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1.
Carbohydr Res ; : 109177, 2024 Jun 06.
Article En | MEDLINE | ID: mdl-38880715

Chitin oligosaccharides have garnered significant attention due to their biological activities, particularly their immunomodulatory properties. However, O-acetylation in chemically preparing chitin oligosaccharides seems inevitable and leads to some uncertainty on the bioactivity of chitin oligosaccharides. In this study, an O-acetyl-free chitin oligosaccharides and three different O-acetylated chitin oligosaccharides with degree of polymerization ranging from 2 to 6 were prepared using ammonia hydrolysis, and their structures and detailed components were further characterized with FTIR, NMR and MS. Subsequently, the effects of O-acetylation on the immunomodulatory activity of chitin oligosaccharides were investigated in vitro and in vivo. The results suggested that the chitin oligosaccharides with O-acetylation exhibited better inflammatory inhibition than pure chitin oligosaccharides, significantly reducing the expression of inflammatory factors, such as IL-6 and iNOS, in the LPS-induced RAW264.7 macrophage. The chitin oligosaccharides with a degree of O-acetylation of 93 % was found to effectively alleviate LPS-induced endotoxemia in mice, including serum inflammation indices reduction and damage repairment of the intestinal liver, and kidney tissues.

2.
J Orthop Surg (Hong Kong) ; 32(2): 10225536241265445, 2024.
Article En | MEDLINE | ID: mdl-38896879

OBJECTIVE: Local infiltration analgesia (LIA), adductor canal block (ACB), and infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) are popular multimodal analgesia techniques used during total knee arthroplasty (TKA). This study aimed to explore the efficacy of adding the IPACK technique to ACB and LIA in patients undergoing TKA. METHODS: In this retrospective cohort study, patients who underwent primary unilateral TKA were divided into two groups based on their date of admission. Sixty-three patients underwent IPACK, ACB and LIA (IPACK group) during surgery, while 60 patients underwent ACB and LIA (control group). The primary outcome was the postoperative administration of morphine hydrochloride as a rescue analgesic. Secondary outcomes included time to first rescue analgesia, postoperative pain assessed using the visual analog scale (VAS), functional recovery assessed by knee range of motion and ambulation distance, time until hospital discharge, and complication rates. RESULTS: The two groups were similar in average postoperative 0-to-24-h morphine consumption (11.8 mg for the control group vs 12.7 mg for the IPACK group, p = .428) and average total morphine consumption (18.2 mg vs 18.0 mg, p = .983) during hospitalization. There were also no significant differences in the secondary outcomes. CONCLUSIONS: The addition of IPACK to ACB and LIA did not provide any clinical analgesic benefits. Orthopedic surgeons and anesthesiologists are justified in using ACB and LIA without IPACK for TKA.


Arthroplasty, Replacement, Knee , Nerve Block , Pain, Postoperative , Popliteal Artery , Humans , Retrospective Studies , Arthroplasty, Replacement, Knee/methods , Male , Female , Aged , Popliteal Artery/surgery , Nerve Block/methods , Pain, Postoperative/prevention & control , Pain, Postoperative/etiology , Pain, Postoperative/diagnosis , Pain, Postoperative/drug therapy , Middle Aged , Analgesics, Opioid/administration & dosage , Morphine/administration & dosage , Anesthetics, Local/administration & dosage , Pain Measurement , Anesthesia, Local/methods , Analgesia/methods , Pain Management/methods
3.
Front Vet Sci ; 11: 1389185, 2024.
Article En | MEDLINE | ID: mdl-38903681

Orf is a zoonosis caused by the Orf virus (ORFV), which is endemic in goats, sheep, and wild ruminants worldwide. Orf infection is prevalent in China, with outbreaks reported in several provinces. Currently, there is limited information available regarding the characterization of ORFV strains in Jiangxi province. This study investigated an acute outbreak of Orf that occurred in 2021 in a goat herd in the Jiangxi province of China. Clinical signs in this case included lesions on the lips, nose, and inside the mouth. The presence of ORFV was confirmed from tissue samples by polymerase chain reaction (PCR). The nucleotide sequences of the B2L and F1L genes were fully sequenced and used to construct phylogenetic trees. The results of this investigation identified the ORFV JXxy2021 as the cause of the outbreak. The phylogenetic analysis revealed that the ORFV strain JXxy2021 had the highest similarity to the ORFV strains GO and FJ-SL from the neighboring province of Fujian. This suggests that JXxy2021 was likely transmitted from Fujian province. The results have provided valuable information on the genetic characteristics of JXxy2021 and the endemic situations of Orf in China.

