Dihydromyricetin protects sevoflurane-induced mitochondrial dysfunction in HT22 hippocampal cells.

Sevoflurane (Sev) is a commonly used inhalation anaesthetic that has been shown to cause hippocampus dysfunction through multiple underlying molecular processes, including mitochondrial malfunction, oxidative stress and inflammation. Dihydromyricetin (DHM) is a 2,3-dihydroflavonoid with various biological properties, such as anti-inflammation and anti-oxidative stress. The purpose of this study was to investigate the effect of DHM on Sev-induced neuronal dysfunction. HT22 cells were incubated with 10, 20 and 30 µM of DHM for 24 h, and then stimulated with 4% Sev for 6 h. The effects and mechanism of DHM on inflammation, oxidative stress and mitochondrial dysfunction were explored in Sev-induced HT22 cells by Cell Counting Kit-8, flow cytometry, enzyme-linked immunosorbent assay, reverse transcription-quantitative polymerase chain reaction, colorimetric detections, detection of the level of reactive oxygen species (ROS), mitochondrial ROS and mitochondrial membrane potential (MMP), immunofluorescence and western blotting. Our results showed that DHM increased Sev-induced cell viability of HT22 cells. Pretreatment with DHM attenuated apoptosis, inflammation, oxidative stress and mitochondrial dysfunction in Sev-elicited HT22 cells by remedying the abnormality of the indicators involved in these progresses, including apoptosis rate, the cleaved-caspase 3 expression, as well as the level of tumour necrosis factor α, interleukin (IL)-1ß, IL-6, malondialdehyde, superoxide dismutase, catalase, ROS, mitochondrial ROS and MMP. Mechanically, pretreatment with DHM restored the Sev-induced the expression of SIRT1/FOXO3a pathway in HT22 cells. Blocking of SIRT1 counteracted the mitigatory effect of DHM on apoptosis, inflammation, oxidative stress and mitochondrial dysfunction in Sev-elicited HT22 cells. Collectively, pretreatment with DHM improved inflammation, oxidative stress and mitochondrial dysfunction via SIRT1/FOXO3a pathway in Sev-induced HT22 cells.

Targeting colorectal cancer with Herba Patriniae and Coix seed: Network pharmacology, molecular docking, and in vitro validation.

BACKGROUND: Herba Patriniae and Coix seed (HC) constitute a widely utilized drug combination in the clinical management of colorectal cancer (CRC) that is known for its diuretic, anti-inflammatory, and swelling-reducing properties. Although its efficacy has been demonstrated in a clinical setting, the active compounds and their mechanisms of action in CRC treatment remain to be fully elucidated. AIM: To identify the active, CRC-targeting components of HC and to elucidate the mechanisms of action involved. METHODS: Active HC components were identified and screened using databases. Targets for each component were predicted. CRC-related targets were obtained from human gene databases. Interaction targets between HC and CRC were identified. A "drug-ingredient-target" network was created to identify the core components and targets involved. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to elucidate the key pathways involved. Molecular docking between core targets and key components was executed. In vitro experiments validated core monomers. RESULTS: Nineteen active components of HC were identified, with acacetin as the primary active compound. The predictive analysis identified 454 targets of the active compounds in HC. Intersection mapping with 2685 CRC-related targets yielded 171 intervention targets, including 30 core targets. GO and KEGG analyses indicated that HC may influence the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. Molecular docking showed that acacetin exhibited an optimal interaction with AKT1, identifying PI3K, AKT, and P53 as key genes likely targeted by HC during CRC treatment. Acacetin inhibited HT-29 cell proliferation and migration, as well as promoted apoptosis, in vitro. Western blotting analysis revealed increased p53 and cleaved caspase-3 expression and decreased levels of p-PI3K, p-Akt, and survivin, which likely contributed to CRC apoptosis. CONCLUSION: Acacetin, the principal active compound in the HC pair, inhibited the proliferation and migration of HT-29 cells and promoted apoptosis through the PI3K/Akt/p53 signaling pathway.

Anaesthesia modality on endovascular therapy outcomes in patients with large infarcts: a post hoc analysis of the ANGEL-ASPECT trial.

