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BACKGROUND: Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this Article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9. METHODS: This single-arm, single-centre trial enrolled children (aged 1-18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063181, and is ongoing. FINDINGS: Between Oct 19, 2022, and June 9, 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1-2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40-57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5-4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery. INTERPRETATION: AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9. FUNDING: National Natural Science Foundation of China, National Key R&D Program of China, Science and Technology Commission of Shanghai Municipality, and Shanghai Refreshgene Therapeutics.
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Dependovirus , Terapia Genética , Humanos , Terapia Genética/métodos , Dependovirus/genética , Niño , Masculino , Preescolar , Femenino , Adolescente , Lactante , Vectores Genéticos , Resultado del Tratamiento , Sordera/genética , Sordera/terapia , Mutación , Proteínas de la MembranaRESUMEN
The adeno-associated virus (AAV) gene therapy has been widely applied to mouse models for deafness. But, AAVs could transduce non-targeted organs after inner ear delivery due to their low cell-type specificity. This study compares transgene expression and biodistribution of AAV1, AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB after round window membrane (RWM) injection in neonatal mice. The highest virus concentration was detected in the injected cochlea. AAV2, Anc80L65, AAV9, AAV-PHP.B, and AAV-PHP.eB transduced both inner hair cells (IHCs) and outer hair cells (OHCs) with high efficiency, while AAV1 transduced IHCs with high efficiency but OHCs with low efficiency. All AAV subtypes finitely transduced contralateral inner ear, brain, heart, and liver compared with the injected cochlea. In most brain regions, the enhanced green fluorescent protein (eGFP) expression of AAV1 and AAV2 was lower than that of other four subtypes. We suggested the cochlear aqueduct might be one of routes for vectors instantaneously infiltrating into the brain from the cochlea through a dye tracking test. In summary, our results provide available data for further investigating the biodistribution of vectors through local inner ear injection and afford a reference for selecting AAV serotypes for gene therapy toward deafness.
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Sordera , Vectores Genéticos , Animales , Ratones , Distribución Tisular , Vectores Genéticos/genética , Cóclea/metabolismo , Terapia Genética/métodos , Sordera/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Transducción GenéticaRESUMEN
The catalytic transformation of N2 to NH3 by transition metal complexes is of great interest and importance but has remained a challenge to date. Despite the essential role of vanadium in biological N2 fixation, well-defined vanadium complexes that can catalyze the conversion of N2 to NH3 are scarce. In particular, a V(NxHy) intermediate derived from proton/electron transfer reactions of coordinated N2 remains unknown. Here, we report a dinitrogen-bridged divanadium complex bearing POCOP (2,6-(tBu2PO)2-C6H3) pincer and aryloxy ligands, which can serve as a catalyst for the reduction of N2 to NH3 and N2H4. Low-temperature protonation and reduction of the dinitrogen complex afforded the first structurally characterized neutral metal hydrazido(2-) species ([V]âNNH2), which mediated 15N2 conversion to 15NH3, indicating that it is a plausible intermediate of the catalysis. DFT calculations showed that the vanadium hydrazido complex [V]âNNH2 possessed a N-H bond dissociation free energy (BDFEN-H) of as high as 59.1 kcal/mol. The protonation of a vanadium amide complex ([V]-NH2) with [Ph2NH2][OTf] resulted in the release of NH3 and the formation of a vanadium triflate complex, which upon reduction under N2 afforded the vanadium dinitrogen complex. These transformations model the final steps of a vanadium-catalyzed N2 reduction cycle. Both experimental and theoretical studies suggest that the catalytic reaction may proceed via a distal pathway to liberate NH3. These findings provide unprecedented insights into the mechanism of N2 reduction related to FeV nitrogenase.
