ABSTRACT
Supersolid, an exotic quantum state of matter that consists of particles forming an incompressible solid structure while simultaneously showing superfluidity of zero viscosity1, is one of the long-standing pursuits in fundamental research2,3. Although the initial report of 4He supersolid turned out to be an artefact4, this intriguing quantum matter has inspired enthusiastic investigations into ultracold quantum gases5-8. Nevertheless, the realization of supersolidity in condensed matter remains elusive. Here we find evidence for a quantum magnetic analogue of supersolid-the spin supersolid-in the recently synthesized triangular-lattice antiferromagnet Na2BaCo(PO4)2 (ref. 9). Notably, a giant magnetocaloric effect related to the spin supersolidity is observed in the demagnetization cooling process, manifesting itself as two prominent valley-like regimes, with the lowest temperature attaining below 100 mK. Not only is there an experimentally determined series of critical fields but the demagnetization cooling profile also shows excellent agreement with the theoretical simulations with an easy-axis Heisenberg model. Neutron diffractions also successfully locate the proposed spin supersolid phases by revealing the coexistence of three-sublattice spin solid order and interlayer incommensurability indicative of the spin superfluidity. Thus, our results reveal a strong entropic effect of the spin supersolid phase in a frustrated quantum magnet and open up a viable and promising avenue for applications in sub-kelvin refrigeration, especially in the context of persistent concerns about helium shortages10,11.
ABSTRACT
Efficient coupling in broad wavelength range is desirable for wide-spectrum infrared light detection, yet this is a challenge for intersubband transition in semiconductor quantum wells (QWs). High-Q cavities mostly intensify the absorption at peak wavelengths but with shrinking bandwidth. Here, we propose a novel approach to expand the operating spectral range of the Quantum Well Infrared Photodetectors (QWIPs). By processing the QWs into asymmetric micro-pillar array structure, the device demonstrates a substantial enhancement in spectral response across the wavelength from 7.1 µm to 12.3 µm with guided mode resonance (GMR) effects. The blackbody responsivity is then increased by 3 times compared to that of the 45° polished edge-coupled counterpart. Meanwhile, the dark current density remains unchanged after the deep etching process, which will benefit the electrical performance of the detector with reduced volume duty ratio. In contrast to the symmetric micro-pillar array that contains simple resonance mode, the detectivity of QWIP in asymmetric pillar structure is found to be improved by 2-4 times within the range of 9.5 µm to 15 µm.
ABSTRACT
A series of novel quinazoline-derived EGFR/HER-2 dual-target inhibitors were designed and synthesized by heterocyclic-containing tail approach. The inhibitory activities against four human epidermal growth factor receptor (HER) isozymes (EGFR, HER-2, HER-3 and HER-4) of all new compounds so designed were investigated in vitro. Compound 12k was found to be the most effective and rather selective dual-target inhibitor of EGFR and HER-2 with inhibitory constant (IC50) values of 6.15 and 9.78 nM, respectively, which was more potent than the clinical used agent Lapatinib (IC50 = 8.41 and 9.41 nM). Meanwhile, almost all compounds showed excellent antiproliferative activities against four cancer cell models (A549, NCI-H1975, SK-BR-3 and MCF-7) and low damage to healthy cells. Among them, compound 12k also exhibited the most prominent antitumor activity. Moreover, the hit compound 12k could bind to EGFR and HER-2 stably in molecular docking and dynamics studies. The following wound healing assay revealed that compound 12k could inhibit the migration of SK-BR-3 cells. Further studies found that compound 12k could arrest cell cycle in the G0/G1 phase and induce SK-BR-3 cells apoptosis. Notably, compound 12k could effectively inhibit breast cancer growth with little toxicity in the SK-BR-3 cell xenograft model. Taken together, in vitro and in vivo results disclosed that compound 12k had high drug potential as a dual-target inhibitor of EGFR/HER-2 to inhibit breast cancer growth.