OBJECTIVES: Endovascular therapy (EVT) now penetrates the once obscure realm of large infarct core volume acute ischaemic stroke (LICV-AIS). This research aimed to investigate the potential correlation between different anaesthetic approaches and post-EVT outcomes in LICV-AIS patients. METHODS: Between October 2020 and May 2022, the China ANGEL-Alberta Stroke Programme Early CT Score (ASPECT) trial studied patients with LICV-AIS, randomly assigning them to the best medical management (BMM) or BMM with EVT. This post hoc subgroup analysis categorised subjects receiving BMM with EVT into general anaesthesia (GA) and non-GA groups based on anaesthesia type. We applied multivariable logistic regression to evaluate the relationship between anaesthesia during EVT and patient functional outcomes, as measured by the modified Rankin scale (mRS), in addition to the occurrence of complications. Further adjustment for selection bias was achieved through propensity score matching (PSM). RESULTS: In total, 230 patients with LICV-AIS were enrolled (GA 84 vs Non-GA 146). No significant difference was observed between the two groups in terms of the proportion of patients who achieved an mRS score of 0-2 at 90 days (27.4% for the GA group vs 31.5% for the non-GA group, p=0.51). However, the GA group had significantly longer median surgical times (142 min vs 122 min, p=0.03). Furthermore, GA was associated with an increased risk of postoperative pneumonia (adjusted OR 2.03, 95% CI 1.04 to 3.98). The results of PSM analysis agreed with the results of the multivariate regression analysis. No significant difference in intracranial haemorrhage incidence or mortality rate was observed between the groups. CONCLUSION: This post hoc analysis of subgroups of the ANGEL-ASPECT trial suggested that there may be no significant association between the choice of anaesthesia and neurological outcomes in LICV-AIS patients. However, compared with non-GA, GA prolongs the duration of EVT and is associated with a greater postoperative pneumonia risk. TRIAL REGISTRATION NUMBER: NCT04551664.

Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.

The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.

One-step enrichment and stepwise elution of glycoproteins and phosphoproteins by hydrophilic Ti4+-immobilized dendrimer poly(glycidyl methacrylate) microparticles functionalized with polyethylenimine and phytic acid.

Glycosylation and phosphorylation rank as paramount post-translational modifications, and their analysis heavily relies on enrichment techniques. In this work, a facile approach was developed for the one-step simultaneous enrichment and stepwise elution of glycoproteins and phosphoproteins. The core of this approach was the application of the novel titanium (IV) ion immobilized poly(glycidyl methacrylate) microparticles functionalized with dendrimer polyethylenimine and phytic acid. The microparticles possessed dual enrichment capabilities due to their abundant titanium ions and hydroxyl groups on the surface. They demonstrate rapid adsorption equilibrium (within 30 min) and exceptional adsorption capacity for ß-casein (1107.7 mg/g) and horseradish peroxidase (438.6 mg/g), surpassing that of bovine serum albumin (91.7 mg/g). Furthermore, sodium dodecyl sulfate-polyacrylamide gel electrophoresis was conducted to validate the enrichment capability. Experimental results across various biological samples, including standard protein mixtures, non-fat milk, and human serum, demonstrated the remarkable ability of these microparticles to enrich low-abundance glycoproteins and phosphoproteins from biological samples.

Evaluation of multiparametric MRI differentiating pleomorphic adenoma from schwannoma in parapharyngeal space.

