Two Novel Diterpenoid Alkaloids from Aconitum Pendulum.

Two previously uncharacterized compounds, an aconitine-type C19-diterpenoid alkaloid (1) and a napelline-type diterpenoid alkaloid C20-diterpenoid alkaloid (2), as well as ten known compounds (3-12), were isolated from Aconitum pendulum. Their structures were elucidated based on spectroscopic data, including 1D and 2D NMR, IR, HR-ESI-MS, and single-crystal X-ray diffraction analysis. The anti-insecticidal activities of these compounds were evaluated by contact toxicity tests against two-spotted spider mites, and compounds 1, 2, and 9 showed moderate contact toxicity, with LC50 values of 0.86±0.09, 0.95±0.23, and 0.89±0.19 mg/mL, respectively. This study highlights the potential use of diterpenoid alkaloids as natural plant-derived pesticides for the management of plant pests.

Comparative Study on the Satisfaction of Healthcare Service Providers with the Synergistic Development of Rural Healthcare Systems in China: Medical Alliance Counties vs. Non-Medical Alliance Counties.

Introduction: This study aimed to explore whether the establishment of county medical alliances can improve satisfaction with the vertical integration of healthcare systems among rural medical and healthcare service provider managers and service providers. Our study also sought to provide recommendations for the sustainable development of vertical integration in healthcare systems. Methods: A semi-structured interview with 30 healthcare service providers was employed in this research, and Nvivo software was utilized to analyze factors that influence vertical integration. From April to July 2021, a multi-stage random sampling method was used to select participants. The sample included two leading hospitals in medical consortia, 15 member units (healthcare service providers and medical staff), two county-level hospitals, and 15 township health centers/community healthcare service centers from non-medical consortia. Questionnaire surveys were conducted with these groups. Factor analysis was used to calculate satisfaction scores for healthcare service providers with the cross-institutional synergistic development of healthcare systems in both medical and non-medical consortia (denoted as M(IQR)). Propensity score matching was employed to reduce confounding factors between groups. The Mann-Whitney U test was used to compare satisfaction differences between groups. Results: The overall satisfaction scores for lead-county hospital managers, member institution managers, medical staff at the lead-county hospital, and medical staff at member institutions were 4.80 (1.00), 4.17 (1.17), 4.00 (1.38), and 4.00 (1.12), respectively. Lead-county hospital managers' satisfaction with cross-institutional collaboration, development capacity enhancement, and structure and resource integration in the Medical Alliance group showed higher satisfaction than the Non-Medical Alliance. Similarly, lead-county hospital medical staff in the Medical Alliance group reported greater satisfaction with collaboration efforts, supportive environment, and development capacity enhancement. Notably, while the Medical Alliance group's satisfaction scores were higher, the differences between the two groups were not statistically significant for lead-county hospital managers and medical staff. The Medical Alliance group did show statistically significant differences in member institution managers' satisfaction with collaboration, development capacity enhancement, and structure and resource integration. Additionally, medical staff of member institutions in the Medical Alliance group reported statistically significant higher satisfaction with collaboration, supportive environment, development capacity enhancement, healthcare service integration, and human resource development. Conclusion: To facilitate the establishment of county medical alliances, managers of leading county-level hospitals should adopt a healthcare system integration strategy. This strategy involves evolution from being a member of a single institution to a coordinator of cross-institutional vertical integration of medical and healthcare services. Additionally, revamping remuneration and appraisal systems for members of county medical alliances is necessary. This will encourage cooperation among healthcare institutions within the three-tiered system and their medical staff, ultimately facilitating the provision of integrated services.

Single-Shot Intensity- and Phase-Sensitive Compressive Sensing-Based Coherent Modulation Ultrafast Imaging.

