ABSTRACT
Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R-famoxadone was 1.5 times more toxic to HepG2 cells than S-famoxadone. R-famoxadone induced more pronounced ferroptosis compared to S-famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R-famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R-famoxadone in mice was six times higher than that of S-famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19, and CYP2E1 for R-famoxadone caused its preferential accumulation. Overall, R-famoxadone poses a higher risk than S-famoxadone due to its greater cytotoxicity and persistence. This study provides the first evidence of ferroptosis-induced stereoselective toxicity, offering insights for the comprehensive health risk assessment of chiral famoxadone and valuable references for the application of high-efficiency, low-risk pesticide enantiomers.
Subject(s)
Ferroptosis , Fungicides, Industrial , Strobilurins , Fungicides, Industrial/toxicity , Fungicides, Industrial/chemistry , Animals , Humans , Ferroptosis/drug effects , Hep G2 Cells , Stereoisomerism , Risk Assessment , Strobilurins/toxicity , Strobilurins/chemistry , Molecular Docking Simulation , Mice , Male , Cytochrome P-450 Enzyme System/metabolism , Reactive Oxygen Species/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Lipid Peroxidation/drug effects , Cell Survival/drug effectsABSTRACT
Background: Neuroblastoma (NB), characterized by its marked heterogeneity, is the most common extracranial solid tumor in children. The status and functionality of mitochondria are crucial in regulating NB cell behavior. While the significance of mitochondria-related genes (MRGs) in NB is still missing in key knowledge. Materials and methods: This study leverages consensus clustering and machine learning algorithms to construct and validate an MRGs-related signature in NB. Single-cell data analysis and experimental validation were employed to characterize the pivotal role of FEN1 within NB cells. Results: MRGs facilitated the classification of NB patients into 2 distinct clusters with considerable differences. The constructed MRGs-related signature and its quantitative indicators, mtScore and mtRisk, effectively characterize the MRGs-related patient clusters. Notably, the MRGs-related signature outperformed MYCN in predicting NB patient prognosis and was adept at representing the tumor microenvironment (TME), tumor cell stemness, and sensitivity to the chemotherapeutic agents Cisplatin, Topotecan, and Irinotecan. FEN1, identified as the most contributory gene within the MRGs-related signature, was found to play a crucial role in the communication between NB cells and the TME, and in the developmental trajectory of NB cells. Experimental validations confirmed FEN1's significant influence on NB cell proliferation, apoptosis, cell cycle, and invasiveness. Conclusion: The MRGs-related signature developed in this study offers a novel predictive tool for assessing NB patient prognosis, immune infiltration, stemness, and chemotherapeutic sensitivity. Our findings unveil the critical function of FEN1 in NB, suggesting its potential as a therapeutic target.
Subject(s)
Gene Expression Profiling , Neuroblastoma , Single-Cell Analysis , Transcriptome , Humans , Neuroblastoma/genetics , Neuroblastoma/pathology , Mitochondria/genetics , Gene Expression Regulation, Neoplastic , Tumor Microenvironment/genetics , Cell Line, Tumor , Biomarkers, Tumor/genetics , PrognosisABSTRACT
As the rate-limiting enzyme in fatty acid biosynthesis, Staphylococcus aureus enoyl-acyl carrier protein reductase (SaFabI) emerges as a compelling target for combating methicillin-resistant S. aureus (MRSA) infections. Herein, compound 1, featuring a 4-(1H-benzo[d]imidazol-2-yl)pyrrolidin-2-one scaffold, was identified as a potent SaFabI inhibitor (IC50 = 976.8 nM) from an in-house library. Subsequent optimization yielded compound n31, with improved inhibitory efficacy on enzymatic activity (IC50 = 174.2 nM) and selective potency against S. aureus (MIC = 1-2 µg/mL). Mechanistically, n31 directly inhibited SaFabI in cellular contexts. Moreover, n31 exhibited favorable safety and pharmacokinetic profiles, and dose-dependently treated MRSA-induced skin infections, outperforming the approved drug, linezolid. The chiral separation of n31 resulted in (S)-n31, with superior activities (IC50 = 94.0 nM, MIC = 0.25-1 µg/mL) and in vivo therapeutic efficacy. In brief, our research proposes (S)-n31 as a promising candidate for SaFabI-targeted therapy, offering specific anti-S. aureus efficacy and potential for further development.