4.
Nature ; 2024 Jun 05.
Article En | MEDLINE | ID: mdl-38839959

The recent discovery of superconductivity in La3Ni2O7-δ under high pressure with a transition temperature around 80 K (ref. 1) has sparked extensive experimental2-6 and theoretical efforts7-12. Several key questions regarding the pairing mechanism remain to be answered, such as the most relevant atomic orbitals and the role of atomic deficiencies. Here we develop a new, energy-filtered, multislice electron ptychography technique, assisted by electron energy-loss spectroscopy, to address these critical issues. Oxygen vacancies are directly visualized and are found to primarily occupy the inner apical sites, which have been proposed to be crucial to superconductivity13,14. We precisely determine the nanoscale stoichiometry and its correlation to the oxygen K-edge spectra, which reveals a significant inhomogeneity in the oxygen content and electronic structure within the sample. The spectroscopic results also reveal that stoichiometric La3Ni2O7 has strong charge-transfer characteristics, with holes that are self-doped from Ni sites into O sites. The ligand holes mainly reside on the inner apical O and the planar O, whereas the density on the outer apical O is negligible. As the concentration of O vacancies increases, ligand holes on both sites are simultaneously annihilated. These observations will assist in further development and understanding of superconducting nickelate materials. Our imaging technique for quantifying atomic deficiencies can also be widely applied in materials science and condensed-matter physics.

5.
Biomed Opt Express ; 15(6): 3541-3554, 2024 Jun 01.
Article En | MEDLINE | ID: mdl-38867784

The hippocampus is a critical brain region. Transcriptome data provides valuable insights into the structure and function of the hippocampus at the gene level. However, transcriptome data is often incomplete. To address this issue, we use the convolutional neural network model to repair the missing voxels in the hippocampus region, based on Allen institute coronal slices in situ hybridization (ISH) dataset. Moreover, we analyze the gene expression correlation between coronal and sagittal dataset in the hippocampus region. The results demonstrated that the trend of gene expression correlation between the coronal and sagittal datasets remained consistent following the repair of missing data in the coronal ISH dataset. In the last, we use repaired ISH dataset to identify novel genes specific to hippocampal subregions. Our findings demonstrate the accuracy and effectiveness of using deep learning method to repair ISH missing data. After being repaired, ISH has the potential to improve our comprehension of the hippocampus's structure and function.

6.
Chem Asian J ; 19(12): e202400211, 2024 Jun 17.
Article En | MEDLINE | ID: mdl-38709109

The growing demand for wearable electronics has driven the development of flexible thermoelectric (TE) generators which can harvest waste body heat as a renewable power source. Despite carbon nanotube (CNT) yarns have attracted significant attention as a promising candidate for TE materials, challenges still exist in improving their TE efficiency for commercial applications. Herein, we developed high performance CNT/polyaniline (PANI) yarns by engineering the coating of polyaniline emeraldine base (PANIeb), in which CNT yarns were firstly coated by PANIeb layer and further doped by HCl vapor treatment. With the incorporation of PANIeb, σ and S were simultaneously increased to 1796 S cm-1 and 74.8 µV K-1 for CNT/PANIeb 4-2d fibers, respectively. Further HCl vapor treatment induced greatly increased σ to 3194 S cm-1, but maintained be 83 % value before doping, giving rise to the highest power factor of 1224 µW m-1K-2, higher than pristine CNT yarns of 576 µW m-1K-2. Combining outstanding high TE performance and bending durability, a flexible TE generator was constructed to deliver high out power of 187 nW with temperature gradients of about 30 K. These results demonstrate the potential promise of high-performance CNT/PANI-HCl yarns to harvest waste body heat for sustainable power supply.

