The interest in covalent drugs has resurged in recent decades, spurring the development of numerous specialized computational docking tools to facilitate covalent ligand design and screening. Herein, we present CarsiDock-Cov, a new paradigm distinguishing itself as the first deep learning (DL)-guided approach for covalent docking. CarsiDock-Cov retains the core components of its non-covalent predecessor, leveraging a DL model pretrained on millions of docking complexes to predict protein-ligand distance matrices, along with a dedicated-designed geometric optimization procedure to convert these distances into refined binding poses. Additionally, it incorporates several key enhancements specifically tailored to optimize the protocol for covalent docking applications. Our approach has been extensively validated on multiple public datasets regarding the docking and screening of covalent ligands, and the results indicate that our approach not only achieves comparably improved applicability compared to its non-covalent predecessor, but also exhibits competitive performance against various state-of-the-art covalent docking tools. Collectively, our approach represents a significant advance in covalent docking methodology, offering an automated and efficient solution that shows considerable promise for accelerating covalent drug discovery and design.

BACKGROUND:Clinical treatment for colon cancer mainly includes fluorouracil,irinotecan and oxaliplatin-based therapy.Studies have shown that membrane transport proteins such as ATP-binding cassette transport protein of G2(ABCG2)mediate the transport of these drugs.However,when patients develop resistance to these chemotherapeutic drugs,the high expression of ABCG2 leads to a significant decrease in the therapeutic effect and raises the problem of drug resistance in colon cancer.New drugs and treatments are urgently needed to improve the efficacy.Lycium barbarum polysaccharide has a wide range of biological activities.It can be used as anti-tumor drug to overcome the damage to normal cells in the process of chemotherapy and radiotherapy in tumor patients. OBJECTIVE:To explore the reversal effect of Lycium barbarum polysaccharide in combination with oxaliplatin on colon cancer drug-resistant cells through in vitro experiments to investigate the possible molecular mechanism of Lycium barbarum polysaccharide reversal on colon cancer drug-resistant cells. METHODS:Colon cancer cell line HCT116 and oxaliplatin-resistant cell line HCT116-OXR were selected for in vitro experiments.The optimal intervention concentration and intervention time of Lycium barbarum polysaccharide and oxaliplatin were determined by CCK8 assay of cell proliferation.Samples were further divided into the HCT116 control group,HCT116-OXR blank treatment group,Lycium barbarum polysaccharide group(2.5 mg/mL Lycium barbarum polysaccharide),and oxaliplatin group(10 μmol/L oxaliplatin),and Lycium barbarum polysaccharide + oxaliplatin group(2.5 mg/mL Lycium barbarum polysaccharide +10 μmol/L oxaliplatin).Cell apoptosis was detected by flow cytometry.The protein expression levels of phosphomannose isomerase(PMI)and ABCG2 were detected by immunofluorescence and western blot assay.Phosphatidylinositol3-kinase(PI3K),protein kinase B(AKT),B-cell lymphoma 2(Bcl-2)and BCL2-Associated X(Bax)were detected by western blot assay. RESULTS AND CONCLUSION:(1)HCT116-OXR was more sensitive to Lycium barbarum polysaccharide compared to HCT116(P<0.05).(2)Compared with the HCT116-OXR blank group,Lycium barbarum polysaccharide + oxaliplatin could promote apoptosis of HCT116-OXR cells(P<0.05).The protein expression of Bcl-2 was significantly down-regulated(P<0.05);the protein expression of Bax was significantly up-regulated(P<0.05);the protein expression of ABCG2,PMI,PI3K and AKT was significantly down-regulated(P<0.05).(3)These results indicate that Lycium barbarum polysaccharide reverses drug resistance in colon cancer by inhibiting PMI/PI3K/AKT signaling pathway,which lays the foundation for studying the molecular mechanism of Lycium barbarum polysaccharide's sensitizing chemotherapeutic effects.

