule group, with statistically significant differences (all P<0.05).LT and LV in the zonular weakness group were (5.14±0.45)mm and (1.22±0.53)mm, respectively, which were larger than (4.27±0.52)mm and (0.32±0.30)mm in the normal zonule group, and the differences were statistically significant (both P<0.05).Magnitude of lens decentration and tilt in the zonular weakness were 0.34 (0.13, 0.45)mm and 6.44 (3.67, 7.32)°, respectively, which were significantly larger than 0.19 (0.12, 0.25)mm and 4.88 (3.85, 5.65)° in the normal zonule group (both P<0.05).No obvious pattern was found in the direction of decentration and tilt.Logistic regression analysis showed that LV and lens decentration were risk factors of zonular weakness (odds ratios [ OR]=706.170, 335.339; both P<0.05), and RAL was a protective factor of zonular weakness ( OR=0.239, P<0.05). Conclusions:Age-related cataract patients with zonular weakness often present with a decrease in ACV due to increased anterior convexity of the lens.Decreased RAL, increased lens decentration and elevated LV are risk factors for zonular weakness.

The thalamic reticular nucleus (TRN) plays a crucial role in regulating sensory encoding, even at the earliest stages of visual processing, as evidenced by numerous studies. Orientation selectivity, a vital neural response, is essential for detecting objects through edge perception. Here, we demonstrate that somatostatin (SOM)-expressing and parvalbumin (PV)-expressing neurons in the TRN project to the dorsal lateral geniculate nucleus and modulate orientation selectivity and the capacity for visual information processing in the primary visual cortex (V1). These findings show that SOM-positive and PV-positive neurons in the TRN are powerful modulators of visual information encoding in V1, revealing a novel role for this thalamic nucleus in influencing visual processing.
Animals ; Somatostatin/metabolism* ; Parvalbumins/metabolism* ; Neurons/physiology* ; Thalamic Nuclei/physiology* ; Visual Pathways/physiology* ; Mice ; Mice, Inbred C57BL ; Visual Perception/physiology* ; Male ; Mice, Transgenic ; Visual Cortex/physiology* ; Primary Visual Cortex/cytology*

Ferroptosis of chondrocytes is a significant contributor to osteoarthritis (OA), for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis. Here, we screen for anti-ferroptotic drugs in Food and Drug Administration (FDA)-approved drug library via a high-throughput manner in chondrocytes. We identified a group of FDA-approved anti-ferroptotic drugs, among which vitamin K showed the most powerful protective effect. Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix (ECM) degradation in chondrocytes. Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus (DMM) mouse model. Mechanistically, transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6 (Gas6). Furthermore, exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase (AXL)/phosphatidylinositol 3-kinase (PI3K)/AKT serine/threonine kinase (AKT) axis. Together, we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis, indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

BACKGROUND: Molecular subtyping is an essential complementarity after pathological analyses for targeted therapy. This study aimed to investigate the consistency of next-generation sequencing (NGS) results between circulating tumor DNA (ctDNA)-based and tissue-based in non-small cell lung cancer (NSCLC) and identify the patient characteristics that favor ctDNA testing. METHODS: Patients who diagnosed with NSCLC and received both ctDNA- and cancer tissue-based NGS before surgery or systemic treatment in Lung Cancer Center, Sichuan University West China Hospital between December 2017 and August 2022 were enrolled. A 425-cancer panel with a HiSeq 4000 NGS platform was used for NGS. The unweighted Cohen's kappa coefficient was employed to discriminate the high-concordance group from the low-concordance group with a cutoff value of 0.6. Six machine learning models were used to identify patient characteristics that relate to high concordance between ctDNA-based and tissue-based NGS. RESULTS: A total of 85 patients were enrolled, of which 22.4% (19/85) had stage III disease and 56.5% (48/85) had stage IV disease. Forty-four patients (51.8%) showed consistent gene mutation types between ctDNA-based and tissue-based NGS, while one patient (1.2%) tested negative in both approaches. Patients with advanced diseases and metastases to other organs would be suitable for the ctDNA-based NGS, and the generalized linear model showed that T stage, M stage, and tumor mutation burden were the critical discriminators to predict the consistency of results between ctDNA-based and tissue-based NGS. CONCLUSION ctDNA-based NGS showed comparable detection performance in the targeted gene mutations compared with tissue-based NGS, and it could be considered in advanced or metastatic NSCLC.
Humans ; Carcinoma, Non-Small-Cell Lung/pathology* ; Circulating Tumor DNA/blood* ; High-Throughput Nucleotide Sequencing/methods* ; Female ; Male ; Lung Neoplasms/pathology* ; Middle Aged ; Mutation/genetics* ; Aged ; Adult ; Aged, 80 and over