7.
Int J Biol Macromol ; 271(Pt 1): 132474, 2024 Jun.
Article En | MEDLINE | ID: mdl-38777019

Prime editing is a programmable genetic method that can precisely generate any desired small-scale variations in cells without requiring double-strand breaks and DNA donors. However, higher editing efficiency is greatly desirable for wide practical applications. In this study, we developed a target-specific prime editing reporter (tsPER) and a universal prime editing reporter (UPER) to facilitate rapid selection of desired edited cells through puromycin screening. The modification efficiency of HEK3_i1CTT_d5G in HEK293T cells improved from 36.37 % to 64.84 % with the incorporation of tsPER. The target sequence of interested genes could be custom inserted into a selection cassette in tsPER to establish personalized reporters. The UPER demonstrated PE3 editing efficiency up to 74.49 % on HEK3_i1CTT_d5G and 73.52 % on HEK3_i1His6, achieved through co-selection with an additional pegRNA (puro) to repair the mutant PuroR cassette. Overall, tsPER and UPER robustly improved the efficiency of prime editing. Both of these approaches expand enrichment strategies for genomically modified cells and accelerate the generation of genetically modified models.


Gene Editing , Humans , Gene Editing/methods , HEK293 Cells , Genes, Reporter , CRISPR-Cas Systems , Puromycin/pharmacology
8.
IEEE Trans Med Imaging ; PP2024 May 27.
Article En | MEDLINE | ID: mdl-38801691

Tooth instance segmentation of dental panoramic X-ray images represents a task of significant clinical importance. Teeth demonstrate symmetry within the upper and lower jawbones and are arranged in a specific order. However, previous studies frequently overlook this crucial spatial prior information, resulting in misidentifications of tooth categories for adjacent or similarly shaped teeth. In this paper, we propose SPGTNet, a spatial prior-guided transformer method, designed to both the extracted tooth positional features from CNNs and the long-range contextual information from vision transformers for dental panoramic X-ray image segmentation. Initially, a center-based spatial prior perception module is employed to identify each tooth's centroid, thereby enhancing the spatial prior information for the CNN sequence features. Subsequently, a bi-directional cross-attention module is designed to facilitate the interaction between the spatial prior information of the CNN sequence features and the long-distance contextual features of the vision transformer sequence features. Finally, an instance identification head is employed to derive the tooth segmentation results. Extensive experiments on three public benchmark datasets have demonstrated the effectiveness and superiority of our proposed method in comparison with other state-of-the-art approaches. The proposed method demonstrates the capability to accurately identify and analyze tooth structures, thereby providing crucial information for dental diagnosis, treatment planning, and research.

9.
Plants (Basel) ; 13(10)2024 May 17.
Article En | MEDLINE | ID: mdl-38794470

As global arid conditions worsen and groundwater resources diminish, drought stress has emerged as a critical impediment to plant growth and development globally, notably causing declines in crop yields and even the extinction of certain cultivated species. Numerous studies on drought resistance have demonstrated that DNA methylation dynamically interacts with plant responses to drought stress by modulating gene expression and developmental processes. However, the precise mechanisms underlying these interactions remain elusive. This article consolidates the latest research on the role of DNA methylation in plant responses to drought stress across various species, focusing on methods of methylation detection, mechanisms of methylation pattern alteration (including DNA de novo methylation, DNA maintenance methylation, and DNA demethylation), and overall responses to drought conditions. While many studies have observed significant shifts in genome-wide or gene promoter methylation levels in drought-stressed plants, the identification of specific genes and pathways involved remains limited. This review aims to furnish a reference for detailed research into plant responses to drought stress through epigenetic approaches, striving to identify drought resistance genes regulated by DNA methylation, specific signaling pathways, and their molecular mechanisms of action.

10.
J Pharm Pharmacol ; 2024 May 10.
Article En | MEDLINE | ID: mdl-38727186

OBJECTIVES: Bile acids (BAs), as signaling molecules to regulate metabolism, have received considerable attention. Genipin is an iridoid compound extracted from Fructus Gradeniae, which has been shown to relieve adiposity and metabolic syndrome. Here, we investigated the mechanism of genipin counteracting obesity and its relationship with BAs signals in diet-induced obese (DIO) rats. METHODS: The DIO rats were received intraperitoneal injections of genipin for 10 days. The body weight, visceral fat, lipid metabolism in the liver, thermogenic genes expressions in brown fat, BAs metabolism and signals, and key enzymes for BAs synthesis were determined. KEY FINDINGS: Genipin inhibited fat synthesis and promoted lipolysis in the liver, and upregulated thermogenic gene expressions in brown adipose tissue of DIO rats. Genipin increased bile flow rate and upregulated the expressions of aquaporin 8 and the transporters of BAs in liver. Furthermore, genipin changed BAs composition by promoting alternative pathways and inhibiting classical pathways for BAs synthesis and upregulated the expressions of bile acid receptors synchronously. CONCLUSIONS: These results suggest that genipin ameliorate obesity through BAs-mediated signaling pathways.

