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BACKGROUND: There is still a lack of effective treatment for sepsis-induced myocardial dysfunction (SIMD), while the pathogenesis of SIMD still remains largely unexplained. METHODS: RNA sequencing results (GSE267388 and GSE79962) were used for cross-species integrative analysis. Bioinformatic analyses were used to delve into function, tissue- and cell- specificity, and interactions of genes. External datasets and qRT-PCR experiments were used for validation. L1000 FWD was used to predict targeted drugs, and 3D structure files were used for molecular docking. RESULTS: Based on bioinformatic analyses, ten differentially expressed genes were selected as genes of interest, seven of which were verified to be significantly differential expression. Bucladesine was considered as a potential targeted drug for SIMD, which banded to seven target proteins primarily by forming hydrogen bonds. CONCLUSION: It was considered that Cebpd, Timp1, Pnp, Osmr, Tgm2, Cp, and Asb2 were novel disease genes, while bucladesine was a potential therapeutic drug, of SIMD.

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INTRODUCTION: Liver fibrosis is primarily driven by the activation of hepatic stellate cells (HSCs), which involves various epigenetic modifications. OBJECTIVES: N6-methyladenosine (m6A), the most prevalent RNA modification in eukaryotic cells, influences numerous physiological and pathological processes. Nevertheless, the role of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a reader gene mediating m6A modifications, in liver fibrosis remains unclear. METHODS AND RESULTS: This study demonstrated that IGF2BP3 knockout reduces liver fibrosis by promoting HSC ferroptosis (FPT) and inactivating HSCs. Multi-omics analysis revealed that HSC-specific IGF2BP3 knockout decreased m6A content in Jagged1 (Jag1), a key component of the Notch signalling pathway. Furthermore, IGF2BP3 deficiency significantly reduced the expression of hairy and enhancer of split-1 (Hes1), a transcription factor in the Notch/Jag1 signalling pathway, with mRNA levels declining to 35%-62% and protein levels to 28%-35%. Additionally, it suppressed glutathione peroxidase 4 (GPX4) (decreased to approximately 31%-38%), a negative regulator of FPT, thereby facilitating HSC FPT progression and reducing profibrotic gene expression. CONCLUSION: These findings uncover a novel IGF2BP3/Notch/Jag1 signalling pathway involving HSC FPT, suggesting promising targets for ameliorating liver fibrosis. KEY POINTS/HIGHLIGHTS: IGF2BP3 deficiency inactivates Jag1 signalling. IGF2BP3 deficiency-mediated m6A modifications promote HSC ferroptosis. IGF2BP3 inhibition facilitates ferroptosis in HSCs via the Hes1/GPX4 axis. IGF2BP3 deficiency inactivates Jag1/Notch1/3/Hes1 signalling pathway inactivation, leading to the decrease in GPX4, which contributes to HSC ferroptosis.

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OBJECTIVES: Ventricular septal defect (VSD) is a prevalent congenital cardiac anomaly. By enhancing the occluder design and optimizing procedural approaches, the indications for VSD closure can be broadened while minimizing associated complications. The utilization of fully biodegradable occluder holds promising potential in resolving conduction block issues encountered during VSD closure. This study aims to compare the results of the fully biodegradable occluder with the metal occluder in transoesophageal echocardiography-guided VSD closure via lower sternal level minor incision at the interim follow-up, and to find risk factors for the occurrence of electrocardiographic and valvular abnormalities postoperatively. METHODS: We reviewed the postoperative and 3-year follow-up data of all patients who underwent the randomized controlled study of VSD closure from January 1 to November 7, 2019 in the Second Xiangya Hospital of Central South University. The safety and efficacy of the procedure were assessed and compared between the 2 groups by electrocardiogram and echocardiography results, and the risk factors for the occurrence of postoperative electrocardiogram and valve abnormalities were studied with Logistic regression analysis. RESULTS: Twelve and fifteen patients underwent VSD closure with the metallic occluder and the fully biodegradable occluder, respectively. All patients survived during the follow-up period without major complications such as atrioventricular block, significant residual shunt, too rapid absorption of the occluder, and significant valvular regurgitation. There were no significant differences in the results of electrocardiograph and color Doppler ultrasonography the metal occluder group and the fully biodegradable occluder group 1, 2, and 3 years after operation (all P>0.05). The size of the occluder were risk factors for tricuspid regurgitation at 2 and 3 years postoperatively, and the difference between the occluder size and the VSD defect size were risk factors for tricuspid regurgitation at 2 years postoperatively (P<0.05). CONCLUSIONS: This study adequately demonstrates the safety and efficacy of fully biodegradable occluders in small VSD closure and shows the same postoperative effects as conventional nitinol occluders.

