ABSTRACT
Natural antimicrobial peptides (AMPs) and enzymes (AMEs) are promising non-antibiotic candidates against antimicrobial resistance but suffer from low efficiency and poor stability. Here, we develop peptide nanozymes which mimic the mode of action of AMPs and AMEs through de novo design and peptide assembly. Through modelling a minimal building block of IHIHICI is proposed by combining critical amino acids in AMPs and AMEs and hydrophobic isoleucine to conduct assembly. Experimental validations reveal that IHIHICI assemble into helical ß-sheet nanotubes with acetate modulation and perform phospholipase C-like and peroxidase-like activities with Ni coordination, demonstrating high thermostability and resistance to enzymatic degradation. The assembled nanotubes demonstrate cascade antifungal actions including outer mannan docking, wall disruption, lipid peroxidation and subsequent ferroptotic death, synergistically killing >90% Candida albicans within 10 min on disinfection pad. These findings demonstrate an effective de novo design strategy for developing materials with multi-antimicrobial mode of actions.
Subject(s)
Antifungal Agents , Candida albicans , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Candida albicans/drug effects , Microbial Sensitivity Tests , Nanotubes/chemistry , Antimicrobial Peptides/pharmacology , Antimicrobial Peptides/chemistry , Lipid Peroxidation/drug effects , Peptides/pharmacology , Peptides/chemistryABSTRACT
Metformin shows promise in breast cancer prevention, but its underlying mechanisms remain unclear. This study investigated the impact of metformin on the repopulation dynamics of mammary epithelial cells (MECs) and the signaling pathways in non-tumorigenic FVB/N mice. This study aimed to enhance our understanding of the role of metformin in reducing the susceptibility of MECs in premalignant tissues to oncogenic factors. In this study, female mice were administered 200 mg/kg/day of metformin via intraperitoneal (i.p.) injection from 8 to 18 weeks of age. After this treatment period, morphogenesis, flow cytometry, analyses of MEC stemness, and RNA sequencing were performed. The study findings indicated that metformin treatment in adult mice reduced mammary gland proliferation, as demonstrated by decreased Ki67+ cells and lateral bud formation. Additionally, metformin significantly reduced both basal and mammary repopulating unit subpopulations, indicating an impact on mammary epithelial cell repopulation. Mammosphere, colony-forming cell, and 3D culture assays revealed that metformin adversely affected mammary epithelial cell stemness. Furthermore, metformin downregulated signaling in key pathways including AMPK/mTOR, MAPK/Erk, PI3K/Akt, and ER, which contribute to its inhibitory effects on mammary proliferation and stemness. Transcriptome analysis with RNA sequencing indicated that metformin induced significant downregulation of genes involved in multiple critical pathways. KEGG-based pathway analysis indicated that genes in PI3K/Akt, focal adhesion, ECM-receptor, small cell lung cancer and immune-modulation pathways were among the top groups of differentially regulated genes. In summary, our research demonstrates that metformin inhibits MEC proliferation and stemness, accompanied by the downregulation of intrinsic signaling. These insights suggest that the regulatory effects of metformin on premalignant mammary tissues could potentially delay or prevent the onset of breast cancer, offering a promising avenue for developing new preventive strategies.
ABSTRACT
Core 1 ß 1,3-galactosyltransferase 1 (C1GALT1) acts as an important glycosyltransferase in the occurrence and development of tumor glycosylation. However, the regulatory mechanisms of C1GALT1 in thyroid cancer (TC) is still unclear. In this study, we discovered that the expression level of C1GALT1 was significantly increased in thyroid adenocarcinoma tissues and cell lines (p < 0.01). Meanwhile, gene silencing of C1GALT1 inhibited the proliferation (CCK-8 assay), migration (wound healing), and invasion (Transwell) of TC cells (p < 0.05). Further investigation indicated that miR-141-3p had a negative correlation with C1GALT1 and suppressed cancer carcinogenesis in TC cells. Moreover, we first found that glucose transporter 1 (GLUT1) was a downstream element of C1GALT1 and was positively correlated with C1GALT1 levels in TC. The GLUT1 could reverse the inhibitory effects of siRNA C1GALT1 on cell development (p < 0.05). These data suggest that the miR-141-3p/C1GALT1/GLUT1 axis plays an essential role during TC progression and may be a probable biomarker or therapeutic target for thyroid cancer patients.
