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Molecular glues are typically small chemical molecules that act at the interface between a target protein and degradation machinery to trigger ternary complex formation. Identifying molecular glues is challenging. There is a scarcity of target-specific upregulating molecular glues, which are highly anticipated for numerous targets, including P53. P53 is degraded in proteasomes through polyubiquitination by specific E3 ligases, whereas deubiquitinases (DUBs) remove polyubiquitination conjugates to counteract these E3 ligases. Thus, small-molecular glues that enhance P53 anchoring to DUBs may stabilize P53 through deubiquitination. Here, using small-molecule microarray-based technology and unbiased screening, we identified three potential molecular glues that may tether P53 to the DUB, USP7, and elevate the P53 level. Among the molecular glues, bromocriptine (BC) is an FDA-approved drug with the most robust effects. BC was further verified to increase P53 stability via the predicted molecular glue mechanism engaging USP7. Consistent with P53 upregulation in cancer cells, BC was shown to inhibit the proliferation of cancer cells in vitro and suppress tumor growth in a xenograft model. In summary, we established a potential screening platform and identified potential molecular glues upregulating P53. Similar strategies could be applied to the identification of other types of molecular glues that may benefit drug discovery and chemical biology studies.
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Proteína p53 Supresora de Tumor , Peptidasa Específica de Ubiquitina 7 , Regulación hacia Arriba , Peptidasa Específica de Ubiquitina 7/metabolismo , Peptidasa Específica de Ubiquitina 7/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Humanos , Animales , Regulación hacia Arriba/efectos de los fármacos , Ratones , Línea Celular Tumoral , Ubiquitinación/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones DesnudosRESUMEN
A numerical study was conducted on an axial compressor, the NASA Stage 35, with three nonuniform tip clearances to understand the effect of a different shape tip clearances rotor on the compressor's performance. The results demonstrated that by modifying the traditional parallel tip clearance to sine-type tip clearance (STC), hump-type tip clearance (HTC), and concave-type tip clearance (CTC), the compressor's peak efficiency showed remarkable improvement and the SMI was significantly improved. In comparison to the design rotor, the SMI of STC, HTC, and CTC increased by 3.102 %, 2.672 %, and 0.645 %, respectively. The leakage distribution at the tip-clearance region from LE to TE exhibited an inverse pattern to that of the tip curve. The leakage's magnitude could not reflect the TLF's intensity, and the leakage in the middle of the blade tip had a role in the size of the TLV. Leakage at the tip's TE influenced the corner separation's scale in the casing. The STC and HTC schemes' total pressure ratio improved, the low-velocity zone's area, high-entropy area, and high absolute vorticity area at the LE of rotor's PS decreased, the detached shock moved backward, the leading-edge spillage flow decreased, the shock action position of the rotor suction surface moved forward, the BLS increased, the TPL in the stator channel decreased, and the CTC exhibited the opposite trend. A nonuniform tip clearance was achieved by reducing the leakage and TLV intensity, thereby reducing the size of the TLV, induced vortex, or CSV in rotor passage and increasing the compressor's SMI.
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Gartland type-â ¢ supracondylar humerus fracture (SCHF) is a severe lesion with the feature of difficult reduction. Due to the high failure rate of traditional reduction, a more practical and safer method is needed. This retrospective study aimed to explore the effectiveness of the double joystick technique during the closed reduction of children with type-III fractures. Forty-one children with Gartland type-â ¢ SCHF underwent closed reduction and percutaneous fixation using the double joystick technique at our hospital between June 2020 and June 2022, and 36 (87.80%) patients were successfully followed up. The affected elbow was evaluated by the joint motion, radiographs, and Flynn's criteria then contrasted with the contralateral elbow at the last follow-up. A group of 29 boys and seven girls with an average age of 6.33â ±â 2.68â years. The mean time of surgery and hospital stay was 26.61â ±â 7.51â min and 4.64â ±â 1.23â days, respectively. After a mean follow-up of 12.85â months, the average Baumann angle was 73.43â ±â 3.78°, although the average carrying angle (11.33â ±â 2.17°), flexion angle (143.03â ±â 5.15°), and extension angle (0.89â ±â 3.23°) of the affected elbow were less than those of the contralateral elbow ( P â <â 0.05), the mean range of motion difference between two sides is only 3.39â ±â 1.59°, with no complications. Furthermore, 100% of patients recovered satisfactorily, with excellent outcomes (91.67%) and good outcomes (8.33%). The double joystick technique is a safe and effective method that facilitates the closed reduction of Gartland type-â ¢ SCHF in children without raising the risk of complications.
