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The broad applications of rechargeable batteries urge people to develop alternative energy storage devices with sustainable resources, high capacity, long cycling life, and wide-temperature operability. Aqueous proton batteries are considered as a state-of-the-art energy storage system due to their intrinsic safety and low cost. However, aqueous electrolytes have a low boiling point and narrow electrochemical stability window, limiting their applications in wide-temperature and high-energy batteries. Herein, a hybrid organic ionic liquid electrolyte with organic alkali 1-methyl-1,2,4-triazole (MTA) protonated by organic acid bis(trifluoromethysulfonyl)imide (HTFSI) as proton carriers and tetramethylene sulfone (TMS) as the solvent, noted as HTFSI-MTA-TMS, exhibited the stable electrochemical windows exceeding 5 V at -20 °C and 3.5 V at 80 °C. Benefiting from this electrolyte, the assembled MnO2-S//MoO3 button proton full battery can display an operation voltage up to 1.8 V, energy density of 44.8 Wh kg-1, and good cycling stability at room temperature when bis(trifluoromethanesulfonyl)imide manganese (II) salt (Mn(TFSI)2) is introduced into the electrolyte, and run well in a wide-temperature range (-20 °C-60 °C). The work reveals the potential of organic acid-alkali coregulated electrolytes to meet the need of energy storage in a wide-temperature range and will advance the development of high-energy proton batteries.
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The simultaneous presence of microplastics (MPs) and cadmium (Cd) in soil environments has raised concerns regarding their potential interactive effects on soil-plant ecosystems. This study explores how polyethylene (PE) at concentrations of 0.5 % (w/w), 1 % (w/w), and 2 % (w/w), and Cd at concentrations of 3 mg kg-1 and 12 mg kg-1, either alone or combined, impact soil physicochemical properties, microbial community structures, and bok choy growth through a 40-day pot experiment. Our findings reveal that the addition of 2 % (w/w) PE significantly increased soil organic carbon (SOC). However, when 2 % PE coexisted with Cd, SOC levels decreased, potentially due to a reduction in enzyme activity (ß-1,4-glucosidase). PE increased the proportion of 1-2 mm soil aggregates, while the coexistence of 2 % PE and Cd significantly increased the content of soil aggregates larger than 2 mm. The coexistence of PE and Cd increased available potassium (AK) in the soil by approximately 13 % to 41 %. Regarding bok choy growth, the aboveground biomass under 2 % PE was approximately 210 % of that under 0.5 % PE, possibly because of the enhancement in soil nutrients. The presence of Cd, however, reduced the chlorophyll content of bok choy by approximately 18 % to 34 %. Notably, the coexistence of high PE concentration (2 % w/w) and low Cd concentration (3 mg kg-1) resulted in the highest aboveground biomass among all coexistence treatments. Furthermore, the addition of PE and Cd significantly altered the structure of soil bacterial and fungal communities, with fungi showing a greater response. Bacteria were significantly associated with soil inorganic N content and plant growth. This study provides new insights into the interactions of microplastics and Cd within microbial-soil-plant systems.
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To improve the treatment performance of constructed wetlands under low-temperature conditions, this study investigated the effects of plant species on wastewater treatment performance at low temperature and the associated microbiological characteristics in a subsurface vertical-flow constructed wetland (VFCW) with step-feeding. The results showed that the redox microenvironment in the VFCW filter with step-feeding could be restored and optimized by planting appropriate species that can tolerate low temperature, ensuring a high nitrification performance for the system. Correspondingly, the abundance and activity of three functional microbes (namely nitrifiers, denitrifiers, and anammox bacteria) increased to different degrees in the system, eventually ensuring ideal nitrogen removal by the VFCW. Compared with the VFCW planted with Phragmites australis and Acorus gramineus, the operation performance of the VFCW planted with Iris wilsonii could be recovered at low temperature, and its chemical oxygen demand, total phosphorus, total nitrogen, and ammonium nitrate removal rates could respectively reach 95.7%, 99.2%, 93.0%, and 94.4%, respectively. Moreover, nitrogen removal in the system relied on the nitrification/denitrification and partial denitrification - anaerobic ammonium oxidation processes. Nitrosomonas, Nitrospira, Thauera, and Candidatus Brocadia were the four dominant bacterial genera in the filter layer.
