Knowledge mapping of graph neural networks for drug discovery: a bibliometric and visualized analysis.

Introduction: In recent years, graph neural network has been extensively applied to drug discovery research. Although researchers have made significant progress in this field, there is less research on bibliometrics. The purpose of this study is to conduct a comprehensive bibliometric analysis of graph neural network applications in drug discovery in order to identify current research hotspots and trends, as well as serve as a reference for future research. Methods: Publications from 2017 to 2023 about the application of graph neural network in drug discovery were collected from the Web of Science Core Collection. Bibliometrix, VOSviewer, and Citespace were mainly used for bibliometric studies. Results and Discussion: In this paper, a total of 652 papers from 48 countries/regions were included. Research interest in this field is continuously increasing. China and the United States have a significant advantage in terms of funding, the number of publications, and collaborations with other institutions and countries. Although some cooperation networks have been formed in this field, extensive worldwide cooperation still needs to be strengthened. The results of the keyword analysis clarified that graph neural network has primarily been applied to drug-target interaction, drug repurposing, and drug-drug interaction, while graph convolutional neural network and its related optimization methods are currently the core algorithms in this field. Data availability and ethical supervision, balancing computing resources, and developing novel graph neural network models with better interpretability are the key technical issues currently faced. This paper analyzes the current state, hot spots, and trends of graph neural network applications in drug discovery through bibliometric approaches, as well as the current issues and challenges in this field. These findings provide researchers with valuable insights on the current status and future directions of this field.

Knockdown of circ-Gatad1 alleviates LPS induced HK2 cell injury via targeting miR-22-3p/TRPM7 axis in septic acute kidney.

BACKGROUND: Sepsis is a life-threatening, systemic inflammatory disease that can lead to a variety of conditions, including septic acute kidney injury (AKI). Recently, multiple circular Rnas (circRNAs) have been implicated in the development of this disease. METHODS: In this study, we aimed to elucidate the role of circ-Gatad1 in sepsis induced AKI and its potential mechanism of action. High-throughput sequencing was used to investigate abnormal expression of circRNA in AKI and healthy volunteer. Bioinformatics analysis and luciferase reporting analysis were used to clarify the interacted relationship among circRNA, miRNA and mRNA. HK2 cells were treated with lipopolysaccharide (LPS) to establish septic AKI cell model. HK2 cells were employ to analysis the ROS, inflammatory cytokines expression, proliferation and apoptosis under LPS condition. RESULTS: The result show that the expression of circ-Gatad1 was increased in septic acute kidney patients. Downregulation circ-Gatad1 suppressed LPS-treated induced HK2 cells injury including apoptosis, proliferation ability, ROS and inflammatory cytokines level. Bioinformatics and luciferase report analysis confirmed that both miR-22-3p and TRPM7 were downstream targets of circ-Gatad1. Overexpression of TRPM7 or downregulation of miR-22-3p reversed the protective effect of si-circ-Gatad1 to HK2 after exposure to LPS (5 µg/ml) microenvironment. CONCLUSION: In conclusion, knockdown of circ-Gatad1 alleviates LPS induced HK2 cell injury via targeting miR-22-3p/TRPM7 axis in septic acute kidney.

Mechanical Enhancement of the Gelatin/Poly(zinc acrylate) Hydrogel Stent in Bile.

Hydrogels with the features of softness, biocompatibility, and modifiability have emerged as excellent materials in the biomedical field. However, the poor mechanical properties of the hydrogels limit their further practical applications. Double-network and metal ion coordination, such as Cu2+ and Zn2+, have achieved a significant reinforcement of the mechanical strength of the hydrogels. Herein, we report a Zn2+-enhanced polyelectrolyte double-network hydrogel stent with a mechanical enhancement phenomenon in bile. The gelatin/poly(zinc acrylate) (PZA) stent was constructed by dip-coating and UV irradiation. Although the mechanical strength of the as-prepared stent was quite weak, it was discovered to be mechanically enhanced by the natural bile. After exploring the effect of different components on the stents according to the components of bile, we found that Ca2+ in bile made a contribution to the mechanical enhancement of the stent. It is envisioned that this bile-enhanced gelatin/PZA stent provides a train of thought for the potential application of hydrogels in the biliary environment.