Ultrafast imaging can capture the dynamic scenes with a nanosecond and even femtosecond temporal resolution. Complementarily, phase imaging can provide the morphology, refractive index, or thickness information that intensity imaging cannot represent. Therefore, it is important to realize the simultaneous ultrafast intensity and phase imaging for achieving as much information as possible in the detection of ultrafast dynamic scenes. Here, we report a single-shot intensity- and phase-sensitive compressive sensing-based coherent modulation ultrafast imaging technique, shortened as CS-CMUI, which integrates coherent modulation imaging, compressive imaging, and streak imaging. We theoretically demonstrate through numerical simulations that CS-CMUI can obtain both the intensity and phase information of the dynamic scenes with ultrahigh fidelity. Furthermore, we experimentally build a CS-CMUI system and successfully measure the intensity and phase evolution of a multimode Q-switched laser pulse and the dynamical behavior of laser ablation on an indium tin oxide thin film. It is anticipated that CS-CMUI enables a profound comprehension of ultrafast phenomena and promotes the advancement of various practical applications, which will have substantial impact on fundamental and applied sciences.

Phages enhance both phytopathogen density control and rhizosphere microbiome suppressiveness.

Bacteriophages, viruses that specifically target plant pathogenic bacteria, have emerged as a promising alternative to traditional agrochemicals. However, it remains unclear how phages should be applied to achieve efficient pathogen biocontrol and to what extent their efficacy is shaped by indirect interactions with the resident microbiota. Here, we tested if the phage biocontrol efficacy of Ralstonia solanacearum phytopathogenic bacterium can be improved by increasing the phage cocktail application frequency and if the phage efficacy is affected by pathogen-suppressing bacteria already present in the rhizosphere. We find that increasing phage application frequency improves R. solanacearum density control, leading to a clear reduction in bacterial wilt disease in both greenhouse and field experiments with tomato. The high phage application frequency also increased the diversity of resident rhizosphere microbiota and enriched several bacterial taxa that were associated with the reduction in pathogen densities. Interestingly, these taxa often belonged to Actinobacteria known for antibiotics production and soil suppressiveness. To test if they could have had secondary effects on R. solanacearum biocontrol, we isolated Actinobacteria from Nocardia and Streptomyces genera and tested their suppressiveness to the pathogen in vitro and in planta. We found that these taxa could clearly inhibit R. solanacearum growth and constrain bacterial wilt disease, especially when combined with the phage cocktail. Together, our findings unravel an undiscovered benefit of phage therapy, where phages trigger a second line of defense by the pathogen-suppressing bacteria that already exist in resident microbial communities. IMPORTANCE: Ralstonia solanacearum is a highly destructive plant-pathogenic bacterium with the ability to cause bacterial wilt in several crucial crop plants. Given the limitations of conventional chemical control methods, the use of bacterial viruses (phages) has been explored as an alternative biological control strategy. In this study, we show that increasing the phage application frequency can improve the density control of R. solanacearum, leading to a significant reduction in bacterial wilt disease. Furthermore, we found that repeated phage application increased the diversity of rhizosphere microbiota and specifically enriched Actinobacterial taxa that showed synergistic pathogen suppression when combined with phages due to resource and interference competition. Together, our study unravels an undiscovered benefit of phages, where phages trigger a second line of defense by the pathogen-suppressing bacteria present in resident microbial communities. Phage therapies could, hence, potentially be tailored according to host microbiota composition to unlock the pre-existing benefits provided by resident microbiota.

Therapeutic targeting of ARID1A-deficient cancer cells with RITA (Reactivating p53 and inducing tumor apoptosis).

ARID1A, a component of the SWI/SNF chromatin-remodeling complex, is frequently mutated in various cancer types and has emerged as a potential therapeutic target. In this study, we observed that ARID1A-deficient colorectal cancer (CRC) cells showed synthetic lethal effects with a p53 activator, RITA (reactivating p53 and inducing tumor apoptosis). RITA, an inhibitor of the p53-MDM2 interaction, exhibits increased sensitivity in ARID1A-deficient cells compared to ARID1A wild-type cells. Mechanistically, the observed synthetic lethality is dependent on both p53 activation and DNA damage accumulation, which are regulated by the interplay between ARID1A and RITA. ARID1A loss exhibits an opposing effect on p53 targets, leading to decreased p21 expression and increased levels of proapoptotic genes, PUMA and NOXA, which is further potentiated by RITA treatment, ultimately inducing cell apoptosis. Meanwhile, ARID1A loss aggravates RITA-induced DNA damage accumulation by downregulating Chk2 phosphorylation. Taken together, ARID1A loss significantly heightens sensitivity to RITA in CRC, revealing a novel synthetic lethal interaction between ARID1A and RITA. These findings present a promising therapeutic approach for colorectal cancer characterized by ARID1A loss-of-function mutations.