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Alkaline zinc-iron flow batteries (AZIFBs) are well suited for energy storage because of their good safety, high cell voltage, and low cost. However, the occurrence of irreversible anodic parasitic reactions results in a diminished coulombic efficiency (CE), unbalanced charge state of catholyte/anolyte and subsequently, a poor cycling performance. Here, a universal CE compensation strategy centered around the oxygen evolution reaction (OER) on the cathodic side, is reported. This strategy aims to equalize the charge state of the [Fe(CN)6]3-/4--based catholyte and counteract pH fluctuations. The OER process can be implemented either directly on the electrode through electrochemical reaction or in an external catalytic reactor column via a redox-mediated process. This innovative approach effectively mitigates the gradual accumulation of [Fe(CN)6]3- in discharged catholyte and [Zn(OH)4]2- in charged anolyte by consuming the extra OH- during a continuous cycling process. As a result, AZIFBs demonstrate exceptional cycling performance with an extremely low capacity fading rate of 0.0128%/day (or 0.0005%/cycle) over 600 cycles at 80% state of charge (SOC). The proposed CE compensation strategy not only provides an effective way to address the CE loss issue for AZIFBs, but also can be applied to diverse battery technologies encountering CE loss caused by water/oxygen-induced parasitic reactions.
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Rechargeable aqueous proton batteries with small organic molecule anodes are currently considered promising candidates for large-scale energy storage due to their low cost, stable safety, and environmental friendliness. However, the practical application is limited by the poor cycling stability caused by the shuttling of soluble organic molecules between electrodes. Herein, a cell separator is modified by a GO-casein-Cu2+ layer with a brick-and-mortar structure to inhibit the shuttling of small organic molecules. Experimental and calculation results indicate that, attributed to the synergistic effect of physical blocking of casein molecular chains and electrostatic and coordination interactions of Cu2+, bulk dissolution and shuttling of multiple small molecules can be inhibited simultaneously, while H+ transfer across the separators is not almost affected. With the protection of the GO-casein-Cu2+ separator, soluble small molecules, such as diquinoxalino[2,3-a:2',3'-c]phenazine,2,3,8,9,14,15-hexacyano (6CN-DQPZ) exhibit a high reversible capacity of 262.6 mA h g-1 and amazing stability (capacity retention of 92.9% after 1000 cycles at 1 A g-1). In addition, this strategy is also proved available to other active conjugated small molecules, such as indanthrone (IDT), providing a general green sustainable strategy for advancing the use of small organic molecule electrodes in proton cells.
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Organic materials with rich active sites are good candidates of high-capacity anodes in aqueous batteries, but commonly low utilization of active sites limits their capacity. Herein, two isomers, symmetric and asymmetric hexaazatribenzanthraquinone (s-HATBAQ and a-HATBAQ), with rich active sites have been synthesized in a controllable manner. It has been revealed for the first time that a sulfuric acid catalyst can facilitate the stereoselective formation of s-HATBAQ. Attributed to the reduced steric hindrance in favor of proton insertion as well as the amorphous structure conducive to electrochemical dynamics, s-HATBAQ exhibits 1.5 times larger specific capacity than a-HATBAQ. Consequently, the electrode of s-HATBAQ with 50% reduced graphene oxide (s-HATBAQ-50%rGO) delivers a record high specific capacity of 405 mAh g-1 in H2SO4 electrolyte. Moreover, the assembled MnO2//s-HATBAQ-50%rGO aqueous proton full batteries show an exceptional cycling stability at 25°C and can maintain â¼92% capacity after 1000 cycles at 0.5 A g-1 at -80°C. This work demonstrates the controllable synthesis of isomers, showcases a wide-temperature-range prototype proton battery and highlights the significance of precise molecular structure modulation in organic energy storage.