ABSTRACT
The JNK signaling pathway plays crucial roles in various physiological processes, including cell proliferation, differentiation, migration, apoptosis, and stress response. Dysregulation of this pathway is closely linked to the onset and progression of numerous major diseases, such as developmental defects and tumors. Identifying and characterizing novel components of the JNK signaling pathway to enhance and refine its network hold significant scientific and clinical importance for the prevention and treatment of associated cancers. This study utilized the model organism Drosophila and employed multidisciplinary approaches encompassing genetics, developmental biology, biochemistry, and molecular biology to investigate the interplay between Tip60 and the JNK signaling pathway, and elucidated its regulatory mechanisms. Our findings suggest that loss of Tip60 acetyltransferase activity results in JNK signaling pathway activation and subsequent induction of JNK-dependent apoptosis. Genetic epistasis analysis reveals that Tip60 acts downstream of JNK, paralleling with the transcription factor FOXO. The biochemical results confirm that Tip60 can bind to FOXO and acetylate it. Introduction of human Tip60 into Drosophila effectively mitigates apoptosis induced by JNK signaling activation, underscoring conserved regulatory role of Tip60 in the JNK signaling pathway from Drosophila to humans. This study further enhances our understanding of the regulatory network of the JNK signaling pathway. By revealing the role and mechanism of Tip60 in JNK-dependent apoptosis, it unveils new insights and potential therapeutic avenues for preventing and treating associated cancers.
Subject(s)
Apoptosis , Drosophila Proteins , Forkhead Transcription Factors , Animals , Drosophila Proteins/metabolism , Drosophila Proteins/genetics , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Histone Acetyltransferases/metabolism , Histone Acetyltransferases/genetics , Drosophila/genetics , Drosophila/metabolism , MAP Kinase Signaling System , Humans , Signal Transduction , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , JNK Mitogen-Activated Protein Kinases/metabolism , JNK Mitogen-Activated Protein Kinases/geneticsABSTRACT
Rheumatoid arthritis(RA) is a condition in which the joints are in a weakly acidic environment. In RA, RA fibroblastlike synoviocytes( RAFLS) in the joints become abnormally activated and secrete a large amount of matrix metalloproteinases(MMPs), and the receptor protein CD44 on the cell membrane is specifically upregulated. Xuetongsu(XTS), an active ingredient in the Tujia ethnomedicine Xuetong, is known to inhibit the proliferation of RAFLS. However, its development and utilization have been limited due to poor targeting ability. A biomimetic XTS-Prussian blue nanoparticles(PB NPs) drug delivery system called THMPX NPs which can target CD44 was constructed in this study. The surface of THMPX NPs was modified with hyaluronic acid(HA) and a long chain of triglycerol monostearate(TGMS) and 3-aminobenzeneboronic acid(PBA)(PBA-TGMS). The overexpressed MMPs and H+ in inflammatory RAFLS can synergistically cleave the PBA-TGMS on the surface of the nanoparticles, exposing HA to interact with CD44. This allows THMPX NPs to accumulate highly in RAFLS, and upon near-infrared light irradiation, generate heat and release XTS, thereby inhibiting the proliferation and migration of RAFLS. Characterization revealed that THMPX NPs were uniform cubes with a diameter of(190. 3±4. 7) nm and an average potential of(-15. 3± 2. 3) m V. Upon near-infrared light irradiation for 5 min, the temperature of THMPX NPs reached 41. 5 â, indicating MMPs and H+-triggered drug release. Safety assessments showed that THMPX NPs had a hemolysis rate of less than 4% and exhibited no cytotoxicity against normal RAW264. 7 and human fibroblast-like synoviocytes(HFLS). In vitro uptake experiments demonstrated the significant targeting ability of THMPX NPs to RAFLS. Free radical scavenging experiments revealed excellent free radical clearance capacity of THMPX NPs, capable of removing reactive oxygen species in RAFLS. Cell counting kit-8 and scratch assays demonstrated that THMPX NPs significantly suppressed the viability and migratory ability of RAFLS. This study provides insights into the development of innovative nanoscale targeted drugs from traditional ethnic medicines for RA treatment.