PURPOSE: This study aimed to investigate whether multiparametric magnetic resonance imaging (MRI) including dynamic contrast-enhanced (DCE) and diffusion weighted (DW) MRI can differentiate pleomorphic adenoma (PA) from schwannoma in the parapharyngeal space. METHODS: Forty-six patients with pathologically proven PAs and 47 schwannomas in the parapharyngeal space were enrolled. All patients underwent conventional MRI, and DW-MRI and DCE-MRI were performed in 30 and 33 patients, respectively. Fisher's exact, Mann-Whitney-U tests and Independent samples t-test were used to compare variables between PAs and schwannomas. Multivariate logistic regression analysis was used to examine the diagnostic performance of MRI parameters. RESULTS: The PAs usually show lobulation sign, posterior displacement of ICA and attached to the parotid gland deep leaf, while bird beak configuration, anterior displacement of ICA and involvement of foramen jugular were more commonly seen in the schwannomas(all p < 0.001). The washout rate of PAs was found to be higher than that of schwannomas (p = 0.035), whereas no significance was found in the other DCE-MRI parameters and in ADCs(p > 0.05). Using a combination of conventional MRI features including lobulation sign, bird beak configuration, direction of internal carotid artery(ICA) displacement and attached to the parotid gland in multivariate logistic regression analysis, sensitivity, specificity, and accuracy in differential diagnosis of PAs and schwannomas were 97.8%, 91.5% and 94.6%, respectively. CONCLUSION: Conventional MRI can effectively differentiate PAs from schwannomas in the parapharyngeal space with a high diagnostic accuracy. The DCE-MRI and DWI have limited added diagnostic value to conventional MRI in the differential diagnosis.

Hysteroscopic cervical biopsy for women with persistent human papillomavirus infection after loop electrosurgical excision procedure: A case report.

BACKGROUND: Almost all cases of cervical cancer can be attributed to human papillomavirus (HPV) infection. The loop electrosurgical excision procedure (LEEP) is widely used to treat HPV-mediated disease; thus, cervical cancer is highly preventable. However, LEEP does not necessarily clear HPV rapidly and may affect the accuracy of the results of ThinPrep cytology test (TCT) and cervical biopsy due to the formation of cervical scars. CASE SUMMARY: A 40-year-old woman underwent LEEP for cervical intraepithelial neoplasia grade 1 approximately 10 years ago. Subsequent standard cervical cancer screening suggested persistent HPV-52 infection, but TCT results were negative. Cervical biopsy under colposcopy was performed thrice over a 10-year period, yielding negative pathology results. She developed abnormal vaginal bleeding after sexual activity, persisting for approximately 1 year, and underwent hysteroscopy in our hospital. Histopathologic evaluation confirmed adenocarcinoma in situ of the uterine cervix. CONCLUSION: Patients with long-term persistent, high-risk HPV infection and negative pathology results of cervical biopsy after LEEP are at risk of cervical cancer. Hysteroscopic resection of cervical canal tissue is recommended as a supplement to cervical biopsy because it helps define the lesion site and may yield a pathologic diagnosis.

Changes in the combination of the triglyceride-glucose index and obesity indicators estimate the risk of cardiovascular disease.

BACKGROUND: Cardiovascular disease (CVD) is closely associated with the triglyceride glucose (TyG) index and its related indicators, particularly its combination with obesity indices. However, there is limited research on the relationship between changes in TyG-related indices and CVD, as most studies have focused on baseline TyG-related indices. METHODS: The data for this prospective cohort study were obtained from the China Health and Retirement Longitudinal Study. The exposures were changes in TyG-related indices and cumulative TyG-related indices from 2012 to 2015. The K-means algorithm was used to classify changes in each TyG-related index into four classes (Class 1 to Class 4). Multivariate logistic regressions were used to evaluate the associations between the changes in TyG-related indices and the incidence of CVD. RESULTS: In total, 3243 participants were included in this study, of whom 1761 (54.4%) were female, with a mean age of 57.62 years at baseline. Over a 5-year follow-up, 637 (19.6%) participants developed CVD. Fully adjusted logistic regression analyses revealed significant positive associations between changes in TyG-related indices, cumulative TyG-related indices and the incidence of CVD. Among these changes in TyG-related indices, changes in TyG-waist circumference (WC) showed the strongest association with incident CVD. Compared to the participants in Class 1 of changes in TyG-WC, the odds ratio (OR) for participants in Class 2 was 1.41 (95% confidence interval (CI) 1.08-1.84), the OR for participants in Class 3 was 1.54 (95% CI 1.15-2.07), and the OR for participants in Class 4 was 1.94 (95% CI 1.34-2.80). Moreover, cumulative TyG-WC exhibited the strongest association with incident CVD among cumulative TyG-related indices. Compared to the participants in Quartile 1 of cumulative TyG-WC, the OR for participants in Quartile 2 was 1.33 (95% CI 1.00-1.76), the OR for participants in Quartile 3 was 1.46 (95% CI 1.09-1.96), and the OR for participants in Quartile 4 was 1.79 (95% CI 1.30-2.47). CONCLUSIONS: Changes in TyG-related indices are independently associated with the risk of CVD. Changes in TyG-WC are expected to become more effective indicators for identifying individuals at a heightened risk of CVD.