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The chemokines/chemokine receptors pathway significantly influences cell migration, particularly in recruiting immune cells to the tumor microenvironment (TME), impacting tumor progression and treatment outcomes. Emerging research emphasizes the involvement of chemokines in drug resistance across various tumor therapies, including immunotherapy, chemotherapy, and targeted therapy. This review focuses on the role of chemokines/chemokine receptors in pancreatic cancer (PC) development, highlighting their impact on TME remodeling, immunotherapy, and relevant signaling pathways. The unique immunosuppressive microenvironment formed by the interaction of tumor cells, stromal cells and immune cells plays an important role in the tumor proliferation, invasion, migration and therapeutic resistance. Chemokines/chemokine receptors, such as chemokine ligand (CCL) 2, CCL3, CCL5, CCL20, CCL21, C-X-C motif chemokine ligand (CXCL) 1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12, CXCL13, CXCL14, CXCL16, CXCL17, and C-X3-C motif chemokine ligand (CX3CL)1, derived mainly from leukocyte cells, cancer-related fibroblasts (CAFs), pancreatic stellate cells (PSCs), and tumor-associated macrophages (TAMs), contribute to PC progression and treatment resistance. Chemokines recruit myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), and M2 macrophages, inhibiting the anti-tumor activity of immune cells. Simultaneously, they enhance pathways like epithelial-mesenchymal transition (EMT), Akt serine/threonine kinase (AKT), extracellular regulated protein kinases (ERK) 1/2, and nuclear factor kappa-B (NF-κB), etc., elevating the risk of PC metastasis and compromising the efficacy of radiotherapy, chemotherapy, and anti-PD-1/PD-L1 immunotherapy. Notably, the CCLx-CCR2 and CXCLx-CXCR2/4 axis emerge as potential therapeutic targets in PC. This review integrates recent findings on chemokines and receptors in PC treatment, offering valuable insights for innovative therapeutic approaches.
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Neoplasias Pancreáticas , Receptores de Quimiocina , Humanos , Receptores de Quimiocina/metabolismo , Ligandos , Proteínas Proto-Oncogénicas c-akt , Quimiocinas/metabolismo , Neoplasias Pancreáticas/terapia , Carcinogénesis , Microambiente TumoralRESUMEN
Riboswitches are regulatory elements found in the untranslated regions (UTRs) of certain mRNA molecules. They typically comprise two distinct domains: an aptamer domain that can bind to specific small molecules, and an expression platform that controls gene expression. Riboswitches work by undergoing a conformational change upon binding to their specific ligand, thus activating or repressing the genes downstream. This mechanism allows gene expression regulation in response to metabolites or small molecules. To systematically summarise riboswitch structures and their related ligand binding functions, we present Ribocentre-switch, a comprehensive database of riboswitches, including the information as follows: sequences, structures, functions, ligand binding pockets and biological applications. It encompasses 56 riboswitches and 26 orphan riboswitches from over 430 references, with a total of 89 591 sequences. It serves as a good resource for comparing different riboswitches and facilitating the identification of potential riboswitch candidates. Therefore, it may facilitate the understanding of RNA structural conformational changes in response to ligand signaling. The database is publicly available at https://riboswitch.ribocentre.org.
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Bases de Datos de Ácidos Nucleicos , Riboswitch , Ligandos , Conformación de Ácido Nucleico , Secuencias Reguladoras de Ácidos Nucleicos , Transducción de SeñalRESUMEN
Mineral fertilizers are a new type of sustainable fertilizers, containing natural ores as the primary raw material with various nutrients and organic matters. This study combines two methods of bibliometric analysis to comprehensively review the progress of mineral fertilizers from 2000 to 2021. The results showed that the research on mineral fertilizers has increased in the past 21 years, especially after 2014. Developed countries studied mineral fertilizers more extensively than developing countries, but some developing countries, such as China and India, are also paying attention to this area in recent years. Chinese Academic of Sciences, Agriculture and Agri-Food Canada, and Chinese Academy of Agricultural Sciences were the main publishing institutions. Nutrient elements, changes in soil properties, and the effects on promoting crop growth were the main contents of the research. Still, such issues as bioremediation, soil environment improvement, and crop resistance are becoming hot spots. The field of mineral fertilizers showed a strong interdisciplinary nature and an increasingly comprehensive research perspective. The goal is that this synthesis will be used as a starting point for a broader study on responsible environmental management and research on improving fertilizer use efficiency.
