Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

Objective To summarize and analyze the clinical diagnosis, surgical treatment and prognosis of multiple pulmonary nodules (MPNs). Methods The clinical data of lung cancer patients who received surgical treatment in our hospital from 2018 to 2020 were collected. The short-term efficacy of surgical treatment for MPNs was analyzed. Results A total of 97 patients were enrolled, including 30 males and 67 females with an average age of 56.1±10.0 years at onset ill. There were 62 patients with double lesions, 22 patients with three lesions, 4 patients with four lesions, and 9 patients with more than four lesions. A total of 213 lesions were surgically treated, including 88 pure ground-glass nodules, 81 partially solid nodules, and 7 solid nodules. There were 87 simultaneous surgeries and 10 staged surgeries, with an average operation interval of 5.2 months. The pathological combination type included adenocarcinoma-adenocarcinoma in 96 (99.0%) patients, squamous cell carcinoma-squamous cell carcinoma in 1 (1.0%) patient, and no lymph node metastasis was found. The 2-year disease-free survival (DFS) rate was 92.1%, and the overall survival (OS) rate was 100.0%. Univariate analysis showed that high-risk lesion size>2 cm (P=0.316), residual lesions (P=0.782) and pathological combination type (P=0.913) had statistical effect on the 2-year DFS rate. Conclusion MPNs are mainly diagnosed with multiple primary lung cancers, and the pathological combination is mostly adenocarcinoma-adenocarcinoma combination. Imaging examination is of great help to the surgical approach selection, diagnosis and differential diagnosis of MPNs. During the operation, maximal preservation of lung function and complete resection of high-risk nodules should be taken as the principle, and the prognosis is satisfactory.

Objective To explore the predictive value of lung ultrasound score on the severity of neonatal respiratory distress syndrome(NRDS).Methods The clinical data of 65 children with NRDS in our NICU from July 2021 to July 2022 were retrospectively analyzed,and 65 children were included in the NRDS group,while 40 children with other common pulmonary diseases(neonatal wet lung and infectious pneumonia)were selected as the other pulmonary disease group during the same period,and all children were examined by pulmonary ultrasound and X-ray to observe the children in both groups.The lung conditions of the two groups of children were observed:abnormal pleural line,disappearance of A line,isolated B line,fused B line,diffuse B line,lung consolidation,with or without bronchial inflation sign,and other lung ultrasound manifestations.The lung ultrasound scores of the two groups of children were compared,and the X-ray grading distribution of children in the NRDS group was analyzed,correlation between lung ultrasound scoring and X-ray grading was used by Pearson correlation analysis.The clinical value of lung ultrasound score in the differential diagnosis of NRDS and the severity of the disease was analyzed by receiver operator characteristic(ROC)curve.Results The proportion of solid lung,abnormal pleural line,disappearance of A-line,white lung detection,fused B-line,and bronchial inflation sign was significantly higher in the NRDS group than in the other lung disease groups,and the proportion of isolated B-line and double lung point detection was significantly lower than in the other lung disease groups,with statistically significant differences(P<0.05).The lung ultrasound scores of both lungs,left lung,right lung,bilateral lung,and base of both lungs were significantly higher in the NRDS group than in the other lung disease groups(P<0.05).With the increase of X-ray grading,the lung ultrasound score gradually increased,and there was a statistically significant difference between groups at each grade(P<0.05).Pearson correlation analysis showed that there was a significant positive correlation between lung ultrasound score and X-ray grade(r=0.704,P<0.05).The area under curve(AUC)of lung ultrasound score in differentiating NRDS from common lung diseases was 0.907,with sensitivity and specificity of 89.0%and 92.5%,respectively;the AUC of mild and moderate,moderate and severe NRDS in the differential diagnosis by lung ultrasound score was 0.914 and 0.933,respectively,which had high clinical value.Conclusion The lung ultrasound score has certain value in identifying NRDS.The lung ultrasound score can quantitatively assess the changes in the condition of NRDS,and the lung ultrasound and X-ray grading have good consistency,it has the advantages of radiation free,fast,and intuitive,and can be used as an effective method for early diagnosis of NRDS and evaluation of the severity of the disease.

