ABSTRACT
BACKGROUND: The selection of appropriate second-line therapy for liver cancer after first-line treatment failure poses a significant clinical challenge due to the lack of direct comparative studies and standard treatment protocols. A network meta-analysis (NMA) provides a robust method to systematically evaluate the clinical outcomes and adverse effects of various second-line treatments for hepatocellular carcinoma (HCC). METHODS: We systematically searched PubMed, Embase, Web of Science and the Cochrane Library to identify phase III/IV randomized controlled trials (RCTs) published up to March 11, 2024. The outcomes extracted were median overall survival (OS), median progression-free survival (PFS), time to disease progression (TTP), disease control rate (DCR), objective response rate (ORR), and adverse reactions. This study was registered in the Prospective Register of Systematic Reviews (CRD42023427843) to ensure transparency, novelty, and reliability. RESULTS: We included 16 RCTs involving 7,005 patients and 10 second-line treatments. For advanced HCC patients, regorafenib (HR = 0.62, 95%CI: 0.53-0.73) and cabozantinib (HR = 0.74, 95%CI: 0.63-0.85) provided the best OS benefits compared to placebo. Cabozantinib (HR = 0.42, 95%CI: 0.32-0.55) and regorafenib (HR = 0.46, 95% CI: 0.31-0.68) also offered the most significant PFS benefits. For TTP, apatinib (HR = 0.43, 95% CI: 0.33-0.57), ramucirumab (HR = 0.44, 95% CI: 0.34-0.57), and regorafenib (HR = 0.44, 95% CI: 0.38-0.51) showed significant benefits over placebo. Regarding ORR, ramucirumab (OR = 9.90, 95% CI: 3.40-42.98) and S-1 (OR = 8.68, 95% CI: 1.4-154.68) showed the most significant increases over placebo. Apatinib (OR = 3.88, 95% CI: 2.48-6.10) and cabozantinib (OR = 3.53, 95% CI: 2.54-4.90) provided the best DCR benefits compared to placebo. Tivantinib showed the most significant advantages in terms of three different safety outcome measures. CONCLUSIONS: Our findings suggest that, in terms of overall efficacy and safety, regorafenib and cabozantinib are the optimal second-line treatment options for patients with advanced HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Network Meta-Analysis , Pyridines , Randomized Controlled Trials as Topic , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/mortality , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/mortality , Pyridines/therapeutic use , Pyridines/adverse effects , Anilides/therapeutic use , Anilides/adverse effects , Phenylurea Compounds/therapeutic use , Phenylurea Compounds/adverse effects , Ramucirumab , Treatment Outcome , Progression-Free Survival , Antibodies, Monoclonal, Humanized/therapeutic useABSTRACT
Metal vanadates as negative electrode materials for lithium-ion batteries have attracted widespread attention, attributed to their substantial capacity, broad availability, and exceptional safety. In this study, NiCo2V2O8@NC microspheres featuring a yolk-double shell structure were successfully synthesized via ion exchange reactions and surface deposition techniques, employing metal glycerolate as a template. Owing to the bimetallic cobalt-nickel synergistic effect and the N-doped carbon network, this configuration not only optimizes the pore structure but also enhances conductivity, thereby augmenting the stability of the overall structure. The unique yolk-double shell design significantly enhances the utilization of active components and reduces the ion transport distance, thereby achieving high capacity. Thanks to the synergistic effects of this bimetallic and intricate structure, the material demonstrates exceptional capacity and cycle stability in lithium storage. The initial discharge capacity possesses 1522 mAh g-1 at a current density of 0.2 A g-1, with the reversible capacity still maintained at 1197 mAh g-1 after 100 cycles. In addition, at a high current density of 0.5 A g-1, the initial discharge capacity is 1487 mAh g-1, with a reversible capacity of 747 mAh g-1 maintained after 500 cycles. This study offers a perspective and methodology for the design and fabrication of complex porous double shell nanostructures.