Cloning and Expression Analysis of HAT1 and HDAC1 in the Testes of Mature Yaks and Their Sterile Hybrids.

The objective of this study was to explore the molecular mechanism of male sterility in yak hybrids based on HAT1 and HDAC1. Total RNA was extracted from the testes of adult yaks (n = 11) and sterile cattle-yaks (n = 11) followed by reverse transcription. The coding sequence (CDS) of yak HAT1 and HDAC1 were obtained by conventional polymerase chain reaction (PCR) and gene cloning. The testicular mRNA and protein levels of HAT1 and HDAC1 in yaks and cattle-yaks were detected by quantitative PCR (qPCR) and Western blotting, respectively, and the histone H3 lysine 9 (H3K9) histone acetylation level in the testes of yaks and cattle-yaks was assayed using enzyme linked immunosorbent assay (ELISA). The results showed that the CDS of HAT1 and HDAC1 were 1242 bp and 1449 bp in length, encoding 413 and 482 amino acids, respectively; yaks had a similar mRNA sequence as cattle in both genes. The testicular mRNA and protein levels of HAT1 of cattle-yaks were significantly lower than those of yaks, and the protein level of HDAC1 was significantly higher than that of yaks. ELISA showed that the acetylation level of testicular H3K9 was significantly lower in yak hybrids than that of yaks. The present results suggest that the decreased level of HAT1 and increased level of HDAC1 may result in the decreased H3K9 acetylation in cattle-yaks and might be associated with their sterility.

Clostridium perfringens and Escherichia coli Bacteremia in a Patient with Acute Obstructive Suppurative Cholangitis: A Case Report and Review of the Literature.

BACKGROUND Clostridium perfringens (CP), one of several clostridial species gram-positive bacteria, is a major cause of animal necrosis enteritis and traumatic gangrene. In some reports, CP can cause acute emphysematous cholecystitis in patients with biliary tract infections. However, C. perfringens combined with other aerobic bacteria (eg, E. coli) in bloodstream co-infection is extremely rare and often fatal. Herein, we present a case of co-infection to underscore this unusual situation so that clinicians can adequately evaluate and treat patients in time. CASE REPORT A 74-year-old man presented to the Emergency Department half a day after the onset of acute abdominal pain accompanied by nausea, vomiting, and chills. The patient was admitted, following development of jaundice, chills, high fever, confusion, and shock. Computed tomography (CT) revealed that the patient had cholangiectasis with acute obstructive suppurative cholangitis (AOSC). We subsequently performed percutaneous transhepatic gallbladder drainage surgery combined with antibiotics, including ceftriaxone, levofloxacin, and metronidazole. C. perfringens and Escherichia coli infections were identified by in vitro blood culture. Fortunately, the patient responded favorably to treatment in our hospital and was cured within 1 week. CONCLUSIONS We report a rare case of C. perfringens and E. coli bloodstream co-infection in a patient with AOSC. We suggest that anaerobic and aerobic co-infection should be considered in future clinical diagnoses. Effective antibiotic treatment combined with surgical drainage is crucial if mixed infection occurs.

Developing a far-red fluorogenic beta-galactosidase probe for senescent cell imaging and photoablation.

A methylene blue (MB)-based beta-galactosidase (ß-gal) activatable molecule, Gal-MB, was developed for senescence imaging and light-triggered senolysis. When in contact with LacZ ß-gal or senescence-associated ß-gal (SA-ß-gal), the photoinsensitive Gal-MB becomes fluorescent. Gal-MB also offered selective phototoxicity toward LacZ ß-gal expressing cells and drug-induced senescent cells, which express SA-ß-gal, after light illumination at 665 nm.

ELK1 Enhances Pancreatic Cancer Progression Via LGMN and Correlates with Poor Prognosis.