Subject(s)
Cell Movement , Cell Proliferation , Matrix Metalloproteinases , Nanoparticles , Cell Proliferation/drug effects , Cell Proliferation/radiation effects , Nanoparticles/chemistry , Humans , Cell Movement/drug effects , Cell Movement/radiation effects , Matrix Metalloproteinases/metabolism , Matrix Metalloproteinases/genetics , Ferrocyanides/chemistry , Hydrogen-Ion Concentration , Synoviocytes/drug effects , Synoviocytes/radiation effects , Synoviocytes/metabolism , Lasers , Hyaluronan Receptors/metabolism , Hyaluronan Receptors/genetics , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/pharmacology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolismABSTRACT
Lithium iron phosphate (LFP)/graphite batteries have long dominated the energy storage battery market and are anticipated to become the dominant technology in the global power battery market. However, the poor fast-charging capability and low-temperature performance of LFP/graphite batteries seriously hinder their further spread. These limitations are strongly associated with the interfacial Li-ion transport. Here we report a wide-temperature-range ester-based electrolyte that exhibits high ionic conductivity, fast interfacial kinetics and excellent film-forming ability by regulating the anion chemistry of Li salt. The interfacial barrier of the battery is quantitatively unraveled by employing three-electrode system and distribution of relaxation time technique. The superior role of the proposed electrolyte in preventing Li0 plating and sustaining homogeneous and stable interphases are also systematically investigated. The LFP/graphite cells exhibit rechargeability in an ultrawide temperature range of -80°C to 80°C and outstanding fast-charging capability without compromising lifespan. Specially, the practical LFP/graphite pouch cells achieve 80.2% capacity retention after 1200 cycles (2 C) and 10-min charge to 89% (5 C) at 25°C and provides reliable power even at -80°C.
ABSTRACT
With the development of mobile applications, location-based services (LBSs) have been incorporated into people's daily lives and created huge commercial revenues. However, when using these services, people also face the risk of personal privacy breaches due to the release of location and query content. Many existing location privacy protection schemes with centralized architectures assume that anonymous servers are secure and trustworthy. This assumption is difficult to guarantee in real applications. To solve the problem of relying on the security and trustworthiness of anonymous servers, we propose a Geohash-based location privacy protection scheme for snapshot queries. It is named GLPS. On the user side, GLPS uses Geohash encoding technology to convert the user's location coordinates into a string code representing a rectangular geographic area. GLPS uses the code as the privacy location to send check-ins and queries to the anonymous server and to avoid the anonymous server gaining the user's exact location. On the anonymous server side, the scheme takes advantage of Geohash codes' geospatial gridding capabilities and GL-Tree's effective location retrieval performance to generate a k-anonymous query set based on user-defined minimum and maximum hidden cells, making it harder for adversaries to pinpoint the user's location. We experimentally tested the performance of GLPS and compared it with three schemes: Casper, GCasper, and DLS. The experimental results and analyses demonstrate that GLPS has a good performance and privacy protection capability, which resolves the reliance on the security and trustworthiness of anonymous servers. It also resists attacks involving background knowledge, regional centers, homogenization, distribution density, and identity association.
ABSTRACT
This comprehensive review elucidates the complex interplay between gut microbiota and constipation in Parkinson's disease (PD), a prevalent non-motor symptom contributing significantly to patients' morbidity. A marked alteration in the gut microbiota, predominantly an increase in the abundance of Proteobacteria and Bacteroidetes, is observed in PD-related constipation. Conventional treatments, although safe, have failed to effectively alleviate symptoms, thereby necessitating the development of novel therapeutic strategies. Microbiological interventions such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) hold therapeutic potential. While prebiotics improve bowel movements, probiotics are effective in enhancing stool consistency and alleviating abdominal discomfort. FMT shows potential for significantly alleviating constipation symptoms by restoring gut microbiota balance in patients with PD. Despite promising developments, the causal relationship between changes in gut microbiota and PD-related constipation remains elusive, highlighting the need for further research in this expanding field.