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PURPOSE: The detection rate of Salmonella enterica serovar 1,4,[5], 12: i: - (S. 1,4,[5], 12: i: -) has increased as the most common serotype globally. A S. 1,4,[5], 12: i: - strain named ST3606 (sequence type 34), isolated from a fecal specimen of a child with acute diarrhea hospitalized in a tertiary hospital in China, was firstly reported to be resistant to carbapenem and ceftazidime-avibactam. The aim of this study was to characterize the whole-genome sequence of S. 1,4,[5], 12: i: - isolate, ST3606, and explore its antibiotic resistance genes and their genetic environments. METHODS: The genomic DNA of S. 1,4,[5], 12: i: - ST3606 was extracted and performed with single-molecule real-time sequencing. Resistance genes, plasmid replicon type, mobile elements, and multilocus sequence types (STs) of ST3606 were identified by ResFinder 3.2, PlasmidFinder, OriTfinder database, ISfinder database, and MLST 2.0, respectively. The conjugation experiment was utilized to evaluate the conjugation frequency of pST3606-2. Protein expression and enzyme kinetics experiments of CTX-M were performed to analyze hydrolytic activity of a novel CTX-M-261 enzyme toward several antibiotics. RESULTS: Single-molecule real-time sequencing revealed the coexistence of a 109-kb IncI1-Iα plasmid pST3606-1 and a 70.5-kb IncFII plasmid pST3606-2. The isolate carried resistance genes, including blaNDM-5, sul1, qacE, aadA2, and dfrA12 in pST3606-1, blaTEM-1B, aac(3)-lld, and blaCTX-M-261, a novel blaCTX-M-1 family member, in pST3606-2, and aac(6')-Iaa in chromosome. The blaCTX-M-261 was derived from blaCTX-M-55 by a single-nucleotide mutation 751G>A leading to amino acid substitution of Val for Met at position 251 (Val251Met), which conferred CTX-M increasing resistance to ceftazidime verified by antibiotics susceptibility testing of transconjugants carrying pST3606-2 and steady-state kinetic parameters of CTX-M-261. pST3606-1 is an IncI1-α incompatibility type that shares homology with plasmids of pC-F-164_A-OXA140, pE-T654-NDM-5, p_dm760b_NDM-5, and p_dmcr749c_NDM-5. The conjugation experiment demonstrated that pST3606-2 was successfully transferred to the Escherichia coli recipient C600 with four modules of OriTfinder. CONCLUSION: Plasmid-mediated horizontal transfer plays an important role in blaNDM-5 and blaCTX-M-261 dissemination, which increases the threat to public health due to the resistance to most ß-lactam antibiotics. This is the first report of blaCTX-M-261 and blaNDM-5 in S. 1,4,[5], 12: i: -. The work provides insights into the enzymatic function and demonstrates the ongoing evolution of CTX-M enzymes and confirms urgency to control resistance of S. 1,4,[5], 12: i: -.
Subject(s)
Anti-Bacterial Agents , Azabicyclo Compounds , Ceftazidime , Drug Combinations , Microbial Sensitivity Tests , Salmonella Infections , Salmonella enterica , beta-Lactamases , Ceftazidime/pharmacology , Humans , China , beta-Lactamases/genetics , beta-Lactamases/metabolism , Azabicyclo Compounds/pharmacology , Anti-Bacterial Agents/pharmacology , Salmonella enterica/genetics , Salmonella enterica/drug effects , Salmonella enterica/enzymology , Salmonella Infections/microbiology , Whole Genome Sequencing , Drug Resistance, Multiple, Bacterial/genetics , Serogroup , Plasmids/genetics , Feces/microbiology , Genome, BacterialABSTRACT
Panax notoginseng has the effect of stimulating circulation to end stasis. Our study was designed to evaluate the anti-thrombotic effect of protoparaxotriol saponins (PTS) from Panax notoginseng and the involved mechanisms. A thrombosis model was constructed, and the anti-thrombotic activity of PTS was determined by erythrocyte staining, heart rate, and blood flow velocity. In addition, quantitative real-time polymerase chain reaction (qPCR) was used to identify changes in the expression of genes related to coagulation, inflammation, and apoptosis. PTS alleviated arachidonic acid (AA)-induced caudal vein thrombosis, restored blood flow, and increased the area of cardiac erythrocyte staining, heart rate and blood flow velocity. It reduced the ponatinib-induced cerebral thrombus area and decreased the intensity of erythrocyte staining. The qPCR data showed that the anti-thrombotic effect of PTS was mediated by suppression of genes related to coagulation, inflammation and apoptosis, and also involved inhibition of NF-κB and PI3K/Akt pathways.