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BACKGROUND: Acute appendicitis (AA) is the most common cause of acute abdomen in children. Anesthesia significantly influences the surgical treatment of AA in children, making the scientific and effective selection of anesthetics crucial. AIM: To assess the clinical effect of atropine (ATR) in combination with remifentanil (REMI) in children undergoing surgery for AA. METHODS: In total, 108 cases of pediatric AA treated between May 2020 and May 2023 were selected, 58 of which received ATR + REMI [research group (RG)] and 50 who received REMI [control group (CG)]. Comparative analyses were conducted on the time to loss of eyelash reflex, pain resolution time, recovery time from anesthesia, incidence of adverse events (AEs; respiratory depression, hypoxemia, bradycardia, nausea and vomiting, and hypotension), intraoperative responses (head shaking, limb activity, orientation recovery, safe departure time from the operating room), hemodynamic parameters [oxygen saturation (SPO2), mean arterial pressure, heart rate, and respiratory rate], postoperative sedation score (Ramsay score), and pain level [the Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Scale]. RESULTS: Compared with the CG, the RG showed significantly shorter time to loss of eyelash reflex, pain resolution, recovery from anesthesia, and safe departure from the operating room. Furthermore, the incidence rates of overall AEs (head shaking, limb activity, etc.) were lower, and influences on intraoperative hemodynamic parameters and stress response indexes were fewer. The Ramsay score at 30 min after extubation and the FLACC score at 60 min after extubation were significantly lower in the RG than in the CG. CONCLUSION: ATR + REMI is superior to REMI alone in children undergoing AA surgery, with a lower incidence of AEs, fewer influences on hemodynamics and stress responses, and better post-anesthesia recovery.

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The corrosion behavior of carbon steel under the coexistence of carbon dioxide and SRB was studied by means of corrosion weight loss, SEM, EDS, in situ pH test, and other methods. The results showed that Chloride ions, temperature, pH, and oxygen coexist with iron bacteria will affect the corrosion under the coexistence of CO2 and SRB, and SRB tends to grow in a favorable environment for itself, and the corrosion rate of X52N at 42 days is slightly higher than that at 21 days. However, the pitting depth increased sharply from 21.20 µm in 21 days to 39.79 µm in 42 days. So that the corrosion can be divided into two stages. First, SRB catalyze the dissolution of FeCO3, leading to local uniform corrosion. Second, SRB directly obtain electrons from the metal surface, resulting in local pitting. In addition, the environment under the stable mineralized biofilm was found to be slightly alkaline.

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Clear cell renal cell carcinoma (ccRCC) is the most common form of RCC. It is characterized by resistance to traditional radiotherapy and chemotherapy, as well as an unfavorable clinical prognosis. Although TYMP is implicated in the advancement of tumor progression, the role of TYMP in ccRCC is still not understood. Heightened TYMP expression was identified in ccRCC through database mining and confirmed in RCC cell lines. Indeed, TYMP knockdown impacted RCC cell proliferation, migration, and invasion in vitro. TYMP showed a positive correlation with clinicopathological parameters (histological grade, pathological stage). Moreover, patients with high TYMP expression were indicative of poor prognosis in TCGA-ccRCC and external cohorts. The results of single-cell analysis showed that the distribution of TYMP was predominantly observed in monocytes and macrophages. Furthermore, there is a significant association between TYMP and immune status. Methylation analysis further elucidated the relationship between TYMP expression and multiple methylation sites. Drug sensitivity analysis unveiled potential pharmaceutical options. Additionally, mutation analyses identified an association between TYMP and the ccRCC driver genes like BAP1 and ROS1. In summary, TYMP may serve as a reliable prognostic indicator for ccRCC.

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Long noncoding RNA small nucleolar RNA host gene 5 (SNHG5) is an oncogene found in various human cancers. However, it is unclear what role SNHG5 plays in activating hepatic stellate cells (HSCs) and liver fibrosis. In this study, SNHG5 was found to be upregulated in activated HSCs in vitro and in primary HSCs isolated from fibrotic liver in vivo, and inhibition of SNHG5 suppressed HSC activation. Notably, Neurofibromin 2 (NF2), the main activator for Hippo signalling, was involved in the effects of SNHG5 on HSC activation. The interaction between SNHG5 and NF2 protein was further confirmed, and preventing the combination of the two could effectively block the effects of SNHG5 inhibition on EMT process and Hippo signaling. Additionally, higher SNHG5 was found in chronic hepatitis B patients and associated with the fibrosis stage. Altogether, we demonstrate that SNHG5 could serve as an activated HSCs regulator via regulating NF2 and Hippo pathway.