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Lesiones de Codo , Articulación del Codo , Fracturas del Húmero , Niño , Masculino , Femenino , Humanos , Preescolar , Estudios Retrospectivos , Fracturas del Húmero/diagnóstico por imagen , Fracturas del Húmero/cirugía , Codo , Articulación del Codo/diagnóstico por imagen , Articulación del Codo/cirugía , Resultado del Tratamiento , Fijación Interna de FracturasRESUMEN
With CdSe/CdS/ZnS core/shell/shell quantum dots (QDs) as the model system, time- and potential-resolved spectroelectrochemical measurements are successfully applied for studying the general mechanisms and kinetics of electrochemiluminescence (ECL) generation. The rate constant of electron injection from the cathode into a QD to form a negatively charged QD (QD-) increases monotonically from -0.88 V to -1.2 V (vs Ag/AgCl). Mainly due to the deep LUMO of the QDs, the resulting QD- as the key intermediate for ECL generation is structurally stable and possesses very slow spontaneous deionization channels. The latter (the main non-ECL channels) are usually 3-4 orders of magnitude slower than the rate constant of the successive hole injection from an active co-reactant into a QD-. The kinetic studies quantify the internal ECL quantum yield of ideal QD ECL emitters to be nearly identical to that of photoluminescence, which is near unity for the current system. Identification of the key intermediate, discovery of the related elementary steps, and determination of all rate constants not only establish a general framework for understanding ECL generation but also offer basic design rules for ECL emitters.
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A molecularly imprinted electrochemical sensor was designed for the selective determination of gatifloxacin (GTX) based on dual functional monomers. Multi-walled carbon nanotube (MWCNT) enhanced the current intensity and zeolitic imidazolate framework 8 (ZIF8) provided a large surface area to produce more imprinted cavities. In the electropolymerization of molecularly imprinted polymer (MIP), p-aminobenzoic acid (p-ABA) and nicotinamide (NA) were used as dual functional monomers, and GTX was the template molecule. Taking [Fe(CN)6]3-/4- as an electrochemical probe, an oxidation peak on the glassy carbon electrode was located at about 0.16 V (vs. saturated calomel electrode). Due to the diverse interactions among p-ABA, NA, and GTX, the MIP-dual sensor exhibited higher specificity towards GTX than MIP-p-ABA and MIP-NA sensors. The sensor had a wide linear range from 1.00 × 10-14 to 1.00 × 10-7 M with a low detection limit of 2.61 × 10-15 M. Satisfactory recovery between 96.5 and 105% with relative standard deviation from 2.4 to 3.7% in real water samples evidenced the potential of the method in antibiotic contaminant determination.
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Impresión Molecular , Polímeros , Polímeros/química , Gatifloxacina , Técnicas Electroquímicas/métodos , Impresión Molecular/métodos , Límite de Detección , Polímeros Impresos Molecularmente , Ácido 4-AminobenzoicoRESUMEN
To solve the problem of dispersion of magnetic nanoparticles in ultralight electromagnetic absorption field, checkerboard-like nickel nanoislands/defect graphene aerogel (NIDG) with enhanced surface plasmon resonance was designed and prepared through electrostatic self-assembly method. This special structure successfully overcame the aggregation phenomenon of magnetic metals and built high-density gap regions to enhance surface plasmon resonance. And the NIDG has achieved excellent electromagnetic wave absorption performance in C band. Specially, NIDG is superior in ultra-lightness with only 6.2 wt%, compared to some recently reported magnetic electromagnetic wave absorbers. Such great performance can be attributed to the enhanced surface plasmon resonance and improved impedance matching. This work is significant for achieving effective dielectric loss and designing lightweight low-frequency EMW absorbing materials.