ABSTRACT
INTRODUCTION: Ulcerative colitis (UC) is an incurable and highly complex chronic inflammatory bowel disease (IBD) affecting millions of people worldwide. C-phycocyanin (C-PC) has been reported to possess outstanding anti-inflammatory activities and can effectively inhibit various inflammation-related diseases. Whether C-PC-derived bioactive peptides can inhibit intestinal inflammation is worth research and consideration. METHODS: The inhibition activities of three anti-neuroinflammatory peptides were evaluated using 2-4-6-trinitrobenzen sulfonic acid (TNBS)-induced zebrafish colitis model. Subsequently, the abilities of peptides to promote gastrointestinal motility were also examined. The changes in the intestinal pathological symptoms and ultrastructure of intestinal, reactive oxygen species (ROS) levels, and antioxidant enzymes were then determined after co-treatment with peptides and TNBS. Transcriptome analysis was used to investigate the underlying ameliorating TNBS-induced colitis effects molecular mechanisms of better activity peptide. Furthermore, quantitative reverse-transcription polymerase chain reaction and molecular docking techniques verified the mRNA sequencing results. RESULTS: Three peptides, MHLWAAK, MAQAAEYYR and MDYYFEER, which significantly inhibit macrophage migration, were synthesized. The results showed that these peptides could effectively alleviate the inflammatory responses in the TNBS-induced zebrafish model of colitis. In addition, co-treatment with TNBS and C-PC peptides could decrease ROS production and increase antioxidant enzyme activities in zebrafish larvae. Moreover, MHLWAAK had the most significantly therapeutic effects on colitis in zebrafish. The transcriptome analysis suggests that the effect of MHLWAAK on TNBS-induced colitis may be associated with the modulation of nuclear factor-erythroid 2-related factor 2 (Nrf2) and mitogen-activated protein kinase (MAPK) signaling pathway associated genes. In addition, molecular docking was conducted to study the prospective interaction between peptides and the key proteins that streamline the Nrf2 and MAPK signaling pathways. IL-6, JNK3, TNF-α, KEAP1-NRF2 complex and MAPK may be the core targets of MHLWAAK in treating colitis. CONCLUSION: The results suggested that the three C-PC-derived peptides could ameliorate TNBS-induced colitis in zebrafish, and these peptides might be a promising therapeutic candidate for UC treatment.
Subject(s)
Colitis , Inflammatory Bowel Diseases , Animals , Zebrafish/metabolism , NF-E2-Related Factor 2/metabolism , Phycocyanin/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Antioxidants/metabolism , Reactive Oxygen Species/metabolism , Molecular Docking Simulation , Prospective Studies , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/metabolism , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , MAP Kinase Signaling System , Inflammation , Disease Models, AnimalABSTRACT
Marine natural products are important sources of novel drugs. In this study, we isolated 4-hydroxyphenylacetic acid (HPA) from the marine-derived fungus Emericellopsis maritima Y39-2. The antithrombotic activity and mechanism of HPA were reported for the first time. Using a zebrafish model, we found that HPA had a strong antithrombotic activity because it can significantly increase cardiac erythrocytes, blood flow velocity, and heart rate, reduce caudal thrombus, and reverse the inflammatory response caused by Arachidonic Acid (AA). Further transcriptome analysis and qRT-PCR validation demonstrated that HPA may regulate autophagy by inhibiting the PI3K/AKT/mTOR signaling pathway to exert antithrombotic effects.