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Hepatic stellate cell (HSC) activation is considered as a central driver of liver fibrosis and effective suppression of HSC activation contributes to the treatment of liver fibrosis. Circular RNAs (circRNAs) have been reported to be important in tumor progression. However, the contributions of circRNAs in liver fibrosis remain largely unclear. The liver fibrosis-specific circRNA was explored by a circRNA microarray and cVIM (a circRNA derived from exons 4 to 8 of the vimentin gene mmu_circ_32994) was selected as the research object. Further studies revealed that cVIM, mainly expressed in the cytoplasm, may act as a sponge for miR-122-5p and miR-9-5p to enhance expression of type I TGF-ß receptor (TGFBR1) and TGFBR2 and promotes activation of the TGF-ß/Smad pathway, thereby accelerating the progression of liver fibrosis. Our results demonstrate a vital role for cVIM in promoting liver fibrosis progression and provide a fresh perspective on circRNAs in liver fibrosis.

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INTRODUCTION: Emergence delirium is a common postoperative neurological complication in children after general anesthesia. There is no valid tool to predict emergence delirium. Wavelet index, pain threshold index, anxiety index, and comfort index are real-time brain status parameters extracted from the electroencephalogram, which have recently been developed. The aim is to evaluate the association between real-time brain status parameters during emergence and emergence delirium in children undergoing general anesthesia. METHODS: One hundred and thirty patients between 3 and 6 years of age undergoing dental surgery under general anesthesia were enrolled in the study. Real-time electroencephalogram data were recorded at four different time points from end of anesthetics administration (T1), end of surgery (T2), extubation (T3), and response (eye opening, movement) to verbal stimulation (T4). Each patient was assessed for emergence delirium using the Pediatric Anesthesia Emergence Delirium scale. Receiver operating characteristics curves and the associated areas under the curves were computed to analyze the ability of wavelet index, pain threshold index, anxiety index, and comfort index to predict emergence delirium. RESULTS: One hundred and sixteen patients were included for final analysis. During recovery from general anesthesia, brain status parameters increased significantly from T1 (wavelet index, 59.5 ± 6.2; pain threshold index, 61.7 ± 5.3; anxiety index, 9.2 ± 2.5; comfort index, 21.6 ± 8.7) to T4 (wavelet index, 67.4 ± 9.4; pain threshold index, 73.2 ± 9.1; anxiety index, 38.6 ± 11.2; comfort index, 66.1 ± 16.5; p < .001). To predict emergence delirium, areas under the curves [95% CI] for anxiety index were 0.84 [0.75-0.93] (p < .001), and comfort index was 0.89 [0.81-0.96] (p < .001). The Pediatric Anesthesia Emergence Delirium scale scores of 37 patients were higher than 10 indicating emergence delirium, and the incidence of emergence delirium was 31.90%. The sensitivity and specificity of anxiety index with corresponding cutoff values in predicting emergence delirium were 73.0% and 89.9%, and the sensitivity and specificity of comfort index in predicting emergence delirium were 91.9% and 83.5%. The best cutoff values for anxiety index and comfort index to predict emergence delirium were 46.5 and 68.5, respectively. The areas under the curves [95% CI] of wavelet index to predict emergence delirium were 0.43 [0.31-0.35] (p = .27), while the areas under the curves [95% CI] of pain threshold index to predict emergence delirium were 0.49 [0.37-0.62] (p = .73). DISCUSSION: Both anxiety index and comfort index derived from electroencephalogram wavelet analysis were associated with emergence delirium in pediatric patients undergoing general anesthesia for dental surgery. Wavelet index and pain threshold index were not associated with emergence delirium during general anesthesia for dental surgery in children. CONCLUSIONS: AnXi and CFi might be used to guide anesthesiologists to identify and intervene ED in children.