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Amoníaco , Vanadio , Amoníaco/química , Oxidación-Reducción , Nitrogenasa/metabolismo , Protones , CatálisisRESUMEN
OBJECTIVES: The aim of this study was two-fold: (1) to develop and externally validate a multiparameter MR-based machine learning model to predict the pathological complete response (pCR) in locally advanced rectal cancer (LARC) patients after neoadjuvant chemoradiotherapy (nCRT), and (2) to compare different classifiers' discriminative performance for pCR prediction. METHODS: This retrospective study includes 151 LARC patients divided into internal (centre A, n = 100) and external validation set (centre B, n = 51). The clinical and MR radiomics features were derived to construct clinical, radiomics, and clinical-radiomics model. Random forest (RF), support vector machine (SVM), logistic regression (LR), K-nearest neighbor (KNN), naive Bayes (NB), and extreme gradient boosting (XGBoost) were used as classifiers. The predictive performance was assessed using the receiver operating characteristic (ROC) curve. RESULTS: Eleven radiomics and four clinical features were chosen as pCR-related signatures. In the radiomics model, the RF algorithm achieved 74.0% accuracy (an AUC of 0.863) and 84.4% (an AUC of 0.829) in the internal and external validation sets. In the clinical-radiomics model, RF algorithm exhibited high and stable predictive performance in the internal and external validation datasets with an AUC of 0.906 (87.3% sensitivity, 73.7% specificity, 76.0% accuracy) and 0.872 (77.3% sensitivity, 88.2% specificity, 86.3% accuracy), respectively. RF showed a better predictive performance than the other classifiers in the external validation datasets of three models. CONCLUSIONS: The multiparametric clinical-radiomics model combined with RF algorithm is optimal for predicting pCR in the internal and external sets, and might help improve clinical stratifying management of LARC patients. KEY POINTS: ⢠A two-centre study showed that radiomics analysis of pre- and post-nCRT multiparameter MR images could predict pCR in patients with LARC. ⢠The combined model was superior to the clinical and radiomics model in predicting pCR in locally advanced rectal cancer. ⢠The RF classifier performed best in the current study.
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Neoplasias del Recto , Humanos , Estudios Retrospectivos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Imagen por Resonancia Magnética , Teorema de Bayes , Recto/patologíaRESUMEN
Intractable skin defects, which involve excessive inflammation and bacterial infections, caused by burns, trauma, and diabetes are a major challenge for clinicians. Compared with traditional skin transplantation, tissue-engineered skin has the advantages of a wide range of sources, prominent biological activity, and no damage to the donor area during the operation. Therefore, an effective wound-healing mat with antibacterial, anti-inflammatory, and microvascularization bioactivities is urgent to be developed. In this study, we have synthesized a poly(ester-urethane)urea/silk fibroin/magnolol nanofibrous composite mat (PSM) through electrospinning and post-hydrogen bond cross-linking. The results show that the hybrid magnolol has no adverse effect on the microstructure, porosity, wettability, and mechanical properties of PSM. Antibacterial experiments and cytocompatibility in vitro have proved that the addition of magnolol significantly improves the antibacterial ability and promotes cell adhesion and proliferation of PSM. In addition, the wound model of rat back and H&E staining, Masson trichrome staining, and CD31 and CD68 immunofluorescence staining were performed for evaluating the therapeutic efficiency of PSM. All the results show that the better wound treatment effect of magnolol hybrid nanofibrous mats in infectious skin tissue defected repair indicates their great potential for wound healing clinically.
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Nanofibras , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antiinflamatorios/farmacología , Compuestos de Bifenilo , Lignanos , Nanofibras/química , Ratas , Cicatrización de HeridasRESUMEN
OBJECTIVES: To investigate the utility of 3D amide proton transfer (APT) MRI in predicting pathologic factors for rectal adenocarcinoma, in comparison with diffusion kurtosis imaging. METHODS: Sixty-one patients with rectal adenocarcinoma were enrolled in this prospective study. 3D APT and diffusion kurtosis imaging (DKI) were performed. Mean APT-weighted signal intensity (APTw SI), mean kurtosis (MK), mean diffusivity (MD), and ADC values of tumors were calculated on these maps. Pathological analysis included WHO grades, pT stages, pN stages, and extramural venous invasion (EMVI) status. Student's t test, Spearman correlation, and receiver operating characteristics (ROC) analysis were used for statistical analysis. RESULTS: High-grade rectal adenocarcinoma showed significantly higher mean APTw SI and MK values (2.771 ± 0.384 vs 2.108 ± 0.409, 1.167 ± 0.216 vs 1.045 ± 0.175, respectively; p < 0.05). T3 rectal adenocarcinoma demonstrated higher mean APTw SI and MK than T2 tumors (2.433 ± 0.467 vs 1.900 ± 0.302, p < 0.05). No kurtosis, diffusivity, and ADC differences were found between T2 and T3 tumors. Tumors with lymph node metastasis and EMVI involvement showed significantly higher mean APTw SI, MK. No difference was found in diffusivity and ADC between pN0 and pN1-2 groups, and EMVI-negative and EMVI-positive statuses. Mean APTw SI exhibited a significantly high positive correlation with WHO grades, demonstrating 92.31% sensitivity and 79.17% specificity for distinguishing low- from high-grade rectal adenocarcinoma, providing a better diagnostic capacity than MK, MD, and mean ADC values. CONCLUSION: 3D-APT could serve as a non-invasive biomarker for evaluating prognostic factors of rectal adenocarcinoma. KEY POINTS: ⢠Mean APTw SI was significantly higher in high-grade compared to low-grade rectal adenocarcinoma. ⢠Mean APTw SI was significantly higher in T3 stage rectal adenocarcinoma, with lymph node metastasis, or in EMVI-positive status. ⢠APTw SI exhibited greater diagnostic capability in discriminating low-grade from high-grade rectal adenocarcinoma, compared with kurtosis, diffusivity, and ADC.