Subject(s)
Autophagy , Fibrinolytic Agents , Phenylacetates , Zebrafish , Animals , Phenylacetates/pharmacology , Autophagy/drug effects , Fibrinolytic Agents/pharmacology , Signal Transduction/drug effects , Biological Products/pharmacology , Thrombosis/drug therapy , Disease Models, Animal , Aquatic OrganismsABSTRACT
BACKGROUND: The challenge of early and rapid diagnosis of periprosthetic joint infection (PJI) remains important. This study aimed to assess the efficacy of dual-energy computed tomography (CT) (DECT) iodine maps for diagnosing PJI in total hip arthroplasty. METHODS: We prospectively enrolled 68 patients who had postoperative joint pain after hip arthroplasty. All patients underwent preoperative DECT iodine imaging to quantify iodine concentration (IC) in periprosthetic tissues during arterial and venous phases. The diagnostic efficacy of DECT iodine maps was evaluated by constructing receiver operating characteristic (ROC) curves according to the Musculoskeletal Infection Society criteria. RESULTS: Compared with erythrocyte sedimentation rate (Area Under the Curve (AUC) = 0.837), polymorphonuclear cell percentage (AUC = 0.703), and C-reactive protein (AUC = 0.837), periprosthetic tissue venous-phase iodine concentration (IC) (AUC = 0.970) and arterial-phase IC (AUC = 0.964) exhibited outstanding discriminative capability between PJI and aseptic failure. The PJI cut-off point was venous IC = 1.225 mg/ml, with a sensitivity of 92.31% and specificity of 90.48%; for arterial IC = 1.065 mg/ml, the sensitivity was 96.15%, and a specificity was 90.70%. CONCLUSION: This study demonstrates the great potential of DECT iodine maps for the diagnosis of PJI around hip arthroplasty, which helps to differentiate between periprosthetic infection and aseptic failure after hip arthroplasty.
ABSTRACT
Remote sensing image classification (RSIC) is designed to assign specific semantic labels to aerial images, which is significant and fundamental in many applications. In recent years, substantial work has been conducted on RSIC with the help of deep learning models. Even though these models have greatly enhanced the performance of RSIC, the issues of diversity in the same class and similarity between different classes in remote sensing images remain huge challenges for RSIC. To solve these problems, a duplex-hierarchy representation learning (DHRL) method is proposed. The proposed DHRL method aims to explore duplex-hierarchy spaces, including a common space and a label space, to learn discriminative representations for RSIC. The proposed DHRL method consists of three main steps: First, paired images are fed to a pretrained ResNet network for extracting the corresponding features. Second, the extracted features are further explored and mapped into a common space for reducing the intra-class scatter and enlarging the inter-class separation. Third, the obtained representations are used to predict the categories of the input images, and the discrimination loss in the label space is minimized to further promote the learning of discriminative representations. Meanwhile, a confusion score is computed and added to the classification loss for guiding the discriminative representation learning via backpropagation. The comprehensive experimental results show that the proposed method is superior to the existing state-of-the-art methods on two challenging remote sensing image scene datasets, demonstrating that the proposed method is significantly effective.
ABSTRACT
Abscisic acid (ABA) is one of the many naturally occurring phytohormones widely found in plants. This study focused on refining APAn, a series of previously developed agonism/antagonism switching probes. Twelve novel APAn analogues were synthesized by introducing varied branched or oxygen-containing chains at the C-6' position, and these were screened. Through germination assays conducted on A. thaliana, colza, and rice seeds, as well as investigations into stomatal movement, several highly active ABA receptor antagonists were identified. Microscale thermophoresis (MST) assays, molecular docking, and molecular dynamics simulation showed that they had stronger receptor affinity than ABA, while PP2C phosphatase assays indicated that the C-6'-tail chain extending from the 3' channel effectively prevented the ligand-receptor binary complex from binding to PP2C phosphatase, demonstrating strong antagonistic activity. These antagonists showed effective potential in promoting seed germination and stomatal opening of plants exposed to abiotic stress, particularly cold and salt stress, offering advantages for cultivating crops under adverse conditions. Moreover, their combined application with fluridone and gibberellic acid could provide more practical agricultural solutions, presenting new insights and tools for overcoming agricultural challenges.