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OBJECTIVES: For patients with tetralogy of Fallot (TOF) who are not suitable candidates for primary corrective surgery or have a high surgical risk, transcatheter right ventricular outflow tract (RVOT) stent implantation is considered a safe and effective palliative intervention. This study aims to investigate the therapeutic outcomes of RVOT stent implantation in neonates and infants with TOF in comparison with the modified Blalock-Taussig shunt (mBTS) and to compare the impact of the 2 palliative interventions on arterial oxygen saturation and pulmonary artery development in pediatric patients. METHODS: Clinical data of 32 patients with TOF admitted to the Second Xiangya Hospital of Central South University from March 2011 to March 2021 were retrospectively collected. The patients were divided into an mBTS group (undergoing mBTS, n=15) and a stent implantation group (undergoing RVOT stenting, n=17) according to the surgical procedures. The 2 groups were assessed and compared in the surgical-related arterial oxygen saturation, postoperative complication rate, mortality rate, and re-intervention rate. The development of the patients' main pulmonary artery, right pulmonary artery, and left pulmonary artery was assessed by z-scores according to echocardiographic results. RESULTS: The children in the stent implantation group were younger and less weighed compared with the mBTS group (both P<0.05). Compared with the preoperative period, children in the stent implantation group had significantly higher arterial oxygen saturation [(75±17)% vs (96±3)%, P=0.026]; z-scores of pulmonary trunk [(-2.82±1.27) points vs (0.86±0.77) points, P=0.014], right pulmonary artery [(-1.88±0.59) points vs (-0.28±0.71) points, P=0.011], and left pulmonary artery [(-2.34±0.36) points vs (-1.67±0.36) points, P=0.036] were significantly increased. However, there were no significant differences in arterial oxygen saturation and pulmonary artery z-scores between pre- and post-mBTS procedures (all P>0.05). CONCLUSIONS: RVOT stent would have good surgical outcomes used in TOF patients with low weight and severe comorbidities. It also leads to an higher postoperative oxygen saturation and better promotion of pulmonary artery growth with RVOT stent compared to mBTS.

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OBJECTIVES: Emerging evidence indicates a connection between oxidative stress, immune-inflammatory processes, and the negative symptoms of schizophrenia. In addition to possessing potent antioxidant and anti-inflammatory properties, sulforaphane (SFN) has shown promise in enhancing cognitive function among individuals with schizophrenia. This study aims to investigate the efficacy of combined treatment with SFN in patients with schizophrenia who experience negative symptoms and its effect on the levels of superoxide dismutase (SOD) and the inflammatory marker, high-sensitivity C-reactive protein (HsCRP). DESIGN: Forty-five patients with schizophrenia were recruited, who mainly experienced negative symptoms during a stable period. In addition to the original treatments, the patients received SFN tablets at a daily dose of 90 mg for 24 weeks. At baseline, 12 weeks, and 24 weeks, the participants were interviewed and evaluated. The reduction rate of the Positive and Negative Syndrome Scale (PANSS) was used to assess each participant. The side effects scale of Treatment Emergent Symptom Scale (TESS) was applied to assess the adverse reactions. Additionally, the levels of the SOD, HsCRP, and other indicators were examined. RESULTS: The study findings revealed a significant decrease in PANSS negative subscale scores (P < 0.001). Furthermore, there was a significant increase in SOD activity and HsCRP levels (P < 0.001 and P < 0.05). Notably, the group of participants who exhibited a reduction in PANSS negative subscale scores demonstrated a significant improvement in HsCRP levels (P < 0.05). CONCLUSIONS: Our study suggests that SFN may potentially serve as a safe adjunctive intervention to improve the negative symptoms of schizophrenia. The potential mechanism by which SFN improves negative symptoms in schizophrenia patients may involve its anti-inflammatory properties, specifically its ability to reduce HsCRP levels. Trial registration ClinicalTrial.gov (ID: NCT03451734).

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Protein phosphorylation, catalyzed by protein kinases (PKs), is one of the most important post-translational modifications (PTMs), and involved in regulating almost all of biological processes. Here, we report an updated server, Group-based Prediction System (GPS) 6.0, for prediction of PK-specific phosphorylation sites (p-sites) in eukaryotes. First, we pre-trained a general model using penalized logistic regression (PLR), deep neural network (DNN), and Light Gradient Boosting Machine (LightGMB) on 490 762 non-redundant p-sites in 71 407 proteins. Then, transfer learning was conducted to obtain 577 PK-specific predictors at the group, family and single PK levels, using a well-curated data set of 30 043 known site-specific kinase-substrate relations in 7041 proteins. Together with the evolutionary information, GPS 6.0 could hierarchically predict PK-specific p-sites for 44046 PKs in 185 species. Besides the basic statistics, we also offered the knowledge from 22 public resources to annotate the prediction results, including the experimental evidence, physical interactions, sequence logos, and p-sites in sequences and 3D structures. The GPS 6.0 server is freely available at https://gps.biocuckoo.cn. We believe that GPS 6.0 could be a highly useful service for further analysis of phosphorylation.