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Fertilizantes , Suelo , Fertilizantes/análisis , Agricultura/métodos , Minerales , BibliometríaRESUMEN
Stable picosecond dissipative soliton pulses were observed in an ytterbium-doped fiber laser employing a high-quality mixture of BP/SnSe2-PVA saturable absorber (SA). The modulation depth, saturation intensity, and non-saturable loss of the mixture of BP/SnSe2-PVA SA were measured with values of 5.98%, 18.37 MW/cm2, and 33%, respectively. Within the pump power range of 150-270 mW, stable dissipative soliton pulses were obtained with an output power of 1.68-4 mW. When the minimum pulse duration is 1.28 ps, a repetition rate of 0.903 MHz, center wavelength of 1064.38 nm and 3 dB bandwidth of 2 nm were obtained. The maximum pulse energy of 4.43 nJ and the signal-to-noise ratio up to 72 dB were achieved at pump power of 270 mW. The results suggest that the BP/SnSe2-PVA mixture SA has outstanding nonlinear saturable absorption characteristics and broad ultrafast laser applications.
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k-Junctions are elaborated forms of kink turns with an additional helix on the nonbulged strand, thus forming a three-way helical junction. Two were originally identified in the structures of Arabidopsis and Escherichia coli thiamine pyrophosphate (TPP) riboswitches, and another called DUF-3268 was tentatively identified from sequence information. In this work we show that the Arabidopsis and E. coli riboswitch k-junctions fold in response to the addition of magnesium or sodium ions, and that atomic mutations that should disrupt key hydrogen bonding interactions greatly impair folding. Using X-ray crystallography, we have determined the structure of the DUF-3268 RNA and thus confirmed that it is a k-junction. It also folds upon the addition of metal ions, though requiring a 40-fold lower concentration of either divalent or monovalent ions. The key difference between the DUF-3268 and riboswitch k-junctions is the lack of nucleotides inserted between G1b and A2b in the former. We show that this insertion is primarily responsible for the difference in folding properties. Finally, we show that the DUF-3268 can functionally substitute for the k-junction in the E. coli TPP riboswitch such that the chimera can bind the TPP ligand, although less avidly.
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Arabidopsis , Riboswitch , Riboswitch/genética , Escherichia coli/metabolismo , Arabidopsis/genética , Pliegue del ARN , Tiamina Pirofosfato/genética , Tiamina Pirofosfato/metabolismo , Iones , Conformación de Ácido NucleicoRESUMEN
Granulosa cells (GCs) are the ovary's most critical cells since they undergo cell differentiation and hormone synthesis changes closely associated with follicle development. While micro RNA 140-3p (miRNA-140-3p) has an apparent cell signaling role, particularly in cell proliferation, its biological role in chicken ovarian follicle growth and development remains elusive. This study explored miR-140-3p's effects on chicken GC proliferation and steroid hormone synthesis. MiR-140-3p dramatically increased GC proliferation, prevented apoptosis, increased progesterone synthesis, and enhanced gene expression related to steroid hormone synthesis. In addition, the anti-Müllerian hormone (AMH) gene was identified as a direct miR-140-3p target. MiR-140-3p abundance correlated negatively with AMH mRNA and protein levels in GCs. Our findings show that miR-140-3p influences chicken GC proliferation and steroid hormone synthesis by suppressing AMH expression.
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Pollos , MicroARNs , Femenino , Animales , Pollos/genética , Pollos/metabolismo , Folículo Ovárico/metabolismo , Células de la Granulosa/metabolismo , Proliferación Celular , MicroARNs/genética , MicroARNs/metabolismo , Esteroides/metabolismo , Hormonas/metabolismo , Hormona Antimülleriana/genética , Hormona Antimülleriana/metabolismoRESUMEN
Taihang chickens are a domestic breed distributed throughout Hebei province in the Taihang Mountains of China and are characterized by their high meat and egg quality. However, the relatively limited egg production by this breed constrains their more widespread commercial utilization. The follicle selection process is closely linked to oocyte development and ovulation, making it a key determinant of laying performance and fecundity in hens. To understand the biological basis for such follicle selection and to identify the associated regulatory pathways, we conducted a genome-wide analysis of long noncoding RNAs (lncRNAs) and mRNAs from the pre-hierarchical follicles and hierarchical follicles of Taihang laying hens. We identified 81 lncRNAs and 528 mRNAs that were differentially expressed during follicle selection, and integrated network analyses suggested that these RNAs were associated with the cell cycle, focal adhesion, oocyte meiosis, peroxisome proliferator-activated receptor signaling, and steroid hormone biosynthesis pathways. The identified lncRNAs were also predicted to influence a series of target genes in cis and trans, suggesting that they may be important regulators of ovarian follicular development. Overall, the present analysis of lncRNA and mRNA expression patterns associated with ovarian follicle development offers a new foundation for future studies of reproductive physiology in Taihang chickens, highlighting new opportunities to improve the laying performance of this important domestic breed.