Subject(s)
Parkinson Disease , Probiotics , Humans , Parkinson Disease/complications , Parkinson Disease/therapy , Parkinson Disease/microbiology , Constipation/etiology , Constipation/therapy , Fecal Microbiota Transplantation/adverse effects , Prebiotics , Probiotics/therapeutic useABSTRACT
Biological activated carbon (BAC) is one of the important treatment processes in wastewater and advanced water treatment. However, the BAC process has been reported to have antimicrobial resistance (AMR) risks. In this study, a new BAC-related treatment process was developed to reduce AMR caused by BAC treatment: ozone/peroxymonosulfate-BAC (O3/PMS-BAC). The O3/PMS-BAC showed better treatment performance on the targeted five antibiotics and dissolved organic matter removal than O3-BAC and BAC treatments. The O3/PMS-BAC process had better control over the AMR than the O3-BAC and BAC processes. Specifically, the amount of targeted antibiotic-resistant bacteria in the effluent and biofilm of O3/PMS-BAC was only 0.01-0.03 and 0.11-0.26 times that of the BAC process, respectively. Additionally, the O3/PMS-BAC process removed 1.76 %-62.83 % and 38.14 %-99.27 % more of the targeted ARGs in the effluent and biofilm than the BAC process. The total relative abundance of the targeted 12 ARGs in the O3/PMS-BAC effluent was decreased by 86 % compared to the effluent after BAC treatment. In addition, Proteobacteria and Bacteroidetes were probably the main hosts for transmitting ARGs in this study, and their relative abundance decreased by 9.6 % and 6.0 % in the effluent of the O3/PMS-BAC treatment compared to that in BAC treatment. The relationship analysis revealed that controlling antibiotic discharge was crucial for managing AMR, as antibiotics were closely related to both ARGs and bacteria associated with their emergence. The results showed that the newly developed treatment process could reduce AMR caused by BAC treatment while ensuring effluent quality. Therefore, O3/PMS-BAC is a promising alternative to BAC treatment for future applications.
Subject(s)
Anti-Bacterial Agents , Charcoal , Ozone , Ozone/pharmacology , Anti-Bacterial Agents/pharmacology , Charcoal/chemistry , Charcoal/pharmacology , Water Purification , Peroxides , Biofilms/drug effects , Wastewater/chemistry , Waste Disposal, Fluid , Drug Resistance, Microbial , Bacteria/drug effectsABSTRACT
Bacterial infections remain a formidable threat to human health, a situation exacerbated by the escalating problem of antibiotic resistance. While alternative antibacterial strategies such as oxidants, heat treatments, and metal nanoparticles (NPs) have shown potential, they come with significant drawbacks, ranging from non-specificity to potential environmental concerns. In the face of these challenges, the rapid evolution of micro/nanomotors (MNMs) stands out as a revolutionary development in the antimicrobial arena. MNMs harness various forms of energy and convert it into a substantial driving force, offering bright prospects for combating microbial threats. MNMs' mobility allows for swift and targeted interaction with bacteria, which not only improves the carrying potential of therapeutic agents but also narrows the required activation range for non-drug antimicrobial interventions like photothermal and photodynamic therapies, substantially improving their bacterial clearance rates. In this review, we summarized the diverse propulsion mechanisms of MNMs employed in antimicrobial applications and articulated their multiple functions, which include direct bactericidal action, capture and removal of microorganisms, detoxification processes, and the innovative detection of bacteria and associated toxins. Despite MNMs' potential to revolutionize antibacterial research, the translation from laboratory to clinical use remains challenging. Based on the current research status, we summarized the potential challenges and possible solutions and also prospected several key directions for future studies of MNMs for antimicrobial purposes. Collectively, by highlighting the important knowns and unknowns of antimicrobial MNMs, our present review would help to light the way forward for the field of antimicrobial MNMs and prevent unnecessary blindness and detours.