Subject(s)
Anti-Bacterial Agents , Drug Discovery , Methicillin-Resistant Staphylococcus aureus , Microbial Sensitivity Tests , Staphylococcal Infections , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/therapeutic use , Anti-Bacterial Agents/chemical synthesis , Animals , Humans , Structure-Activity Relationship , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/antagonists & inhibitors , Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)/metabolism , Mice , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Enzyme Inhibitors/chemical synthesisABSTRACT
BACKGROUND: Robotic Roux-en-Y gastric bypass (RRYGB) and conventional laparoscopic Roux-en-Y gastric bypass (LRYGB) are commonly performed as primary bariatric procedures. The aim of this article was to assess the role of RRYGB in patients undergoing primary bariatric procedures. METHODS: All of the qualified studies were selected from the PubMed, Embase, and Web of Science databases, etc. We mainly compared the outcomes and safety between RRYGB and LRYGB. The outcomes evaluation included surgical effect and surgical safety. RESULT: In total, 35 studies containing 426,463 patients were selected. The mortalities of patients adopting these 2 bariatric procedures were similar (RRYGB: 59/28,023, 0.21%; LRYGB: 612/397,945, 0.15%). We found no significant difference between RRYGB and LRYGB in the incidence of postoperative complications (30-day: OR=1.06, P =0.18; 1-y: OR=1.06, P =0.92). The incidence of 30-day readmission after the operation was higher in RRYGB patients (OR=1.24, P =0.003). However, we found that the RRYGB group had a lower incidence of anastomotic stricture 1 year after the operation when compared with LRYGB (OR=0.35, P =0.0004). The 1-year %EBMIL of these 2 groups was similar (78.53% vs. 76.02%). There was no significant difference in length of hospital stay (LOS) (WMD=-0.03d, P =0.59), conversion rate (OR=0.84, P =0.75), or anastomotic leak (OR=1.00, P =0.99) between these 2 groups. The mean hospital charges were higher in the RRYGB group ($11234.75 vs. $9468.58). CONCLUSION: This systematic review and meta-analysis showed no significant advantage of RRYGB in surgical effect or reduction of intraoperative complications. RRYGB may reduce the incidence of some postoperative long-term complications. The mean hospital charges of RRYGB were higher.
Subject(s)
Gastric Bypass , Laparoscopy , Obesity, Morbid , Postoperative Complications , Robotic Surgical Procedures , Humans , Gastric Bypass/methods , Robotic Surgical Procedures/methods , Robotic Surgical Procedures/adverse effects , Obesity, Morbid/surgery , Laparoscopy/methods , Laparoscopy/adverse effects , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Treatment Outcome , Length of Stay/statistics & numerical data , Patient Readmission/statistics & numerical data , Operative Time , FemaleABSTRACT
Creatures in nature make extensive use of structural color adaptive camouflage to survive. Cholesteric liquid crystals, with nanostructures similar to those of natural organisms, can be combined with actuators to produce bright structural colors in response to a wide range of stimuli. Structural colors modulated by nano-helical structures can continuously and selectively reflect specific wavelengths of light, breaking the limit of colors recognizable by the human eye. In this review, the current state of research on cholesteric liquid crystal photonic actuators and their technological applications is presented. First, the basic concepts of cholesteric liquid crystals and their nanostructural modulation are outlined. Then, the cholesteric liquid crystal photonic actuators responding to different stimuli (mechanical, thermal, electrical, light, humidity, magnetic, pneumatic) are presented. This review describes the practical applications of cholesteric liquid crystal photonic actuators and summarizes the prospects for the development of these advanced structures as well as the challenges and their promising applications.