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Proteostasis is fundamental for maintaining organismal health. However, the mechanisms underlying its dynamic regulation and how its disruptions lead to diseases are largely unclear. Here, we conduct in-depth propionylomic profiling in Drosophila, and develop a small-sample learning framework to prioritize the propionylation at lysine 17 of H2B (H2BK17pr) to be functionally important. Mutating H2BK17 which eliminates propionylation leads to elevated total protein level in vivo. Further analyses reveal that H2BK17pr modulates the expression of 14.7-16.3% of genes in the proteostasis network, and determines global protein level by regulating the expression of genes involved in the ubiquitin-proteasome system. In addition, H2BK17pr exhibits daily oscillation, mediating the influences of feeding/fasting cycles to drive rhythmic expression of proteasomal genes. Our study not only reveals a role of lysine propionylation in regulating proteostasis, but also implements a generally applicable method which can be extended to other issues with little prior knowledge.

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Background: Sepsis-induced myocardial dysfunction (SIMD) has a significant contribution to sepsis-caused death in critically ill patients. In recent years, the number of published articles related to SIMD has increased rapidly. However, there was no literature that systematically analyzed and evaluated these documents. Thus, we aimed to lay a foundation for researchers to quickly understand the research hotspots, evolution processes and development trends in the SIMD field via a bibliometric analysis. Methods: Articles related to SIMD were retrieved and extracted from the Web of Science Core Collection on July 19th, 2022. CiteSpace (version 6.1.R2) and VOSviewer (version 1.6.18) were used for performing visual analysis. Results: A total of 1,076 articles were included. The number of SIMD-related articles published each year has increased significantly. These publications mainly came from 56 countries, led by China and the USA, and 461 institutions, but without stable and close cooperation. As authors, Li Chuanfu published the most articles, while Rudiger Alain had the most co-citations. Shock was the journal with the most studies, and Critical Care Medicine was the most commonly cited journal. All keywords were grouped into six clusters, some of which represented the current and developing research directions of SIMD as the molecular mechanisms. Conclusion: Research on SIMD is flourishing. It is necessary to strengthen cooperation and exchanges between countries and institutions. The molecular mechanisms of SIMD, especially oxidative stress and regulated cell death, will be critical subjects in the future.

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Objectives: We investigated how device-measured physical activity (PA) volume (PA energy expenditure [PAEE]) and intensity (fraction of PAEE from moderate-to-vigorous PA [FMVPAEE]) were associated with the incidence of type 2 diabetes mellites (T2DM). Methods: This population-based prospective cohort study included 90,044 participants. The primary exposures were PAEE and FMVPAEE. The secondary exposures were energy expenditure exerted during light, moderate, and vigorous PA and their fraction of PAEE. Results: Each 1-SD increase in PAEE was associated with a 17% lower risk of T2DM (hazard ratio [HR]: 0.83, 95% confidence interval [CI]: 0.78-0.98). Each 1-SD increase in FMVPAEE was associated with a 21% lower incidence of T2DM (HR: 0.79, 95% CI: 0.74-0.83). Achieving the same PA volume (KJ/kg/day) through vigorous PA (HR: 0.88, 95% CI: 0.85-0.91) was more effective in preventing T2DM than moderate PA (HR: 0.97, 95% CI: 0.96-0.98) and light PA (HR: 0.99, 95% CI: 0.98-1.00). Conclusion: A higher PA volume is associated with a lower incidence of T2DM. Achieving the same PA volumes through higher-intensity PA is more effective than low-intensity PA in reducing T2DM incidence.