ObjectiveTo genotype Oncomelania hupensis， based on microsatellites， in different snail-bearing environments in Jiaxing City， Zhejiang Province， for population genetics analysis in order to explore the reasons and influencing factors for the existence or proliferation of snails and to provide scientific basis for effective monitoring and control of snails. MethodsA total of 90 snail samples from three populations were collected in Yaobang Village （YB） and Sanxing Village （SX） in Pinghu City， and Yunhe Farm （YH） in Xiuzhou District， all were selected for snail checking in key snail habitats of Jiaxing City in 2022. DNA of the snails was genotyped and analyzed for population genetics using nine microsatellite loci. ResultsA total of 84 alleles were observed， and the mean number of alleles （Na） was 7.889， 5.667， and 3.778 for YB， SX， and YH respectively； the number of effective alleles （NeA） was 4.807， 3.329， and 2.294， respectively； and the coefficients of inbreeding （F_IS） were 0.400， 0.377， and 0.493， respectively. Under the Infinite Allele Model （IAM）， the SX and YH might have a recent bottleneck. The NEstimator and LDNe software calculated effective population sizes （Ne） were above 31.9. AMOVA analysis showed that the variation of snails in the three populations mainly existed among individuals， accounting for 41.4% of the total variation. The value of the index of genetic differentiation between populations （F_ST） was 0.286， indicating a high degree of genetic differentiation. The results of the principal component analysis and phylogenetic tree were consistent， and the three populations were divided into two lineages， YB and SX were one lineage， and YH belonged to another independent lineage. Population history and dynamics analysis showed that the gene flow of the three populations was insufficient， population divergence history indicated that YH might have diverged from SX first， and YB was produced by the contact fusion of SX and YH. ConclusionThe genetic diversity of snail populations in Jiaxing City is generally low， and the snail populations are unstable， with a great degree of genetic differentiation and insufficient gene flow among populations. This study can provide a basis for evaluating the effectiveness of the control of the snail as well as monitoring the trend of the spread of the snail.

Obiective Alzheimer’s disease (AD) is a degenerative disease of the central nervous system (CNS) caused by a variety of risk factors. There are various pathological changes, but apoptosis of the neurological meridian cells is one of the most important pathological bases. Hyperlipidemia is a high-risk factor for the development of AD, which can lead to increased levels of oxidized low-density lipoprotein (ox-LDL) in brain tissues. PCSK9 is a protease closely related to lipid metabolism, but studies have shown that it may be related to the development of AD. LRP1 is abundantly expressed in neuronal cells, and it is an important transporter for the clearance of Aβ. There is now a large amount of literature confirming that PCSK9 can induce the degradation of LRP1. PI3K/AKT is an important signaling pathway in vivo, which plays an important role in apoptosis, and there is now a large amount of literature confirming that LRP1 activates the PI3K/AKT pathway, which has an anti-apoptotic effect. So can PCSK9 affect the PI3K/AKT pathway through LRP1 and thus regulate neuronal apoptosis? This deserves further investigation.The aim of this study was to explore the role of PCSK9 in mediating ox-LDL pro-apoptotic neuronal cell death and its mechanism, and then further elaborate the mechanism of hyperlipidemia leading to neurodegenerative diseases such as AD. MethodsFirstly, PC12 cells were treated with different concentrations of ox-LDL (0, 25, 50, 75 and 100 mg/L) for 24 h. Oil red O staining was used to detect lipid accumulation in PC12 cells, Hoechst33258 staining and flow cytometry to detect apoptosis in PC12 cells, ELISA to detect the content of Aβ secreted by PC12, Western blot to detect expression of SREBP2, PCSK9 and LRP1. Then PC12 cells were treated with 75 mg/L ox-LDL for different times (0, 6, 12, 24, 48 h), and Western blot were performed to detect the expression of SREBP2, PCSK9 and LRP1. Finally, after transfecting 100 nmol/L PCSK9 siRNA into PC12 cells for 48 h, PC12 cells were treated with 75 mg/L ox-LDL for 24 h, Hoechst33258 staining and flow cytometry to detect apoptosis rate of PC12 cells, and Western blot to detect PCSK9, LRP1, PI3K, AKT, P-PI3K , P-AKT, NF-κB, Bcl-2, Bax, Caspase-9 and Caspase-3 expression, and ELISA detected Aβ content secreted by PC12 cells. Resultsox-LDL increased lipid accumulation and promoted apoptosis and Aβ secretion in PC12 cells, as well as increasing the expression of SREBP2 and PCSK9 and decreasing the expression of LRP1 in PC12 cells. pCsk9 siRNA could be inhibited through the PI3K/AKT pathway and the NF-κB-Bcl-2/Bax-Caspase-9/3 pathway to inhibit ox-LDL-induced apoptosis in PC12 cells while increasing Aβ secretion in PC12 cells. Conclusionox-LDL plays a bidirectional regulatory role in ox-LDL-induced apoptosis of PC12 cells by inducing an increase in PCSK9 expression and a decrease in LRP1 expression in PC12 cells, which in turn affects different signaling pathways downstream.