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Two fullerene derivatives C60-MP and C60-ETPA were designed and synthesized for tin-halide perovskite solar cells. The introduction of an electron-withdrawing group and an alkyl chain reduced the electron affinity, resulting in a shallower lowest unoccupied molecular orbital (LUMO) energy level than that of common phenyl-C61-butyric acid methyl ester (PC61BM). Moreover, the smaller energy level offset provided efficient carrier transport and suppressed charge recombination. As a result, the devices with C60-ETPA achieved an open-circuit voltage of 0.76 V and a power conversion efficiency of over 10%, which were substantially higher than 0.63 V and 8.25% for the control devices with PC61BM, respectively.
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It was discovered the bimetallic Zn-Sb nanoparticles supported on carbon nanotubes can electrocatalyze CO2 into formate efficiently, comprising the best performance to date for Sb-based catalysts under moderate overpotential. This project was accomplished by a versatile two-step alcoholysis precipitation strategy with tunable Zn : Sb ratios, and the performance of optimized Zn2.33 Sb0.67 O4 was locked in the electrochemical CO2 reduction reaction. During the subsequent electrolysis, the mixed phases of metallic Zn and Sb served as active centers. The Zn-Sb heterostructure and the electron relocation were confirmed. By means of interactions and possible additional binding sites for reaction intermediate *OCHO, the material displayed different catalytic properties from either Zn or Sb, and was selective for formate up to 92%, which was ca. 6.1â times or 4.6â times than that of each single component. The encouraging results highlight the power of the interaction between binary metallic components to synergistically electrocatalyze CO2 conversion.
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Background: Infections are not common but important in patients with acute myocardial infarction, and are associated with worse outcomes. Infection was proved to be associated with the use of proton pump inhibitor (PPI) in several cohorts. It remains unclear whether PPI usage affects infection in patients with acute myocardial infarction. Methods: We consecutively enrolled patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) from January 2010 to June 2018. All patients were divided into the PPI group and non-PPI group according to whether the PPI was used. The primary endpoint was the development of infection during hospitalization. Results: A total of 3027 patients were finally enrolled, with a mean age of 62.2 ± 12.6 years. 310 (10.2%) patients were developed infection during hospitalization. Baseline characteristics were similar between the PPI and non-PPI groups (n = 584 for each group) after propensity score analysis. PPI usage was significantly associated with infection based on the propensity score matching analysis (adjusted OR = 1.62, 95% CI = 1.02-2.57, P = 0.041). Comparing to patients with non-PPI usage, PPI administration was positively associated with higher risk of in-hospital all-cause mortality (adjusted OR = 3.25, 95% CI = 1.06-9.97, P = 0.039) and in-hospital major adverse clinical events (adjusted OR = 3.71, 95% CI = 1.61-8.56, P = 0.002). Subgroup analysis demonstrated that the impact of PPI on infection was not significantly different among patients with or without diabetes and patients with age ≥65 years or age <65 years. Conclusion: PPI usage was related to a higher incidence of infection during hospitalization, in-hospital all-cause mortality, and in-hospital major adverse clinical events (MACE) in STEMI patients.
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Magnetoencephalography (MEG) signals have demonstrated their practical application to reading human minds. Current neural decoding studies have made great progress to build subject-wise decoding models to extract and discriminate the temporal/spatial features in neural signals. In this paper, we used a compact convolutional neural network-EEGNet-to build a common decoder across subjects, which deciphered the categories of objects (faces, tools, animals, and scenes) from MEG data. This study investigated the influence of the spatiotemporal structure of MEG on EEGNet's classification performance. Furthermore, the EEGNet replaced its convolution layers with two sets of parallel convolution structures to extract the spatial and temporal features simultaneously. Our results showed that the organization of MEG data fed into the EEGNet has an effect on EEGNet classification accuracy, and the parallel convolution structures in EEGNet are beneficial to extracting and fusing spatial and temporal MEG features. The classification accuracy demonstrated that the EEGNet succeeds in building the common decoder model across subjects, and outperforms several state-of-the-art feature fusing methods.