Minimalistic approach to left atrial appendage occlusion guided by cardiac computed tomography angiography.

OBJECTIVE: To assess the feasibility and safety of the minimalistic approach to left atrial appendage occlusion (LAAO) guided by cardiac computed tomography angiography (CCTA). METHODS: Ninety consecutive patients who underwent LAAO, with or without CCTA-guided, were matched (1:2). Each step of the LAAO procedure in the computed tomography (CT) guidance group (CT group) was directed by preprocedural CT planning. In the control group, LAAO was performed using the standard method. All patients were followed up for 12 months, and device surveillance was conducted using CCTA. RESULTS: A total of 90 patients were included in the analysis, with 30 patients in the CT group and 60 matched patients in the control group. All patients were successfully implanted with Watchman devices. The mean ages for the CT group and the control group were 70.0 ± 9.4 years and 68.4 ± 11.9 years (P = 0.52), respectively. The procedure duration (45.6 ± 10.7 min vs. 58.8 ± 13.0 min, P < 0.001) and hospital stay (7.5 ± 2.4 day vs. 9.6 ± 2.8 day, P = 0.001) in the CT group was significantly shorter compared to the control group. However, the total radiation dose was higher in the CT group compared to the control group (904.9 ± 348.0 mGy vs. 711.9 ± 211.2 mGy, P = 0.002). There were no significant differences in periprocedural pericardial effusion (3.3% vs. 6.3%, P = 0.8) between the two groups. The rate of postprocedural adverse events (13.3% vs. 18.3%, P = 0.55) were comparable between both groups at 12 months follow-up. CONCLUSIONS: CCTA is capable of detailed LAAO procedure planning. Minimalistic LAAO with preprocedural CCTA planning was feasible and safe, with shortened procedure time and acceptable increased radiation and contras consumption. For patients with contraindications to general anesthesia and/or transesophageal echocardiography, this promising method may be an alternative to conventional LAAO.

RSU-1 regulates the integrity of dense bodies in muscle cells of aging Caenorhabditis elegans.

Muscle contraction is vital for animal survival, and the sarcomere is the fundamental unit for this process. However, the functions of many conserved sarcomere proteins remain unknown, as their mutants do not exhibit obvious defects. To address this, Caenorhabditis elegans was utilized as a model organism to investigate RSU-1 function in the body wall muscle. RSU-1 is found to colocalize with UNC-97 at the dense body and M-line, and it is particularly crucial for regulating locomotion in aging worms, rather than in young worms. This suggests that RSU-1 has a specific function in maintaining muscle function during aging. Furthermore, the interaction between RSU-1 and UNC-97/PINCH is essential for RSU-1 to modulate locomotion, preserve filament structure, and sustain the M-line and dense body throughout aging. Overall, these findings highlight the significant contribution of RSU-1, through its interaction with UNC-97, in maintaining proper muscle cell function in aging worms.

Peri-device leakage and delayed endothelialization of the Watchman device: a computed tomography study.