ABSTRACT
Lysozyme is a ß-1,4-glycosidase that hydrolyzes the polysaccharide backbone of bacterial cell walls. With an additional bactericidal function mediated by a separate protein domain, lysozyme is considered a uniquely important antimicrobial molecule contributing to the host's innate immune response to infection. Elevated lysozyme production is found in various inflammatory conditions while patients with genetic risks for inflammatory bowel diseases demonstrate abnormal lysozyme expression, granule packaging, and secretion in Paneth cells. However, it remains unclear how a gain- or loss-of-function in host lysozyme may impact the host inflammatory responses to pathogenic infection. We challenged Lyz1-/- and ectopic Lyz1-expressing (Villin-Lyz1TG) mice with S. Typhimurium and then comprehensively assessed the inflammatory disease progression. We conducted proteomics analysis to identify molecules derived from human lysozyme-mediated processing of live Salmonella. We examined the barrier-impairing effects of these identified molecules in human intestinal epithelial cell monolayer and enteroids. Lyz1-/- mice are protected from infection in terms of morbidity, mortality, and barrier integrity, whereas Villin-Lyz1TG mice demonstrate exacerbated infection and inflammation. The growth and invasion of Salmonella in vitro are not affected by human or chicken lysozyme, whereas lysozyme encountering of live Salmonella stimulates the release of barrier-disrupting factors, InvE-sipC and Lpp1, which directly or indirectly impair the tight junctions. The direct engagement of host intestinal lysozyme with an enteric pathogen such as Salmonella promotes the release of virulence factors that are barrier-impairing and pro-inflammatory. Controlling lysozyme function may help alleviate the inflammatory progression.
Subject(s)
Muramidase , Salmonella typhimurium , Muramidase/metabolism , Animals , Salmonella typhimurium/metabolism , Salmonella typhimurium/pathogenicity , Mice , Humans , Salmonella Infections/microbiology , Salmonella Infections/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Mice, Knockout , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Microfilament ProteinsABSTRACT
Objective: Choroidal neovascularization (CNV) represents the predominant form of advanced wet Age-related Macular Degeneration (wAMD). Macrophages play a pivotal role in the pathological progression of CNV. Meteorin-like (Metrnl), a novel cytokine known for its anti-inflammatory properties in macrophages, is the focus of our investigation into its mechanism of action and its potential to impede CNV progression. Methods: Cell viability was evaluated through CCK-8 and EdU assays following Metrnl treatment. Expression levels of inflammatory cytokines and proteins were assessed using quantitative reverse-transcription polymerase chain reaction(qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and western blot techniques. Protein-protein interactions were identified through protein mass spectrometry and co-immunoprecipitation (Co-IP). Additionally, in vivo and in vitro neovascularization models were employed to evaluate angiogenesis. Results: Our results revealed downregulated Metrnl levels in the choroid-sclera complex of CNV mice, the aqueous humor of wAMD patients, and activated macrophages. Metrnl overexpression demonstrated a reduction in pro-inflammatory cytokine production, influenced endothelial cell function, and suppressed angiogenesis in choroid explants and CNV models. Through protein mass spectrometry and Co-IP, we confirmed Metrnl binds to UCHL-1 to modulate the NF-κB signaling pathway. This interaction inhibited the transcription and expression of pro-inflammatory cytokines, ultimately suppressing angiogenesis. Conclusion: In summary, our findings indicate that Metrnl down-regulates macrophage pro-inflammatory cytokine secretion via the UCHL-1/NF-κB signaling pathway. This mechanism alleviates the inflammatory microenvironment and effectively inhibits choroidal neovascularization.