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Adenocarcinoma , Protones , Adenocarcinoma/diagnóstico por imagen , Amidas , Imagen de Difusión por Resonancia Magnética , Humanos , Imagen por Resonancia Magnética , Pronóstico , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
The reductive coupling of carbon monoxide (CO) by metal hydrides is of fundamental interest and practical importance. Herein we report an unprecedented hydrodeoxygenative cyclotetramerization of CO by a trinuclear titanium polyhydride complex [(C5Me4SiMe3)Ti]3(µ3-H)(µ2-H)6 (1). The reaction of CO with 1 at -78 °C gave an ethen-1,2-diyl species [CHâCH]2- through the hydrodeoxygenative dimerization of two molecules of CO, which upon cycloaddition to another two molecules of CO afforded a cyclobuten-3,4-diyl-1,2-diolate unit [C4H2O2]4-. The hydrogenolysis of the [C4H2O2]4- species with H2 yielded a tetrahydrocyclobuten-1,2-diolate species [C4H4O2]2-, which on heating at 100 °C gave a cyclobuten-2-yl-1-olate product [C4H4O]2-. The acidolysis of the [C4H2O2]4- and [C4H4O]2- species with HCl afforded γ-butyrolactone and cyclobutanone, respectively.
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BACKGROUND: The evaluation of prognostic factors in rectal carcinoma patients has important clinical significance. P53 status and the Ki-67 index have served as prognostic factors in rectal carcinoma. Amide proton transfer (APT) imaging has shown great potential in tumor diagnosis. However, few studies reported the value of APT imaging in evaluating p53 and Ki-67 status of rectal carcinoma. PURPOSE: To investigate the feasibility of amide proton transfer MRI in assessing p53 and Ki-67 expression of rectal adenocarcinoma, and compare it with conventional diffusion-weighted imaging (DWI). STUDY TYPE: Retrospective. POPULATION: Forty-three patients with rectal adenocarcinoma (age: 34-85 years). FIELD STRENGTH/SEQUENCE: 3T/APT imaging using a 3D turbo spin echo (TSE)-Dixon pulse sequence with chemical shift-selective fat suppression, 2D DWI, and 2D T2 -weighted TSE. ASSESSMENT: Mean tumor APT signal intensity (SImean ) and apparent diffusion coefficient (ADCmean ) were measured. Traditional tumor pathological analysis included WHO grades, pT (pathologic tumor) stages, and pN (pathologic node) stages. Expression levels of p53 and Ki-67 were determined by immunohistochemical assay. STATISTICAL TESTS: One-way analysis of variance (ANOVA); Student's t-test; Spearman's correlation coefficient; receiver operating characteristic (ROC) curve analysis. RESULTS: High-grade tumors, more advanced stage tumors, and tumors with lymph node involvement had higher APT SImean values: high grade (n = 15) vs. low-grade (n = 28), P < 0.001; pT2 (n = 10) vs. pT3 (n = 20) vs. pT4 (N = 13), P = 0.021; pN0 (n = 24) vs. pN1-2 (n = 19), P = 0.019. ADCmean differences were found in tumors with different pT stage: pT2 (n = 10) vs. pT3 (n = 20) vs. pT4 (N = 13), P = 0.013, but not in tumors with different histologic grade: high grade (n = 15) vs. low-grade (n = 28), P = 0.3536; or pN stage: pN0 (n = 24) vs. pN1-2 (n = 19), P = 0.624. Tumor with p53 positive status had higher APT SImean than tumor with negative p53 status (2.363 ± 0.457 vs. 2.0150 ± 0.3552, P = 0.014). There was no difference in ADCmean with p53 status (1.058 ± 0.1163 10-3 mm2 /s vs. 1.055 ± 0.128 10-3 mm2 /s, P = 0.935). APT SImean and ADCmean were significantly different in tumors with low and high Ki-67 status (1.7882 ± 0.11386 vs. 2.3975 ± 0.41586, P < 0.001; 1.1741 ± 0.093 10-3 mm2 /s vs. 1.0157 ± 0.10459 10-3 mm2 /s, P < 0.001, respectively). APT SImean exhibited a positive correlation with p53 labeling index and Ki-67 labeling index (r = 0.3741, P = 0.0135; r = 0.7048; P < 0.001, respectively). ADCmean showed no correlation with p53 