Subject(s)
Abscisic Acid , Germination , Molecular Docking Simulation , Abscisic Acid/chemistry , Germination/drug effects , Arabidopsis/drug effects , Arabidopsis/metabolism , Plant Growth Regulators/chemistry , Plant Growth Regulators/pharmacology , Seeds/drug effects , Seeds/chemistry , Seeds/growth & development , Oryza/drug effects , Oryza/metabolism , Oryza/growth & development , Arabidopsis Proteins/antagonists & inhibitors , Arabidopsis Proteins/metabolism , Molecular Dynamics Simulation , Agriculture/methods , Gibberellins/chemistry , Gibberellins/metabolism , PyridonesABSTRACT
Silibinin is a flavonoid compound extracted from the seeds of Silybum marianum (L.) Gaertn. It has the functions of liver protection, blood-lipid reduction and anti-tumor effects. However, the potential molecular mechanism of silibinin against tumors is still unknown. This study aimed to assess the anti-tumor effects of silibinin in adenoid cystic carcinoma (ACC2) cells and Balb/c nude mice, and explore its potential mechanism based on network pharmacology prediction and experimental verification. A total of 347 targets interacting with silibinin were collected, and 75 targets related to the tumor growth process for silibinin were filtrated. Based on the PPI analysis, CASP3, SRC, ESR1, JAK2, PRKACA, HSPA8 and CAT showed stronger interactions with other factors and may be the key targets of silibinin for treating tumors. The predicted target proteins according to network pharmacology were verified using Western blot analysis in ACC2 cells and Balb/c nude mice. In the pharmacological experiment, silibinin was revealed to significantly inhibit viability, proliferation, migration and induce the apoptosis of ACC2 cells in vitro, as well as inhibit the growth and development of tumor tissue in vivo. Western blot analysis showed that silibinin affected the expression of proteins associated with cell proliferation, migration and apoptosis, such as MMP3, JNK, PPARα and JAK. The possible molecular mechanism involved in cancer pathways, PI3K-Akt signaling pathway and viral carcinogenesis pathway via the inhibition of CASP3, MMP3, SRC, MAPK10 and CDK6 and the activation of PPARα and JAK. Overall, our results provided insight into the pharmacological mechanisms of silibinin in the treatment of tumors. These results offer a support for the anti-tumor uses of silibinin.
Subject(s)
Apoptosis , Cell Proliferation , Network Pharmacology , Silybin , Silybin/pharmacology , Animals , Mice , Cell Proliferation/drug effects , Humans , Apoptosis/drug effects , Cell Line, Tumor , Mice, Nude , Xenograft Model Antitumor Assays , Mice, Inbred BALB C , Cell Movement/drug effects , Signal Transduction/drug effects , Cell Survival/drug effects , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents/pharmacologyABSTRACT
We have proposed a tunable topological slow-light in a photonic crystal (PC) waveguide with unified magnetic field. The waveguide is constructed by bringing close two gyromagnetic photonic crystals (GPCs) with different structural parameters and introducing a row of Al2O3 rods as the coupling layer. The two GPCs are applied with a unified external static magnetic field (ESMF) instead of two opposite ESMFs. Such waveguide supports a slow-light state originated from the coupling effect of two one-way edge states on both sides of the waveguide. By simply changing the strength of ESMF, one can achieve a tunable slow-light state with large normalized delay-bandwidth product (NDBP) (0.36< NDBP <0.84). Based on these excellent properties, we further design an optical delayer with a compact structure and expansibility simultaneously. This unique topological slow-light state with simple unified magnetic condition, high maneuverability and strong immunity to defects holds promise for many fields such as signal processing, optical modulation, and the design of various slow-light devices.
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The transcription factor IRF3 is a central regulator of type I interferon (IFN) signaling. The mechanisms underlying deactivation of IRF3 are poorly understood although many studies suggest that IRF3 activity is terminated through degradation after viral infection. Here we report that IRF3 is deactivated via dephosphorylation mediated by the serine and threonine phosphatase PP2A and its adaptor protein RACK1. The PP2A-RACK1 complex negatively regulated the IRF3 pathway after LPS or poly(I:C) stimulation or Sendai virus (SeV) infection. After challenge with LPS, poly(I:C), or low-titer SeV, activated IRF3 was dephosphorylated and returned to resting state without being degraded, although high-titer SeV infection triggered the degradation of IRF3. Furthermore, PP2A-deficient macrophages showed enhanced type I IFN signaling upon LPS, poly(I:C), and SeV challenge and protected mice from lethal vesicular stomatitis virus infection. Therefore, dephosphorylation of IRF3 is a deactivation mechanism that contributes to termination of IRF3-type I IFN signaling.