Subject(s)
Choroidal Neovascularization , NF-kappa B , Signal Transduction , Choroidal Neovascularization/metabolism , Choroidal Neovascularization/pathology , Choroidal Neovascularization/genetics , Animals , Mice , Humans , NF-kappa B/metabolism , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Disease Models, Animal , Mice, Inbred C57BL , Macrophages/metabolism , Macrophages/immunology , Choroid/metabolism , Choroid/pathology , Choroid/blood supply , Male , Wet Macular Degeneration/metabolism , Wet Macular Degeneration/genetics , Wet Macular Degeneration/pathology , Inflammation/metabolism , Cytokines/metabolismABSTRACT
BACKGROUND: The increase in antimicrobial resistance leads to complications in treatments, prolonged hospitalization, and increased mortality. Glabridin (GLA) is a hydroxyisoflavan from Glycyrrhiza glabra L. that exhibits multiple pharmacological activities. Colistin (COL), a last-resort antibiotic, is increasingly being used in clinic against Gram-negative bacteria. Previous reports have shown that GLA is able to sensitize first line antibiotics such as norfloxacin and vancomycin on Staphylococcus aureus, implying that the use of GLA as an antibiotic adjuvant is a promising strategy for addressing the issue of drug resistance. However, the adjuvant effect on other antibiotics, especially COL, on Gram-negative bacteria such as Escherichia coli has not been studied. PURPOSE: The objective of our study was to investigate the targets of GLA and the synergistic effect of GLA and COL in E. coli, and to provide further evidence for the use of GLA as an antibiotic adjuvant to alleviate the problem of drug resistance. METHODS: We first investigated the interaction between GLA and enoyl-acyl carrier protein reductase, also called "FabI", through enzyme inhibition assay, differential scanning fluorimetry, isothermal titration calorimetry and molecular docking assay. We tested the transmembrane capacity of GLA on its own and combined it with several antibiotics. The antimicrobial activities of GLA and COL were evaluated against six different susceptible and resistant E. coli in vitro. Their interactions were analyzed using checkerboard assay, time-kill curve and CompuSyn software. A series of sensitivity tests was conducted in E. coli overexpressing the fabI gene. The development of COL resistance in the presence of GLA was tested. The antimicrobial efficacy of GLA and COL in a mouse model of urinary tract infection was assessed. The anti-biofilm effects of GLA and COL were investigated. RESULTS: In this study, enzyme kinetic analysis and thermal analysis provided evidence for the interaction between GLA and FabI in E. coli. GLA enhanced the antimicrobial effect of COL and synergistically suppressed six different susceptible and resistant E. coli with COL. Overexpression experiments showed that targeted inhibition of FabI was a key mechanism by which GLA synergistically enhanced COL activity. The combination of GLA and COL slowed the development of COL resistance in E. coli. Combined GLA and COL treatment significantly reduced bacterial load and mitigated urinary tract injury in a mouse model of E. coli urinary tract infection. Additionally, GLA + COL inhibited the formation and eradication of biofilms and the synthesis of curli. CONCLUSION: Our findings indicate that GLA synergistically enhances antimicrobial activities of COL by targeting inhibition of FabI in E. coli. GLA is expected to continue to be developed as an antibiotic adjuvant to address drug resistance issues.
