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Ectopic expression of lineage-specific transcription factors (TFs) of another cell type can induce cell fate reprogramming. However, the heterogeneity of reprogramming cells has been a challenge for data interpretation and model evaluation. Here, we present a protocol to characterize cells expressing defined factors during direct cell reprogramming using a factor-indexing approach based on single-nuclei multiome sequencing (FI-snMultiome-seq). We describe the steps for barcoding TFs, converting human fibroblasts to pancreatic ductal-like cells using defined TFs, and preparing library for FI-snMultiome-seq analysis. For complete details on the use and execution of this protocol, please refer to Fei et al.1.
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The dysbiosis of microbiota has been reported to be associated with numerous human pathophysiological processes, including inflammatory bowel disease (IBD). With advancements in high-throughput sequencing, various methods have been developed to study the alteration of microbiota in the development and progression of diseases. However, a suitable approach to assess the global stability of the microbiota in disease states through time-series microbiome data is yet to be established. In this study, we have introduced a novel Energy Landscape construction method, which incorporates the Latent Dirichlet Allocation (LDA) model and the pairwise Maximum Entropy (MaxEnt) model for their complementary advantages, and demonstrate its utility by applying it to an IBD time-series dataset. Through this approach, we obtained the microbial assemblages' energy profile of the whole microbiota under the IBD condition and uncovered the hidden stable stages of microbiota structure during the disease development with time-series microbiome data. The Bacteroides-dominated assemblages presenting in multiple stable states suggest the potential contribution of Bacteroides and interactions with other microbial genera, like Alistipes, and Faecalibacterium, to the development of IBD. Our proposed method provides a novel and insightful tool for understanding the alteration and stability of the microbiota under disease states and offers a more holistic view of the complex dynamics at play in microbiota-mediated diseases.
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Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Doenças Inflamatórias Intestinais/microbiologia , Humanos , Bactérias/genética , Bactérias/classificação , Bactérias/isolamento & purificação , Entropia , Disbiose/microbiologia , Bacteroides/genéticaRESUMO
Expanded graphite (EG) stands out as a promising material for the negative electrode in potassium-ion batteries. However, its full potential is hindered by the limited diffusion pathway and storage sites for potassium ions, restricting the improvement of its electrochemical performance. To overcome this challenge, defect engineering emerges as a highly effective strategy to enhance the adsorption and reaction kinetics of potassium ions on electrode materials. This study delves into the specific effectiveness of defects in facilitating potassium storage, exploring the impact of defect-rich structures on dynamic processes. Employing ball milling, we introduce surface defects in EG, uncovering unique effects on its electrochemical behavior. These defects exhibit a remarkable ability to adsorb a significant quantity of potassium ions, facilitating the subsequent intercalation of potassium ions into the graphite structure. Consequently, this process leads to a higher potassium voltage. Furthermore, the generation of a diluted stage compound is more pronounced under high voltage conditions, promoting the progression of multiple stage reactions. Consequently, the EG sample post-ball milling demonstrates a notable capacity of 286.2 mAh g-1 at a current density of 25 mA g-1, showcasing an outstanding rate capability that surpasses that of pristine EG. This research not only highlights the efficacy of defect engineering in carbon materials but also provides unique insights into the specific manifestations of defects on dynamic processes, contributing to the advancement of potassium-ion battery technology.
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Continuous and effective hydrogen evolution under high current densities remains a challenge for water electrolysis owing to the rapid performance degradation under continuous large-current operation. In this study, theoretical calculations, operando Raman spectroscopy, and CO stripping experiments confirm that Ru nanocrystals have a high resistance against deactivation because of the synergistic adsorption of OH intermediates (OHad) on the Ru and single atoms. Based on this conceptual model, we design the Ni single atoms modifying ultra-small Ru nanoparticle with defect carbon bridging structure (UP-RuNiSAs/C) via a unique unipolar pulse electrodeposition (UPED) strategy. As a result, the UP-RuNiSAs/C is found capable of running steadily for 100 h at 3 A cm-2, and shows a low overpotential of 9 mV at a current density of 10 mA cm-2 under alkaline conditions. Moreover, the UP-RuNiSAs/C allows an anion exchange membrane (AEM) electrolyzer to operate stably at 1.95 Vcell for 250 h at 1 A cm-2.