Subject(s)
Interferon Regulatory Factor-3/metabolism , Interferon Type I/metabolism , Neuropeptides/metabolism , Protein Phosphatase 2/metabolism , Toll-Like Receptor 3/metabolism , Toll-Like Receptor 4/metabolism , Animals , HeLa Cells , Humans , Membrane Proteins/metabolism , Mice , Mice, Transgenic , Nerve Tissue Proteins/metabolism , Phosphorylation , Protein Binding , Protein Phosphatase 2/genetics , Receptors for Activated C Kinase , Receptors, Cell Surface , Sendai virus/immunology , Signal Transduction , Toll-Like Receptor 3/genetics , Toll-Like Receptor 4/genetics , Transgenes/genetics , Vesicular Stomatitis/immunology , Vesicular stomatitis Indiana virus/immunologyABSTRACT
A waterborne polyurethane pressure-sensitive adhesive (WPUPSA) has the advantages of low pollution and good viscoelasticity. However, its poor thermo-tolerance limits its application in the field of high temperatures. Hence, a novel silicone-modified strong thermo-tolerant waterborne polyurethane/polyimide pressure-sensitive adhesive is developed as a way to remedy this problem. The single-chain structure of waterborne polyurethane (WPU) is transformed into a network structure by introducing the three-position network structure to increase the cohesive energy and heat resistance of the WPUPSA. Meanwhile, the primary chain of waterborne polyurethane (WPU) is modified by the reaction between pyromellitic dianhydride (PMDA) and isophorone diisocyanate (IPDI) to include an imide ring and a benzene ring with more stable structures and heat resistance. Characterization results of the prepared WPUPSA show that the thermo-tolerance index of the WPUPSA increases by 15.2% and the room temperature 180° peel strength and shear resistance of the WPUPSA increase by 80.9 and 231.8%, respectively. Meanwhile, the temperature corresponding to the maximum thermal decomposition rate of the samples is improved. More importantly, at 80 and 100 °C, the 180° peel strength and shear resistance of the modified samples are stronger than those of the unmodified samples. In addition, the energy storage modulus of WPUPSAs is also greater than the loss and increases with the increase of the frequency. Viscoelasticity dominates in the samples. This will provide new insight for the development of WPUPSAs in the field of high-temperature resistance.
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A series of Cp*Ir (Cp* = pentamethylcyclopentadienyl) complexes with amidated 8-aminoquinoline ligands were synthesized and tested for formic acid (FA) dehydrogenation. These complexes showed improved activities compared to pristine 8-anminquinoline (L1). Specially, amidation changed the outer coordination sphere of the complex (3) bearing N-8-quinolinylformamide (L3), and 3 was proved to be a proton-responsive catalyst. Our experimental results and DFT calculations demonstrated that the deprotonated carbanion in L3 could interact with a water molecule to stabilize the transition states and lower the reaction energy barrier, which improved the reaction activity. A turnover frequency of 206250 h-1 was achieved by 3 under optimized conditions. This study presents a method to develop new ligands and modify the existing ligands for efficient FA dehydrogenation.
ABSTRACT
A chemical investigation of the marine sponge Phakellia sp. from the South China Sea yielded five new cyclopeptides, phakellisins A-E (1-5). Structures of these compounds were determined by comprehensive analysis of 1D/2D NMR, HRESIMS/MS spectroscopic data and the advanced Marfey's method. All compounds were evaluated for their cytotoxic activity. Compound 1 showed a strong inhibitory activity against WSU-DLCL-2 cells with an IC50 value of 5.25 ± 0.2 µM by induction of G0/G1 cell cycle arrest and apoptosis.