OBJECTIVES: This study aimed to explore the endothelialization process and assess the potential association between endothelialization and peri-device leak (PDL) following Watchman implantation via a quantitative method. METHODS: This is a single-center retrospective study of consecutive patients undergoing LAAO between December 2015 and November 2021. Device endothelialization, compared between PDL and non-PDL group, were quantitatively analyzed based on hypoattenuated thickening in cardiac computed tomography angiography (CCTA). Advancement in endothelialization over time were explored using the Cochran-Armitage test and generalized estimating equation approach. Potential risk factors of delayed endothelialization were analyzed using the Cox proportional-hazards model. RESULTS: A total of 172 patients (mean age, 68 years ± 10 [standard deviation], 114 men) were finally included. The average endothelialization ratio of the study population was 89.8 ± 7.2 percent. In the follow-up period of postprocedural 3 months to more than 12 months, an incremental trend of endothelialization over time was observed with the ratio of 85.8 ± 8.0, 89.6 ± 7.6, 92.2 ± 4.5, 94.3 ± 2.9 percent, respectively (p < 0.0001). Notably, patients without PDL exhibited a swifter advancement in endothelialization compared to those with PDL, irrespective of device size. The multivariable Cox regression model showed that PDL (HR = 2.113, 95%CI: 1.300-3.435, p = 0.003), DSP (HR = 1.717, 95%CI: 1.113-2.647, p = 0.014) were independent risk factors of delayed endothelialization. CONCLUSION: CCTA holds promise as an effective means of quantitatively assessing device endothelialization. Endothelialization advanced gradually over time, with PDL potentially impeding device endothelialization. CLINICAL RELEVANCE STATEMENT: A comprehensive understanding of the correlation between endothelialization ratio, time, and residual shunt can establish a more dependable foundation for determining the appropriate anticoagulation treatment following left atrial appendage closure. KEY POINTS: Current recommendations for postleft atrial appendage occlusion anti-platelet and anticoagulation therapy are based on animal studies. Cardiac computed tomography angiography (CCTA) combined with the UNet neural network model enables the quantitative assessment of device endothelialization. This technique will allow for additional studies to better understand device endothelialization to optimize treatments in this population.

Polysaccharide-Based Micro/Nanomotors for Active Ingredient Delivery in Food.

Micro/nanomotors (MNMs) are miniature devices that can generate energy through chemical reactions or physical processes, utilizing this energy for movement. By virtue of their small size, self-propulsion, precise positioning within a small range, and ability to access microenvironments, MNMs have been applied in various fields including sensing, biomedical applications, and pollutant adsorption. However, the development of food-grade MNMs and their application in food delivery systems have been scarcely reported. Currently, there are various issues with the decomposition, oxidation, or inability to maintain the activity of some nutrients or bioactive substances, such as the limited application of curcumin (Cur) in food. Compared to traditional delivery systems, MNMs can adjust the transport speed and direction as needed, effectively protecting bioactive substances during delivery and achieving efficient transportation. Therefore, this study utilizes polysaccharides as the substrate, employing a simple, rapid, and pollution-free template method to prepare polysaccharide-based microtubes (PMTs) and polysaccharide-based micro/nanomotors (PMNMs). PMNMs can achieve multifunctional propulsion by modifying ferrosoferric oxide (Fe3O4), platinum (Pt), and glucose oxidase (GOx). Fe-PMNMs and Pt-PMNMs exhibit excellent photothermal conversion performance, showing promise for applications in photothermal therapy. Moreover, PMNMs can effectively deliver curcumin, achieving the effective delivery of nutrients and exerting the anti-inflammatory performance of the system.

Proteomic biomarkers for noninvasive left atrial appendage thrombus prediction in patients with atrial fibrillation.

INTRODUCTION AND OBJECTIVES: The CHA2DS2-VASc score, used to assess the risk of left atrial appendage thrombus (LAAT) formation in patients with atrial fibrillation (AF), has limited predictive value. Moreover, transesophageal echocardiography imaging, the gold standard diagnostic method to identify thrombi, is semi-invasive. Consequently, there is a need for alternative and noninvasive diagnostic methods for LAAT risk assessment. METHODS: Deep proteomic analysis was conducted in plasma samples from 8 patients with nonvalvular AF, divided into thrombus and control groups (4 patients in each group) based on the presence or absence of LAAT. Biomarkers associated with LAAT were validated using an enzyme-linked immunosorbent assay in a cohort of 179 patients with available clinical, transthoracic, and transesophageal echocardiography data. Predictive models were developed to assess the improvement in LAAT identification. RESULTS: The LAAT group had higher CHA2DS2-VASc scores, larger LA diameter, and lower LAA flow velocities. Deep proteomic analysis identified 30 differentially expressed proteins, including myosin light chain 4, prenylcysteine oxidase 1 (PCYOX1), and decorin as potential diagnostic biomarkers of LAAT. The model showed that PCYOX1 and decorin provided an area under the curve (AUC) of 0.970 for LAAT prediction compared with 0.672 in a model including the CHA2DS2-VASc score and LAA cauliflower morphology. The incremental value of proteomic biomarkers for LAAT in patients with nonvalvular AF was further confirmed with the net reclassification improvement and integrated discrimination improvement indices. CONCLUSIONS: Protein levels of PCYOX1 and decorin improve the predictive performance for LAAT in patients with nonvalvular AF.