Objective To understand the changing distribution and antimicrobial resistance profiles of Proteus,Morganella and Providencia in hospitals across China from January 1,2015 to December 31,2021 in the CHINET Antimicrobial Resistance Surveillance Program.Methods Antimicrobial susceptibility testing was carried out following the unified CHINET protocol.The results were interpreted in accordance with the breakpoints in the 2021 Clinical & Laboratory Standards Institute(CLSI)M100(31 st Edition).Results A total of 32 433 Enterobacterales strains were isolated during the 7-year period,including 24 160 strains of Proteus,6 704 strains of Morganella,and 1 569 strains of Providencia.The overall number of these Enterobacterales isolates increased significantly over the 7-year period.The top 3 specimen source of these strains were urine,lower respiratory tract specimens,and wound secretions.Proteus,Morganella,and Providencia isolates showed lower resistance rates to amikacin,meropenem,cefoxitin,cefepime,cefoperazone-sulbactam,and piperacillin-tazobactam.For most of the antibiotics tested,less than 10％of the Proteus and Morganella strains were resistant,while less than 20％of the Providencia strains were resistant.The prevalence of carbapenem-resistant Enterobacterales(CRE)was 1.4％in Proteus isolates,1.9％in Morganella isolates,and 15.6％in Providencia isolates.Conclusions The overall number of clinical isolates of Proteus,Morganella and Providencia increased significantly in the 7-year period from 2015 to 2021.The prevalence of CRE strains also increased.More attention should be paid to antimicrobial resistance surveillance and rational antibiotic use so as to prevent the emergence and increase of antimicrobial resistance.

Objective:To analyze the efficacy and prognosis of different treatment regimens in patients with uncomplicated brucellosis, and to provide guidance for clinical treatment.Methods:The patients diagnosed with brucellosis in the Sixth People′s Hospital of Shenyang from September 2014 to June 2019 were enrolled. The clinical data of patients with uncomplicated brucellosis were collected. The two most frequent treatment regimens were screened, after conducting propensity score matching with 1∶4, and the clinical characteristics, prognosis, and adverse reactions in patients with two regimens were retrospectively analyzed. The primary outcome was clinical cure. The secondary outcomes were disease progression and relapse. Statistical analysis was performed using chi-square test, Wilcoxon rank sum test and log-rank method.Results:A total of 1 570 patients clinically diagnosed with brucellosis were included, and 939(59.8%) showed uncomplicated infection. There were 608(38.7%) patients who received doxycycline and rifampicin treatment, and 65(4.1%) received doxycycline and levofloxacin treatment. By propensity score matching, 223 patients (DR group) who used doxycycline and rifampicin were included, while 65 patients (DL group) who used doxycycline and levofloxacin were included. The cure rate, progression rate, symptom persistence rate and recurrence rate of DR group were 94.6%(211/223), 1.8%(4/223), 2.2%(5/223) and 1.3%(3/223), respectively. In DL group, those were 95.4%(62/65), 3.1%(2/65), 1.5%(1/65) and 0(0/65), respectively. And there was no significant difference between the two groups ( χ2=0.18, P=0.632). No significant difference of symptom durations between the two groups was observed (29.0(28.0, 30.0) d vs 28.0(26.1, 29.9) d, hazard ratio ( HR)=0.966, 95% confidence interval ( CI) 0.723 to 1.290, χ2=1.01, P=0.315), while treatment course of DR group was statistically longer than DL group (90.0(84.1, 95.9) d vs 44.0(37.3, 50.7) d, HR=0.489, 95% CI 0.361 to 0.662, χ2=14.18, P<0.001). Procalcitonin (0.02(0.02, 0.05) μg/L and 0.02(0.02, 0.04) μg/L) and C-reactive protein (8(3, 17) mg/L and 18(7, 55) mg/L) levels in DR group and DL group had decreased significantly after treatment than before treatment (0.09(0.04, 0.16) μg/L and 0.19(0.08, 0.25) μg/L, 106(19, 274) mg/L and 255(50, 494) mg/L), and the differences were statistically significant ( W=2.55, 2.04, 3.66 and 2.19, respectively, all P<0.05). The adverse reaction (ADR) rate in DR group was 4.2%(8/191), and five patients showed liver function injury. The ADR rate in DL group was 2.0%(1/51), which showed liver function injury. There was no significant difference of ADR between the two groups ( P>0.05). Conclusions:Doxycycline combined with rifampicin and doxycycline combined with levofloxacin have similar efficacy and adverse reaction rates for treating uncomplicated brucellosis.