ABSTRACT
Rationale: Magnetic resonance imaging (MRI) is a powerful diagnostic technology by providing high-resolution imaging. Although MRI is sufficiently valued in its resolving morphology, it has poor sensitivity for tracking biomarkers. Therefore, contrast agents are often used to improve MRI diagnostic sensitivity. However, the clinically used Gd chelates are limited in improving MRI sensitivity owing to their low relaxivity. The objective of this study is to develop a novel contrast agent to achieve a highly sensitive tracking of biomarkers in vivo. Methods: A Gd-based nanoprobe composed of a gadolinium nanoparticle encapsulated within a human H-ferritin nanocage (Gd-HFn) has been developed. The specificity and sensitivity of Gd-HFn were evaluated in vivo in tumor-bearing mice and apolipoprotein E-deficient mice (Apoe-/-) by MRI. Results: The Gd-HFn probe shows extremely high relaxivity values (r1 = 549 s-1mM-1, r2 = 1555 s-1mM-1 under a 1.5-T magnetic field; and r1 = 428 s-1mM-1 and r2 = 1286 s-1mM-1 under a 3.0-T magnetic field), which is 175-fold higher than that of the clinically standard Dotarem (Gd-DOTA, r1 =3.13 s-1mM-1) under a 1.5-T magnetic field, and 150-fold higher under a 3.0-T magnetic field. Owing to the substantially enhanced relaxivity values, Gd-HFn achieved a highly sensitive tracking for the tumor targeting receptor of TfR1 and enabled the in vivo MRI visualization of tumors approaching the angiogenic switch. Conclusions: The developed Gd-HFn contrast agent makes MRI a more powerful tool by simultaneously providing functional and morphological imaging information, which paves the way for a new perspective in molecular imaging.
Subject(s)
Nanoparticles , Neoplasms , Mice , Animals , Humans , Contrast Media , Gadolinium , Apoferritins , Neoplasms/diagnostic imaging , Magnetic Resonance Imaging/methods , Molecular Imaging , BiomarkersABSTRACT
Coal workers' pneumoconiosis (CWP) is one of the most common inhalation occupational diseases. It is no effective treatment methods. Early diagnosis of CWP could reduce mortality. Lipid mediators (LMs) as key mediators in the generation and resolution of inflammation, are natural biomarkers for diagnosis inflammatory disease, such as CWP. The UHPLC-MRM technique was used to detect LMs in urine. The metabolic network of LMs in CWP and CT group samples was comprehensively analyzed. Screening for major difference compounds between the two groups. Aimed to contribute to the early diagnosis and treatment of CWP. Urinary levels of 13-OxoODE, 9-OxoODE, and 9,10-EpOME were significantly higher in the CWP group compared with the CT group (P < 0.05). In the model group, the area under the receiver operating characteristic (ROC) for 9-OxoODE,13-OxoODE,9,10-EpOME was 84.4%, 73.3%, and 80.9%, respectively. In the validation group, the area under the ROC was 87.0%, 88.8%, and 68.8% for 9-OxoODE,13-OxoODE,9,10-EpOME, respectively. According to the logistic regression model, the area under the ROC was 80.4% in the model group and 86.7% in the validation group. 13-OxoODE,9-OxoODE,9,10-EpOME could be used as biomarkers for early diagnosis. Significant abnormalities of LOX and CYP450 enzyme pathways were seen in CWP organisms. Changes in the CYP450 enzyme pathway may be associated with PAHs.