Artificial intelligence for diagnosis and prognosis prediction of natural killer/T cell lymphoma using magnetic resonance imaging.

Accurate diagnosis and prognosis prediction are conducive to early intervention and improvement of medical care for natural killer/T cell lymphoma (NKTCL). Artificial intelligence (AI)-based systems are developed based on nasopharynx magnetic resonance imaging. The diagnostic systems achieve areas under the curve of 0.905-0.960 in detecting malignant nasopharyngeal lesions and distinguishing NKTCL from nasopharyngeal carcinoma in independent validation datasets. In comparison to human radiologists, the diagnostic systems show higher accuracies than resident radiologists and comparable ones to senior radiologists. The prognostic system shows promising performance in predicting survival outcomes of NKTCL and outperforms several clinical models. For patients with early-stage NKTCL, only the high-risk group benefits from early radiotherapy (hazard ratio = 0.414 vs. late radiotherapy; 95% confidence interval, 0.190-0.900, p = 0.022), while progression-free survival does not differ in the low-risk group. In conclusion, AI-based systems show potential in assisting accurate diagnosis and prognosis prediction and may contribute to therapeutic optimization for NKTCL.

Noncanonical mutations in ribosome nascent peptide exit tunnel confer clarithromycin resistance in Mycobacterium abscessus complex.

OBJECTIVES: Mycobacterium abscessus is a non-tuberculous mycobacterial pathogen that causes pulmonary and skin infections globally. Clarithromycin plays a pivotal role in treating M. abscessus infections, with resistance often leading to treatment failure. While canonical mutations in the 23S rRNA residue 2270/2271 are recognized as the primary mechanism for acquired clarithromycin resistance, resistant isolates lacking these mutations have been widely reported. This study aims to identify new mechanisms of clarithromycin resistance in M. abscessus. METHODS: We selected spontaneous resistant mutants derived from two parental strains characterized by erm(41) T28 and C28 sequevars, respectively. Whole-genome sequencing was performed on mutants lacking the 23S rRNA 2270/2271 mutations. Site-directed mutagenesis was used to confirm the resistance phenotypes of newly identified mutations. Bioinformatic analysis of publicly available genomes was conducted to evaluate the presence of these mutations in clinical isolates. The spatial localization of these mutations in the ribosome was analyzed to investigate potential mechanisms of resistance. RESULTS: A total of 135 resistant mutants were selected from the parental strains. Sequencing of the 78 mutants lacking the 23S rRNA 2270/2271 mutations identified mutations within the peptidyl-transferase center and hairpin loops 35, 49, and 74 of the 23S rRNA. These noncanonical mutations were identified in 57 of 1875 genomes of clinical isolates. Thirteen representative mutations were introduced into the bacterial genome, and their contributions to macrolide resistance were confirmed. The newly identified mutations all localized at the entrance of the nascent peptide exit tunnel, potentially contributing to resistance by disrupting the macrolide binding pocket. CONCLUSION: Several noncanonical 23S rRNA mutations conferring clarithromycin resistance were identified. These mutations enhance our understanding of macrolide resistance in M. abscessus and could serve as important markers for diagnosing clarithromycin resistance.

IDO1 promotes CSFV replication by mediating tryptophan metabolism to inhibit NF-κB signaling.