Subject(s)
Anti-Bacterial Agents , Colistin , Drug Resistance, Multiple, Bacterial , Drug Synergism , Escherichia coli , Isoflavones , Microbial Sensitivity Tests , Molecular Docking Simulation , Phenols , Isoflavones/pharmacology , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Colistin/pharmacology , Drug Resistance, Multiple, Bacterial/drug effects , Animals , Phenols/pharmacology , Mice , Escherichia coli Infections/drug therapy , Glycyrrhiza/chemistryABSTRACT
Neuroblastoma (NB) is the most prevalent extracranial solid tumor in pediatric patients, and its treatment failure often associated with metastasis. In this study, LASSO, SVM-RFE, and random forest tree algorithms, was used to identify the pivotal gene involved in NB metastasis. NB cell lines (SK-N-AS and SK-N-BE2), in conjunction with NB tissue were used for further study. ABLIM3 was identified as the hub gene and can be an independent prognostic factor for patients with NB. The immunohistochemical analysis revealed that ABLIM3 is negatively correlated with the metastasis of NB. Patients with low expression of ABLIM3 had a poor prognosis. High ABLIM3 expression correlated with APC co-stimulation and Type1 IFN response, and TIDE analysis indicated that patients with low ABLIM3 expression exhibited enhanced responses to immunotherapy. Downregulation of ABLIM3 by shRNA transfection increased the migration and invasion ability of NB cells. Gene Set Enrichment Analysis (GSEA) revealed that genes associated with ABLIM3 were primarily enriched in the cell adhesion molecules (CAMs) pathway. RT-qPCR and western blot analyses demonstrated that downregulation of ABLIM3 led to decreased expression of ITGA3, ITGA8, and KRT19, the key components of CAMs. This study indicated that ABLIM3 can be an independent prognostic factor for NB patients, and CAMs may mediate the effect of ABLIM3 on the metastasis of NB, suggesting that ABLIM3 is a potential therapeutic target for NB metastasis, which provides a novel strategy for future research and treatment strategies for NB patients.
ABSTRACT
The high lethality of Staphylococcus aureus infections and the emergence of antibiotic resistance make the development of new antibiotics urgent. Our previous work identified a hit compound h1 (AF-353) as a novel Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitor. Herein, we analyzed the antimicrobial profile of h1 and performed a comprehensive structure-activity relationship (SAR) assay based on h1. The representative compound j9 exhibited potent antibacterial activity against S. aureus without cross-resistance to other antimicrobial classes. Multiple genetic and biochemical approaches showed that j9 directly binds to SaDHFR, resulting in strong inhibition of its enzymatic activity (IC50 = 0.97 nM). Additionally, j9 had an acceptable in vivo safety profile and oral bioavailability (F = 40.7%) and also showed favorable efficacy in a mouse model of methicillin-resistant S. aureus (MRSA) skin infection. Collectively, these findings identified j9 as a novel SaDHFR inhibitor with the potential to combat drug-resistant S. aureus infections.
Subject(s)
Folic Acid Antagonists , Methicillin-Resistant Staphylococcus aureus , Phenyl Ethers , Pyrimidines , Staphylococcal Infections , Animals , Mice , Staphylococcus aureus , Folic Acid Antagonists/pharmacology , Anti-Bacterial Agents/chemistry , Staphylococcal Infections/drug therapy , Microbial Sensitivity TestsABSTRACT
Inflammatory bowel disease (IBD) is a chronic immune-mediated disease associated with a high recurrence rate and an elevated risk of colon cancer. In this study, we screened a bioactive compound library using a luciferase reporter assay and identified the compound TAK875 as a novel inhibitor of signal transducer and activator of transcription 3 (STAT3). Surface plasmon resonance analysis, differential scanning fluorimetry, and isothermal titration calorimetry demonstrated that TAK875 directly bound to recombinant STAT3. TAK875 suppressed the lipopolysaccharide (LPS)-induced release of nitric oxide, inducible nitric oxide synthase, and inflammatory factors in RAW264.7 cells, likely by inhibiting STAT3 phosphorylation. In addition, TAK875 inhibited the differentiation of CD4+ T cells into T-helper 17 cells, which may partially account for its anti-inflammatory effect. TAK875 also alleviated the LPS-induced accumulation of intracellular reactive oxygen species, thus displaying its antioxidant effects. Finally, we demonstrated its satisfactory anti-inflammatory effect in a dextran sulfate sodium-induced mouse model of ulcerative colitis. In conclusion, this study presented TAK875 as a novel STAT3 inhibitor and demonstrated its anti-inflammatory and antioxidant effects both in vitro and in vivo.