Subject(s)
Anthracosis , Humans , Anthracosis/diagnosis , Inflammation , BiomarkersABSTRACT
BACKGROUND: Asthma affects 3% of the global population, leading to over 0.25 million deaths. Due to its complexity, asthma is difficult to cure or prevent, and current therapies have limitations. This has led to a growing demand for alternative asthma treatments. We found rosmarinic acid (RosA) as a potential new drug candidate from natural medicine. However, RosA has poor bioavailability and remains mainly in the gastrointestinal tract after oral administration, suggesting the involvement of gut microbiota in its bioactivity. PURPOSE: To investigate the mechanism of RosA in alleviating allergic asthma by gut-lung axis. METHODS: We used 16S rRNA gene sequencing and metabolites analysis to investigate RosA's modulation of gut microbiota. Techniques of molecular biology and metabolomics were employed to study the pharmacological mechanism of RosA. Cohousing was used to confirm the involvement of gut microbiota in RosA-induced improvement of allergic asthma. RESULTS: RosA decreased cholate levels from spore-forming bacteria, leading to reduced 5-hydroxytryptamine (5-HT) synthesis, bronchoconstriction, vasodilation, and inflammatory cell infiltration. It also increased short-chain fatty acids (SCFAs) levels, facilitating the expression of intestinal tight junction proteins to promote intestinal integrity. SCFAs upregulated intestinal monocarboxylate transporters (MCTs), thereby improving their systemic delivery to reduce Th2/ILC2 mediated inflammatory response and suppress eosinophil influx and mucus production in lung. Additionally, RosA inhibited lipopolysaccharide (LPS) production and translocation, leading to reduced TLR4-NFκB mediated pulmonary inflammation and oxidative stress. CONCLUSIONS: The anti-asthmatic mechanism of oral RosA is primarily driven by modulation of gut microbiota-derived 5-HT, SCFAs, and LPS, achieving a combined synergistic effect. RosA is a safe, effective, and reliable drug candidate that could potentially replace glucocorticoids for asthma treatment.
Subject(s)
Asthma , Rosmarinic Acid , Humans , Immunity, Innate , RNA, Ribosomal, 16S/genetics , Lipopolysaccharides , Serotonin , Lymphocytes , Asthma/drug therapy , Asthma/metabolism , Lung/metabolism , Fatty Acids, Volatile/metabolismABSTRACT
The Gabija system is a newly discovered bacterial immune system that consists of GajA and GajB. Here we report the cryo-EM structure of the Gabija complex from Bacillus cereus VD045 at 3.6 Å, which provides the direct evidence of interactions between GajA and GajB. The Gabija complex is an octameric ring structure with four GajA and four GajB. GajA is an OLD nucleases family protein, while GajB belongs to the SF1 helicases. The Gabija complex has sequence-specific DNA nuclease activity and prefers circular rather than linear DNA as substrate, its activity is more sensitive to concentrations change of nucleotides compared to GajA alone. Our data suggest a mechanism of Gabija immunity: the nuclease activity of Gabija complex is inhibited under physiological conditions, while it is activated by depletion of NTP and dNTP upon the replication and transcription of invading phages and cleave the circular DNA to prevent phage DNA replication.
Subject(s)
Bacteriophages , DNA , DNA/metabolism , Bacteriophages/genetics , Bacteriophages/metabolism , Bacillus cereus/metabolism , Endonucleases , Immune System/metabolismABSTRACT
INTRODUCTION: Brain arteriovenous malformation (bAVM) might have a higher risk of rupture after partial embolization, and previous studies have shown that some metrics of vascular stability are related to bAVM rupture risk. OBJECTIVE: To analyze vascular stability of bAVM in patients after partial embolization. METHODS: Twenty-four patients who underwent partial embolization were classified into the short-term, medium-term, and long-term groups, according to the time interval between partial embolization and surgery. The control group consisted of 9 bAVM patients who underwent surgery alone. Hemodynamic changes after partial embolization were measured by angiogram. The inflammatory infiltrates and cell-cell junctions were evaluated by MMP-9 and VE-cadherin. At the protein level, the proliferative and apoptotic events of bAVMs were analyzed by immunohistochemical staining of VEGFA, eNOS, and caspase-3. Finally, neovascularity and apoptotic cells were assessed by CD31 staining and TUNEL staining. RESULTS: Immediately after partial embolization, the blood flow velocity of most bAVMs increased. The quantity of MMP-9 in the medium-term group was the highest, and VE-cadherin in the medium-term group was the lowest. The expression levels of VEGFA, eNOS, and neovascularity were highest in the medium-term group. Similarly, the expression level of caspase-3 and the number of apoptotic cells were highest in the medium-term group. CONCLUSION: The biomarkers for bAVM vascular stability were most abnormal between 1 and 28 days after partial embolization.