labeling index, but a negative correlation with Ki-67 labeling index (r = -0.5543, P < 0.0001). ROC curves demonstrated that APT SImean had significantly higher diagnostic ability for differentiation of high Ki-67 expression of rectal adenocarcinoma than ADCmean (81.2% vs. 78.12%, 90.91% vs. 63.64; P < 0.001 vs. P = 0.017), while no difference was found in predicting p53 status (92.86% vs. 71.4%, 53.33% vs. 66.7%; P < 0.001 vs. P = 0.0471). DATA CONCLUSION: APT SImean was related to p53 and Ki-67 expression levels in rectal adenocarcinoma. APT imaging may serve as a noninvasive biomarker for assessing genetic prognostic factors of rectal adenocarcinoma. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.
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Adenocarcinoma , Protones , Adenocarcinoma/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Amidas , Imagen de Difusión por Resonancia Magnética , Humanos , Antígeno Ki-67/metabolismo , Imagen por Resonancia Magnética , Persona de Mediana Edad , Estudios Retrospectivos , Proteína p53 Supresora de TumorRESUMEN
Electromagnetic interference protection in optoelectronic devices is challenging because of the dual requirements of optical transmittance and high shielding effectiveness (SE). Herein, we propose a novel silver nanowire (AgNW)/polyethylene terephthalate (PET) multi-layer mesh pattern structure for transparent electromagnetic shielding obtained via laser marking and transfer printing. A three-layer composite shielding film with an optical transmittance of 67.8% exhibits a SE of 44 dB at 10 GHz, which is superior to most of the reported transparent shielding films composed of AgNWs to date. The newly designed multi-layer composite structure can enhance the transparent shielding properties of the shielding film via optimization of the AgNW distribution and the shielding film structure. It is expected that this multi-layer mesh composite structure will have splendid application prospects in electromagnetic shielding films, which require both light transmittance and high SE.
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The cleavage of carbon-carbon (C-C) bonds by transition metals is of great interest, especially as this transformation can be used to produce fuels and other industrially important chemicals from natural resources such as petroleum and biomass. Carbon-carbon bonds are quite stable and are consequently unreactive under many reaction conditions. In the industrial naphtha hydrocracking process, the aromatic carbon skeleton of benzene can be transformed to methylcyclopentane and acyclic saturated hydrocarbons through C-C bond cleavage and rearrangement on the surfaces of solid catalysts. However, these chemical transformations usually require high temperatures and are fairly non-selective. Microorganisms can degrade aromatic compounds under ambient conditions, but the mechanistic details are not known and are difficult to mimic. Several transition metal complexes have been reported to cleave C-C bonds in a selective fashion in special circumstances, such as relief of ring strain, formation of an aromatic system, chelation-assisted cyclometallation and ß-carbon elimination. However, the cleavage of benzene by a transition metal complex has not been reported. Here we report the C-C bond cleavage and rearrangement of benzene by a trinuclear titanium polyhydride complex. The benzene ring is transformed sequentially to a methylcyclopentenyl and a 2-methylpentenyl species through the cleavage of the aromatic carbon skeleton at the multi-titanium sites. Our results suggest that multinuclear titanium hydrides could serve as a unique platform for the activation of aromatic molecules, and may facilitate the design of new catalysts for the transformation of inactive aromatics.