Subject(s)
Hyperthermia, Induced , Metal Nanoparticles , Humans , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Blindness , Metabolic Clearance RateABSTRACT
In order to examine the mechanical properties and rotational bending fatigue performance of 40CrNi2MoE steel subsequent to tempering at varying temperatures, the steel specimen was subjected to tempering within the range of 400~460 °C. SEM, EBSD, and TEM were used to analyze the microstructure as well as precipitates. The strain hardening law was studied using the modified Crussard-Jaoult method. Investigations were undertaken to reveal the rotational bending fatigue life with respect to the tempering temperature. The findings indicate that the strength and fatigue life of the examined steels exhibit a decline as the tempering temperature increases, with the primary factor affecting this trend being the alteration in dislocation density. No notable impact on the fatigue fracture morphology exerted by tempering temperature was found within the range of the experiment. The C-J model analysis reveals that the work-hardening behavior of the trial steels is influenced by dislocations and the second phase.
ABSTRACT
BACKGROUND: Paradoxically, patients with T4N0M0 (stage II, no lymph node metastasis) colon cancer have a worse prognosis than those with T2N1-2M0 (stage III). However, no previous report has addressed this issue. AIM: To screen prognostic risk factors for T4N0M0 colon cancer and construct a prognostic nomogram model for these patients. METHODS: Two hundred patients with T4N0M0 colon cancer were treated at Tianjin Medical University General Hospital between January 2017 and December 2021, of which 112 patients were assigned to the training cohort, and the remaining 88 patients were assigned to the validation cohort. Differences between the training and validation groups were analyzed. The training cohort was subjected to multivariate analysis to select prognostic risk factors for T4N0M0 colon cancer, followed by the construction of a nomogram model. RESULTS: The 3-year overall survival (OS) rates were 86.2% and 74.4% for the training and validation cohorts, respectively. Enterostomy (P = 0.000), T stage (P = 0.001), right hemicolon (P = 0.025), irregular review (P = 0.040), and carbohydrate antigen 199 (CA199) (P = 0.011) were independent risk factors of OS in patients with T4N0M0 colon cancer. A nomogram model with good concordance and accuracy was constructed. CONCLUSION: Enterostomy, T stage, right hemicolon, irregular review, and CA199 were independent risk factors for OS in patients with T4N0M0 colon cancer. The nomogram model exhibited good agreement and accuracy.
ABSTRACT
BACKGROUND: Saliva has a crucial role in determining the compatibility between piercing-sucking insects and their hosts. The brown planthopper (BPH) Nilaparvata lugens, a notorious pest of rice in East and Southeast Asia, secretes gelling and watery saliva when feeding on rice sap. Nlsalivap-5 (NlSP5) and Nlsalivap-7 (NlSP7) were identified as potential planthopper-specific gelling saliva components, but their biological functions remain unknown. RESULTS: Here, we showed by transcriptomic analyses that NlSP5 and NlSP7 were biasedly expressed in the salivary glands of BPHs. Using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated genome-editing system, we constructed NlSP5 and NlSP7 homozygous mutants (NlSP5-/- and NlSP7-/-). Electrical penetration graph assay showed that NlSP5-/- and NlSP7-/- mutants exhibited abnormal probing and feeding behaviors. Bioassays revealed that the loss-of-function of NlSP5 and NlSP7 significantly reduced the fitness of BPHs, with extended developmental duration, shortened lifespan, reduced weight, and impaired fecundity and hatching rates. CONCLUSION: These findings deepen our understanding of the BPH-host interaction and may provide potential targets for the management of rice planthoppers. © 2024 Society of Chemical Industry.