11.
BMC Infect Dis ; 24(1): 501, 2024 May 17.
Article En | MEDLINE | ID: mdl-38760687

BACKGROUND: The study aims were to evaluate the species distribution and antimicrobial resistance profile of Gram-negative pathogens isolated from specimens of intra-abdominal infections (IAI), urinary tract infections (UTI), respiratory tract infections (RTI), and blood stream infections (BSI) in emergency departments (EDs) in China. METHODS: From 2016 to 2019, 656 isolates were collected from 18 hospitals across China. Minimum inhibitory concentrations were determined by CLSI broth microdilution and interpreted according to CLSI M100 (2021) guidelines. In addition, organ-specific weighted incidence antibiograms (OSWIAs) were constructed. RESULTS: Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) were the most common pathogens isolated from BSI, IAI and UTI, accounting for 80% of the Gram-negative clinical isolates, while Pseudomonas aeruginosa (P. aeruginosa) was mainly isolated from RTI. E. coli showed < 10% resistance rates to amikacin, colistin, ertapenem, imipenem, meropenem and piperacillin/tazobactam. K. pneumoniae exhibited low resistance rates only to colistin (6.4%) and amikacin (17.5%) with resistance rates of 25-29% to carbapenems. P. aeruginosa exhibited low resistance rates only to amikacin (13.4%), colistin (11.6%), and tobramycin (10.8%) with over 30% resistance to all traditional antipseudomonal antimicrobials including ceftazidime, cefepime, carbapenems and levofloxacin. OSWIAs were different at different infection sites. Among them, the susceptibility of RTI to conventional antibiotics was lower than for IAI, UTI or BSI. CONCLUSIONS: Gram-negative bacteria collected from Chinese EDs exhibited high resistance to commonly used antibiotics. Susceptibilities were organ specific for different infection sites, knowledge which will be useful for guiding empirical therapies in the clinic.


Anti-Bacterial Agents , Emergency Service, Hospital , Gram-Negative Bacteria , Gram-Negative Bacterial Infections , Microbial Sensitivity Tests , Humans , China/epidemiology , Anti-Bacterial Agents/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/isolation & purification , Emergency Service, Hospital/statistics & numerical data , Gram-Negative Bacterial Infections/microbiology , Gram-Negative Bacterial Infections/epidemiology , Urinary Tract Infections/microbiology , Urinary Tract Infections/epidemiology , Respiratory Tract Infections/microbiology , Respiratory Tract Infections/epidemiology , Intraabdominal Infections/microbiology , Intraabdominal Infections/epidemiology , Drug Resistance, Bacterial , Female , Male
12.
Entropy (Basel) ; 26(5)2024 Apr 30.
Article En | MEDLINE | ID: mdl-38785638

Traffic state classification and relevance calculation at intersections are both difficult problems in traffic control. In this paper, we propose an intersection relevance model based on a temporal graph attention network, which can solve the above two problems at the same time. First, the intersection features and interaction time of the intersections are regarded as input quantities together with the initial labels of the traffic data. Then, they are inputted into the temporal graph attention (TGAT) model to obtain the classification accuracy of the target intersections in four states-free, stable, slow moving, and congested-and the obtained neighbouring intersection weights are used as the correlation between the intersections. Finally, it is validated by VISSIM simulation experiments. In terms of classification accuracy, the TGAT model has a higher classification accuracy than the three traditional classification models and can cope well with the uneven distribution of the number of samples. The information gain algorithm from the information entropy theory was used to derive the average delay as the most influential factor on intersection status. The correlation from the TGAT model positively correlates with traffic flow, making it interpretable. Using this correlation to control the division of subareas improves the road network's operational efficiency more than the traditional correlation model does. This demonstrates the effectiveness of the TGAT model's correlation.