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The activation of N2 by a tetranuclear titanium(III) diimide/tetrahydride complex, [(Cp'Ti)4(µ3-NH)2(µ-H)4] (1) (Cp' = C5Me4SiMe3), which was obtained by the reaction of the Cp'-ligated titanium trialkyl complex Cp'Ti(CH2SiMe3)3 with H2 and N2, was investigated in detail by experimental and density functional theory studies. The reaction of 1 in the solid state with N2 (1 atm) at 180 °C gave the dinitride/diimide complex [(Cp'Ti)4(µ3-N)2(µ3-NH)2] (2) through the incorporation, cleavage, and partial hydrogenation of one molecule of N2 and release of two molecules of H2. At 130 °C, the formation of 2 was not observed, but instead, dehydrogenation of 1 took place through cleavage of the N-H bond in an imide ligand, followed by deprotonation of the other imide ligand with a hydride ligand, affording the dinitride/tetrahydride complex [(Cp'Ti)4(µ3-N)2(µ-H)4] (3). Upon heating under N2 (1 atm) at 180 °C, 3 was quantitatively converted to the dinitride/diimide complex 2. This transformation was initiated by migration of a hydride ligand to a nitride ligand to give one imide unit, followed by N2 coordination to a Ti atom and H2 release through the reductive elimination of two hydride ligands. The other imide ligand in 2 was formed by hydride migration to one of the two nitride ligands generated through the cleavage of the newly incorporated N2 unit. The hydrogenation of 2 with H2 (100 atm) at 180 °C afforded the tetraimide complex [(Cp'Ti)4(µ3-NH)4] (4). This reaction was initiated by σ-bond metathesis between H2 and a titanium-nitride bond, followed by migration of the resulting hydride ligand to the remaining nitride ligand. In all of these transformations, the interplay among the hydride, imide, and nitride ligands, including the reversible dehydrogenation/hydrogenation of imide and nitride species, at the multimetallic titanium framework has a critically important role.
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The dynamic changes of active components in stems and leaves of Mentha Haplocalycis Herba(mint) at different harvest periods were investigated, and the optimum harvest time of mint was explored. In this study, hesperidin, diosmin, didymin and buddleoside were selected as flavonoids index components of mint, and the QAMS method was established to measure the contents of these flavonoids in mint. The contents of 4 flavonoid glycosides in the mint stems and leaves from three habitats harvested in different time were studied and evaluated comprehensively using statistical analysis and principal component analysis (PCA). The results showed that the contents of 4 components in the leaves are higher than that in the stems despite of habitats and harvest time, and they all exhibited dynamic changes along with the harvest periods within the same habitat. Three harvest periods in mid April, mid September and late October scored higher in comprehensive evaluation in Jiangsu region, the genuine producing area of Mentha Haplocalycis Herba. Combined with the yield and contents of active compounds, the optimum harvest time of mint in Jiangsu region was mid September and late October, which is basically consistent with the traditional harvesting periods.
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Flavonoides/análisis , Mentha/química , Estaciones del Año , Fitoquímicos/análisis , Extractos Vegetales , Hojas de la Planta/química , Tallos de la Planta/químicaRESUMEN
The hydrogenolysis of the PNP-ligated titanium dialkyl complex {(PNP)Ti(CH2SiMe3)2} (1, PNP = N(C6H3-2-PiPr2-4-CH3)2) with H2 (1 atm) in the presence of N2 (1 atm) afforded a binuclear titanium side-on/end-on dinitrogen complex {[(PNP)Ti]2(µ2,η1,η2-N2)(µ2-H)2} (2) at room temperature, which upon heating at 60 °C with H2 gave a µ2-imido/µ2-nitrido/hydrido complex {[(PNP)Ti]2(µ2-NH)(µ2-N)H} (3) through the cleavage and partial hydrogenation of the N2 unit. The mechanistic aspects of the hydrogenation of the N2 unit in 2 with H2 have been elucidated by the density functional theory calculations.