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ARN Largo no Codificante , Animales , Femenino , ARN Largo no Codificante/genética , ARN Mensajero/genética , Pollos/genética , Folículo Ovárico , Ovulación/genéticaRESUMEN
Aims: Noise damage to auditory hair cells is associated with oxidative stress and mitochondrial dysfunction. This study aimed to investigate the possible effect of sestrin 2 (SESN2), an endogenous antioxidant protein, on noise-induced hearing loss (NIHL) and the underlying mechanisms. Results: We identified SESN2 as a protective factor against oxidative stress in NIHL through activation of Parkin-mediated mitophagy. Consistently, SESN2 expression was increased and mitophagy was induced during the early stage after a temporary threshold shift due to noise exposure or hydrogen peroxide(H2O2) stimulation; conversely, SESN2 deficiency blocked mitophagy and exacerbated acoustic trauma. Mechanistically, SESN2 interacted with Unc-51-like protein kinase 1(ULK1), promoting ULK1 protein-level stabilization by interfering with its proteasomal degradation. This stabilization is essential for mitophagy initiation, since restoring ULK1 expression in SESN2-silenced cells rescued mitophagy defects. Innovation and Conclusion: Our results provide novel insights regarding SESN2 as a therapeutic target against noise-induced cochlear injury, possibly through improved mitophagy. Antioxid. Redox Signal. 38, 115-136.
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Pérdida Auditiva Provocada por Ruido , Mitofagia , Humanos , Sestrinas , Peróxido de Hidrógeno/farmacología , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Homólogo de la Proteína 1 Relacionada con la Autofagia/genética , Homólogo de la Proteína 1 Relacionada con la Autofagia/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
Ribozymes are excellent systems in which to study 'sequence - structure - function' relationships in RNA molecules. Understanding these relationships may greatly help structural modeling and design of functional RNA structures and some functional structural modules could be repurposed in molecular design. At present, there is no comprehensive database summarising all the natural ribozyme families. We have therefore created Ribocentre, a database that collects together sequence, structure and mechanistic data on 21 ribozyme families. This includes available information on timelines, sequence families, secondary and tertiary structures, catalytic mechanisms, applications of the ribozymes together with key publications. The database is publicly available at https://www.ribocentre.org.
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Bases de Datos de Ácidos Nucleicos , ARN Catalítico , Humanos , Secuencia de Bases , Conformación de Ácido Nucleico , ARN Catalítico/químicaRESUMEN
Known ribozymes in contemporary biology perform a limited range of chemical catalysis, but in vitro selection has generated species that catalyze a broader range of chemistry; yet, there have been few structural and mechanistic studies of selected ribozymes. A ribozyme has recently been selected that can catalyze a site-specific methyl transfer reaction. We have solved the crystal structure of this ribozyme at a resolution of 2.3 Å, showing how the RNA folds to generate a very specific binding site for the methyl donor substrate. The structure immediately suggests a catalytic mechanism involving a combination of proximity and orientation and nucleobase-mediated general acid catalysis. The mechanism is supported by the pH dependence of the rate of catalysis. A selected methyltransferase ribozyme can thus use a relatively sophisticated catalytic mechanism, broadening the range of known RNA-catalyzed chemistry.
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ARN Catalítico , Sitios de Unión , Catálisis , Metiltransferasas/metabolismo , Conformación de Ácido Nucleico , ARN Catalítico/metabolismoRESUMEN
k-Turns are widespread key architectural elements that occur in many classes of RNA molecules. We have shown previously that their folding properties (whether or not they fold into their tightly kinked structure on addition of metal ions) and conformation depend on their local sequence, and we have elucidated a series of rules for prediction of these properties from sequence. In this work, we have expanded the rules for prediction of folding properties, and then applied the full set to predict the folding and conformation of four probable k-turns we have identified amongst 224 structured RNA species found in bacterial intergenenic regions by the Breaker lab (1). We have analyzed the ion-dependence of folding of the four k-turns using fluorescence resonance energy transfer, and determined the conformation of two of them using X-ray crystallography. We find that the experimental data fully conform to both the predicted folding and conformational properties. We conclude that our folding rules are robust, and can be applied to new k-turns of unknown characteristics with confidence.