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Currently, the desired research focus in energy storage technique innovation has been gradually shifted to next-generation aqueous batteries holding both high performance and sustainability. However, aqueous Zn-I2 batteries have been deemed to have great sustainable potential, owing to the merits of cost-effective and eco-friendly nature. However, their commercial application is hindered by the serious shuttle effect of polyiodides during reversible operations. In this work, a Janus functional binder based on chitosan (CTS) molecules was designed and prepared; the polar terminational groups impart excellent mechanical robustness to hybrid binders; meanwhile, it can also deliver isochronous enhancement on physical adsorption and redox kinetics toward I2 species. By feat of highly effective remission to shuttle effect, the CTS cell exhibits superb electrochemical storage capacities with long-term robustness, specifically, 144.1 mAh g-1, at a current density of 0.2 mA g-1 after 1500 cycles. Simultaneously, the undesired self-discharging issue could be also well-addressed; the Coulombic efficiency could remain at 98.8 % after resting for 24 h. More importantly, CTS molecules endow good biodegradability and reusable properties; after iodine species were reloaded, the recycled devices could also deliver specific capacities of 73.3 mAh g-1, over 1000 cycles. This Janus binder provides a potential synchronous solution to realize high comprehensive performance with high iodine utilization and further make it possible for sustainable Zn-I2 batteries.
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Cu(II) supramolecular assemblies [Cu2(tipe)2(H2O)2](NO3)4·2.5H2O (CuN4) and [Cu2Cl4(tipe)(CH3CN)]·H2O (CuN2Cl2) (tipe = 1,1,2,2-tetrakis(4-(imidazole-1-yl)phenyl)ethene) were synthesized and utilized for photocatalytic CO2 reduction. CuN4 exhibits CO production of up to 891 µmol gcat-1 with a selectivity of 79.9%, while CuN2Cl2 gives low CO production of 206 µmol gcat-1 but with a high selectivity of >99.9% in 5 h. The experimental and DFT calculation results indicate that the coordination environment and non-covalent interactions within the assemblies have a great impact on the photocatalytic CO2 reduction behavior. This work provides useful insights on Cu(II) assembly catalyzed CO2 photoreduction.
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Sodium-ion batteries (SIBs) have gradually become one of the most promising energy storage techniques in the current era of post-lithium-ion batteries. For anodes, transitional metal selenides (TMSe) based materials are welcomed choices , owing to relatively higher specific capacities and enriched redox active sites. Nevertheless, current bottlenecks are blamed for their poor intrinsic electronic conductivities, and uncontrollable volume expansion during redox reactions. Given that, an interfacial-confined isochronous conversion strategy is proposed, to prepare orthorhombic/cubic biphasic TMSe heterostructure, namely CuSe/Cu3 VSe4 , through using MXene as the precursor, followed by Cu/Se dual anchorage. As-designed biphasic TMSe heterostructure endows unique hierarchical structure, which contains adequate insertion sites and diffusion spacing for Na ions, besides, the surficial pseudocapacitive storage behaviors can be also proceeded like 2D MXene. By further investigation on electronic structure, the theoretical calculations indicate that biphasic CuSe/Cu3 VSe4 anode exhibits well-enhanced properties, with smaller bandgap and thus greatly improves intrinsic poor conductivities. In addition, the dual redox centers can enhance the electrochemical Na ions storage abilities. As a result, the as-designed biphasic TMSe anode can deliver a reversible specific capacity of 576.8 mAh g-1 at 0.1 A g-1 , favorable Na affinity, and reduced diffusion barriers. This work discloses a synchronous solution toward demerits in conductivities and lifespan, which is inspiring for TMSe-based anode development in SIBs systems.
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Since sodium-ion batteries (SIBs) have become increasingly commercialized in recent years, Na3V2(PO4)2O2F (NVPOF) offers promising economic potential as a cathode for SIBs because of its high operating voltage and energy density. According to reports, NVPOF performs poorly in normal commercial poly(vinylidene fluoride) (PVDF) binder systems and performs best in combination with aqueous binder. Although in line with the concept of green and sustainable development for future electrode preparation, aqueous binders are challenging to achieve high active material loadings at the electrode level, and their relatively high surface tension tends to cause the active material on the electrode sheet to crack or even peel off from the collector. Herein, a cross-linkable and easily commercial hybrid binder constructed by intermolecular hydrogen bonding (named HPP) has been developed and utilized in an NVPOF system, which enables the generation of a stable cathode electrolyte interphase on the surface of active materials. According to theoretical simulations, the HPP binder enhances electronic/ionic conductivity, which greatly lowers the energy barrier for Na+ migration. Additionally, the strong hydrogen-bond interactions between the HPP binder and NVPOF effectively prevent electrolyte corrosion and transition-metal dissolution, lessen the lattice volume effect, and ensure structural stability during cycling. The HPP-based NVPOF offers considerably improved rate capability and cycling performance, benefiting from these benefits. This comprehensive binder can be extended to the development of next-generation energy storage technologies with superior performance.