The growth of three plague phages from Qinghai Plateau in two Yersinia pestis strains(plague vaccine strains EV76 and 614F)and four non-Yersinia pestis strains(Yersinia pseudotuberculosis PTB3,PTB5,Escherichia coli V517,and Yersinia enterocolitica 52302-2)were detected through a micromethod based on the OmniLogTM microbial identification system and by the drop method,to provide a scientific basis for future ecological studies and classification based on the host range.For plague vaccine strains EV76 and 614F,successful phage infection and subsequent phage growth were observed in the host bacte-rium.Diminished bacterial growth and respiration and a concomitant decrease in color were observed with the OmniLogTM mi-crobial identification system at 33 ℃ for 48 h.Yersinia pseudotuberculosis PTB5 was sensitive to Yersinia pestis phage 476,but Yersinia pseudotuberculosis PST5 was insensitive to phage 087 and 072204.Three strains of non-Yersinia pestis(Yersinia pseudotuberculosis PTB3,Escherichia coli V517,and Yersinia enterocolitica 52302-2)were insensitive to Yersinia pestis pha-ges 087,072204,and 476 showed similar growth curves.The growth of phages 476 and 087,as determined with the drop method,in two Yersinia pestis strains(plague vaccine strains EV76 and 614F)and four non-Yersinia pestis strains(Yersinia pseudotuberculosis PTB3,Escherichia coli V517,and Yersin-ia enterocolitica 52302-2)showed the same results at 37 ℃,on the basis of comparisons with the OmniLogTM microbial i-dentification system;in contrast,phages 072204 did not show plaques on solid medium at 37 ℃ with plague vaccine strains EV76 and 614F.Determination based on the OmniLogTM detection system can be used as an alternative to the traditional determination of the host range,thus providing favorable application val-ue for determining the interaction between the phage and host bacteria.

Objective:To investigate the current situation of the use of transjugular intrahepatic portosystemic shunt (TIPS) for portal hypertension, which should aid the development of TIPS in China.Methods:The China Portal Hypertension Alliance (CHESS) initiated this study that comprehensively investigated the basic situation of TIPS for portal hypertension in China through network research. The survey included the following: the number of surgical cases, main indications, the development of Early-TIPS, TIPS for portal vein cavernous transformation, collateral circulation embolization, intraoperative portal pressure gradient measurement, commonly used stent types, conventional anticoagulation and time, postoperative follow-up, obstacles, and the application of domestic instruments.Results:According to the survey, a total of 13 527 TIPS operations were carried out in 545 hospitals participating in the survey in 2021, and 94.1% of the hospital had the habit of routine follow-up after TIPS. Most hospitals believed that the main indications of TIPS were the control of acute bleeding (42.6%) and the prevention of rebleeding (40.7%). 48.1% of the teams carried out early or priority TIPS, 53.0% of the teams carried out TIPS for the cavernous transformation of the portal vein, and 81.0% chose routine embolization of collateral circulation during operation. Most of them used coils and biological glue as embolic materials, and 78.5% of the team routinely performed intraoperative portal pressure gradient measurements. In selecting TIPS stents, 57.1% of the hospitals woulel choose Viator-specific stents, 57.2% woulel choose conventional anticoagulation after TIPS, and the duration of anticoagulation was between 3-6 months (55.4%). The limitation of TIPS surgery was mainly due to cost (72.3%) and insufficient understanding of doctors in related departments (77.4%). Most teams accepted the domestic instruments used in TIPS (92.7%).Conclusions:This survey shows that TIPS treatment is an essential part of treating portal hypertension in China. The total number of TIPS cases is far from that of patients with portal hypertension. In the future, it is still necessary to popularize TIPS technology and further standardize surgical indications, routine operations, and instrument application.

Objective To explore the application efficacy and safety of oblique ultrasound-guided techniques in PICC puncture,in order to provide guidance and references for clinical application.Methods Through convenient sampling,654 patients from a tertiary A hospital in Zhejiang Province from March to December 2022 were selected as the study subjects.The random numbers were generated through Excel table functions and they were randomly grouped into 3 groups:A,B,and C.The ultrasound short axis method,long axis method,and oblique axis method were employed to guide PICC puncture catheterization,respectively.The success rate of PICC puncture,the number of subcutaneous adjustments of the puncture needle,puncture time,and the occurrence of puncture complications(such as hematoma,puncture of the posterior wall of blood vessels,accidental injury to arteries,and accidental injury to nerves)were recorded during the catheterization process in 3 groups.Results A total of 654 patients completed the study,including 215 in group A,219 in group B,and 220 in group C.The success rate of first-time puncture in the group C(86.36％)was higher than that in group A(73.95％)and group B(63.93％),and there was a statistically significant difference among 3 groups(P＜0.001).The subcutaneous adjustment frequency of the puncture needle was 1(1,1)in group C,1(1,2)in group A,and 1(1,2)in group B.The difference between 3 groups was statistically significant(P＜0.001);the puncture time of group C was shorter than that of group A and group B,and the difference was statistically significant(P＜0.001).There was a statistically significant difference in the puncture time between 3 groups(P＜0.017);the pairwise comparison of the number of subcutaneous needle adjustments and the success rate of a puncture between 3 groups showed that there was a statistical difference between group C and group A,and between group C and group B(P＜0.017),while there was no statistical difference between group A and group B(P＞0.017).There was statistical significance(P＜0.05)among 3 groups in terms of complications such as accidental nerve injury and puncture of the contralateral vascular wall by puncture needle,but there was no statistical significance in terms of accidental arterial injury and hematoma occurrence among 3 groups.Conclusion Compared with the short axis approach and the long axis approach,the ultrasound oblique axis approach guided PICC puncture has statistical differences in the success rate of a puncture and the incidence of puncture complications,etc.It is recommended to use the ultrasound oblique axis approach during PICC puncture.