Machine Learning Model Based on Radiomics for Preoperative Differentiation of Jaw Cystic Lesions.

OBJECTIVE: This study aims to use machine learning techniques together with radiomics methods to build a preoperative predictive diagnostic model from spiral computed tomography (CT) images. The model is intended for the differential diagnosis of common jaw cystic lesions. STUDY DESIGN: Retrospective, case-control study. SETTING: This retrospective study was conducted at Sun Yat-sen Memorial Hospital of Sun Yat-sen University (Guangzhou, Guangdong, China). All the data used to build the predictive diagnostic model were collected from 160 patients, who were treated at the Department of Oral and Maxillofacial Surgery at Sun Yat-sen Memorial Hospital of Sun Yat-sen University between 2019 and 2023. METHODS: We included a total of 160 patients in this study. We extracted 107 radiomic features from each patient's CT scan images. After a feature selection process, we chose 15 of these radiomic features to construct the predictive diagnostic model. RESULTS: Among the preoperative predictive diagnostic models built using 3 different machine learning methods (support vector machine, random forest [RF], and multivariate logistic regression), the RF model showed the best predictive performance. It demonstrated a sensitivity of 0.923, a specificity of 0.643, an accuracy of 0.825, and an area under the receiver operating characteristic curve of 0.810. CONCLUSION: The preoperative predictive model, based on spiral CT radiomics and machine learning algorithms, shows promising differential diagnostic capabilities. For common jaw cystic lesions, this predictive model has potential clinical application value, providing a scientific reference for treatment decisions.

Biocompatible 2D Materials via Liquid Phase Exfoliation.

2D materials (2DMs), such as graphene, transition metal dichalcogenides (TMDs), and black phosphorus (BP), have been proposed for different types of bioapplications, owing to their unique physicochemical, electrical, optical, and mechanical properties. Liquid phase exfoliation (LPE), as one of the most effective up-scalable and size-controllable methods, is becoming the standard process to produce high quantities of various 2DM types as it can benefit from the use of green and biocompatible conditions. The resulting exfoliated layered materials have garnered significant attention because of their biocompatibility and their potential use in biomedicine as new multimodal therapeutics, antimicrobials, and biosensors. This review focuses on the production of LPE-assisted 2DMs in aqueous solutions with or without the aid of surfactants, bioactive, or non-natural molecules, providing insights into the possibilities of applications of such materials in the biological and biomedical fields.

Biomechanical analysis of the maxillary sinus floor membrane during internal sinus floor elevation with implants at different angles of the maxillary sinus angles.

OBJECTIVE: This study analyzed and compared the biomechanical properties of maxillary sinus floor mucosa with implants at three different maxillary sinus angles during a modified internal sinus floor elevation procedure. METHODS: 3D reconstruction of the implant, maxillary sinus bone, and membrane were performed. The maxillary sinus model was set at three different angles. Two internal maxillary sinus elevation models were established, and finite element analysis was used to simulate the modified maxillary sinus elevation process. The implant was elevated to 10 mm at three maxillary sinus angles when the maxillary sinus floor membrane was separated by 0 and 4 mm. The stress of the maxillary sinus floor membrane was analyzed and compared. RESULTS: When the maxillary sinus floor membrane was separated by 0 mm and elevated to 10 mm, the peak stress values of the implant on the maxillary sinus floor membrane at three different angles were as follows: maxillary sinus I: 5.14-78.32 MPa; maxillary sinus II: 2.81-73.89 MPa; and maxillary sinus III: 2.82-51.87 MPa. When the maxillary sinus floor membrane was separated by 4 mm and elevated to 10 mm, the corresponding values were as follows: maxillary sinus I: 0.50-7.25 MPa; maxillary sinus II: 0.81-16.55 MPa; and maxillary sinus III: 0.49-22.74 MPa. CONCLUSION: The risk of sinus floor membrane rupture is greatly reduced after adequate dissection of the maxillary sinus floor membrane when performing modified internal sinus elevation in a narrow maxillary sinus. In a wide maxillary sinus, the risk of rupture or perforation of the wider maxillary sinus floor is reduced, regardless of whether traditional or modified internal sinus elevation is performed at the same height.