13.
Mar Drugs ; 22(5)2024 Apr 29.
Article En | MEDLINE | ID: mdl-38786596

The escalation of jellyfish stings has drawn attention to severe skin reactions, underscoring the necessity for novel treatments. This investigation assesses the potential of hydroxybenzoic acid derivatives, specifically protocatechuic acid (PCA) and gentisic acid (DHB), for alleviating Nemopilema nomurai Nematocyst Venom (NnNV)-induced injuries. By employing an in vivo mouse model, the study delves into the therapeutic efficacy of these compounds. Through a combination of ELISA and Western blot analyses, histological examinations, and molecular assays, the study scrutinizes the inflammatory response, assesses skin damage and repair mechanisms, and investigates the compounds' ability to counteract venom effects. Our findings indicate that PCA and DHB significantly mitigate inflammation by modulating critical cytokines and pathways, altering collagen ratios through topical application, and enhancing VEGF and bFGF levels. Furthermore, both compounds demonstrate potential in neutralizing NnNV toxicity by inhibiting metalloproteinases and phospholipase-A2, showcasing the viability of small-molecule compounds in managing toxin-induced injuries.


Cnidarian Venoms , Hydroxybenzoates , Skin , Animals , Hydroxybenzoates/pharmacology , Mice , Cnidarian Venoms/pharmacology , Skin/drug effects , Skin/pathology , Skin/metabolism , Gentisates/pharmacology , Nematocyst/drug effects , Disease Models, Animal , Cytokines/metabolism
14.
Adv Mater ; : e2406359, 2024 May 17.
Article En | MEDLINE | ID: mdl-38759156

Lithium metal batteries (LMBs) must have both long cycle life and calendar life to be commercially viable. However, "trial and error" methodologies remain prevalent in contemporary research endeavors to identify favorable electrolytes. Here, a guiding principle for the selection of solvents for LMBs is proposed, which aims to achieve high Coulombic efficiency while minimizing the corrosion. For the first time, this study reveals that the dipole moment and orientation of solvent molecules have significant impacts on lithium metal reversibility and corrosion. Solvents with high dipole moments are more likely to adsorb onto lithium metal surfaces, which also influence the solid electrolyte interphase. Using this principle, the use of LiNO3 is demonstrated as the sole salt in LiNi0.8Co0.1Mn0.1O2/Li cells can achieve excellent cycling stability. Overall, this work bridges the molecular structure of solvents to the reversibility and corrosion of lithium metal, and these concepts can be extended to other metal-based batteries.

15.
Environ Sci Pollut Res Int ; 31(23): 34324-34339, 2024 May.
Article En | MEDLINE | ID: mdl-38700768

The combination of aerated flows and a high-pressure environment in a stilling basin can result in the supersaturation of total dissolved gas (TDG) downstream of hydraulic projects, posing an ecological risk to aquatic populations by inducing gas bubble disease (GBD) or other negative effects. There is limited literature reporting TDG mass transfer experiments on a complete physical dam model; most existing research is based on measurements in prototype tailwaters. In this study, TDG mass transfer experiments were conducted on a physical model of an under-constructed dam, with TDG-supersaturated water as the inflow, and TDG concentrations were meticulously monitored within the stilling basin. The measurements indicate that the TDG saturation at the outlet of the stilling basin decreased by 13.7% and 10.6% compared to the inlet for the two cases, respectively. Subsequently, an improved TDG prediction model was developed by incorporating a sub-grid air entrainment model and a phase-constrained scalar model. The numerical simulation results were compared with experimental data, indicating a maximum error in TDG saturation at all measured points of less than ± 3%. Moreover, the TDG saturation showed an error of only ± 0.3% at the outlet of the stilling basin. This model has broad applicability to various flow types for obtaining TDG mass transfer results and evaluating mitigation measures of TDG supersaturation to reduce the harmful effects on aquatic ecosystems.


Models, Theoretical , Gases , Environmental Monitoring/methods
16.
Int J Biol Macromol ; 269(Pt 2): 132131, 2024 Jun.
Article En | MEDLINE | ID: mdl-38719017

Chitosan oligosaccharide (COS) modification is a feasible way to develop novel green nematicides. This study involved the synthesis of various COS sulfonamide derivatives via hydroxylated protection and deprotection, which were then characterized using NMR, FTIR, MS, elemental analysis, XRD, and TG/DTG. In vitro experiments found that COS-alkyl sulfonamide derivatives (S6 and S11-S13) exhibited high mortality (>98 % at 1 mg/mL) against Meloidogyne incognita second-instar larvaes (J2s) among the derivatives. S6 can cause vacuole-like structures in the middle and tail regions of the nematode body and effectively inhibit egg hatching. In vivo tests have found that S6 has well control effects and low plant toxicity. Additionally, the structure-activity studies revealed that S6 with a high degree of substitution, a low molecular weight, and a sulfonyl bond on the amino group of the COS backbone exhibited increased nematicidal activity. The sulfonamide group is a potential active group for developing COS-based nematicides.