Pancreatic cancer is one of the most lethal cancers and its prognosis is extremely poor. Clarification of molecular mechanisms and identification of prognostic biomarkers are urgently needed. Though we previously found that LGMN was involved in pancreatic carcinoma progression, the upstream regulation of LGMN remains unknown. We used reliable software to search for the potential transcription factors that may be related with LGMN transcription, we found that ELK1 could be a new regulator of LGMN transcription that binded directly to the LGMN promoter. Moreover, knocking down of ELK1 reduced pancreatic cancer cells proliferation, invasion and survival, while LGMN restored the malignancy of pancreatic cancer in vitro and in vivo. Overexpression of ELK1 further increased cancer cells proliferation, invasion and survival. Clinically, ELK1 and LGMN were positively correlated with clinical stage, degree of differentiation and Lymph node infiltration. ELK1 and LGMN were identified as independent prognostic factors for overall survival. The patients with low expression of ELK1/LGMN survived an average of 29.65 months, whereas those with high expression of ELK1/LGMN survived an average of 16.67 months. In conclusive, our results revealed a new mechanism by which ELK1 promoted the progression of pancreatic cancer via LGMN and conferred poor prognosis.

Predictive value of the ratio of venoarterial PCO2 to arteriovenous O2 content difference for organ injury in patients with severe acute pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is a common but severe disease with high mortality. Organ injury is the primary risk factor for death in SAP patients. The purpose of this study was to explore the predictive value of the ratio of venoarterial PCO2 to arteriovenous O2 content difference [P(cv-a)CO2/C(a-cv)O2] for organ injury in patients with SAP to provide evidence for further clinical intervention. METHODS: We retrospectively collected data from 108 patients with SAP admitted to Huzhou Central Hospital between January 2018 and January 2021. Forty-five patients who experienced organ injury were defined as the organ injury group, and 63 patients without organ injury were defined as the control group. The differences in P(cv-a)CO2/C(a-cv)O2, lactate, hematocrit (HCT), Acute Physiology and Chronic Health Evaluation (APACHE II) scores, and Ranson scores between the two groups were analyzed, and a receiver operating characteristic curve (ROC) was used to analyze the value of P(cv-a)CO2/C(a-cv)O2 in the prediction of organ injury in SAP patients. RESULTS: At admission, the organ injury group demonstrated significantly higher Ranson scores and APACHE II scores than the control group (Ranson scores: 6.09±1.35 vs. 3.97±2.02, respectively, P=0.000; APACHE II scores: 11.64±2.91 vs. 10.08±2.91, respectively, P=0.007). The value of P(cv-a)CO2/C(a-cv)O2 was also elevated compared to the control group (1.47±0.41 vs. 1.09±0.33, respectively, P=0.000) as was the level of lactate (3.33±0.86 vs. 2.56±0.70 mmol/L, respectively, P=0.000). There was no significant difference in HCT between the two groups at admission (44.47%±6.29% vs. 44.53%±5.75%, respectively, P=0.957). The Ranson score, APACHE II score, P(cv-a)CO2/C(a-cv)O2 and lactate levels were all significant predictors of organ injury in patients with SAP. The area under the curve of P(cv-a)CO2/C(a-cv)O2 was 0.733 (0.637-0.829), P=0.000. CONCLUSIONS: P(cv-a)CO2/C(a-cv)O2 is a potential predictor of organ injury in patients with SAP.

Near-Infrared Fluorogenic Spray for Rapid Tumor Sensing.

Surgical resection of cancerous tissues is a critical procedure for solid tumor treatment. During the operation, the surgeon mostly identifies the cancerous tissues by naked-eye visualization under white light without aid, therefore, the outcome heavily relies on the surgeon's experience. A near-infrared pH-responsive fluorogenic dye, CypH-11, was designed to be used as a sensitive cancer spray to highlight cancerous tissues during surgical operations, minimizing the surgeon's subjective judgment. CypH-11, pKa 6.0, emits almost no fluorescence at neutral pH but fluoresces brightly in an acidic environment, a ubiquitous consequence of cancer cell proliferation. After topical application, CypH-11 was absorbed quickly, and its fluorescence signal in the cancerous tissue was developed within a minute. The signal-to-background ratio was 1.3 and 1.5 at 1 and 10 min, respectively. The fluorogenic property and near-instant signal development capability enable the "spray-and-see" concept. This fast-acting CypH-11 spray could be a handy and effective tool for fluorescence-guided surgery, identifying small cancerous lesions in real time for optimal resection without systemic toxicity.