Navigation-based endoscopic enucleation (NBEE) of large mandibular cystic lesions involving the ramus.

OBJECTIVE: The aim of this study was to present an innovative surgical protocol, navigation-based endoscopic enucleation (NBEE) for the treatment of large mandibular cystic lesions involving the mandibular ramus. METHODS: Twelve patients who presented with a large mandibular cystic lesion involving the mandibular ramus were enrolled in this study. Preoperative planning and intraoperative navigation were performed in all 12 patients. RESULTS: All patients in this study were treated with navigation-based endoscopic enucleation successfully. The follow-up period ranged from 7 to 10 months. Bone regenerated was found in all patients postoperatively. Three patients experienced temporary mandibular nerve palsy, and all relieved within 2 months. No pathological bone fracture was found during surgery. CONCLUSIONS: The use of navigation-based endoscopic enucleation (NBEE) for the treatment of large mandibular cystic lesions involving the ramus proved to be an effective method for complete and precise enucleation of the cystic lesion that also preserved the surrounding tissue.

Unveiling Liquid-Phase Exfoliation of Graphite and Boron Nitride Using Fluorescent Dyes Through Combined Experiments and Simulations.

Liquid-phase exfoliation (LPE) in aqueous solutions provides a simple, scalable, and green approach to produce 2D materials. By combining atomistic simulations with exfoliation experiments, the interaction between a surfactant and a 2D layer at the molecular scale can be better understood. In this work, two different dyes, corresponding to rhodamine B base (Rbb) and to a phenylboronic acid BODIPY (PBA-BODIPY) derivative, are employed as dispersants to exfoliate graphene and hexagonal boron nitride (hBN) through sonication-assisted LPE. The exfoliated 2D sheets, mostly as few-layers, exhibit good quality and high loading of dyes. Using molecular dynamics (MD) simulations, the binding free energies are calculated and the arrangement of both dyes on the layers are predicted. It has been found that the dyes show a higher affinity toward hBN than graphene, which is consistent with the higher yields of exfoliated hBN. Furthermore, it is demonstrated that the adsorption behavior of Rbb molecules on graphene and hBN is quite different compared to PBA-BODIPY.

Bulk Schottky Junctions-Based Flexible Triboelectric Nanogenerators to Power Backscatter Communications in Green 6G Networks.

This work introduces a novel method to construct Schottky junctions to boost the output performance of triboelectric nanogenerators (TENGs). Perovskite barium zirconium titanate (BZT) core/metal silver shell nanoparticles are synthesized to be embedded into electrospun polyvinylidene fluoride-co-hexafluoropropylene (PVDF-HFP) nanofibers before they are used as tribo-negative layers. The output power of TENGs with composite fiber mat exhibited >600% increase compared to that with neat polymer fiber mat. The best TENG achieved 1339 V in open-circuit voltage, 40 µA in short-circuit current and 47.9 W m-2 in power density. The Schottky junctions increased charge carrier density in tribo-layers, ensuring a high charge transfer rate while keeping the content of conductive fillers low, thus avoiding charge loss and improving performance. These TENGs are utilized to power radio frequency identification (RFID) tags for backscatter communication (BackCom) systems, enabling ultra-massive connectivity in the 6G wireless networks and reducing information communications technology systems' carbon footprint. Specifically, TENGs are used to provide an additional energy source to the passive tags. Results show that TENGs can boost power for BackCom and increase the communication range by 386%. This timely contribution offers a novel route for sustainable 6G applications by exploiting the expanded communication range of BackCom tags.