Subject(s)
Embolization, Therapeutic , Intracranial Arteriovenous Malformations , Humans , Matrix Metalloproteinase 9 , Caspase 3/metabolism , Intracranial Arteriovenous Malformations/diagnostic imaging , Intracranial Arteriovenous Malformations/therapy , Intracranial Arteriovenous Malformations/metabolism , Brain/metabolism , Neovascularization, Pathologic , Retrospective StudiesABSTRACT
Auxin signaling provides a promising approach to controlling root system architecture and improving stress tolerance in plants. However, how the auxin signaling is transducted in this process remains unclear. The Aux indole-3-acetic acid (IAA) repressor IAA17.1 is stabilized by salinity, and primarily expressed in the lateral root (LR) primordia and tips in poplar. Overexpression of the auxin-resistant form of IAA17.1 (IAA17.1m) led to growth inhibition of LRs, markedly reduced salt tolerance, increased reactive oxygen species (ROS) levels, and decreased flavonol content. We further identified that IAA17.1 can interact with the heat shock protein HSFA5a, which was highly expressed in roots and induced by salt stress. Overexpression of HSFA5a significantly increased flavonol content, reduced ROS accumulation, enhanced LR growth and salt tolerance in transgenic poplar. Moreover, HSFA5a could rescue the defective phenotypes caused by IAA17.1m. Expression analysis showed that genes associated with flavonol biosynthesis were altered in IAA17.1m- and HAFA5a-overexpressing plants. Furthermore, we identified that HSFA5a directly activated the expression of key enzyme genes in the flavonol biosynthesis pathway, while IAA17.1 suppressed HSFA5a-mediated activation of these genes. Collectively, the IAA17.1/HSFA5a module regulates flavonol biosynthesis, controls ROS accumulation, thereby modulating the root system of poplar to adapt to salt stress.
Subject(s)
Populus , Salt Tolerance , Reactive Oxygen Species/metabolism , Salt Stress , Indoleacetic Acids/metabolism , Gene Expression Regulation, Plant , Plant Roots/metabolism , Plants, Genetically Modified/metabolismABSTRACT
Resolvin (Rv) and lipoxin (Lx) play important regulative roles in the development of several inflammation-related diseases. The dysregulation of their metabolic network is believed to be closely related to the occurrence and development of asthma. The Hyssopus Cuspidatus Boriss extract (SXCF) has long been used as a treatment for asthma, while the mechanism of anti-inflammatory and anti-asthma action targeting Rv and Lx has not been thoroughly investigated. In this study, we aimed to investigate the effects of SXCF on Rv, Lx in ovalbumin (OVA)-sensitized asthmatic mice. The changes of Rv, Lx before and after drug administration were analyzed based on high sensitivity chromatography-multiple response monitoring (UHPLC-MRM) analysis and multivariate statistics. The pathology exploration included behavioral changes of mice, IgE in serum, cytokines in BALF, and lung tissue sections stained with H&E. It was found that SXCF significantly modulated the metabolic disturbance of Rv, Lx due to asthma. Its modulation effect was significantly better than that of dexamethasone and rosmarinic acid which is the first-line clinical medicine and the main component of Hyssopus Cuspidatus Boriss, respectively. SXCF is demonstrated to be a potential anti-asthmatic drug with significant disease-modifying effects on OVA-induced asthma. The modulation of Rv and Lx is a possible underlying mechanism of the SXCF effects.