Objective To evaluate the role of nuclear factor erythroid 2-related factor 2 ( Nrf2 ) signaling pathway in endoplasmic reticulum stress response during lipopolysaccharide ( LPS)-induced acute lung injury ( ALI) in mice. Methods Forty clean-grade healthy male C57BL∕6 mice, aged 6-8 weeks, weighing 22-26 g, were divided into 4 groups ( n=10 each) using a random number table method: control group ( group C) , group ALI, salubrinal group ( group S) and salubrinal plus brusatol group ( group S+B) . Animals were intratracheally instilled with 5 mg∕kg of LPS diluted in normal saline to establish the model of ALI. Animals were intratracheally instilled with 100 μl of normal saline in group C. Mice in group S were intraperitoneally injected with endoplasmic reticulum stress response inhibitor 1 mg∕kg salubrinal at 1 and 24 h after LPS instillation. Mice of group S+B were intraperitoneally injected with brusatol 2 mg∕kg once every other day for 10 days prior to LPS instillation, and the other treatments were similar to those previously de-scribed in group S. Mice were sacrificed at 48 h after LPS administration, and lungs were removed for mi-croscopic examination of the pathological changes of lung tissues which were scored and for determination of contents of IL-17A, tumor necrosis factor-alpha ( TNF-α) and interleukin-6 ( IL-6) in lung tissues ( by en-zyme-linked immunosorbent assay) and expression of Nrf2, CCAAT∕enhancer-binding protein homologous protein (CHOP) and caspase-12 in lung tissues (by Western blot). Lung water content was calculated. Results Compared with group C, the lung water content and contents of IL-17A, TNF-α and IL-6 were significantly increased, the expression of CHOP and caspase-12 in cytoplasma was up-regulated, and the ex-pression of Nrf2 in nuclei was down-regulated in ALI and S+B groups, and the lung water content and con-tents of IL-17A, TNF-α and IL-6 were significantly increased, the expression of Nrf2 in nuclei and CHOP in cytoplasma was up-regulated, and the expression of caspase-12 was down-regulated in group S ( P<0. 05) . Compared with group ALI, the lung water content and contents of IL-17A, TNF-α and IL-6 were significantly decreased, the expression of CHOP and caspase-12 in cytoplasma was down-regulated, the ex-pression of Nrf2 in nuclei was up-regulated ( P<0. 05) , and the pathological changes were significantly at-tenuated in group S. Compared with group S, the lung water content and contents of IL-17A, TNF-α and IL-6 were significantly increased, the expression of CHOP and caspase-12 in cytoplasma was up-regulated, the expression of Nrf2 in nuclei was down-regulated ( P<0. 05) , and the pathological changes of lung tis-sues were accentuated in group S+B. Conclusion Nrf2 signaling pathway is involved in the process of en-doplasmic reticulum stress response during LPS-induced ALI in mice.

Objective To investigate the antimicrobial resistance profile of the clinical isolates collected from selected hospitals across China. Methods Twenty-nine general hospitals and five children's hospitals were involved in this program. Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or automated systems. Results were interpreted according to CLSI 2017 breakpoints. Results A total of 190 610 clinical isolates were collected from January to December 2017, of which gram negative organisms accounted for 70.8％ (134 951/190 610) and gram positive cocci 29.2％ (55 649/190 610). The prevalence of methicillin-resistant strains was 35.3％ in S. aureus (MRSA) and 80.3％ in coagulase negative Staphylococcus (MRCNS) on average. MR strains showed much higher resistance rates to most of the other antimicrobial agents than MS strains. However, 91.6％ of MRSA strains were still susceptible to trimethoprim-sulfamethoxazole, while 86.2％ of MRCNS strains were susceptible to rifampin. No staphylococcal strains were found resistant to vancomycin. E. faecalis strains showed much lower resistance rates to most of the drugs tested (except chloramphenicol) than E. faecium. Vancomycin-resistant Enterococcus (VRE) was identified in both E. faecalis and E. faecium. The identified VRE strains were mainly vanA, vanB or vanM type based on phenotype or genotype. The proportion of PSSP or PRSP strains in the non-meningitis S.pneumoniae strains isolated from children decreased but the proportion of PISP strains increased when compared to the data of 2016. Enterobacteriaceae strains were still highly susceptible to carbapenems. Overall, less than 10％ of these strains (excluding Klebsiella spp.) were resistant to carbapenems. The prevalence of imipenem-resistant K. pneumoniae increased from 3.0％ in 2005 to 20.9％ in 2017, and meropenem-resistant K. pneumoniae increased from 2.9％ in 2005 to 24.0％ in 2017, more than 8-fold increase. About 66.7％ and 69.3％ of Acinetobacter (A. baumannii accounts for 91.5％) strains were resistant to imipenem and meropenem, respectively. Compared with the data of year 2016, P. aeruginosa strains showed decreasing resistance rate to carbapenems. Conclusions Bacterial resistance is still on the rise. It is necessary to strengthen hospital infection control and stewardship of antimicrobial agents. The communication between laboratorians and clinicians should be further improved in addition to surveillance of bacterial resistance.