Subject(s)
Peptides, Cyclic , Porifera , Animals , Chromatography, Liquid , Peptides, Cyclic/pharmacology , Peptides, Cyclic/chemistry , Tandem Mass Spectrometry , Porifera/chemistry , Magnetic Resonance Spectroscopy , Molecular StructureABSTRACT
BACKGROUND: GGC repeat expansion in NOTCH2NLC has been recently linked to neuronal intranuclear inclusion disease (NIID) via unknown disease mechanisms. Herein, we explore the genetic origin of the sporadic cases and toxic RNA gain-of-function mechanism in NIID. METHODS: Multiple genetic screenings were performed on NIID individuals and their available family members. Methylation status of blood DNA, NOTCH2NLC mRNA level from muscle biopsies and RNA foci from skin biopsies of NIID individuals or asymptomatic carriers were evaluated and compared. RESULTS: In two sporadic NIID families, we identified two clinically and pathologically asymptomatic fathers carrying large GGC repeat expansion, above 300 repeats, with offspring repeat numbers of 172 and 148, respectively. Further evaluation revealed that the GGC repeat numbers in the sperm from two asymptomatic fathers were only 63 and 98, respectively. The CpG island in NOTCH2NLC of the asymptomatic carriers was hypermethylated, and accordingly, the NOTCH2NLC mRNA levels were decreased in the asymptomatic fathers. GGC repeat expansion RNA formed RNA foci and sequestered RNA binding proteins into p62 positive intranuclear inclusions in NIID individuals but not in the control or asymptomatic carrier. CONCLUSION: Our study suggested the GGC repeat expansion in NOTCH2NLC might have a disease-causing number ranging from ~41 to ~300 repeats. The contraction of GGC repeat expansion in sperm could be a possible mechanism for the paternal-biased origin in some sporadic or recessive inherited NIID individuals. The toxic RNA gain-of-function mechanism was identified to be involved in the pathogenicity of this disease.
Subject(s)
Intranuclear Inclusion Bodies , Trinucleotide Repeat Expansion , Humans , Intranuclear Inclusion Bodies/genetics , Neurodegenerative Diseases , RNA/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Trinucleotide Repeat Expansion/geneticsABSTRACT
BACKGROUND: Perivascular epithelioid cell tumor (PEComa) is a mesenchymal tumor with distinct histologic and immunologic features. PEComas that originate in the bladder are extremely rare clinically, with only 35 cases reported in the English literature thus far. Here, we report a case of bladder PEComa resection by transurethral en bloc resection of bladder tumor (ERBT). CASE PRESENTATION: A 66-year-old female with a history of poorly controlled type 2 diabetes with associated complications of frequent urinary tract infections presented to our hospital for a routine physical examination. Outpatient ultrasound examination revealed a strong echogenic mass of approximately 1.5 × 1.3 × 1.3 cm in size on the posterior wall of the bladder. The enhanced computed tomography and enhanced magnetic resonance imaging after admission both suggested a well-defined isolated nodular mass on the posterior wall of the bladder with significant enhancement on the enhanced scan. The tumor was successfully and completely resected by ERBT. Postoperative pathological examination and immunohistochemical results confirmed the mass was a bladder PEComa. No tumor recurrence was observed in the six-month postoperative follow-up. CONCLUSION: Bladder PEComa is an extremely rare mesenchymal tumor of the urinary system. When imaging and cystoscopy reveal a nodular mass with an abundant blood supply in the bladder, PEComa should be included in the differential diagnosis of bladder tumors. Surgical resection is currently the primary option for the treatment of bladder PEComa. For a solitary, pedunculated, narrow-based, small-sized bladder PEComa, resection of the tumor by ERBT was a safe and feasible approach in our patient and may be considered for similar cases in the future.
Subject(s)
Autoimmune Diseases , Diabetes Mellitus, Type 2 , Perivascular Epithelioid Cell Neoplasms , Urinary Bladder Neoplasms , Female , Humans , Aged , Urinary Bladder/diagnostic imaging , Urinary Bladder/surgery , Neoplasm Recurrence, Local , Urinary Bladder Neoplasms/diagnostic imaging , Urinary Bladder Neoplasms/surgery , Perivascular Epithelioid Cell Neoplasms/diagnostic imaging , Perivascular Epithelioid Cell Neoplasms/surgeryABSTRACT
Seven main ginsenosides, including ginsenoside Re, ginsenoside Rb1, pseudoginsenoside F11, ginsenoside Rb2, ginsenoside Rb3, ginsenoside Rd, and ginsenoside F2, were identified by LC-QTOF MS/MS from root, leaf and flower extracts of Panax quinquefolius. These extracts promoted intersegmental vessel growth in a zebrafish model, indicating their potential cardiovascular health benefits. Network pharmacology analysis was then conducted to reveal the potential mechanisms of ginsenoside activity in the treatment of coronary artery disease. GO and KEGG enrichment analyses elucidated that G protein-coupled receptors played a critical role in VEGF-mediated signal transduction and that the molecular pathways associated with ginsenoside activity are involved in neuroactive ligand-receptor interaction, cholesterol metabolism, the cGMP-PKG signaling pathway, etc. Moreover, VEGF, FGF2, and STAT3 were confirmed as the major targets inducing proliferation of endothelial cells and driving the pro-angiogenic process. Overall, ginsenosides could be potent nutraceutical agents that act to reduce the risks of cardiovascular disease. Our findings will provide a basis to utilize the whole P. quinquefolius plant in drugs and functional foods.