Subject(s)
Anti-Asthmatic Agents , Asthma , Lipoxins , Mice , Animals , Lipoxins/pharmacology , Asthma/chemically induced , Asthma/drug therapy , Asthma/metabolism , Anti-Asthmatic Agents/adverse effects , Lung/metabolism , Cytokines/metabolism , Plant Extracts/pharmacology , Mice, Inbred BALB C , Disease Models, AnimalABSTRACT
Natural bioactive compounds (NBCs) are widely used in clinical treatment. For example, Tripterygium wilfordii Hook f. is commonly known in China as Lei-Gong-Teng which means thunder god vine. This herb is widely distributed in Eastern and Southern China, Korea, and Japan. The natural bioactive compounds of this herb can be extracted and made into tripterygium glycoside tablets. It is one of the most commonly used and effective traditional Chinese herbal medicines against rheumatoid arthritis (RA), nephrotic syndrome (NS), autoimmune hepatis (AIH), and so on. However, many NBCs are difficult to reliably quantify in the serum due to the effects of matrix and RSD. In addition, the targeted compound's internal standard (IS) is rarely sold due to the complex isotope internal standard synthesis pathway. In this study, a new quantitation method for 18O labeling combined with off-line SPE was formulated. We contrasted the recoveries and matrix effects of various separation methods in order to choose the best method. Furthermore, we optimized the conditions for SPE loading and washing. An isotopic internal standard was prepared by the 16O/18O exchanging reaction in order to eliminate the matrix effects. The method's accuracy and precision met the requirements for method validation. The recovery of this method was close to 60%. The relative standard deviation (RSD) of the high-concentration sample was 2%, and the limit of detection (LOD) was 1 ng/mL. This method could be used to analyze the clinical serum concentration of demethylzeylasteral. Sixty samples were collected from 10 patients with diabetes nephropathy. The quantitation results of demethylzeylasteral in patients' serum obtained using this method exhibited a correlation between therapeutic drug monitoring (TDM) and decreased urinary protein. This work may have broad implications for the study of drug metabolism in vivo and the clinical application of low-abundance and difficult-to-quantify NBCs.
Subject(s)
Arthritis, Rheumatoid , Drugs, Chinese Herbal , Triterpenes , Humans , Arthritis, Rheumatoid/drug therapy , GlycosidesABSTRACT
Drought stress caused by global warming has resulted in significant tree mortality, driving the evolution of water conservation strategies in trees. Although phytohormones have been implicated in morphological adaptations to water deficits, the molecular mechanisms underlying these processes in woody plants remain unclear. Here, we report that overexpression of PtoMYB142 in Populus tomentosa results in a dwarfism phenotype with reduced leaf cell size, vessel lumen area, and vessel density in the stem xylem, leading to significantly enhanced drought resistance. We found that PtoMYB142 modulates gibberellin catabolism in response to drought stress by binding directly to the promoter of PtoGA2ox4, a GA2-oxidase gene induced under drought stress. Conversely, knockout of PtoMYB142 by the CRISPR/Cas9 system reduced drought resistance. Our results show that the reduced leaf size and vessel area, as well as the increased vessel density, improve leaf relative water content and stem water potential under drought stress. Furthermore, exogenous GA3 application rescued GA-deficient phenotypes in PtoMYB142-overexpressing plants and reversed their drought resistance. By suppressing the expression of PtoGA2ox4, the manifestation of GA-deficient characteristics, as well as the conferred resistance to drought in PtoMYB142-overexpressing poplars, was impeded. Our study provides insights into the molecular mechanisms underlying tree drought resistance, potentially offering novel transgenic strategies to enhance tree resistance to drought.