Objective:To investigate the current status of endoscopic treatment for gastroesophageal varices in portal hypertension in China, and to provide supporting data and reference for the development of endoscopic treatment.Methods:In this study, initiated by the Liver Health Consortium in China (CHESS), a questionnaire was designed and distributed online to investigate the basic condition of endoscopic treatment for gastroesophageal varices in portal hypertension in 2022 in China. Questions included annual number and indication of endoscopic procedures, adherence to guideline for preventing esophagogastric variceal bleeding (EGVB), management and timing of emergent EGVB, management of gastric and isolated varices, and improvement of endoscopic treatment. Proportions of hospitals concerning therapeutic choices to all participant hospitals were calculated. Guideline adherence between secondary and tertiary hospitals were compared by using Chi-square test.Results:A total of 836 hospitals from 31 provinces (anotomous regions and municipalities) participated in the survey. According to the survey, the control of acute EGVB (49.3%, 412/836) and the prevention of recurrent bleeding (38.3%, 320/836) were major indications of endoscopic treatment. For primary [non-selective β-blocker (NSBB) or endoscopic therapies] and secondary prophylaxis (NSBB and endoscopic therapies) of EGVB, adherence to domestic guideline was 72.5% (606/836) and 39.2% (328/836), respectively. There were significant differences in the adherence between secondary and tertiary hospitals in primary prophylaxis of EGVB [71.0% (495/697) VS 79.9% (111/139), χ2=4.11, P=0.033] and secondary prophylaxis of EGVB [41.6% (290/697) VS 27.3% (38/139), χ2=9.31, P=0.002]. A total of 78.2% (654/836) hospitals preferred endoscopic therapies treating acute EGVB, and endoscopic therapy was more likely to be the first choice for treating acute EGVB in tertiary hospitals (82.6%, 576/697) than secondary hospitals [56.1% (78/139), χ2=46.33, P<0.001]. The optimal timing was usually within 12 hours (48.5%, 317/654) and 12-24 hours (36.9%, 241/654) after the bleeding. Regarding the management of gastroesophageal varices type 2 and isolated gastric varices type 1, most hospitals used cyanoacrylate injection in combination with sclerotherapy [48.2% (403/836) and 29.9% (250/836), respectively], but substantial proportions of hospitals preferred clip-assisted therapies [12.4% (104/836) and 26.4% (221/836), respectively]. Improving the skills of endoscopic doctors (84.2%, 704/836), and enhancing the precision of pre-procedure evaluation and quality of multidisciplinary team (78.9%, 660/836) were considered urgent needs in the development of endoscopic treatment. Conclusion:A variety of endoscopic treatments for gastroesophageal varices in portal hypertension are implemented nationwide. Participant hospitals are active to perform emergent endoscopy for acute EGVB, but are inadequate in following recommendations regarding primary and secondary prophylaxis of EGVB. Moreover, the selection of endoscopic procedures for gastric varices differs greatly among hospitals.

Objective To study changes in immune cells and cytokines during the reactivation stage of varicella-zoster virus(VZV)in patients with herpes zoster.Methods A total of 50 patients with herpes zoster and 30 healthy individuals were selected from Xi'an Ninth Hospital between May 2022 and October 2022.Flow cytometry was used to detect the proportion of peripheral blood CD3+cells,CD4+cells,CD8+T cells,B cells and NK cells,as well as levels of cytokines IL-2,IFN-γ,IL-10 and IL-6.We analyzed the immune mechanism of VZV reactivation stage in herpes zoster patients.Results Compared with the healthy control group,the proportion of CD3+cells and CD4+T cells in herpes zoster patients decreased significantly;the proportion of NK cells significantly increased;the levels of IFN-γ,IL-10 and IL-6 significantly increased;the proportion of CD8+T cells,B cells and IL-2 content showed an increasing trend,but there was no significant difference.In addition,the severity of neurological involvement in herpes zoster patients might affect changes in cytokine levels.Conclusion During the reactivation period of VZV,changes in the proportion of immune cells and cytokine expression levels are closely related to the occurrence and development of herpes zoster.