Aim To investigate the protective effects of Aplysin on ethanol-induced oxidative damage in rat pri-mary hepatocytes. Methods Rat primary hepatocytes were obtained via the portal vein collagenaseⅣin situ perfusion technique followed by a Percoll density gradi-ent centrifuge. MTT test was used to determine the op-timum dose of Aplysin and ethanol, and detect the cell vitality in primary hepatocytes. Supernatants of primary hepatocytes were harvested to measure AST and LDH level, and the SOD, GSH-PX activities and MDA con-tent in primary hepatocytes were observed. Flow cy-tometry was used to detect the cell apoptosis rate. DNA damage in primary hepatocytes was detected by single-cell gel electrophoresis assay. The level of mitochon-drial membrane potential in primary hepatocytes was tested by fluorogenic probe JC-1 . The CYP2 E1 activity in primary hepatocytes was detected by colorimetry. The proteins of CYP2 E1 were detected by Western blot. Results 300 mmol·L-1 dose of ethanol and 30 mg·L-1 dose of Aplysin were the optimal dosages and were used in the subsequent experiments. Hepatocyte vitality was significantly increased in Aplysin group compared to that in ethanol group, and Aplysin inhibi-ted the release of AST and LDH(P<0. 05). For Apl-ysin treatment group, the activities of hepatocyte SOD and GSH were significantly increased, and MDA was markedly lowered as compared with those in ethanol group( P <0. 05 ) . Aplysin could alleviate hepatocyte apoptosis significantly, and hepatocyte DNA damage rates of Ⅱ ~Ⅲ level and Ⅳ level were significantly lowered in Aplysin treatment group as compared with those in ethanol group, and Aplysin had evident im-provement in alcohol induced mitochondria damage of hepatocyte. Primary hepatocyte activities and protein expression of CYP2 E1 were markedly lowered in Aply-sin treatment group as compared with those in ethanol group(P<0. 05). Conclusion Aplysin has protective effects on liver oxidative damage induced by alcohol of primary cultured rat hepatocytes by blocking CYP2 E1 activation, relieving oxidative stress, and sharpening the oxidation resistance ability.

Objective To explore the application value of Mammotome biopsy system in diagnosis and treatment of breast lesions. Methods Summed up the experience of 318 breast lesions in 192 patients who were treated with mammotome. Results 316 lesions were re-sected safely and completely. Skin hematoma was found in 17 patients and ecchymosis was found in 8 patients after operation. All patients had no recurrence and residual. Conclusion The Mammotome biopsy system has many advantages for the diagnosis and treatment of breast lesions, including accurate localization, minimal invasion, safety and good cosmetology.

OBJECTIVE To make the patients using the central venous catheter safely when given chemotherapy and intravenous nutritional therapy,and to decrease the catheter infection by establishing effective infection-preventing systems. METHODS Many infection-preventing actions were carried out,including a three-level management,improving the workers′ training in catheter operation and maintenance,and health education. RESULTS Comparing with the matched group,the infection rate of the experimental group was much lower after the actions.The actions prevented the increase of infection effectively. CONCLUSIONS Building and carrying out the systems are proved to be important measures to decrease the catheter infection and ensure the quality of life among patients during the therapy in hospital.

Summary: This experiment aimed to investigate the effect of adrenergic system in the subnucleus commissuriu of nucleus solitrius tractus (CNTS) on renal nerve discharges. Norepinephrine (NE) was microinjected into the CNTS of rabbits and mean arterial blood pressure (MAP) and renal nerve discharges (FRND) were synchronously recorded. The results indicated that (1) microinjection of norepinephine into the CNTS of rabbit could significantly attenuate the frequency of renal nerve discharge, and at the same time decrease markedly the mean arterial pressure. (2) Microinjection of 0.3 nmol yohimbin into CNTS had no significant influence on FRND and MAP, but could attenuate and even reverse the effects of NE on FRND and MAP. These results suggest that microinjection of NE into CNTS may activate the alpha-adrenorecptor located in CNTS and secondarily produce a depressor effect by attenuating the activity of peripheral sympathetic nervous system.