Pulmonary Toxicity of Boron Nitride Nanomaterials Is Aspect Ratio Dependent.

Boron nitride (BN) nanomaterials have drawn a lot of interest in the material science community. However, extensive research is still needed to thoroughly analyze their safety profiles. Herein, we investigated the pulmonary impact and clearance of two-dimensional hexagonal boron nitride (h-BN) nanosheets and boron nitride nanotubes (BNNTs) in mice. Animals were exposed by single oropharyngeal aspiration to h-BN or BNNTs. On days 1, 7, and 28, bronchoalveolar lavage (BAL) fluids and lungs were collected. On one hand, adverse effects on lungs were evaluated using various approaches (e.g., immune response, histopathology, tissue remodeling, and genotoxicity). On the other hand, material deposition and clearance from the lungs were assessed. Two-dimensional h-BN did not cause any significant immune response or lung damage, although the presence of materials was confirmed by Raman spectroscopy. In addition, the low aspect ratio h-BN nanosheets were internalized rapidly by phagocytic cells present in alveoli, resulting in efficient clearance from the lungs. In contrast, high aspect ratio BNNTs caused a strong and long-lasting inflammatory response, characterized by sustained inflammation up to 28 days after exposure and the activation of both innate and adaptive immunity. Moreover, the presence of granulomatous structures and an indication of ongoing fibrosis as well as DNA damage in the lung parenchyma were evidenced with these materials. Concurrently, BNNTs were identified in lung sections for up to 28 days, suggesting long-term biopersistence, as previously demonstrated for other high aspect ratio nanomaterials with poor lung clearance such as multiwalled carbon nanotubes (MWCNTs). Overall, we reveal the safer toxicological profile of BN-based two-dimensional nanosheets in comparison to their nanotube counterparts. We also report strong similarities between BNNTs and MWCNTs in lung response, emphasizing their high aspect ratio as a major driver of their toxicity.

Fracture identification and characteristics of carbonate underground gas storage: an example from the eastern area of Sulige gas field, ordos Basin, China.

The carbonate rock formations have obvious dual media characteristics, fracture development and good physical conditions, which are the main seepage channels and storage spaces for gas after the reconstruction of underground gas storage. The carbonate strata of the Ordovician system are important natural gas reservoirs in the eastern area of Sulige Gas Field in the Ordos Basin, and the identification and characterization of their fractures are of great significance for the modeling of fractures in the later stage and the improvement of the operation scheme of the gas storage. At present, there is little research on fractures, which restricts exploration and development. Therefore, taking the 39-61 gas storage reservoir in the eastern area of Sulige Gas Field in the Ordos Basin as the research object, this paper identifies and studies the characteristics of the fractures by core, microscopic, conventional logging curves, and imaging logging identification. The results show that the fracture length ranges from 5 to 15 cm and the width ranges from 0.1 to 3 mm. The fracture angles are mostly between 75° and 90° and the main direction is NW-SE. In conventional logging curves, porosity logging has a good response to fractures, while resistivity logging has a general response to fractures; In layers with more developed fractures, natural gamma values are mostly higher than 40API, rock volume density is less than 2.8 g/cm3, neutron porosity is greater than 12.5%, and acoustic time difference is greater than 160 µ s/m. This study is of great significance for improving the identification of carbonate fractures, enriching the relevant theories, and providing guidance for the construction of carbonate gas storage.

ZnS/CoS@C Derived from ZIF-8/67 Rhombohedral Dodecahedron Dispersed on Graphene as High-Performance Anode for Sodium-Ion Batteries.