Ferroptosis of chondrocytes is a significant contributor to osteoarthritis(OA),for which there is still a lack of safe and effective therapeutic drugs targeting ferroptosis.Here,we screen for anti-ferroptotic drugs in Food and Drug Administration(FDA)-approved drug library via a high-throughput manner in chondrocytes.We identified a group of FDA-approved anti-ferroptotic drugs,among which vitamin K showed the most powerful protective effect.Further study demonstrated that vitamin K effectively inhibited ferroptosis and alleviated the extracellular matrix(ECM)degradation in chondrocytes.Intra-articular injection of vitamin K inhibited ferroptosis and alleviated OA phenotype in destabilization of the medial meniscus(DMM)mouse model.Mechanistically,transcriptome sequencing and knockdown experiments revealed that the anti-ferroptotic effects of vitamin K depended on growth arrest-specific 6(Gas6).Furthermore,exogenous expression of Gas6 was found to inhibit ferroptosis through the AXL receptor tyrosine kinase(AXL)/phosphatidylinositol 3-kinase(PI3K)/AKT serine/threonine kinase(AKT)axis.Together,we demonstrate that vitamin K inhibits ferroptosis and alleviates OA progression via enhancing Gas6 expression and its downstream pathway of AXL/PI3K/AKT axis,indicating vitamin K as well as Gas6 to serve as a potential therapeutic target for OA and other ferroptosis-related diseases.

Alzheimer's disease(AD), a neurodegenerative disorder associated with aging, is the most prevalent form of dementia.As the aging population continues to expand, AD presents significant health and caregiving challenges for families and society, making it a pressing international public health concern.In recent years, numerous countries have implemented dementia prevention and treatment strategies that emphasize community-based comprehensive approaches.Currently, the community-based AD prevention and treatment model in China is still in the exploratory phase, with community efforts lacking organization.In alignment with China's action plan for advancing dementia prevention and treatment, and to achieve the strategic objective of "healthy aging, " this consensus is based on the principle of three-level prevention and is tailored to the characteristics of AD disease progression.It aims to develop a comprehensive prevention and treatment strategy for AD that is suitable for communities in China, providing technical guidance and support to establish a scientific basis for formulating community AD prevention and treatment models.

The morbidity and mortality rate of cardiogenic stroke caused by atrial fibrillation is high,and anticoagulant therapy is the first therapeutic choice in the management of atrial fibrillation.International normalized ratio of warfarin should be strictly controlled at 2.0-3.0.The efficacy of direct oral anticoagulants for preventing embolism events is non-inferior to warfarin,but the risk of bleeding is significantly lower.Severe renal function decline has a great impact on the efficacy and safety of oral anticoagulants.The use of oral anticoagulants in patients with end-stage renal disease is now still controversial.This article reviews the research progress of oral anticoagulant therapy in patients with non-valvular atrial fibrillation complicated with end-stage renal disease.