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Iones/química , Metales/química , Conformación de Ácido Nucleico , ARN/química , Actinomyces/química , Actinomyces/genética , Cristalografía por Rayos X , Transferencia Resonante de Energía de Fluorescencia , Haloarcula marismortui/química , Haloarcula marismortui/genética , Magnesio/química , Modelos Moleculares , Pliegue del ARN , ARN Bicatenario/químicaRESUMEN
AIM: To explore a segmentation algorithm based on deep learning to achieve accurate diagnosis and treatment of patients with retinal fluid. METHODS: A two-dimensional (2D) fully convolutional network for retinal segmentation was employed. In order to solve the category imbalance in retinal optical coherence tomography (OCT) images, the network parameters and loss function based on the 2D fully convolutional network were modified. For this network, the correlations of corresponding positions among adjacent images in space are ignored. Thus, we proposed a three-dimensional (3D) fully convolutional network for segmentation in the retinal OCT images. RESULTS: The algorithm was evaluated according to segmentation accuracy, Kappa coefficient, and F1 score. For the 3D fully convolutional network proposed in this paper, the overall segmentation accuracy rate is 99.56%, Kappa coefficient is 98.47%, and F1 score of retinal fluid is 95.50%. CONCLUSION: The OCT image segmentation algorithm based on deep learning is primarily founded on the 2D convolutional network. The 3D network architecture proposed in this paper reduces the influence of category imbalance, realizes end-to-end segmentation of volume images, and achieves optimal segmentation results. The segmentation maps are practically the same as the manual annotations of doctors, and can provide doctors with more accurate diagnostic data.
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OBJECTIVES: To evaluate the efficacy and safety of anti-vascular endothelial growth factor (VEGF) agents and corticosteroids for the treatment of macular oedema (ME) secondary to central retinal vein occlusion (CRVO). DESIGN: Systematic review and network meta-analysis. PARTICIPANTS: Patients from previously reported randomised controlled trials (RCTs) comparing anti-VEGF and corticosteroids for the treatment of ME secondary to CRVO. METHODS: Literature searches were conducted using PubMed, Medline, Embase, Cochrane Library and clinicaltrials.gov until March 2017. Therapeutic effects were estimated using the proportions of patients gaining/losing ≥15 letters, best-corrected visual acuity (BCVA) and central retinal thickness (CRT). Treatment safety was estimated using the proportions of adverse events, namely increased intraocular pressure (IOP), cataracts, vitreous haemorrhage (VH) and retinal tear. The software ADDIS (V.1.16.8) was used for analysis. Treatment effect and safety of different drugs could be ranked based on simulation. RESULTS: Eleven RCTs comprising 2060 patients were identified. Regarding patients gaining ≥15 letters, aflibercept and ranibizumab were significantly more effective than sham/placebo at 6 months. Regarding patients losing ≥15 letters at 6 months, ranibizumab showed significant improvement compared with dexamethasone. Aflibercept, bevacizumab or ranibizumab showed greater improvements in BCVA than sham/placebo at 6 months. Intravitreal ranibizumab injection demonstrated greater CRT reduction than both sham and dexamethasone did. Dexamethasone had a higher risk of increased IOP than aflibercept and ranibizumab. Ranibizumab demonstrated a greater risk of cataracts than dexamethasone. Aflibercept and ranibizumab demonstrated low incidence of VH and retinal tear, respectively. Aflibercept had a slight advantage over ranibizumab as assessed by benefit-risk analysis. CONCLUSIONS: Anti-VEGF agents have advantages in the treatment of ME secondary to CRVO. Aflibercept and ranibizumab showed marked BCVA improvement and CRT reduction. Aflibercept may have a slight advantage over ranibizumab. The results of this study can serve as a reference for clinicians to provide patient-tailored treatment. PROSPERO REGISTRATION NUMBER: CRD42017064076.