Metal sulfides are highly promising anode materials for sodium-ion batteries due to their high theoretical capacity and ease of designing morphology and structure. In this study, a metal-organic framework (ZIF-8/67 dodecahedron) was used as a precursor due to its large specific surface area, adjustable pore structure, morphology, composition, and multiple active sites in electrochemical reactions. The ZIF-8/67/GO was synthesized using a water bath method by introducing graphene; the dispersibility of ZIF-8/67 was improved, the conductivity increased, and the volume expansion phenomenon that occurs during the electrochemical deintercalation of sodium was prevented. Furthermore, vulcanization was carried out to obtain ZnS/CoS@C/rGO composite materials, which were tested for their electrochemical properties. The results showed that the ZnS/CoS@C/rGO composite was successfully synthesized, with dodecahedrons dispersed in large graphene layers. It maintained a capacity of 414.8 mAh g-1 after cycling at a current density of 200 mA g-1 for 70 times, exhibiting stable rate performance with a reversible capacity of 308.0 mAh g-1 at a high current of 2 A g-1. The excellent rate performance of the composite is attributed to its partial pseudocapacitive contribution. The calculation of the diffusion coefficient of Na+ indicates that the rapid sodium ion migration rate of this composite material is also one of the reasons for its excellent performance. This study highlights the broad application prospects of metal-organic framework-derived metal sulfides as anode materials for sodium-ion batteries.

Development of breeder chip for gene detection and molecular-assisted selection by target sequencing in wheat.

Wheat is an essential food crop and its high and stable yield is suffering from great challenges due to the limitations of current breeding technology and various stresses. Accelerating molecularly assisted stress-resistance breeding is critical. Through a meta-analysis of published loci in wheat over the last two decades, we selected 60 loci with main breeding objectives, high heritability, and reliable genotyping, such as stress resistance, yield, plant height, and resistance to spike germination. Then, using genotyping by target sequencing (GBTS) technology, we developed a liquid phase chip based on 101 functional or closely linked markers. The genotyping of 42 loci was confirmed in an extensive collection of Chinese wheat cultivars, indicating that the chip can be used in molecular-assisted selection (MAS) for target breeding goals. Besides, we can perform the preliminary parentage analysis with the genotype data. The most significant contribution of this work lies in translating a large number of molecular markers into a viable chip and providing reliable genotypes. Breeders can quickly screen germplasm resources, parental breeding materials, and intermediate materials for the presence of excellent allelic variants using the genotyping data by this chip, which is high throughput, convenient, reliable, and cost-efficient. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01359-3.

Anti-inflammatory ent-cleistanthane-type diterpenoids from Phyllanthus rheophyticus.

A bioactivity-guided isolation from the aerial parts of Phyllanthus rheophyticus obtained 17 undescribed ent-cleistanthane-type diterpenoids, namely phyllarheophols A-Q, as well as 12 known analogs. Their structures were characterized by a combination of spectroscopic data interpretation, single-crystal X-ray diffraction and ECD analysis. The anti-inflammatory activities of these compounds were evaluated by measuring their inhibitory effects on NO production in LPS-stimulated RAW264.7 macrophages, and their preliminary structure-activity relationships were also discussed. Further study showed that promising compounds phyllarheophol D and phyacioid B significantly suppressed the expressions of cytokines and nitric oxide synthase through the NF-κB signaling pathway.

The pattern from the first three rounds of vaccination: declining vaccination rates.