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The design and synthesis of metal-organic frameworks (MOFs) as photocatalytic molecular reactors for varied reactions have drawn great attention. In this work, we designed a novel photoactive perylenediimides-based (PDI) carboxylate ligand N,N'-di(3',3",5',5"-tetrakis(4-carboxyphenyl))-1,2,6,7-tetrachloroperylene-3,4,9,10-tetracarboxylic acid diimide (Cl-PDI-TA) and use it to successfully synthesize a novel Zr(IV)-based MOF 1 constructed from [Zr6 O8 (H2 O)8 ]8+ clusters bridged by Cl-PDI-TA ligands. Structural analysis revealed that Zr-MOF 1 manifests a 3D framework with (4,8)-connected csq topology and possesses triangular channels of ~17â Å and mesoporous hexagonal channels of ~26â Å along c-axis. Moreover, the synthesized Zr-MOF 1 exhibits visible-light absorption and efficient photoinduced free radical generation property, making it a promising photocatalytic molecular reactor. When Zr-MOF 1 was used as a photocatalyst for the aerobic oxidation of sulfides under irradiation of visible light, it could afford the corresponding sulfoxides with high yield and selectivity. Experimental results demonstrated that the substrate sulfides could be fixed in the pores of 1 and directly transformed to the products sulfoxides in the solid state. Furthermore, the mechanism for the photocatalytic transformation was also investigated and the results revealed that the singlet oxygen (1 O2 ) and superoxide radical (O2 â - ) generated by the energy transfer and electron transfer from the photoexcited Zr-MOF to oxidants were the main active species for the catalytic reactions. This work offers a perceptive comprehension of the mechanism in PDI-based MOFs for further study on photocatalytic reactions.
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Cell fate can be reprogrammed by ectopic expression of lineage-specific transcription factors (TFs). However, the exact cell state transitions during transdifferentiation are still poorly understood. Here, we have generated pancreatic exocrine cells of ductal epithelial identity from human fibroblasts using a set of six TFs. We mapped the molecular determinants of lineage dynamics using a factor-indexing method based on single-nuclei multiome sequencing (FI-snMultiome-seq) that enables dissecting the role of each individual TF and pool of TFs in cell fate conversion. We show that transition from mesenchymal fibroblast identity to epithelial pancreatic exocrine fate involves two deterministic steps: an endodermal progenitor state defined by activation of HHEX with FOXA2 and SOX17 and a temporal GATA4 activation essential for the maintenance of pancreatic cell fate program. Collectively, our data suggest that transdifferentiation-although being considered a direct cell fate conversion method-occurs through transient progenitor states orchestrated by stepwise activation of distinct TFs.
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Epigenoma , Pâncreas , Humanos , Fibroblastos , Diferenciação Celular/genética , Transdiferenciação Celular/genéticaRESUMO
OBJECTIVES: Meal timing is a major risk factor for metabolic disease. The aim of this study was to assess the relationship between dinner timing and glucose metabolism in the rural Chinese population. METHODS: This cross-sectional study included 7701 participants from a Henan rural cohort study. Basic information was collected by in-person questionnaires. Multiple linear regression analysis was used to evaluate the relationship between dinner timing and fasting insulin (FINS), fasting plasma glucose (FPG), and homeostatic model assessment for insulin resistance (HOMA-IR). Restricted cubic spline was employed to investigate the dose-response relationship between dinner timing and FINS, FPG, and HOMA-IR. A generalized linear model was used to explore the interaction effect of age and dinner timing on FINS, FPG, and HOMA-IR. RESULTS: After adjusting for confounding factors, FINS concentration was reduced by 0.482 mmol/L (P < 0.001) for each hour delay in dinner timing. Furthermore, the HOMA-IR index decreased by 0.122 mmol/L for each hour delay. The results indicated a noticeable trend of decreasing values associated with later dinner timing (FINS: Poverall association < 0.001, Pnonlinear association = 0.144; HOMA-IR: Poverall association = 0.001, Pnonlinear association = 0.186). The interaction between age and dinner time significantly correlated with FINS and HOMA-IR (P < 0.05). This relationship was statistically significant before 69 y (P < 0.05). CONCLUSION: A significant association between dinner timing and glucose metabolism was observed in the rural Chinese population. Delayed dinner timing may be associated with lower fasting insulin. The negative effect of dinner timing on FINS and HOMA-IR was diminished with age.