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To alleviate the impact of insufficient labels in less-labeled classification problems, self-supervised learning improves the performance of graph neural networks (GNNs) by focusing on the information of unlabeled nodes. However, none of the existing self-supervised pretext tasks perform optimally on different datasets, and the choice of hyperparameters is also included when combining self-supervised and supervised tasks. To select the best-performing self-supervised pretext task for each dataset and optimize the hyperparameters with no expert experience needed, we propose a novel auto graph self-supervised learning framework and enhance this framework with a one-shot active learning method. Experimental results on three real world citation datasets show that training GNNs with automatically optimized pretext tasks can achieve or even surpass the classification accuracy obtained with manually designed pretext tasks. On this basis, compared with using randomly selected labeled nodes, using actively selected labeled nodes can further improve the classification performance of GNNs. Both the active selection and the automatic optimization contribute to semi-supervised node classification.
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A cross-reactive sensor array is powerful for high-throughput discrimination of various kinds of metal ions. However, the construction of a multicomponent sensor array is always time-consuming and cost-ineffective. Herein, a practical four-component X1-based sensor array (X1SA) was obtained by simply dissolving a single dye molecule X1 in respective solvents such as methanol, ethanol, dimethyl sulfoxide, and acetonitrile. In this design, X1 exhibits strong solvatochromic fluorescence properties via an excited-state intramolecular proton transfer and intramolecular charge transfer combined mechanism. Moreover, rotation of the C-N bond between the pyridine and coumarin units in X1 enabled it to coordinate with metal ions through different binding modes, which acted as an additional dimension of the sensor array. Inspired by this C-N bond rotation strategy, X1SA was determined to be powerful in discriminating 20 kinds of metal ions in both phosphate-buffered saline and 5% serum media in a range of 0.1-100 µM. In addition, the sensor array was also successfully applied in differentiating similar and mixed metal ions such as Fe3+/Fe2+, Cd2+/Hg2+, and Sn2+/Pb2+ in serum samples, which is meaningful for investigating the biological roles of iron and early diagnosis of related metal poisoning accidents.
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Cumarinas , Metales , Fluorescencia , Iones , PiridinasRESUMEN
Outstanding photoluminescence (PL) and electroluminescence properties of quantum dots (QDs) promise possibilities for them to meet challenging expectations of electrochemiluminescence (ECL), which at present relies on inefficient and spectral-irresolvable emitters based on transition-metal complexes (such as Ru(bpy)3 2+). However, ECL is reported to be extremely sensitive to the surface traps on the QDs likely because of the spatially and temporally separated electrochemical charge injections. Results here reveal that, by engineering the interior inorganic structure (CdSe/CdS/ZnS core/shell/shell structure) and inorganic-organic interface using new synthetic methods, the trap-insensitive QDs with near-unity PL quantum yield and monoexponential PL decay dynamics in water generated narrow band-edge ECL with efficiencies about six orders of magnitude higher than that of the standard Ru(bpy)3 2+. The band-edge and spectrally resolved ECL from CdSe/CdS/ZnS core/shell/shell QDs demonstrated a new readout scheme using electrochemical potential. Excellent ECL performance of QDs uncovered here offer opportunities to realize the full potential of ECL for biomedical detection and diagnosis.