Subject(s)
Drought Resistance , Populus , Gibberellins/metabolism , Populus/metabolism , Transcription Factors/metabolism , Gene Expression Regulation, Plant , Water/metabolism , Droughts , Plants, Genetically Modified/geneticsABSTRACT
Recent advances in large model and neuroscience have enabled exploration of the mechanism of brain activity by using neuroimaging data. Brain decoding is one of the most promising researches to further understand the human cognitive function. However, current methods excessively depends on high-quality labeled data, which brings enormous expense of collection and annotation of neural images by experts. Besides, the performance of cross-individual decoding suffers from inconsistency in data distribution caused by individual variation and different collection equipments. To address mentioned above issues, a Join Domain Adapative Decoding (JDAD) framework is proposed for unsupervised decoding specific brain cognitive state related to behavioral task. Based on the volumetric feature extraction from task-based functional Magnetic Resonance Imaging (tfMRI) data, a novel objective loss function is designed by the combination of joint distribution regularizer, which aims to restrict the distance of both the conditional and marginal probability distribution of labeled and unlabeled samples. Experimental results on the public Human Connectome Project (HCP) S1200 dataset show that JDAD achieves superior performance than other prevalent methods, especially for fine-grained task with 11.5%-21.6% improvements of decoding accuracy. The learned 3D features are visualized by Grad-CAM to build a combination with brain functional regions, which provides a novel path to learn the function of brain cortex regions related to specific cognitive task in group level.
Subject(s)
Brain , Connectome , Humans , Brain/diagnostic imaging , Magnetic Resonance Imaging/methods , Connectome/methods , Neuroimaging , CognitionABSTRACT
Delayed recanalization at days or weeks beyond the therapeutic window was shown to improve functional outcomes in acute ischemic stroke (AIS) patients. However, the underlying mechanisms remain unclear. Previous preclinical study reported that trefoil factor 3 (TFF3) was secreted by liver after cerebral ischemia and acted a distant neuroprotective factor. Here, we investigated the liver-derived TFF3-mediated neuroprotective mechanism enhanced by delayed recanalization after AIS. A total of 327 male Sprague-Dawley rats and the model of middle cerebral artery occlusion (MCAO) with permanent occlusion (pMCAO) or with delayed recanalization at 3 d post-occlusion (rMCAO) were used. Partial hepatectomy was performed within 5 min after MCAO. Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) siRNA was administered intracerebroventricularly at 48 h after MCAO. Recombinant rat TFF3 (rr-TFF3, 30 µg/Kg) or recombinant rat epidermal growth factor (rr-EGF, 100 µg/Kg) was administered intranasally at 1 h after recanalization, and EGFR inhibitor Gefitinib (75 mg/Kg) was administered intranasally at 30 min before recanalization. The evaluation of outcomes included neurobehavior, ELISA, western blot and immunofluorescence staining. TFF3 in hepatocytes and serum were upregulated in a similar time-dependent manner after MCAO. Compared to pMCAO, delayed recanalization increased brain TFF3 levels and attenuated brain damage with the reduction in neuronal apoptosis, infarct volume and neurological deficits. Partial hepatectomy reduced TFF3 levels in serum and ipsilateral brain hemisphere, and abolished the benefits of delayed recanalization on neuronal apoptosis and neurobehavioral deficits in rMCAO rats. Intranasal rrTFF3 treatment reversed the changes associated with partial hepatectomy. Delayed recanalization after MCAO increased the co-immunoprecipitation of TFF3 and LINGO2, as well as expressions of p-EGFR, p-Src and Bcl-2 in the brain. LINGO2 siRNA knockdown or EGFR inhibitor reversed the effects of delayed recanalization on apoptosis and brain expressions of LINGO2, p-EGFR, p-Src and Bcl-2 in rMCAO rats. EGFR activator abolished the deleterious effects of LINGO2 siRNA. In conclusion, our investigation demonstrated for the first time that delayed recanalization may enhance the entry of liver-derived TFF3 into ischemic brain upon restoring blood flow after MCAO, which attenuated neuronal apoptosis and neurological deficits at least in part via activating LINGO2/EGFR/Src pathway.