Objective To analyze the characteristics of spirometry and type 2 inflammation indicators of patients with CVA,ACO and CA to determine their clinical utility in identifying and distinguishing among CVA,ACO and CA patients.Methods Clinical data from 483 patients diagnosed with bronchial asthma,CVA,and bronchial asthma combined with chronic obstructive pulmonary disease in the outpatient department of the First Affiliated Hospital of Soochow University from July 2023 to June 2024 were collected and divided into CA,CVA and ACO groups according to diagnosis.Comparison of spirometry,fractional exhaled nitric oxide(FeNO),blood eosinophil(EOS),serum total immunoglobulin E(tIgE)and other tests between CA and CVA,CA and ACO groups.Perform logistic regression analysis on significant test results,then construct receiver operating characteristic(ROC)curves to compare the area under the curve and corresponding cut-off values.Result There was a statistically significant difference in tIgE between the CVA and CA groups(P=0.018),whereas no significant differences were observed in FeNO and EOS.Additionally,no notable differences were found between the ACO and CA groups in tIgE,FeNO,or EOS.Finally,FEV1％pred(OR=1.086,P=0.019),FEV1/FVC(OR=1.153,P=0.023),and MEF50％pred(OR=0.922,P=0.045)were used to construct the discriminative model between CA and CVA.ROC curves were plotted,with FEV1％pred showing an AUC of 0.680(P<0.001),a Youden index of 0.358,and a corresponding cutoff value of 89.200.FEV1/FVC had an AUC of 0.684(P<0.001),a Youden index of 0.334,and a cutoff value of 76.075.MEF50％pred had an AUC of 0.668(P<0.001),a Youden index of 0.309,and a cutoff value of 59.800.The combined sensitivity of these three measures was 0.909,specificity was 0.514,positive predictive value was 0.600,negative predictive value was 0.873,and the AUC was 0.773(P<0.001),with a Youden index of 0.423.FEV1(OR=0.002,P=0.045),FEV1％pred(OR=1.490,P=0.006),and FEV1/FVC(OR=0.749,P=0.005)were used to construct the discriminative model between CA and ACO.ROC curves were plotted,with FEV1 showing an AUC of 0.819(P<0.001),a Youden index of 0.532,and a corresponding cutoff value of 2.060.FEV1％pred had an AUC of 0.788(P<0.001),a Youden index of 0.501,and a cutoff value of 75.000.FEV1/FVC had an AUC of 0.891(P<0.001),a Youden index of 0.678,and a cutoff value of 68.620.The combined sensitivity of these three measures was 1.000,specificity was 0.904,positive predictive value was 0.771,negative predictive value was 1.000,and the AUC was 0.973(P<0.001),with a Youden index of 0.904.Conclusions Differences exist in the spirometry among CVA,ACO and CA.The spirometry results incor-porated into the discriminative models provide good discriminative value for distinguishing between CA and CVA patients with similar clinical symptoms,as well as for identifying ACO in the CA population.

Objective:To investigate the differences in hippocampal subfield volumes and structural covariance network between participants with subjective cognitive decline (SCD) and healthy individuals, and to analyze the correlations of the volumes of the different subfields and altered covariance brain regions with memory function.Methods:A total of 57 SCD individuals(SCD group) and 44 normal controls(NC group) participants were assessed for memory function using composite scores from the auditory verbal learning test (AVLT) and the Wechsler memory scale visual reproduction (VR) test from June 2022 to October 2023.T1-weighted structural magnetic resonance imaging (MRI) data were collected from all participants, and hippocampal subfields, cortical regions, and subcortical nuclei were segmented using FreeSurfer to measure the gray matter volume of each structure. A structural covariance network was constructed based on the correlation of gray matter volumes across regions. Statistical analysis was performed using R 4.3.1 software. Inter-group differences in hippocampal subfield volumes were compared using multivariate analysis of covariance. Differences in structural covariance connectivity between groups were assessed using Z-test, while network topology differences were compared through permutation testing. Finally, partial correlation analysis was used to examine correlation of the volumes of the differential hippocampal subfields and covariance brain regions with memory function. Results:The SCD group exhibited significantly lower years of education, AVLT-immediate score, AVLT-delayed score, VR-immediate score, VR-delayed score, and memory function Z-score compared to the NC group ( t=2.064, 3.888, 2.622, 3.222, 4.761, 5.184, all P<0.05). The volumes of the right subiculum((387.75±55.20)mm 3, (352.70±70.25)mm 3), left presubiculum((263.12±38.52)mm 3, (239.79±46.02)mm 3), left subiculum((388.12±49.34)mm 3, (351.74±67.30)mm 3) and left CA1((571.01±80.01)mm 3, (526.51±98.80)mm 3) in the SCD group were smaller than the corresponding volumes in NC group ( F=9.139, 8.039, 11.207, 7.266, all P<0.05, FDR correction). Differences in structural covariance connectivity were found between the SCD and NC groups in the following pairs: right CA1-right subiculum, right CA1-left subiculum, right CA3-left parasubiculum and right hippocampus-amygdala transition area-left subiculum ( Z=-3.848, -3.896, -3.597, -3.895, all P<0.05, FDR correction).Partial correlation analysis revealed that in the SCD group, the volume of the left subiculum ( r=0.359, P=0.007), left CA1 ( r=0.430, P=0.001), right entorhinal cortex ( r=0.296, P=0.029), right middle temporal gyrus ( r=0.361, P=0.007), right parahippocampal gyrus ( r=0.313, P=0.021)were positively correlated with the total memory function score. Conclusion:Hippocampal subfields atrophy, as well as alterations in structural covariance network, have been found in SCD individuals. Furthermore, the decline in memory function may be closely associated with atrophy in hippocampal subfields and structurally covariant regions.