Subject(s)
Hemiptera , Insect Proteins , Salivary Proteins and Peptides , Animals , Female , Feeding Behavior , Genetic Fitness , Hemiptera/genetics , Hemiptera/physiology , Insect Proteins/genetics , Insect Proteins/metabolism , Oryza , Salivary Proteins and Peptides/genetics , Salivary Proteins and Peptides/metabolismABSTRACT
Objective: Examining the current situation of test anxiety among first year senior high school students in Yanji City and investigating the factors that contribute to exam anxiety. Methods: Using cluster sampling, a survey was conducted on 1,550 first-year high school students from three high schools in Yanji City in April-May 2023. The survey utilized general information questionnaires, the Minnesota Multiphasic Personality Inventory (MMPI), and the Self-Rating Anxiety Scale (SAS). Logistic regression analysis was used to determine the influencing factors of test anxiety. Results: A total of 1,550 first-year high school students were included in the analysis, with a test anxiety occurrence rate of 79.8%. Test anxiety exhibited statistical differences among different genders, ethnicities, family economic levels, frequency of communication with parents, and relationships with parents (with results of 53.44, 10.42, 17.31, 20.42, 31.95, all p < 0.05). Scores of hypochondriasis (Hs), depression (D), psychasthenia (Pt), paranoia (Pa), psychopathic deviate (Pd), schizophrenia (Sc), and hypomania (Ma) in the 10 clinical personality scales were significantly positively correlated. Logistic regression analysis revealed that gender, ethnicity, frequency of communication with parents, and scores of hypochondriasis (Hs), depression (D), psychasthenia (Pt), paranoia (Pa), and hypomania (Ma) in the 10 clinical personality scales were the main influencing factors for test anxiety in first-year high school students (all p < 0.05). Conclusion: The test anxiety level of high school students in Yanji City is relatively high, with variations in test anxiety levels among students of different genders, ethnicities, parental communication styles, and deviant personality traits. It is recommended that schools and teachers should give more consideration to test anxiety among high school students, particularly targeting those with potential risk factors. Parents should also be more attentive to their children's development and advancement, and improve their family education principles.
ABSTRACT
Silent information regulator 2 (Sir2) proteins typically catalyze NAD+-dependent protein deacetylation. The recently identified bacterial Sir2 domain-containing protein, defense-associated sirtuin 2 (DSR2), recognizes the phage tail tube and depletes NAD+ to abort phage propagation, which is counteracted by the phage-encoded DSR anti-defense 1 (DSAD1), but their molecular mechanisms remain unclear. Here, we determine cryo-EM structures of inactive DSR2 in its apo form, DSR2-DSAD1 and DSR2-DSAD1-NAD+, as well as active DSR2-tube and DSR2-tube-NAD+ complexes. DSR2 forms a tetramer with its C-terminal sensor domains (CTDs) in two distinct conformations: CTDclosed or CTDopen. Monomeric, rather than oligomeric, tail tube proteins preferentially bind to CTDclosed and activate Sir2 for NAD+ hydrolysis. DSAD1 binding to CTDopen allosterically inhibits tube binding and tube-mediated DSR2 activation. Our findings provide mechanistic insight into DSR2 assembly, tube-mediated DSR2 activation, and DSAD1-mediated inhibition and NAD+ substrate catalysis in bacterial DSR2 anti-phage defense systems.