Subject(s)
Brain Ischemia , Ischemic Stroke , Neuroprotective Agents , Humans , Rats , Male , Animals , Rats, Sprague-Dawley , Neuroprotection , Infarction, Middle Cerebral Artery/metabolism , Trefoil Factor-3/pharmacology , Trefoil Factor-3/therapeutic use , Signal Transduction , Apoptosis , ErbB Receptors/metabolism , ErbB Receptors/pharmacology , ErbB Receptors/therapeutic use , Liver , RNA, Small Interfering/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic useABSTRACT
Alzheimer's disease (AD) is an irreversible neurodegenerative disease with a high prevalence in the elderly population over 65 years of age. Intervention in the early stages of AD is of great significance to alleviate the symptoms. Recent advances in deep learning have shown extreme advantages in computer-aided diagnosis of AD. However, most studies only focus on extracting features from slices in specific directions or whole brain images, ignoring the complementarity between features from different angles. To overcome the above problem, attention-based multi-view slice fusion (AMSF) is proposed for accurate early diagnosis of AD. It adopts the fusion of three-dimensional (3D) global features with multi-view 2D slice features by using an attention mechanism to guide the fusion of slice features for each view, to generate a comprehensive representation of the MRI images for classification. The experiments on the public dataset demonstrate that AMSF achieves 94.3% accuracy with 1.6-7.1% higher than other previous promising methods. It indicates that the better solution for AD early diagnosis depends not only on the large scale of the dataset but also on the organic combination of feature construction strategy and deep neural networks.
ABSTRACT
Amyloid-like assembly is not only associated with pathological events, but also leads to the development of novel nanomaterials with unique properties. Herein, using Fmoc diphenylalanine peptide (Fmoc-F-F) as a minimalistic model, we found that histidine can modulate the assembly behavior of Fmoc-F-F and induce enzyme-like catalysis. Specifically, the presence of histidine rearranges the ß structure of Fmoc-F-F to assemble nanofilaments, resulting in the formation of active site to mimic peroxidase-like activity that catalyzes ROS generation. A similar catalytic property is also observed in Aß assembled filaments, which is correlated with the spatial proximity between intermolecular histidine and F-F. Notably, the assembled Aß filaments are able to induce cellular ROS elevation and damage neuron cells, providing an insight into the pathological relationship between Aß aggregation and Alzheimer's disease. These findings highlight the potential of histidine as a modulator in amyloid-like assembly of peptide nanomaterials exerting enzyme-like catalysis.
Subject(s)
Histidine , Nanostructures , Reactive Oxygen Species , Amyloidogenic Proteins , PeptidesABSTRACT
In the pursuit of automating the entire underground drilling process in coal mines, the automatic rod feeding technology of drilling robots plays a crucial role. However, the current lack of positional accuracy in automatic rod feeding leads to frequent accidents. To address this issue, this paper presents an algorithm for compensating positioning errors in automatic rod feeding. The algorithm is based on a theoretical mathematical model and manual teaching methods. To enhance the positioning accuracy, we first calibrate the pull rope sensor to correct its measurement precision. Subsequently, we establish a theoretical mathematical model for rod feeding positions by employing spatial coordinate system transformations. We determine the target rod feeding position using a manual teaching-based approach. Furthermore, we analyze the relationship between the theoretical rod delivery position and the target rod delivery position and propose an anisotropic spatial difference compensation technique that considers both distance and direction. Finally, we validate the feasibility of our proposed algorithm through automatic rod feeding tests conducted on a coal mine underground drilling robot. The results demonstrate that our algorithm significantly improves the accuracy of rod feeding positions for coal mine underground drilling robots.