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Colon adenocarcinoma (COAD) is the primary factor responsible for cancer-related mortalities in western countries, and its development and progression are affected by altered sphingolipid metabolism. The current study aimed at investigating the effects of sphingolipid metabolism-related (SLP) genes on multiple human cancers, especially on COAD. We obtained 1287 SLP genes from the GeneCard and MsigDb databases along with the public transcriptome data and the related clinical information. The univariate Cox regression analysis suggested that 26 SLP genes were substantially related to the prognosis of COAD, and a majority of SLP genes served as the risk genes for the tumor, insinuating a potential pathogenic effect of SLP in COAD development. Pan-cancer characterization of SLP genes summarized their expression traits, mutation traits, and methylation levels. Subsequently, we focused on the thorough research of COAD. With the help of unsupervised clustering, 1008 COAD patients were successfully divided into two distinct subtypes (C1 and C2). C1 subtype is characterized by a poor prognosis, activation of SLP pathways, high expression of SLP genes, disordered carcinogenic pathways, and immune microenvironment. Based on the clusters of SLP, we developed and validated a novel prognostic model, consisting of ANO1, C2CD4A, EEF1A2, GRP, HEYL, IGF1, LAMA2, LSAMP, RBP1, and TCEAL2, to quantitatively evaluate the clinical outcomes of COAD. The Kaplain-Meier survival curves and ROC curves highlighted the accuracy of our SLP model in both internal and external cohorts. Compared to normal colon tissues, expression of C2CD4A was detected to be significantly higher in COAD; whereas, expression levels of EEF1A2, IGF1, and TCEAL2 were detected to be significantly lower in COAD. Overall, our research emphasized the pathogenic role of SLP in COAD and found that targeting SLP might help improve the clinical outcomes of COAD. The risk model based on SLP metabolism provided a new horizon for prognosis assessment and customized patient intervention.

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Programmed cell death (PCD) is an essential biological process involved in many human pathologies. According to the continuous discovery of new PCD forms, a large number of proteins have been found to regulate PCD. Notably, post-translational modifications play critical roles in PCD process and the rapid advances in proteomics have facilitated the discovery of new PCD proteins. However, an integrative resource has yet to be established for maintaining these regulatory proteins. Here, we briefly summarize the mainstream PCD forms, as well as the current progress in the development of public databases to collect, curate and annotate PCD proteins. Further, we developed a comprehensive database, with integrated annotations for programmed cell death (iPCD), which contained 1,091,014 regulatory proteins involved in 30 PCD forms across 562 eukaryotic species. From the scientific literature, we manually collected 6493 experimentally identified PCD proteins, and an orthologous search was then conducted to computationally identify more potential PCD proteins. Additionally, we provided an in-depth annotation of PCD proteins in eight model organisms, by integrating the knowledge from 102 additional resources that covered 16 aspects, including post-translational modification, protein expression/proteomics, genetic variation and mutation, functional annotation, structural annotation, physicochemical property, functional domain, disease-associated information, protein-protein interaction, drug-target relation, orthologous information, biological pathway, transcriptional regulator, mRNA expression, subcellular localization and DNA and RNA element. With a data volume of 125 GB, we anticipate that iPCD can serve as a highly useful resource for further analysis of PCD in eukaryotes.

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INTRODUCTION: Complex ectopic drainage of body veins is a rare congenital disease. Its preoperative diagnosis and surgical choice can be considerable challenges. CASE SUMMARY: A 5-year-old patient was diagnosed precisely by preoperative transthoracic echocardiography, computed tomography (CT), three-dimensional (3D) reconstruction, and three-dimensional (3D) printing of the heart and great blood vessels. The operation was performed successfully using flexible intraoperative intubation strategies. CONCLUSION: 3D printing technology can assist in the formulation of surgical protocols for complex body vein ectopic drainage. Flexible intubation strategies can increase the success of the operation.

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As an important post-translational modification, lysine ubiquitination participates in numerous biological processes and is involved in human diseases, whereas the site specificity of ubiquitination is mainly decided by ubiquitin-protein ligases (E3s). Although numerous ubiquitination predictors have been developed, computational prediction of E3-specific ubiquitination sites is still a great challenge. Here, we carefully reviewed the existing tools for the prediction of general ubiquitination sites. Also, we developed a tool named GPS-Uber for the prediction of general and E3-specific ubiquitination sites. From the literature, we manually collected 1311 experimentally identified site-specific E3-substrate relations, which were classified into different clusters based on corresponding E3s at different levels. To predict general ubiquitination sites, we integrated 10 types of sequence and structure features, as well as three types of algorithms including penalized logistic regression, deep neural network and convolutional neural network. Compared with other existing tools, the general model in GPS-Uber exhibited a highly competitive accuracy, with an area under curve values of 0.7649. Then, transfer learning was adopted for each E3 cluster to construct E3-specific models, and in total 112 individual E3-specific predictors were implemented. Using GPS-Uber, we conducted a systematic prediction of human cancer-associated ubiquitination events, which could be helpful for further experimental consideration. GPS-Uber will be regularly updated, and its online service is free for academic research at http://gpsuber.biocuckoo.cn/.

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