Antinematodal Agents , Chitosan , Oligosaccharides , Sulfonamides , Tylenchoidea , Chitosan/chemistry , Chitosan/pharmacology , Animals , Tylenchoidea/drug effects , Antinematodal Agents/pharmacology , Antinematodal Agents/chemistry , Oligosaccharides/chemistry , Oligosaccharides/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Structure-Activity Relationship , Larva/drug effects
17.
Int J Biol Macromol ; 269(Pt 2): 131952, 2024 Jun.
Article En | MEDLINE | ID: mdl-38692541

Thromboembolic diseases pose a serious risk to human health worldwide. Fucosylated chondroitin sulfate (FCS) is reported to have good anticoagulant activity with a low bleeding risk. Molecular weight plays a significant role in the anticoagulant activity of FCS, and FCS smaller than octasaccharide in size has no anticoagulant activity. Therefore, identifying the best candidate for developing novel anticoagulant FCS drugs is crucial. Herein, native FCS was isolated from sea cucumber Cucumaria frondosa (FCScf) and depolymerized into a series of lower molecular weights (FCScfs). A comprehensive assessment of the in vitro anticoagulant activity and in vivo bleeding risk of FCScfs with different molecule weights demonstrated that 10 kDa FCScf (FCScf-10 K) had a greater intrinsic anticoagulant activity than low molecular weight heparin (LMWH) without any bleeding risk. Using molecular modeling combined with experimental validation, we revealed that FCScf-10 K can specifically inhibit the formation of the Xase complex by binding the negatively charged sulfate group of FCScf-10 K to the positively charged side chain of arginine residues on the specific surface of factor IXa. Thus, these data demonstrate that the intermediate molecular weight FCScf-10 K is a promising candidate for the development of novel anticoagulant drugs.


Anticoagulants , Chondroitin Sulfates , Factor IXa , Molecular Weight , Animals , Chondroitin Sulfates/chemistry , Chondroitin Sulfates/pharmacology , Chondroitin Sulfates/isolation & purification , Anticoagulants/pharmacology , Anticoagulants/chemistry , Anticoagulants/isolation & purification , Factor IXa/metabolism , Factor IXa/antagonists & inhibitors , Factor IXa/chemistry , Cucumaria/chemistry , Sea Cucumbers/chemistry , Blood Coagulation/drug effects , Humans , Models, Molecular
18.
Exp Neurol ; 377: 114782, 2024 Jul.
Article En | MEDLINE | ID: mdl-38641126

Elevated transport of Caveolin-1 (CAV-1) vesicles within vascular endothelial cells constitutes a significant secondary pathogenic event contributing to the compromise of the blood-brain barrier (BBB) post-traumatic brain injury (TBI). While Wnt/ß-catenin signaling is recognized for its critical involvement in angiogenesis and the maintenance of BBB integrity, its influence on vascular endothelial transcytosis in the aftermath of TBI is not well-defined. This study aims to elucidate the impact of Wnt/ß-catenin signaling on cerebrovascular vesicular transcytosis following TBI. In this experiment, adult male wild-type (WT) C57BL/6 mice underwent various interventions. TBI was induced utilizing the controlled cortical impact technique. Post-TBI, mice were administered either an inhibitor or an agonist of Wnt signaling via intraperitoneal injection. Recombinant adeno-associated virus (rAAV) was administered intracerebroventricularly to modulate the expression of the CAV-1 inhibitory protein, Major facilitator superfamily domain-containing 2a (Mfsd2a). This research utilized Evans blue assay, Western blot analysis, immunofluorescence, transmission electron microscopy, and neurobehavioral assessments. Post-TBI observations revealed substantial increases in macromolecule (Evans blue and albumin) leakage, CAV-1 transport vesicle count, astrocyte end-feet edema, and augmented aquaporin-4 (AQP4) expression, culminating in BBB disruption. The findings indicate that Wnt signaling pathway inhibition escalates CAV-1 transport vesicle activity and aggravates BBB compromise. Conversely, activating this pathway could alleviate BBB damage by curtailing CAV-1 vesicle presence. Post-TBI, there is a diminution in Mfsd2a expression, which is directly influenced by the modulation of WNT signals. Employing a viral approach to regulate Mfsd2a, we established that its down-regulation undermines the protective benefits derived from reducing CAV-1 transport vesicles through WNT signal enhancement. Moreover, we verified that the WNT signaling agonist LiCl notably ameliorates neurological deficits following TBI in mice. Collectively, our data imply that Wnt/ß-catenin signaling presents a potential therapeutic target for safeguarding against BBB damage and enhancing neurological function after TBI.