ABSTRACT
Drought stress is one of the major limiting factors for the growth and development of perennial trees. Xylem vessels act as the center of water conduction in woody species, but the underlying mechanism of its development and morphogenesis under water-deficient conditions remains elucidation. Here, we identified and characterized an osmotic stress-induced ETHYLENE RESPONSE FACTOR 15 (PtoERF15) and its target, PtoMYC2b, which was involved in mediating vessel size, density, and cell wall thickness in response to drought in Populus tomentosa. PtoERF15 is preferentially expressed in differentiating xylem of poplar stems. Overexpression of PtoERF15 contributed to stem water potential maintaining, thus promoting drought tolerance. RNA-Seq and biochemical analysis further revealed that PtoERF15 directly regulated PtoMYC2b, encoding a switch of JA signaling pathway. Additionally, our findings verify that three sets of homologous genes from NAC (NAM, ATAF1/2, and CUC2) gene family: PtoSND1-A1/A2, PtoVND7-1/7-2, and PtoNAC118/120, as the targets of PtoMYC2b, are involved in the regulation of vessel morphology in poplar. Collectively, our study provides molecular evidence for the involvement of the PtoERF15-PtoMYC2b transcription cascade in maintaining stem water potential through the regulation of xylem vessel development, ultimately improving drought tolerance in poplar.
Subject(s)
Drought Resistance , Populus , Plant Proteins/metabolism , Droughts , Water/metabolism , Signal Transduction , Gene Expression Regulation, Plant , Stress, Physiological/geneticsABSTRACT
BACKGROUND: Oligodendroglioma is known for its relatively better prognosis and responsiveness to radiotherapy and chemotherapy. However, little is known about the evolution of genetic changes as oligodendroglioma progresses. METHODS: In this study, we evaluated gene evolution invivo during tumor progression based on deep whole-genome sequencing data (ctDNA). We analyzed longitudinal genomic data from six patients during tumor evolution, of which five patients developed distant recurrence. RESULTS: Whole-exome sequencing demonstrated that the rate of shared mutations between the primary and recurrent samples was relatively low. In two cases, even well-known major driver mutations in CIC and FUBP1 that were detected in primary tumors were not detected in the relapse samples. Among these cases, two patients had a conversion from the IDH mutation in the originating state to the IDH1 wild state during the process of gene evolution under chemotherapy treatment, indicating that the cell phenotype and genetic characteristics of oligodendroglioma may change during tumor evolution. Two patients received long-term temozolomide (TMZ) treatment before the operation, and we found that recurrence tumors harbored mutations in the PI3K/AKT and Sonic hedgehog (SHh) signaling pathways. Hypermutation occurred with mutations in MMR genes in one patient, contributing to the rapid progression of the tumor. CONCLUSION: Oligodendroglioma displayed great spatial and temporal heterogeneity during tumor evolution. The PI3K/AKT and SHh signaling pathways may play an important role in promoting treatment resistance and distant relapse during oligodendroglioma evolution. In addition, there was a tendency to increase the degree of tumor malignancy during evolution. Distant recurrence may be a later event duringoligodendroglioma progression. CLINICALTRIALS: gov, Identifier: NCT05512325.
Subject(s)
Brain Neoplasms , Oligodendroglioma , Humans , Oligodendroglioma/genetics , Oligodendroglioma/therapy , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Brain Neoplasms/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Hedgehog Proteins/metabolism , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Mutation , Genomics , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolism , DNA-Binding Proteins/genetics , RNA-Binding Proteins/geneticsABSTRACT
The evolutionary trajectories of genomic alterations underlying distant recurrence in glioma remain largely unknown. To elucidate glioma evolution, we analyzed the evolutionary trajectories of matched pairs of primary tumors and relapse tumors or tumor in situ fluid (TISF) based on deep whole-genome sequencing data (ctDNA). We found that MMR gene mutations occurred in the late stage in IDH-mutant glioma during gene evolution, which activates multiple signaling pathways and significantly increases distant recurrence potential. The proneural subtype characterized by PDGFRA amplification was likely prone to hypermutation and distant recurrence following treatment. The classical and mesenchymal subtypes tended to progress locally through subclonal reconstruction, trunk genes transformation, and convergence evolution. EGFR and NOTCH signaling pathways and CDNK2A mutation play an important role in promoting tumor local progression. Glioma subtypes displayed distinct preferred evolutionary patterns. ClinicalTrials.gov, NCT05512325.