Tryptophan metabolism plays a crucial role in facilitating various cellular processes essential for maintaining normal cellular function. Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan (Trp) into kynurenine (Kyn), thereby initiating the degradation of Trp. The resulting Kyn metabolites have been implicated in the modulation of immune responses. Currently, the role of IDO1-mediated tryptophan metabolism in the process of viral infection remains relatively unknown. In this study, we discovered that classical swine fever virus (CSFV) infection of PK-15 cells can induce the expression of IDO1, thereby promoting tryptophan metabolism. IDO1 can negatively regulate the NF-κB signaling by mediating tryptophan metabolism, thereby facilitating CSFV replication. We found that silencing the IDO1 gene enhances the expression of IFN-α, IFN-ß, and IL-6 by activating the NF-κB signaling pathway. Furthermore, our observations indicate that both silencing the IDO1 gene and administering exogenous tryptophan can inhibit CSFV replication by counteracting the cellular autophagy induced by Rapamycin. This study reveals a novel mechanism of IDO1-mediated tryptophan metabolism in CSFV infection, providing new insights and a theoretical basis for the treatment and control of CSFV.IMPORTANCEIt is well known that due to the widespread use of vaccines, the prevalence of classical swine fever (CSF) is shifting towards atypical and invisible infections. CSF can disrupt host metabolism, leading to persistent immune suppression in the host and causing significant harm when co-infected with other diseases. Changes in the host's metabolic profiles, such as increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, can also influence virus replication. Mammals utilize various pathways to modulate immune responses through amino acid utilization, including increased catabolic metabolism of amino acids and the production of immunoregulatory metabolites and their derivatives, thereby limiting viral replication. Therefore, this study proposes that targeting the modulation of tryptophan metabolism may represent an effective approach to control the progression of CSF.

Fish arginase constrains excessive production of nitric oxide and limits mitochondrial damage during Aeromonas hydrophila infection.

Bacteria-enhanced inducible nitric oxide synthase (iNOS) overproduces nitric oxide (NO) leading to mitochondrial and cellular damage. In mammals, arginase (ARG), the enzyme consuming the same substrate l-arginine with iNOS, was believed to inhibit iNOS activity by competing the substrate. But in fish, this conception has been widely challenged. In this study, the gene expression using real-time quantitative PCR (RT-qPCR) technology showed that when stimulated by Aeromonas hydrophila (A. hydrophila), grass carp (gc) iNOS was up-regulated in head kidney monocytes/macrophages (M0/MФ), and its changes were not detected in the whole tissue of liver or spleen, showing a high degree of cell-specific expression pattern. At the same time, gcARG2 had a high basal expression in tissues and was up-regulated by A. hydrophila stimulation. Next, phthalaldehyde-primaquine reaction was first used in the determination of intracellular urea in fish cells. It was found that the induced gcARG2 led to an increase in the intracellular urea content. Moreover, urea and NO production in M0/MФ were increased in a substrate dose-dependent manner from 30 to 100 µM of l-arginine and reached the highest yield at 300 and 3000 µM of l-arginine, respectively. Furthermore, head kidney M0/MФ was cultured in RPMI1640 medium containing physiological concentration (500 µM) of l-arginine to evaluate the effect of ARG. Under A. hydrophila stimulation, treatment with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) showed that inhibition of arginase could further enhance the NO production stimulated by A. hydrophila. This in turn led to a cumulation in peroxynitrite (ONOO-) content and an injury of the mitochondrial membrane potential. Our study showed for the first time that fish ARG in head kidney M0/MФ can limit excessive production of NO and harmful products by iNOS to maintain mitochondrial and cellular homeostasis.

KDGene: knowledge graph completion for disease gene prediction using interactional tensor decomposition.