Subject(s)
Sirtuins , Sirtuins/metabolism , NAD/metabolism , Silent Information Regulator Proteins, Saccharomyces cerevisiae/metabolism , Sirtuin 2 , HydrolysisABSTRACT
To explore the causes of red tides in Qinhuangdao coastal water, we conducted surveys on both water quality and red tides during April to September of 2022 and analyzed the relationships between main environmental factors and red tide organisms through the factor analysis and canonical correspondence analysis. The results showed that there were eight red tides along the coast of Qinhuangdao in 2022, with a cumulative blooming area of 716.1 km2. The red tides could be divided into three kinds based on the major blooming organisms and occurrence time, Noctiluca scintillans bloom, diatom-euglena (Skeletonema costatum, Eutreptiella gymnastica, Pseudo-nitzschia spp.) bloom, and dinoflagellate (Scrippsiella trochoidea and Ceratium furca) bloom. Seasonal factor played roles mainly during July to September, while inorganic nutrients including nitrogen and phosphorus influenced the blooms mainly in April and July. The canonical correspondence analysis suggested that N. scintillans preferred low temperature, and often bloomed with high concentrations of ammonium nitrogen and dissolved inorganic phosphorus. S. costatum, E. gymnastica, and Pseudo-nitzschia spp. could tolerate broad ranges of various environmental factors, but favored high temperature and nitrogen-rich seawater. C. furca and S. trochoidea had higher survival rate and competitiveness in phosphate-poor waters. Combined the results from both analyses, we concluded that the causes for the three kinds of red tide processes in Qinhuangdao coastal areas in 2022 were different. Adequate diet algae and appropriate water temperature were important factors triggering and maintaining the N. scintillans bloom. Suitable temperature, salinity and eutrophication were the main reasons for the diatom-euglena bloom. The abundant nutrients and seawater disturbance promoted the germination of S. trochoidea cysts, while phosphorus limitation caused the blooming organism switched to C. furca and maintained the bloom hereafter.
Subject(s)
Diatoms , Dinoflagellida , Environmental Monitoring , Harmful Algal Bloom , Seawater , China , Dinoflagellida/growth & development , Seawater/analysis , Seawater/chemistry , Diatoms/growth & development , Oceans and Seas , Phosphorus/analysis , Nitrogen/analysis , SeasonsABSTRACT
The challenge of drug resistance in bacteria caused by the over use of biotics is increasing during the therapy process, which has attracted great attentions of the clinicians and scientists around the world. Recently, photodynamic therapy (PDT) triggered by photosensitizer (PS) has become a promising treatment method because of its high efficacy, easy operation, and low side effect. Herein, the poly-l-lysine (PLL) modified metal-organic framework (MOF) nanoparticles, ZIF/PLL-CIP/CUR, were synthesized to allow both reactive oxygen species (ROS) responsive drug release and photodynamic effect for synergistic therapy against drug resistant bacterial infections. The PLL was modified on the shell of the zeolite imidazole framework (ZIF) by the ROS-responsive thioketal linker for controllable CIP release. CUR were encapsulated in ZIF as the photosensitizer for blue light mediated photodynamic effect to produce singlet oxygen (1O2) and superoxide anion radical (O2-) for efficient inhibition towards methicillin-resistant Staphylococcus aureus (MRSA). The charge conversion from negative charge (-4.6 mV) to positive charge (2.6 mV) was observed at pH 7.4 and pH 5.5, and 70.9 % CIP was found released at pH 5.5 in the presence of H2O2, which suggests the good biosafety at physiological pH and ROS-responsive drug release of the as-prepared nanoparticle in the bacterial microenvironment. The as-prepared nanoparticles could effectively kill MRSA and disrupt bacterial biofilm by combination of chemo- and photodynamic therapy. In mice model, the as-prepared nanoparticles exhibited excellent biosafety and synergistic effect with 98.81 % healing rate in treatment of MRSA infection, which is considered as a promising candidate in combating drug resistant bacterial infection.