Subject(s)
Inflammatory Bowel Diseases , STAT3 Transcription Factor , Signal Transduction , Animals , Mice , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Inflammatory Bowel Diseases/drug therapy , Lipopolysaccharides , NF-kappa B/metabolism , STAT3 Transcription Factor/antagonists & inhibitorsABSTRACT
Objective@#To understand the occurrence and predictive factors of depressive symptoms among multi ethnic middle school students in Yunnan Province, so as to provide a referential framework for schools to carry out targeted mental health education.@*Methods@#From October to December 2022, 8 500 first grade students from 23 middle schools were selected from 11 minority areas in Yunnan Province by cluster random sampling method. Demographic information and data relating to the students lifestyles were collected by questionnaire, and the Children s Depression Inventory (CDI) was used to evaluate depressive symptoms. Chi square test was performed to compare differences in the detection rate of depressive symptoms among first grade middle school students for univariate analysis. A decision tree model of depressive symptoms in middle school students was established by using the Chi squared automatic interaction detector (CHAID).@*Results@#The detection rate of depressive symptoms among first grade students from multi ethnic middle schools in Yunnan Province was 28.26%. The decision tree model of depressive symptoms was academic stress ( χ 2=469.08) at the first level, breakfast behaviors (low/moderate academic stress: χ 2=155.49; severe academic stress: χ 2=105.24) at the second level, and the number of close friends (low/moderate academic stress and consuming breakfast 0- 2 days weekly: χ 2=23.15; low/moderate academic stress and consuming breakfast 3-4 days weekly: χ 2=14.99; severe academic stress and consuming breakfast 0-2 days weekly: χ 2=29.26; severe academic stress and consuming breakfast 3-4 days weekly: χ 2=20.15), ethnicity ( χ 2=78.22) and drinking ( χ 2=50.36) at the third level ( P <0.01).@*Conclusions@#The study identifies academic stress, breakfast behaviors, number of close friends, drinking and ethnicity as predictive factors of depressive symptoms among multi ethnic middle school students in Yunnan Province. Schools should develop targeted strategies for preventing and managing depressive symptoms in middle school students, so as to reduce their occurrence.
ABSTRACT
Arachidonic acid 15-lipoxygenases (ALOX15) play a role in mammalian erythropoiesis but they have also been implicated in inflammatory processes. Seven intact Alox genes have been detected in the mouse reference genome and the mouse Alox15 gene is structurally similar to the orthologous genes of other mammals. However, mouse and human ALOX15 orthologs have different functional characteristics. Human ALOX15 converts C20 polyenoic fatty acids like arachidonic acid mainly to the n-6 hydroperoxide. In contrast, the n-9 hydroperoxide is the major oxygenation product formed by mouse Alox15. Previous experiments indicated that Leu353Phe exchange in recombinant mouse Alox15 humanized the catalytic properties of the enzyme. To investigate whether this functional humanization might also work in vivo and to characterize the functional consequences of mouse Alox15 humanization we generated Alox15 knock-in mice (Alox15-KI), in which the Alox15 gene was modified in such a way that the animals express the arachidonic acid 15-lipoxygenating Leu353Phe mutant instead of the arachidonic acid 12-lipoxygenating wildtype enzyme. These mice develop normally, they are fully fertile but display modified plasma oxylipidomes. In young individuals, the basic hematological parameters were not different when Alox15-KI mice and outbred wildtype controls were compared. However, when growing older male Alox15-KI mice develop signs of dysfunctional erythropoiesis such as reduced hematocrit, lower erythrocyte counts and attenuated hemoglobin concentration. These differences were paralleled by an improved ex vivo osmotic resistance of the peripheral red blood cells. Interestingly, such differences were not observed in female individuals suggesting gender specific effects. In summary, these data indicated that functional humanization of mouse Alox15 induces defective erythropoiesis in aged male individuals.