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Carbon-carbon bond cleavage of benzene by transition metals is of great fundamental interest and practical importance, as this transformation is involved in the production of fuels and other important chemicals in the industrial hydrocracking of naphtha on solid catalysts. Although this transformation is thought to rely on cooperation of multiple metal sites, molecular-level information on the reaction mechanism has remained scarce to date. Here, we report the DFT studies of the ring cleavage and contraction of benzene by a molecular trinuclear titanium hydride cluster. Our studies suggest that the reaction is initiated by benzene coordination, followed by H2 release, C6H6 hydrometalation, repeated C-C and C-H bond cleavage and formation to give a MeC5H4 unit, and insertion of a Ti atom into the MeC5H4 unit with release of H2 to give a metallacycle product. The C-C bond cleavage and ring contraction of toluene can also occur in a similar fashion, though some details are different due to the presence of the methyl substituent. Obviously, the facile release of H2 from the metal hydride cluster to provide electrons and to alter the charge population at the metal centers, in combination with the flexible metal-hydride connections and dynamic redox behavior of the trimetallic framework, has enabled this unusual transformation to occur. This work has not only provided unprecedented insights into the activation and transformation of benzene over a multimetallic framework but it may also offer help in the design of new molecular catalysts for the activation and transformation of inactive aromatics.
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Structural color, renowned for its enduring vibrancy, has been extensively developed and applied in the fields of display and anticounterfeiting. However, its limitations in brightness and saturation hinder further application in these areas. Herein, we propose a pendant evaporation self-assembly method to address these challenges simultaneously. By leveraging natural convection and Marangoni flow synchronization, the self-assembly process enhances the dynamics and duration of colloidal nanoparticles, thereby enhancing the orderliness of colloidal photonic crystals. On average, this technique boosts the brightness of structural color by 20% and its saturation by 35%. Moreover, pendant evaporation self-assembly is simple and convenient to operate, making it suitable for industrial production. We anticipate that its adoption will remarkably advance the industrialization of structural color, facilitating its engineering applications across various fields, such as display technology and anticounterfeiting identification.
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Robust anti-counterfeiting techniques aim for easy identification while remaining difficult to forge, especially for high-value items such as currency and passports. However, many existing anti-counterfeiting techniques rely on deterministic processes, resulting in loopholes for duplication and counterfeiting. Therefore, achieving high-level encryption and easy authentication through conventional anti-counterfeiting techniques has remained a significant challenge. To address this, this work proposes a solution that combined fluorescence and structural colors, creating a physically unclonable multiplex encryption system (PUMES). In this study, the physicochemical properties of colloidal photonic inks are systematically adjusted to construct a comprehensive printing phase diagram, revealing the printable region. Furthermore, the brightness and color saturation of inkjet-printed colloidal photonic crystal structural colors are optimized by controlling the substrate's hydrophobicity, printed droplet volume, and the addition of noble metals. Finally, fluorescence is incorporated to build PUMES, including macroscopic fluorescence and structural color patterns, as well as microscopic physically unclonable fluorescence patterns. The PUMES with intrinsic randomness and high encoding capacity are authenticated by a deep learning algorithm, which proved to be reliable and efficient under various observation conditions. This approach can provide easy identification and formidable resistance against counterfeiting, making it highly promising for the next-generation anti-counterfeiting of currency and passports.
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BACKGROUND: Pulmonary arterial hypertension (PAH) and the consequent right heart dysfunction persist with high morbidity and mortality, and the mechanisms and pharmacologic interventions for chronic right-sided heart failure (RHF) have not been adequately investigated. Research has shown that prolonged inflammation is critical in precipitating the progression of PAH-associated right heart pathology. Some research demonstrated that Lingguizhugan decoction (LGZGD), as a classical Chinese medicine formula, had beneficial effects in alleviating PAH and RHF, while its underlying mechanisms involved are not fully elucidated. PURPOSE: Based on that, this study aims to investigate the effects and underlying mechanisms of LGZGD on PAH-induced RHF. STUDY DESIGN: In this study, we identified the serum constituents and deciphered the potential anti-inflammatory mechanism and crucial components of LGZGD using combined approaches of UPLC-HRMS, transcriptomic analysis, and molecular docking techniques. Finally, we used in vivo experiments to verify the expression of key targets in the monocrotaline (MCT)-induced RHF model and the intervene effect of LGZGD. RESULTS: Integrated strategies based on UPLC-HRMS and systems biology approach combined with in vivo experimental validation showed that LGZGD could improve right heart fibrosis and dysfunction via regulating diverse inflammatory signaling pathways and the activity of immune cells, including chemokine family CCL2, CXCR4, leukocyte integrins family ITGAL, ITGB2, and M2 macrophage infiltration, as well as lipid peroxidation-associated HMOX1, NOX4, and 4-HNE. CONCLUSION: The present research demonstrated for the first time that LGZGD might improve PAH-induced RHF through multiple anti-inflammatory signaling and inhibition of ferroptosis, which could provide certain directions for future research in related fields.