Subject(s)
Metal-Organic Frameworks , Methicillin-Resistant Staphylococcus aureus , Nanoparticles , Photochemotherapy , Photosensitizing Agents , Polylysine , Reactive Oxygen Species , Polylysine/chemistry , Polylysine/pharmacology , Photochemotherapy/methods , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Nanoparticles/chemistry , Animals , Mice , Reactive Oxygen Species/metabolism , Hydrogen-Ion Concentration , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Drug Liberation , Curcumin/pharmacology , Curcumin/chemistry , Staphylococcal Infections/drug therapyABSTRACT
N6-methyladenosine (m6A) is the most prevalent modification in cellular RNA which orchestrates diverse physiological and pathological processes during stress response. However, the differential m6A modifications that cope with herbivore stress in resistant and susceptible crop varieties remain unclear. Here, we found that rice stem borer (RSB) larvae grew better on indica rice (e.g., MH63, IR64, Nanjing 11) than on japonica rice varieties (e.g., Nipponbare, Zhonghua 11, Xiushui 11). Then, transcriptome-wide m6A profiling of representative resistant (Nipponbare) and susceptible (MH63) rice varieties were performed using a nanopore direct RNA sequencing approach, to reveal variety-specific m6A modifications against RSB. Upon RSB infestation, m6A methylation occurred in actively expressed genes in Nipponbare and MH63, but the number of methylation sites decreased across rice chromosomes. Integrative analysis showed that m6A methylation levels were closely associated with transcriptional regulation. Genes involved in herbivorous resistance related to mitogen-activated protein kinase, jasmonic acid (JA), and terpenoid biosynthesis pathways, as well as JA-mediated trypsin protease inhibitors, were heavily methylated by m6A, and their expression was more pronounced in RSB-infested Nipponbare than in RSB-infested MH63, which may have contributed to RSB resistance in Nipponbare. Therefore, dynamics of m6A modifications act as the main regulatory strategy for expression of genes involved in plant-insect interactions, which is attributed to differential responses of resistant and susceptible rice varieties to RSB infestation. These findings could contribute to developing molecular breeding strategies for controlling herbivorous pests.
ABSTRACT
The widespread dissemination of carbapenem-resistant Klebsiella pneumoniae (CRKP) and its drug resistance transfer poses a global public health threat. While previous studies outlined CRKP's drug resistance mechanism, there is limited research on strategies inhibiting CRKP drug resistance spread. This study investigates the potential of Bifidobacterium longum (B. longum) FB1-1, a probiotic, in curbing the spread of drug resistance among CRKP by evaluating its cell-free supernatant (CFS) for antibacterial activity. Evaluating the inhibitory effect of FB1-1 CFS on CRKP drug resistance spread involved analyzing its impact on drug resistance and virulence gene expression; drug resistance plasmid transfer FB1-1 CFS exhibited an MIC range of 125 µL/mL against CRKP. After eight hours of co-culture, CFS achieved a 96% and 100% sterilization rate at two and four times the MIC, respectively. At sub-inhibitory concentrations (1/2× MIC), FB1-1 CFS reduced the expression of the bla_KPC gene, which is pivotal for carbapenem resistance, by up to 62.13% across different CRKP strains. Additionally, it markedly suppressed the expression of the uge gene, a key virulence factor, by up to 91%, and the fim_H gene, essential for bacterial adhesion, by up to 53.4%. Our study primarily focuses on determining the inhibitory effect of FB1-1 CFS on CRKP strains harboring the bla_KPC gene, which is a critical resistance determinant in CRKP. Furthermore, FB1-1 CFS demonstrated the ability to inhibit the transfer of drug resistance plasmids among CRKP strains, thus limiting the horizontal spread of resistance genes. This study highlights FB1-1 CFS's inhibitory effect on CRKP drug resistance spread, particularly in strains carrying the bla_KPC gene, thus offering a novel idea and theoretical foundation for developing antibacterial drugs targeting CRKP resistance.
ABSTRACT
Artemdubosides A-E (1-5), the first examples of natural polyacetylenes substituted by 6'-O-crotonyl ß-glucopyranoside, and artemdubosides F-G (6-7) that were two unusual polyacetylenes featuring a 6'-O-acetyl ß-glucopyranoside moiety, were isolated from Artemisia dubia var. subdigitata. Their structures were elucidated based on the spectral data including HRESIMS, UV, IR, 1D and 2D NMR, and ECD calculations. Antihepatoma assay suggested that compound 1 exhibited activity against HepG2, Huh7, and SK-Hep-1 cells with inhibitory ratios of 77.1%, 90.8%, and 73.1% at 200.0 µM, respectively.