Introduction: Vaccination rates for the COVID-19 vaccine have recently been stagnant worldwide. We aim to analyze the potential patterns of vaccination development from the first three doses to reveal the possible trends of the next round of vaccination and further explore the factors influencing vaccination in the selected populations. Methods: On July 2022, a stratified multistage random sampling method in the survey was conducted to select 6,781 people from 4 provinces China, who were above the age of 18 years. Participants were divided into two groups based on whether they had a chronic disease. The data were run through Cochran-Armitage trend test and multivariable regression analyses. Results: A total of 957 participants with chronic disease and 5,454 participants without chronic disease were included in this survey. Vaccination rates for the first, second and booster doses in chronic disease population were93.70% (95% CI: 92.19-95.27%), 91.12% (95%CI: 94.43-95.59%), and 83.18% (95%CI: 80.80-85.55%) respectively. By contrast, the first, second and booster vaccination rates for the general population were 98.02% (95% CI: 97.65-98.39%), 95.01% (95% CI: 94.43-95.59%) and 85.06% (95% CI: 84.11-86.00%) respectively. The widening gap in vaccination rates was observed as the number of vaccinations increases. Higher self-efficacy was a significant factor in promoting vaccination, which has been observed in all doses of vaccines. Higher education level, middle level physical activity and higher public prevention measures play a positive role in vaccination among the general population, while alcohol consumption acts as a significant positive factor in the chronic disease population (p < 0.05). Conclusion: As the number of vaccinations increases, the trend of decreasing vaccination rate is becoming more pronounced. In future regular vaccinations, we may face low vaccination rates as the increasing number of infections and the fatigue associated with the prolonged outbreak hamper vaccination. Measures need to be found to counter this downward trend such as improving the self-efficacy of the population.

Diterpenoids with an unusual tricyclo[10.3.0.02,9]pentadecane skeleton from Pedilanthus tithymaloides as multidrug resistance modulators.

Three new diterpenoids with an unusual carbon skeleton, pedilanins A-C (1-3), and nine new jatrophane diterpenoids, pedilanins D-L (4-12), along with five known ones (13-17), were isolated from Pedilanthus tithymaloides. Compounds 1-3 characterize an unprecedented tricyclo[10.3.0.02,9]pentadecane skeleton. Compounds 4-8 are rare examples of the jatrophanes bearing a cyclic hemiketal substructure. Their structures were determined by an extensive analysis of HRESIMS, NMR, quantum-chemical calculation, DP4+ probability, and X-ray crystallographic data. In the bioassay, compounds 1-12 dramatically reversed multidrug resistance in cancer cells with the fold-reversals ranging from 17.9 to 396.8 at the noncytotoxic concentration of 10 µM. The mechanism results indicated that compounds 2 and 3 inhibited the P-glycoprotein (Pgp) transporter function, thus reversing the drug resistance.

Arabidopsis AUTOPHAGY-RELATED2 is essential for ATG18a and ATG9 trafficking during autophagosome closure.

As a fundamental metabolic pathway, autophagy plays important roles in plant growth and development, particularly under stress conditions. A set of autophagy-related (ATG) proteins is recruited for the formation of a double-membrane autophagosome. Among them, the essential roles of ATG2, ATG18, and ATG9 have been well established in plant autophagy via genetic analysis; however, the underlying molecular mechanism for ATG2 in plant autophagosome formation remains poorly understood. In this study, we focused on the specific role of ATG2 in the trafficking of ATG18a and ATG9 during autophagy in Arabidopsis (Arabidopsis thaliana). Under normal conditions, YFP-ATG18a proteins are partially localized on late endosomes and translocated to ATG8e-labeled autophagosomes upon autophagic induction. Real-time imaging analysis revealed sequential recruitment of ATG18a on the phagophore membrane, showing that ATG18a specifically decorated the closing edges and finally disassociated from the completed autophagosome. However, in the absence of ATG2, most of the YFP-ATG18a proteins are arrested on autophagosomal membranes. Ultrastructural and 3D tomography analysis showed that unclosed autophagosome structures are accumulated in the atg2 mutant, displaying direct connections with the endoplasmic reticulum membrane and vesicular structures. Dynamic analysis of ATG9 vesicles suggested that ATG2 depletion also affects the association between ATG9 vesicles and the autophagosomal membrane. Furthermore, using interaction and recruitment analysis, we mapped the interaction relationship between ATG2 and ATG18a, implying a possible role of ATG18a in recruiting ATG2 and ATG9 to the membrane. Our findings unveil a specific role of ATG2 in coordinating ATG18a and ATG9 trafficking to mediate autophagosome closure in Arabidopsis.