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Wnt pathway dysregulation through genetic and non-genetic alterations occurs in multiple cancers, including ovarian cancer (OC). The aberrant expression of the non-canonical Wnt signaling receptor ROR1 is thought to contribute to OC progression and drug resistance. However, the key molecular events mediated by ROR1 that are involved in OC tumorigenesis are not fully understood. Here, we show that ROR1 expression is enhanced by neoadjuvant chemotherapy, and Wnt5a binding to ROR1 can induce oncogenic signaling via AKT/ERK/STAT3 activation in OC cells. Proteomics analysis of isogenic ROR1-knockdown OC cells identified STAT3 as a downstream effector of ROR1 signaling. Transcriptomics analysis of clinical samples (n = 125) revealed that ROR1 and STAT3 are expressed at higher levels in stromal cells than in epithelial cancer cells of OC tumors, and these findings were corroborated by multiplex immunohistochemistry (mIHC) analysis of an independent OC cohort (n = 11). Our results show that ROR1 and its downstream STAT3 are co-expressed in epithelial as well as stromal cells of OC tumors, including cancer-associated fibroblasts or CAFs. Our data provides the framework to expand the clinical utility of ROR1 as a therapeutic target to overcome OC progression.
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Ovarian high-grade serous carcinoma (HGSC) is typically diagnosed at an advanced stage, with multiple genetically heterogeneous clones existing in the tumors long before therapeutic intervention. Herein we integrate clonal composition and topology using whole-genome sequencing data from 510 samples of 148 patients with HGSC in the prospective, longitudinal, multiregion DECIDER study. Our results reveal three evolutionary states, which have distinct features in genomics, pathways, and morphological phenotypes, and significant association with treatment response. Nested pathway analysis suggests two evolutionary trajectories between the states. Experiments with five tumor organoids and three PI3K inhibitors support targeting tumors with enriched PI3K/AKT pathway with alpelisib. Heterogeneity analysis of samples from multiple anatomical sites shows that site-of-origin samples have 70% more unique clones than metastatic tumors or ascites. In conclusion, these analysis and visualization methods enable integrative tumor evolution analysis to identify patient subtypes using data from longitudinal, multiregion cohorts.
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Cistadenocarcinoma Seroso , Neoplasias das Tubas Uterinas , Neoplasias Ovarianas , Feminino , Humanos , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/genética , Estudos Prospectivos , Cistadenocarcinoma Seroso/metabolismo , Neoplasias das Tubas Uterinas/genéticaRESUMO
Covalent organic frameworks (COFs) have received increased interest in recent years as an advanced class of materials. By virtue of the available monomers, multiple conformations and various linkages, COFs offer a wide range of opportunities for complex structural design and specific functional development of materials, which has facilitated the widespread application in many fields, including multi-valent metal ion batteries (MVMIBs), described as the attractive candidate replacing lithium-ion batteries (LIBs). With their robust skeletons, diverse pores, flexible structures and abundant functional groups, COFs are expected to help realize a high performance MVMIBs. In this review, we present an overview of COFs, describe advances in topology design and synthetic reactions, and study the application of COFs in MVMIBs, as well as discuss challenges and solutions in the preparation of COFs electrodes, in the hope of providing constructive insights into the future direction of COFs.
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Designing highly active and durable oxygen evolution reaction (OER) electrocatalysts is indispensable for promoting the sluggish reaction kinetics of OER to achieve low overpotential. RuO2 is one of the representative oxygen evolution electrocatalysts in acid electrolytes, but it still faces the problem of poor stability. Herein, RuO2 nanocrystal with an ultra-small size of approximately 3.5 nm loaded on N-doped hierarchical porous carbon (NHC) is successfully synthesized by RuCl3 dipping, followed by an annealing process. It is found that NHC is assembled of porous nanosheets with a high specific surface area (BET up to 2107 m2 g-1), which could provide more active sites for RuO2 loading and enable decorated catalysts to be effectively utilized. Combining the advantages of porous NHC and the high electrocatalytic activity of RuO2, the optimized electrocatalyst RuO2/NHC3 achieves a low overpotential of 186 mV at 10 mA cm-2 for acidic water oxidation with a Tafel slope as low as 60 mV dec-1 and maintains excellent long-term stability throughout the 27 h chronopotentiometry test in 0.5 M H2SO4. The elevated acidic OER activity and stability can be attributed to the diminutive size, abundant oxygen vacancies, and enlarged electrochemically active surface area of RuO2/NHC3. This work could provide opportunities to explore efficient anodic electrocatalysts in acidic media.