Subject(s)
Arachidonate 15-Lipoxygenase , Hydrogen Peroxide , Animals , Female , Humans , Male , Mice , Arachidonate 12-Lipoxygenase/genetics , Arachidonate 15-Lipoxygenase/genetics , Arachidonic Acid , MammalsABSTRACT
Brucellosis is a zoonotic disease caused by Brucella spp., with the highest prevalence found in the northern cities of China. In this case report, we present an occurrence of spinal infection caused by B. melitensis in a 67-year-old man residing in a non-endemic area of southern China. The patient initially presented with chest and back pain, which was not accurately diagnosed and treated at a local hospital. Subsequently, due to worsening pain, he was admitted to our hospital. To determine the cause of the infection, we performed CT-guided aspiration biopsy and collected biopsy tissue for metagenomic next-generation sequencing (mNGS) on the second day of hospitalization. Imaging investigations revealed involvement of the thoracic vertebrae, specifically thoracic 4-7 with the main focus on 5-6, accompanied by stenosis of the intervertebral space. The mNGS results indicated that the spine infection was caused by B. melitensis. The patient's history as a shepherd and a positive Rose Bengal plate test (RBPT) further supported the diagnosis of brucella spondylitis. In order to alleviate pain and restore spinal function, the patient underwent posterior internal fixation of the thoracic spine. Treatment was initiated with cefoperazone/sulbactam, followed by doxycycline. Subsequently, the patient was switched to a combination therapy of rifampicin and doxycycline for a duration of six weeks. The patient responded well to treatment, and his condition remained stable. In conclusion, brucellosis is a common disease that can be easily misdiagnosed. This case report highlights the potential value of mNGS in early and rapid diagnosis. We believe that mNGS can serve as an effective tool to improve the diagnosis of spine infections caused by this pathogen.
ABSTRACT
Neuroblastoma is the most common extracranial solid tumor in children. Patients with neuroblastoma have a poor prognosis. The development of therapy targets and the ability to predict prognosis will be enhanced through further exploration of the genetically related genes of neuroblastoma. The present investigation utilized CRISPR-Cas9 genome-wide screening based on the DepMap database to determine essential genes for neuroblastoma cells' continued survival. WGCNA analysis was used to determine the progression-related genes, and a prognostic signature was constructed. The signature gene, NCAPG, was downregulated in neuroblastoma cells to explore its impact on various cellular processes. This research used DepMap and WGCNA to pinpoint 45 progression-related essential genes for neuroblastoma. A risk signature comprising NCAPG and MAD2L1 was established. The suppression of NCAPG prevented neuroblastoma cells from proliferating, migrating, and invading. The results of flow cytometric analysis demonstrated that NCAPG inhibition caused cell cycle arrest during the G2 and S phases and the activation of apoptosis. Additionally, NCAPG downregulation activated the p53-mediated apoptotic pathway, inducing cell apoptosis. The present work showed that NCAPG knockdown reduced neuroblastoma cell progression and may serve as a basis for further investigation into diagnostic indicators and therapy targets for neuroblastoma.
Subject(s)
CRISPR-Cas Systems , Neuroblastoma , Child , Humans , Cell Line, Tumor , CRISPR-Cas Systems/genetics , Genes, Essential , Cell Cycle Proteins/metabolism , Neuroblastoma/metabolismABSTRACT
Tuberculosis (TB) remains a significant public health concern in the 21st century, especially due to drug resistance, coinfection with diseases like immunodeficiency syndrome (AIDS) and coronavirus disease 2019, and the lengthy and costly treatment protocols. In this review, we summarize the pathogenesis of TB infection, therapeutic targets, and corresponding modulators, including first-line medications, current clinical trial drugs and molecules in preclinical assessment. Understanding the mechanisms of Mycobacterium tuberculosis (Mtb) infection and important biological targets can lead to innovative treatments. While most antitubercular agents target pathogen-related processes, host-directed therapy (HDT) modalities addressing immune defense, survival mechanisms, and immunopathology also hold promise. Mtb's adaptation to the human host involves manipulating host cellular mechanisms, and HDT aims to disrupt this manipulation to enhance treatment effectiveness. Our review provides valuable insights for future anti-TB drug development efforts.