A self-designed liver circle for on-demand Pringle's manoeuver in laparoscopic liver resection.

BACKGROUND: Laparoscopic liver resection (LLR) allows minimal incisions and relatively quicker post-operative recovery, while intraoperative massive haemorrhage led to conversion to laparotomy. This study aimed to introduce a new, safe and convenient device to serve as Pringle's manoeuver according to the demand in LLR. METHODS: A liver circle consisting of a hole and a round stem with an obtuse small head was made by medical silica gel. It was applied in LLR to perform on-demand Pringle's manoeuver and developed its function in inferior vena cava (IVC) occlusion. The time of performing Pringle's manoeuver by liver circle, extracorporeal tourniquet and endo intestinal clip under laparoscopic simulator and LLR was compared. RESULTS: The liver circle was successfully applied to perform Pringle's manoeuver, IVC exposure and occlusion. It took less time in the occluding step of Pringle's manoeuver than the extracorporeal tourniquet (4.15 ± 0.35 s vs. 9.90 ± 1.15 s, P < 0.05) and the endo intestinal clip (4.15 ± 0.35 s vs. 47.91 ± 3.98 s, P < 0.05) under LLR. The total manipulating time for Pringle's manoeuver with liver circle remained the shortest, and the advantages were more obvious with increased frequencies of intermittent Pringle's manoeuver. CONCLUSION: The new-designed liver circle is more convenient compared to other techniques in performing Pringle's manoeuver, especially the intermittent Pringle's manoeuver in LLR. It can be used to perform on-demand hepatic blood inflow occlusion in every LLR by pre-circling the hepatoduodenal ligament to control bleeding during surgery. It can also be applied to expose the surgical field of vision and perform IVC occlusion to reduce intraoperative blood loss.

The Prognostic Value of External vs Internal Pancreatic Duct Stents in CR-POPF after Pancreaticoduodenectomy: A Systematic Review and Meta-analysis.

BACKGROUND: There is no specific evidence regarding the benefits of external and internal pancreatic duct stents after pancreaticoduodenectomy since pancreatic fistula (grade A) have been redefined with no clinical treatment effect. We aimed to reevaluate the prognostic value of external and internal stents in clinically relevant postoperative pancreatic fistula over pancreaticoduodenectomy. METHODS: PubMed, Web of Science, EMBASE and the Cochrane Database were specifically searched for pertinent and original articles published before May 2019. The project has been registered in PROSPERO (Registration number: CRD42019137579). RESULTS: Four randomized controlled trials and six nonrandomized controlled trials with a total of 2101 patients were enrolled in this meta-analysis. The use of an external stent resulted in better performance than the use of an internal stent in terms of pancreatic fistula (grade C) (OR 0.58, P = 0.03) but did not reduce the rate of pancreatic fistula (grade B) (OR 0.99, P = 0.94) in all studies. The meta-analysis of randomized controlled trials found that the use of an external stent approached a level of significance for an increased rate of clinically relevant postoperative pancreatic fistula compared to the use of an internal stent (OR 1.40, P = 0.10) but had no significant effect on pancreatic fistula (grade B) (OR 1.34, P = 0.26) or pancreatic fistula (grade C) (OR 1.68, P = 0.62). CONCLUSION: Compared with internal stents, the use of external stent might be associated with a lower rate of pancreatic fistula (grade C). More randomized clinical trials are warranted to further explore safety and efficacy of pancreatic duct external stents.

Selective photo-ablation of glioma cells using an enzyme activatable photosensitizer.

An activatable photosensitizer based on methylene blue was developed and validated for its efficacy in the selective killing of γ-glutamyl transpeptidase expressing cells. The 1O2 deactivation via bond breakage, rapid in situ enzymatic photosensitivity conversion, long lysosomal retention, and nucleus relocation collectively contribute to its strong and selective photodynamic effects.

Early outcomes of implanting larger-sized grafts in deceased donor liver transplantation.