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Most patients with ovarian cancer (OC) are diagnosed at a late stage when there are very few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or an oncogenic addiction that can be targeted pharmacologically, unlike other types of cancer. Here, we identified protein tyrosine kinase 7 (PTK7) as a potential new therapeutic target in OC following a multiomics approach using genetic and pharmacological interventions. We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-γ (SNCG), SALL2, and PP1γ, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab. Our phosphoproteomics analyses demonstrated that PTK7 modulates cell adhesion and Rho-GTPase signaling to sustain epithelial-mesenchymal transition (EMT) and cell plasticity, which was confirmed by high-content image analysis of 3D models. Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer.
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Neoplasias Ovarianas , Receptores Proteína Tirosina Quinases , Carcinoma Epitelial do Ovário/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular Tumoral , Plasticidade Celular , Transição Epitelial-Mesenquimal/genética , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Receptores Proteína Tirosina Quinases/metabolismo , Via de Sinalização WntRESUMO
The magnetic levitation system has been considered as a promising actuator in micromachining areas of study. In order to improve the tracking performance and disturbance rejection of the magnetically levitated rotary table, an iterative learning PID control strategy with disturbance compensation is proposed. The estimated disturbance compensates for the control signals to enhance the active disturbance rejection ability. The iterative learning control is used as a feed-forward unit to further reduce the trajectory tracking error. The convergence and stability of the iterative learning PID with disturbance compensation are analysed. A series of comparative experiments are carried out on the in-house, custom-made, magnetically levitated rotary table, and the experimental results highlight the superiority of the proposed control strategy. The iterative learning PID with disturbance compensation enables the magnetically levitated rotary table to realize good tracking performance with complex external disturbance. The proposed control strategy strengthens the applicability of magnetically levitated systems in the mechanism manufacturing area.
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Coração Auxiliar , MagnetismoRESUMO
In recent years, with the vigorous development and gradual deployment of new energy vehicles, more attention has been paid to the research on lithium-ion batteries (LIBs). Compared with the booming LIBs, lithium primary batteries (LPBs) own superiority in specific energy and self-discharge rate and are usually applied in special fields such as medical implantation, aerospace, and military. Widespread application in special fields also means more stringent requirements for LPBs in terms of energy density, working temperature range and shelf life. Therefore, how to obtain LPBs with high energy density, wide operational temperature range and long storage life is of great importance in future development. In view of the above, this paper reviews the latest research on LPBs in cathode, anode and electrolyte over the years, and puts forward relevant insights for LPBs, along with the intention to explore avenues for the design of LPBs components in the coming decades and promote further development in this field.
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Background: A relevant study found that allergic rhinitis (AR) may be related to the imbalance of nasal flora. Therefore, if the nasal flora of AR patients can be detected quickly, it is of great significance to study the distribution law of nasal flora in AR patients and explore its correlation with AR. Objective: To design a new and convenient nano-DNA sensor for quick screening of nasal flora in allergic rhinitis (AR) patients, so as to provide experimental basis for the prevention and treatment of AR. Methods: We create a synthesized nanostructured DNA biosensor called Nano-TiO2-DNA sensor which can be combined with samples from nasal mucosa or secretion with high efficiency and detect certain flora in situ without DNA extraction or RNA sequencing. In a physical property test, firstly, we tested the permeability, solubility, and storage temperature of nano-TiO2, so as to provide experimental basis for the synthesis of Nano-TiO2-DNA sensor. Subsequently, the permeability of Nano-TiO2-DNA sensor in Staphylococcus aureus was further tested. In a clinical experiment, we selected 60 AR patients treated in our hospital from September 2020 to September 2021 as the AR group and 60 healthy people who underwent physical examination at the same time as the control group. The Nano-TiO2-DNA sensor was used to detect typical nasal flora in AR patients, and Pearson's correlation analysis was used to explore the correlation between nasal flora with serum IgE and eosinophils. Results: As for physicochemical characteristics, this sensor can permeate into certain bacteria directly and specifically. It has high affinity ability with a target, and the combination can be detected by evaluating the released fluorescence qualitatively and quantitatively. It can be stored at -20°C in ethyl alcohol stably. By this sensor, we have successfully detected Staphylococcus aureus, Klebsiella pneumoniae, and viridans streptococci in AR patients compared with healthy people, which will help these patients in the prevention of acute sinusitis and acute or subacute pneumonia. Furthermore, we found Proteus had the strongest positive correlation with AR while Actinomyces had the biggest negative correlation. Conclusion: The Nano-TiO2-DNA sensor will help an outpatient doctor more for quick screening certain nasal flora in AR patients and improve the prevention of AR-related complications.