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Heparin (Hep), widely used in clinics as an anticoagulant drug, has high degrees of heterogeneity and shares a similar disaccharide repeating unit with its GAG analogues. The development of reliable and convenient methods to discriminate Hep from its GAG analogues and detect trace GAG contaminants in Hep is meaningful for safe usage of Hep in clinics. Herein, five porphyrin-GO nanocomposites denoted as PP1-GO, PP2a-GO, PP2b-GO, PP3-GO, and PP4-GO were synthesized by assembling corresponding positively charged porphyrins onto the surface of GO. Controlled by a different number and position of the 4-N-methyl-pyridyl groups substituted at the porphyrins, these nanocomposites were determined to be cross-reactive toward Hep and other three commonly used GAGs including Chs, HA, and DS. A NIR sensor array PP-GO was thus constructed using these nanocomposites for GAGs discrimination and Hep quality control through pattern-based recognition. HCA and LDA calculated results indicated that PP-GO was powerful for discrimination of Hep and its GAG analogues in both PBS and even 10% serum media. Moreover, the PP-GO sensor array was successfully applied for the reliable discrimination of trace GAG contaminants in Hep with 100% accuracy.
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With the development of deep learning in medical image analysis, decoding brain states from functional magnetic resonance imaging (fMRI) signals has made significant progress. Previous studies often utilized deep neural networks to automatically classify brain activity patterns related to diverse cognitive states. However, due to the individual differences between subjects and the variation in acquisition parameters across devices, the inconsistency in data distributions degrades the performance of cross-subject decoding. Besides, most current networks were trained in a supervised way, which is not suitable for the actual scenarios in which massive amounts of data are unlabeled. To address these problems, we proposed the deep cross-subject adaptation decoding (DCAD) framework to decipher the brain states. The proposed volume-based 3D feature extraction architecture can automatically learn the common spatiotemporal features of labeled source data to generate a distinct descriptor. Then, the distance between the source and target distributions is minimized via an unsupervised domain adaptation (UDA) method, which can help to accurately decode the cognitive states across subjects. The performance of the DCAD was evaluated on task-fMRI (tfMRI) dataset from the Human Connectome Project (HCP). Experimental results showed that the proposed method achieved the state-of-the-art decoding performance with mean 81.9% and 84.9% accuracies under two conditions (4 brain states and 9 brain states respectively) of working memory task. Our findings also demonstrated that UDA can mitigate the impact of the data distribution shift, thereby providing a superior choice for increasing the performance of cross-subject decoding without depending on annotations.
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Encéfalo/diagnóstico por imagen , Encéfalo/fisiología , Imagen por Resonancia Magnética/métodos , Procesamiento de Señales Asistido por Computador , Aprendizaje Automático no Supervisado , Adulto , Conectoma , Humanos , Análisis y Desempeño de Tareas , Adulto JovenRESUMEN
Organic-inorganic metal halide perovskite solar cells (PSCs) have recently been considered as one of the most competitive contenders to commercial silicon solar cells in the photovoltaic field. The deposition process of a perovskite film is one of the most critical factors affecting the quality of the film formation and the photovoltaic performance. A hot-casting technique has been widely implemented to deposit high-quality perovskite films with large grain size, uniform thickness, and preferred crystalline orientation. In this review, we first review the classical nucleation and crystal growth theory and discuss those factors affecting the hot-casted perovskite film formation. Meanwhile, the effects of the deposition parameters such as temperature, thermal annealing, precursor chemistry, and atmosphere on the preparation of high-quality perovskite films and high-efficiency PSC devices are comprehensively discussed. The excellent stability of hot-casted perovskite films and integration with scalable deposition technology are conducive to the commercialization of PSCs. Finally, some open questions and future perspectives on the maturity of this technology toward the upscaling deposition of perovskite film for related optoelectronic devices are presented.
