Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

Advancements in artificial intelligence(AI)and emerging technologies are rapidly expanding the exploration of chemical space,facilitating innovative drug discovery.However,the transformation of novel compounds into safe and effective drugs remains a lengthy,high-risk,and costly process.Comprehensive early-stage evaluation is essential for reducing costs and improving the success rate of drug development.Despite this need,no comprehensive tool currently supports systematic evaluation and efficient screening.Here,we present druglikeFilter,a deep learning-based framework designed to assess drug-likeness across four critical dimensions:1)physicochemical rule evaluated by systematic determination,2)toxicity alert investigated from multiple perspectives,3)binding affinity measured by dual-path analysis,and 4)compound synthesizability assessed by retro-route prediction.By enabling automated,multidimensional filtering of compound libraries,druglikeFilter not only streamlines the drug development process but also plays a crucial role in advancing research efforts towards viable drug candidates,which can be freely accessed at https://idrblab.org/drugfilter/.

Advancements in artificial intelligence (AI) and emerging technologies are rapidly expanding the exploration of chemical space, facilitating innovative drug discovery. However, the transformation of novel compounds into safe and effective drugs remains a lengthy, high-risk, and costly process. Comprehensive early-stage evaluation is essential for reducing costs and improving the success rate of drug development. Despite this need, no comprehensive tool currently supports systematic evaluation and efficient screening. Here, we present druglikeFilter, a deep learning-based framework designed to assess drug-likeness across four critical dimensions: 1) physicochemical rule evaluated by systematic determination, 2) toxicity alert investigated from multiple perspectives, 3) binding affinity measured by dual-path analysis, and 4) compound synthesizability assessed by retro-route prediction. By enabling automated, multidimensional filtering of compound libraries, druglikeFilter not only streamlines the drug development process but also plays a crucial role in advancing research efforts towards viable drug candidates, which can be freely accessed at https://idrblab.org/drugfilter/.

Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

Objective: To analyze the diagnostic value of ultrasound guided 14 gauge coreneedle biopsy (US-CNB) in breast nodules. Methods: We retrospectively analyzed the pathological results of US-CNB and surgical excision from 373 breast nodules in Peking University International Hospital from Sep 2016 to Nov 2018 to evaluate the accuracy of 14g US-CNB. Results: A total of 349 patients(373 nodules)underwent US-CNB. US-CNB reported 282 benign lesions(75.6%, 282/373), 20 high-risklesions(5.4%, 20/373), and 71 malignant lesions(19.0%, 71/373). For 282 CNB reported benign lesions, the surgical pathology confirmed 235 lesions , 46 for high-risk lesions and 1 for malignant lesion with a concordancy of 83.3%(235/282)and the underestimation rate was 16.7%(47/282). US-CNB identified 20 high-risk lesions. According to surgical results, 15 were high-risk lesions and 5 were malignant lesions with a concordancy of 75% (15/20)and the underestimation rate was 25%(5/20). When it comes to malignant lesions, the excision results showed that 70 were malignant lesions and 1was high-risk lesion with a concordancy of 98.6%(70/71)and the overestimation rate was 1.4%(1/71). The concordance of the histological type , calculated for 50 invasive carcinomas, was 92% (46/50) with a kappa value of 0.77.The concordance of the histological grade could be calculated for 38 invasive ductal carcinomas with the Elston-Elllis Method . It was 89.5% (34/38) with a kappa value of 0.57. Conclusions The pathology result of 14gUS-CNB is in good consistency with surgical excision for breast benign and malignant lesions.

Objective To synthesize a series of 13-acylmatrine derivatives and evaluate their in vitro antitumor activity . Methods Using sophocarpine as the starting material ,a series of new compounds were synthesized through Michael addition , Staudinger reduction and acylation .The structure of target compounds were confirmed by 1 H NMR and MS techniques .Their antitumoractivityagainsthumanhepatomacells(BEL-7404)andmicemelanomacells(K111)wereevaluated invitrobyMTT assay .Results We synthesized 9 compounds and all the compounds exhibited inhibitory activities against BEL-7404 and K111 . Conclusion Compound 4b and compound 4e exhibit good in vitro antitumor activity to human hepatoma cells (BEL-7404) .

Objective To study clinical characteristics of type 2 diabetic(T2D)patients with metabolic syndrome(MS)and its components in Beijing urban communities.Methods Totally,3295 T2D patients involved in a combined prospective diabetic management study from 15 urban communities in Beijing were classified as four groups, according to 2004 Chinese Diabetes Society's definition of MS, i. e, isolated T2D, T2D with one component of MS, T2D with two components of MS and T2D with three components of MS. Their clinical characteristics were analyzed. Results ( 1 ) Among 3295 T2D patients, 155 (4. 7% )were isolated T2D, 107 (32.6%) T2D with one component of MS, 1386 (42.1%) T2D with two components of MS and 679 (20.6%) T2D with three components of MS, with an overall 62.7% (2065/3295) of T2D patients complicated with MS. (2) In these T2D patients, the more components of MS they had, the higher body mass index (BMI), waist circumference, waist to hip circumference ratio (WHR),systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting serum levels of insulin and triglyceride (TG) and the lower level of high-density lipoprotein-cholesterol (HDL) were presented (P <0. 01 ). (3) Percentage of isolated T2D in women increased from 49. 0% (76/155) to 61.9% (420/679)of those with three components of MS ( P < 0 01 ), with increasing of components of MS. (4) Multiple logistic regression analysis showed that BMI, history of hypertension, decreased HDL, increased TG,increased blood pressure, all were risk factors for T2D patients complicated with MS. Conclusions Among T2D patients in urban communities of Beijing, 95.3% (3140/3295) of them complicated with one or more components of MS, and 61.9% (420/679) of them complicated with MS. So, community diabetic management must be implemented in an all-round way, including control of blood pressure, blood lipids,body weight and so on, in addition to control of blood sugar.