ABSTRACT
Background: Gastric cancer (GC) is among the deadliest diseases with countless incidences and deaths each year. Helicobacter pylori (Hp) is the primary type of microbe that colonizes the stomach. In recent years, increasing evidence has demonstrated that Hp infection is one of the main risk factors for GC. Elucidating the molecular mechanism of how Hp leads to GC will not only benefit the treatment of GC, but also boost the development of therapeutics for other gastric disorders caused by Hp infection. In this study, we aimed to identify innate immunity-related genes in GC and investigate their potentials as prognostic markers and therapeutic targets for Hp-related GC. Methods: Firstly, we analyzed the differentially expressed innate immunity-related genes in GC samples from the TCGA database. Then prognostic correlation analysis was carried out to explore the prognostic value of these candidate genes. By combing transcriptome data, somatic mutation data, and clinical data, co-expression analysis, functional enrichment analysis, tumor mutational burden analysis, and immune infiltration analysis were performed to reveal the pathological relevance of the candidate gene. Finally, ceRNA network was constructed to identify the genes and pathways for the regulation of the candidate gene. Results: We revealed that protein tyrosine phosphatase non-receptor type 20 (PTPN20) is a significant prognostic marker in Hp-related GC. Thus, PTPN20 levels have the potential to efficiently predict the survival of Hp-related GC patients. In addition, PTPN20 is associated with immune cell infiltration and tumor mutation burden in these GC patients. Moreover, we have also identified PTPN20-related genes, PTPN20 protein-protein interactions, and the PTPN20 ceRNA network. Conclusion: Our data suggest that PTPN20 may have critical functions in Hp-related GC. Targeting PTPN20 may be a promising way to treat Hp-related GC.
Subject(s)
Helicobacter Infections , Helicobacter pylori , Stomach Neoplasms , Humans , Stomach Neoplasms/pathology , Helicobacter Infections/complications , Helicobacter Infections/genetics , Helicobacter Infections/metabolism , Biomarkers, Tumor/genetics , Immunity, Innate/geneticsABSTRACT
Recently, referring image segmentation has attracted wide attention given its huge potential in human-robot interaction. Networks to identify the referred region must have a deep understanding of both the image and language semantics. To do so, existing works tend to design various mechanisms to achieve cross-modality fusion, for example, tile and concatenation and vanilla nonlocal manipulation. However, the plain fusion usually is either coarse or constrained by the exorbitant computation overhead, finally causing not enough understanding of the referent. In this work, we propose a fine-grained semantic funneling infusion (FSFI) mechanism to solve the problem. The FSFI introduces a constant spatial constraint on the querying entities from different encoding stages and dynamically infuses the gleaned language semantic into the vision branch. Moreover, it decomposes the features from different modalities into more delicate components, allowing the fusion to happen in multiple low-dimensional spaces. The fusion is more effective than the one only happening in one high-dimensional space, given its ability to sink more representative information along the channel dimension. Another problem haunting the task is that the instilling of high-abstract semantic will blur the details of the referent. Targetedly, we propose a multiscale attention-enhanced decoder (MAED) to alleviate the problem. We design a detail enhancement operator (DeEh) and apply it in a multiscale and progressive way. Features from the higher level are used to generate attention guidance to enlighten the lower-level features to more attend to the detail regions. Extensive results on the challenging benchmarks show that our network performs favorably against the state-of-the-arts (SOTAs).
ABSTRACT
[This corrects the article DOI: 10.1002/mco2.58.].