Blood-Brain Barrier , Brain Injuries, Traumatic , Caveolin 1 , Mice, Inbred C57BL , Transcytosis , Wnt Signaling Pathway , Animals , Blood-Brain Barrier/metabolism , Blood-Brain Barrier/pathology , Blood-Brain Barrier/drug effects , Brain Injuries, Traumatic/metabolism , Brain Injuries, Traumatic/pathology , Mice , Male , Wnt Signaling Pathway/drug effects , Wnt Signaling Pathway/physiology , Transcytosis/drug effects , Transcytosis/physiology , Caveolin 1/metabolism , Symporters
19.
Oncogene ; 43(21): 1581-1593, 2024 May.
Article En | MEDLINE | ID: mdl-38565942

Deubiquitinating enzymes (DUBs) are promising targets for cancer therapy because of their pivotal roles in various physiological and pathological processes. Among these, ubiquitin-specific peptidase 26 (USP26) is a protease with crucial regulatory functions. Our study sheds light on the upregulation of USP26 in colorectal cancer (CRC), in which its increased expression correlates with an unfavorable prognosis. Herein, we evidenced the role of USP26 in promoting CRC tumorigenesis in a parkin RBR E3 ubiquitin-protein ligase (PRKN) protein-dependent manner. Our investigation revealed that USP26 directly interacted with PRKN protein, facilitating its deubiquitination, and subsequently reducing its activity. Additionally, we identified the K129 site on PRKN as a specific target for USP26-mediated deubiquitination. Our research highlights that a K-to-R mutation at the site on PRKN diminishes its potential for activation and ability to mediate mitophagy. In summary, our findings underscore the significance of USP26-mediated deubiquitination in restraining the activation of the PRKN-mediated mitophagy pathway, ultimately driving CRC tumorigenesis. This study not only elucidated the multifaceted role of USP26 in CRC but also introduced a promising avenue for therapeutic exploration through the development of small molecule inhibitors targeting USP26. This strategy holds promise as a novel therapeutic approach for CRC.


Carcinogenesis , Colorectal Neoplasms , Mitophagy , Ubiquitin-Protein Ligases , Ubiquitination , Colorectal Neoplasms/pathology , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Humans , Mitophagy/genetics , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/genetics , Animals , Carcinogenesis/genetics , Carcinogenesis/metabolism , Mice , Cell Line, Tumor , Cysteine Endopeptidases/metabolism , Cysteine Endopeptidases/genetics , Mice, Nude , Gene Expression Regulation, Neoplastic
20.
Nucleic Acids Res ; 2024 Apr 30.
Article En | MEDLINE | ID: mdl-38686791

In plant chloroplasts, certain ribosomal proteins (RPs) and ribosome biogenesis factors (RBFs) are present in nucleoids, implying an association between nucleoids and ribosome biogenesis. In Arabidopsis, the YqeH-type GTPase Brassinazole-Insensitive Pale Green2 (BPG2) is a chloroplast nucleoid-associated RBF. Here, we investigated the relationship between nucleoids and BPG2-involved ribosome biogenesis steps by exploring how BPG2 targets ribosomes. Our findings demonstrate that BPG2 interacts with an essential plastid RP, uS10c, in chloroplast nucleoids in a ribosomal RNA (rRNA)-independent manner. We also discovered that uS10c is a haploinsufficient gene, as the heterozygous deletion of this gene leads to variegated shoots and chlorophyll aggregation. uS10c is integrated into 30S ribosomal particles when rRNA is relatively exposed and also exists in polysome fractions. In contrast, BPG2 exclusively associates with 30S ribosomal particles. Notably, the interaction between BPG2 and 30S particles is influenced by the absence of uS10c, resulting in BPG2 diffusing in chloroplasts instead of targeting nucleoids. Further, our results reveal that the loss of BPG2 function and the heterozygous deletion of uS10c impair the processing of 16S and 23S-4.5S rRNAs, reduce plastid protein accumulation, and trigger the plastid signaling response. Together, these findings indicate that the uS10c-BPG2 module mediates ribosome biogenesis in chloroplast nucleoids.

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