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An ambient cross-linking system based on the Knoevenagel condensation reaction between acetoacetylated sucrose and aromatic dicarboxaldehydes was demonstrated. In this study, we use a rheological instrument to measure the gel time to predict and elucidate the likely reaction mechanism of the system, and we prepare films based on the mechanistic results. Acetoacetylated sucrose and 4,4'-biphenyldicarboxaldehyde were used as raw materials, piperidine was used as the catalyst, and nonvolatile dimethyl sulfoxide (DMSO) was used as the solvent. After mixing 4,4'-biphenyldicarboxaldehyde and piperidine for 30 min, the acetoacetylated sucrose was added, thus producing the shortest gel time. Then, the gel was characterized by Fourier transform infrared spectroscopy. In addition, three films were prepared by this approach with different aromatic dicarboxaldehydes, and the properties of the coatings were characterized by differential scanning calorimeter, dynamic mechanical analysis thermogravimetric analysis, and swelling ratio. It was found that these films have high Young's modulus, high glass transition temperatures, high pencil hardnesses, and low swelling ratios.
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Bio-based coating materials were prepared from epoxidized soybean oil as a renewable source. Acetoacetylated soybean oil was synthesized by the ring-opened and transesterification reaction of epoxidized soybean oil, and its chemical structure was characterized by nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (FTIR), gel permeation chromatography (GPC), and rheometric viscosity analyses. On the basis of acetoacetylated soybean oil, several bio-based coating materials were prepared using different aromatic dicarboxaldehydes (1,2-benzenedialdehyde, 1,3-benzenedialdehyde, 1,4-phthalaldehyde, 4,4'-biphenyldicarboxaldehyde) and characterized. The resulting films possess good performance, including the highest glass transition temperature of 54 °C, a Young's modulus of 24.91 MPa, tensile strength of 5.65 MPa, and an elongation at break of 286%. Thus, this work demonstrates the Knoevenagel condensation reaction, which is based on soybean oil as a potential newer eco-friendly raw material.
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Herein we report the combination of enzyme-linked immunoassay and pattern recognition analysis for extracting both chemical and spatial information from latent fingermarks (LFMs). The development approach basically involves two steps, namely, specific recognition of protein and polypeptide secretions present in the ridge residues of LFMs by horseradish peroxidase (HRP)-labeled antibodies and the HRP-catalyzed chemiluminescent (CL) reaction between luminol and H2O2. The emitted light can spatially resolve the ridges, generating a bright image against the dark object surface for visualization of an LFM. Meanwhile, thanks to the molecular specificity of the immunoassay step, the emission also provides us additional information on the existence of specific substances in LFMs. The developed LFMs are further processed by a set of digital image processing procedures. Quantitative analysis based on minutia features shows that even poorly developed fingermarks can be matched successfully. This work offers the promise of facilitating cross-disciplinary studies between data-processing approaches and fingermark development techniques, such as the extraction of more information from LFM evidence, as well as the establishment of evaluation criteria for an enhancement technique.
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Dermatoglifia/clasificación , Peroxidasa de Rábano Silvestre/análisis , Peróxido de Hidrógeno/análisis , Técnicas para Inmunoenzimas/métodos , Luminiscencia , Luminol/química , Reconocimiento de Normas Patrones Automatizadas , HumanosRESUMEN
A novel plant-based dual-cure coating system based on a Michael addition reaction between bismaleimide (BDM) and modified acetoacetylated castor oil was developed. The BDM has a high reactivity toward acetylacetate groups, and the catalyst 1,4-diazabicyclo[2.2.2]octane (TEDA) was optimized by the rheological viscosity. The gel was characterized by Fourier transform infrared (FTIR) spectroscopy. Then, three films were prepared with the TEDA catalyst and analyzed with solid-state 13C NMR and FTIR spectroscopy. The thermal and mechanical properties of the three films were characterized by differential mechanical analysis, thermogravimetric analysis, and differential scanning calorimetry. We found that the cross-linking density, glass transition temperature (T g), and Young's modulus of the coating films increased with an increase in the ratio of acetylacetate groups from the modified acetoacetylated castor oil. This is the first study of the reaction of BDM with plant-based acetylacetate groups. Importantly, a quantitative ratio of acetylacetate groups can be obtained by a thiol-ene coupling reaction and a transesterification reaction, resulting in the formation of films having excellent performance.