Subject(s)
Coronary Artery Disease , Ginsenosides , Panax , Animals , Ginsenosides/pharmacology , Chromatography, Liquid , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid , Endothelial Cells , Vascular Endothelial Growth Factor A , Zebrafish , Plant Extracts/pharmacologyABSTRACT
As the millet ears are dense, small in size, and serious occlusion in the complex grain field scene, the target detection model suitable for this environment requires high computing power, and it is difficult to deploy the real-time detection of millet ears on mobile devices. A lightweight real-time detection method for millet ears is based on YOLOv5. First, the YOLOv5s model is improved by replacing the YOLOv5s backbone feature extraction network with the MobilenetV3 lightweight model to reduce model size. Then, using the multi-feature fusion detection structure, the micro-scale detection layer is augmented to reduce high-level feature maps and low-level feature maps. The Merge-NMS technique is used in post-processing for target information loss to reduce the influence of boundary blur on the detection effect and increase the detection accuracy of small and obstructed targets. Finally, the models reconstructed by different improved methods are trained and tested on the self-built millet ear data set. The AP value of the improved model in this study reaches 97.78%, F1-score is 94.20%, and the model size is only 7.56 MB, which is 53.28% of the standard YoloV5s model size, and has a better detection speed. Compared with other classical target detection models, it shows strong robustness and generalization ability. The lightweight model performs better in the detection of pictures and videos in the Jetson Nano. The results show that the improved lightweight YOLOv5 millet detection model in this study can overcome the influence of complex environments, and significantly improve the detection effect of millet under dense distribution and occlusion conditions. The millet detection model is deployed on the Jetson Nano, and the millet detection system is implemented based on the PyQt5 framework. The detection accuracy and detection speed of the millet detection system can meet the actual needs of intelligent agricultural machinery equipment and has a good application prospect.
Subject(s)
Agriculture , Millets , Computers, Handheld , Edible Grain , IntelligenceABSTRACT
Opal (SiO2·nH2O, amorphous silica), the by-product of alumina extraction from coal fly ash (CFA), has a strong adsorption capacity and is also an important component of clay minerals in soils. The combining of opal with sand to form artificial soils is an effective disposal strategy for large-scale CFA stockpiles and reduction of environmental risk. Nevertheless, its poor physical condition limits plant growth. Organic matter (OM) amendments have broad potential applications for water-holding and improving soil aggregation. Effects of OMs (vermicompost (VC), bagasse (BA), biochar (BC) and humic acid (HA)) on the formation, stability and pore characteristics of opal/sand aggregates were evaluated through 60-day laboratory incubation experiments. Results demonstrated that four OMs could reduce pH, with BC having the most significant effect, VC significantly increasing the electrical conductivity (EC) and TOC content of the aggregates. Except for HA, other OMs could improve the aggregates' water-holding capacity. The mean weight diameter (MWD) and percentage of >0.25 mm aggregates (R0.25) of BA-treated aggregates were the largest, and BA had the most noticeable contribution to macro-aggregate's formation. The best aggregate stability was obtained with HA treatment, meanwhile the percentage of aggregate destruction (PAD0.25) decreased with the addition of HA. After amendments, the proportion of organic functional groups increased, which favored aggregate's formation and stability; the surface pore characteristics were improved, with the porosity ranging from 70% to 75%, reaching the level of well-structured soil. Overall, the addition of VC and HA can effectively promote aggregates' formation and stabilization. This research may play a key role in converting CFA or opal into artificial soil. The combining of opal with sand to form artificial soil will not only solve the environmental problems caused by large-scale CFA stockpiles but will also enable the comprehensive utilization of siliceous materials in agriculture.