The accurate identification of disease-associated genes is crucial for understanding the molecular mechanisms underlying various diseases. Most current methods focus on constructing biological networks and utilizing machine learning, particularly deep learning, to identify disease genes. However, these methods overlook complex relations among entities in biological knowledge graphs. Such information has been successfully applied in other areas of life science research, demonstrating their effectiveness. Knowledge graph embedding methods can learn the semantic information of different relations within the knowledge graphs. Nonetheless, the performance of existing representation learning techniques, when applied to domain-specific biological data, remains suboptimal. To solve these problems, we construct a biological knowledge graph centered on diseases and genes, and develop an end-to-end knowledge graph completion framework for disease gene prediction using interactional tensor decomposition named KDGene. KDGene incorporates an interaction module that bridges entity and relation embeddings within tensor decomposition, aiming to improve the representation of semantically similar concepts in specific domains and enhance the ability to accurately predict disease genes. Experimental results show that KDGene significantly outperforms state-of-the-art algorithms, whether existing disease gene prediction methods or knowledge graph embedding methods for general domains. Moreover, the comprehensive biological analysis of the predicted results further validates KDGene's capability to accurately identify new candidate genes. This work proposes a scalable knowledge graph completion framework to identify disease candidate genes, from which the results are promising to provide valuable references for further wet experiments. Data and source codes are available at https://github.com/2020MEAI/KDGene.

Intensive Versus Standard Blood Pressure Management after Endovascular Therapy for Acute Ischemic Stroke: A Systematic Review and Meta-analysis.

Prospective clinical studies on blood pressure (BP) management targets after endovascular therapy (EVT) for acute ischemic stroke (AIS) have recently been published. Our objective was to assess the impact on clinical outcomes of BP management guided by established systolic BP (SBP) targets within the first 24 hours after successful EVT. Four randomized controlled trials (RCTs) including 1556 participants across 5 SBP target settings identified from 5 databases up to September 6, 2023 were included in this systematic review and meta-analysis. All the intensive SBP target groups in these RCTs were combined to facilitate head-to-head comparisons. Patients receiving intensive SBP management had lower risk of 90-day functional independence as assessed by the modified Rankin scale score (relative risk [RR], 0.81; 95% confidence interval [CI], 0.72 to 0.91; I2, 12%), excellent outcomes (RR,0.86; 95% CI, 0.75 to 0.99; I2, 7%), favorable outcomes (RR, 0.85; 95% CI, 0.78 to 0.92; I2, 0%), and quality of life (standardized mean difference, -0.22; 95% CI, -0.35 to -0.10; I2,0%). There were no differences in the probability of any intracerebral hemorrhage (RR, 1.04; 95% CI, 0.92 to 1.19; I2,0%), symptomatic intracerebral hemorrhage (RR, 1.10; 95% CI, 0.76 to 1.60; I2, 0%), stroke-related death (RR, 1.16; 95% CI, 0.80 to 1.68; I2, 0%), or parenchymal hematoma (RR, 1.71; 95% CI, 0.74 to 3.98; I2, 47%) between SBP targets. This meta-analysis provides evidence from RCTs suggesting that intensive SBP control (target<160 mm Hg) may be detrimental to clinical outcomes in AIS patients with successful reperfusion after EVT.

Z-scheme heterojunction composed of Fe-doped g-C3N4 and Bi2MoO6 for photo-fenton degradation of antibiotics over a wide pH range: Activity and toxicity assessment.

In photo-Fenton technology, the narrower pH range limits its practical application for antibiotic wastewater remediation. Therefore, in this study, a Z-scheme heterojunction photo-Fenton catalyst was constructed by Fe-doped graphite-phase carbon nitride in combination with bismuth molybdate for the degradation of typical antibiotics. Fe doping can shorten the band gap and increase visible-light absorption. Simultaneously, the constructed Z-scheme heterojunction provides a better charge transfer pathway for the photo-Fenton reaction. Within 30 min, Fe3CN/BMO-3 removed 95.54% of tetracycline hydrochloride (TC), and its remarkable performance was the higher Fe3+/Fe2+ conversion efficiency through the decomposition of H2O2. The Fe3CN/BMO-3 catalyst showed remarkable photo-Fenton degradation performance in a wide pH range (3.0-11.0), and it also had good stability in the treatment of TC wastewater. Furthermore, the order of action of the active species was h+ > ·O2- > 1O2 > ·OH, and the toxicity assessment suggested that Fe3CN/BMO-3 was effective in reducing the biotoxicity of TC. The catalyst proved to be an economically feasible and applicable material for antibiotic photo-Fenton degradation, and this study provides another perspective on the application of elemental doping and constructed heterojunction photo-Fenton technology for antibiotic water environmental remediation.