BACKGROUND: The outcomes of large-sized graft mismatch in deceased donor liver transplantation (LT) have been rarely studied. The aim of this study was to determine whether a large-sized graft for recipient influenced the post-transplant outcomes. METHODS: A total of 273 patients undergoing LT were enrolled and divided into a large and a normal-sized graft group by graft weight to recipient weight (GWRW) >2.5% (n = 76) or GWRW ≤2.5% (n = 197). Post-operative complications and outcomes were retrospectively analysed. RESULTS: The two groups were comparable in demographic characteristics. The rate of complications was significantly higher in the large-sized graft group including early allograft dysfunction (36.8% versus 17.8%, P = 0.001), hepatic necrosis (26.3% versus 13.7%, P = 0.01) and massive hydrothorax (25% versus 14.7%, P = 0.04). The large-sized graft group suffered higher early mortality compared with the normal-sized graft group (30 days: 14.5% versus 5.6%, P = 0.02, 90 days: 21.1% versus 9.6%, P = 0.01). The primary causes of early death were multiple organ failure (10.5% versus 2%, P = 0.002) and sepsis (2.6% versus 1.5%, P = 0.54). Four parameters including donor alanine transaminase, GWRW, estimated blood loss and model for end-stage liver disease score were significant on multivariate analysis, and indicated significant risk factors for the early mortality of recipients. CONCLUSION: In deceased donor LT, GWRW >2.5% is associated with increased liver injury, risk of early mortality and other adverse outcomes. Thus, donor livers should be allocated to recipients with GWRW ≤2.5%.

Cloning and Expression Analysis of Two Kdm Lysine Demethylases in the Testes of Mature Yaks and Their Sterile Hybrids.

The objective of this study was to explore the molecular mechanism for male sterility of yak hybrids based on two demethylases. Total RNA was extracted from the testes of adult yaks (n = 10) and yak hybrids (cattle-yaks, n = 10). The coding sequences (CDS) of two lysine demethylases (KDMs), KDM1A and KDM4B, were cloned by RT-PCR. The levels of KDM1A and KDM4B in yaks and cattle-yaks testes were detected using Real-time PCR and Western blotting for mRNA and protein, respectively. In addition, the histone methylation modifications of H3K36me3 and H3K27me3 were compared between testes of yaks and cattle-yaks using ELISA. The CDS of KDM1A and KDM4B were obtained from yak testes. The results showed that the CDS of KDM1A exhibited two variants: variant 1 has a CDS of 2622 bp, encoding 873 amino acids, while variant 2 has a CDS of 2562 bp, encoding 853 amino acids. The CDS of the KDM4B gene was 3351 bp in length, encoding 1116 amino acids. The mRNA and protein expression of KDM1A and KDM4B, as well as the level of H3K36me3, were dramatically decreased in the testes of cattle-yaks compared with yaks. The present results suggest that the male sterility of cattle-yaks might be associated with reduced histone methylation modifications.

A novel exposure maneuver in laparoscopic right hepatectomy.

BACKGROUND AND OBJECTIVES: Laparoscopic access to the posterosuperior and lateral parts of the right liver is difficult for blocked and deep surgical situations. We invented a novel water bag device (WBD) to improve the exposure of the right liver. METHODS: Eighteen consecutive patients with lesions isolated to the posterosuperior or lateral right liver were included in our research. They underwent laparoscopic right hepatectomy with the help of the device and were compared with previous similar laparoscopic cases of our operating surgeon. RESULTS: The device was successfully employed without related complications and provided enhanced and stable surgical exposure. All patients were operated on without the need for blood transfusions or laparotomy conversion. The median operation time and estimated blood loss were 227 minutes (range, 114-568) and 88 mL (range, 25-250), respectively. In all cases, tumor-free surgical margins were confirmed and no major complications were observed. The results were better than those in previous similar laparoscopic cases. CONCLUSIONS: The WBD is safe and effective for laparoscopic exposure when lesions are located in the posterosuperior and lateral parts of the right liver. With the help of the device, laparoscopic right liver resection is easier to perform instead of undergoing open hepatectomy.

Dietary supplementation of selenium yeast enhances the antioxidant capacity and immune response of juvenile Eriocheir Sinensis under nitrite stress.

This study elucidates the response to nitrite stress and the effect of dietary selenium supplements on the growth, antioxidant activity, immunity and transcriptome of juvenile Chinese mitten crab Eriocheir sinensis. In the control group, the crabs were fed the diet without selenium supplementation and there was no nitrite addition to the water. In the test group, the crabs were fed diets with three levels of selenium 0 (N1), 0.5 (N2) and 1.0 (N3) mg/kg in the water containing 2 mg/L NO2N as a stress factor for eight weeks. Feed conversion ratio (FCR) was improved by adding dietary selenium. There was no significant difference in specific growth rate and weight gain between N1 and the control groups, or among different selenium levels in the test group. The superoxide dismutase (SOD) activity was significantly lower, but malondialdehyde (MDA) was higher in the N1 group than those in the serum and hepatopancreas of the control group. The activities of SOD, glutathione peroxidase (GPx) and acid phosphatase increased at the medium level of selenium but decreased as the level of dietary selenium increased to 1.0 mg/kg. The serum lysozyme (LZM) activity increased but the MDA content in both serum and hepatopancreas decreased with the increase of selenium levels. The total clean reads of the crabs in the control group, N1 and N3 groups reached 390.7M and were assembled into 106 471 transcripts. Compared with the control group, 1196 gene were significantly expressed (588-up and 608-down) in the N1 group under nitrite stress. Between the N1 and N3 groups, the expression of 1537 genes (751-up and 786-down) were significantly different. KEGG pathway analysis reveals that 11 and 19 pathways were significantly different between N1 and control and between N3 and N1 groups, respectively. Transcriptome results demonstrate that nutrient metabolism is much more active in crabs fed additional selenium under nitrite stress. This study indicates that dietary selenium can improve both antioxidant capacity and immune response and alter the protein and carbohydrate metabolism of E. sinensis under nitrite stress.

Natural product pectolinarigenin inhibits proliferation, induces apoptosis, and causes G2/M phase arrest of HCC via PI3K/AKT/mTOR/ERK signaling pathway.

BACKGROUND: Hepatocellular carcinoma (HCC) is characterized by considerable phenotypic and molecular heterogeneity, but the overall survival of HCC patients remains extremely poor. Thus, novel and efficient alternatives to antitumor agents are urgently needed. Pectolinarigenin, a flavonoid compound extract, has been previously reported for the treatment of nasopharyngeal cancer. However, the potential antitumor roles of pectolinarigenin in HCC have not been clearly elaborated. In the present study, we investigated its role in HCC treatment and explored the potential molecular mechanism(s). MATERIALS AND METHODS: HCC cell lines SMMC7721 and PLC5 were cultured and treated with indicated concentrations of pectolinarigenin. For the HCC cell proliferation, after HCC cells were stimulated with indicated concentrations of pectolinarigenin, the cell viability was detected in CCK-8 and colony-forming assays. HCC cell invasion/migration assay was performed by Transwell and wound scratch methods. Additionally, cellular apoptosis and cell cycle arrest analysis was performed with flow cytometric analysis. Finally, the involved underlying signaling pathway, the PI3K/AKT/mTOR/ERK signaling-related molecular markers were detected through Western blot methods with indicated antibodies. Meanwhile, antitumor activity of pectolinarigenin was also assessed in tumor-bearing mice. RESULTS: The results indicated that the treatment with pectolinarigenin significantly inhibited cell proliferation and migratory and invasive abilities of SMMC7721 and PLC5 cells in concentration- and time-dependent manner. Meanwhile, pectolinarigenin markedly induced cell apoptosis and G2/M phase arrest in SMMC7721 and PLC5 cells, which was associated with apoptosis- and cell cycle-related protein levels, respectively. Furthermore, pectolinarigenin inhibited PI3K/AKT/mTOR/ERK signaling pathway. It also significantly suppressed HCC tumor growth in vivo. CONCLUSION: Pectolinarigenin could suppress the viability and motility and cause apoptosis and G2/M phase arrest in HCC cell lines by inhibiting the PI3K/AKT/mTOR/ERK signaling pathway. This might be an appealing potential therapeutic agent for HCC treatment.