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Medicamentos Herbarios Chinos , Hipertensión Arterial Pulmonar , Biología de Sistemas , Remodelación Ventricular , Animales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Masculino , Remodelación Ventricular/efectos de los fármacos , Antiinflamatorios/farmacología , Inflamación/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Ratas Sprague-Dawley , Ratas , Insuficiencia Cardíaca/tratamiento farmacológico , Modelos Animales de Enfermedad , Cromatografía Líquida de Alta PresiónRESUMEN
BACKGROUND: Myocardial injury (MI) after acute ischemic stroke (AIS) poses a significant threat to patient prognosis. However, effective intervention strategies are currently lacking. PURPOSE: To elucidate the mechanism of MI after AIS and effects of Naoxintong capsule (NXT) therapy. METHOD: In vivo, after a rat model of middle cerebral artery occlusion (MCAO)-induced MI was established and assessed. NXT was administered prophylactically to evaluate its pharmacodynamic effects and mechanisms. In vitro, a noradrenaline (NA)-induced damage cell model was constructed. Subsequently, the NXT was applied to the cell models to examine its cardioprotective effects and potential mechanisms. RESULTS: The in vivo findings revealed that following MCAO, there was a notable upregulation of TH expression in the rat brain, which subsequently triggered an increase in serum levels of various biomarkers, including AD, NA, AST, cTnT, CK-MB, and NT-proBNP. Histological analysis employing H&E staining and TUNEL assay disclosed significant pathological alterations and an escalation in apoptotic activity within the myocardial tissue. The myocardial tissue exhibited elevated levels of MDA alongside diminished CAT activity. Additionally, a marked increase in the Bax/Bcl-2 ratio, Cytochrome C release, and Caspase-3 activation was observed, all of which are indicative of heightened apoptotic activity. Administration of the NXT intervention successfully attenuated TH expression in the brains of rats subjected to MCAO, consequently leading to a reduction in circulating levels of catecholamines (CAs). NXT also exhibited significant efficacy at ameliorating cardiac oxidative stress and reducing apoptosis. In vitro, stimulation with NA led to an increase in ROS levels and calcium ion concentration in H9c2 cardiomyocytes. However, the administration of NXT has been found to effectively alleviate these adverse effects, thereby protecting H9c2 cardiomyocytes from the deleterious consequences of oxidative stress and calcium dyshomeostasis. CONCLUSION: Overall, this study has demonstrated that increased CAs synthesis in the brain after AIS in experimental rats led to a surge in circulating CAs, ultimately leading to MI. NXT can alleviate MI due to cerebral ischemia by increasing improving brain catecholamine synthesis, cardiac oxidative stress, and apoptosis.
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Apoptosis , Catecolaminas , Medicamentos Herbarios Chinos , Accidente Cerebrovascular Isquémico , Ratas Sprague-Dawley , Animales , Medicamentos Herbarios Chinos/farmacología , Masculino , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Catecolaminas/metabolismo , Apoptosis/efectos de los fármacos , Ratas , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de Enfermedad , Miocardio/metabolismo , Miocardio/patología , NorepinefrinaRESUMEN
Objective:This study aims to analyze the threshold changes in distortion product otoacoustic emissionsï¼DPOAEï¼ and auditory brainstem responseï¼ABRï¼ in adult Otofî-/- mice before and after gene therapy, evaluating its effectiveness and exploring methods for assessing hearing recovery post-treatment. Methods:At the age of 4 weeks, adult Otofî-/- mice received an inner ear injection of a therapeutic agent containing intein-mediated recombination of the OTOF gene, delivered via dual AAV vectors through the round window membraneï¼RWMï¼. Immunofluorescence staining assessed the proportion of inner ear hair cells with restored otoferlin expression and the number of synapses.Statistical analysis was performed to compare the DPOAE and ABR thresholds before and after the treatment. Results:AAV-PHP. eB demonstrates high transduction efficiency in inner ear hair cells. The therapeutic regimen corrected hearing loss in adult Otofî-/- mice without impacting auditory function in wild-type mice. The changes in DPOAE and ABR thresholds after gene therapy are significantly correlated at 16 kHz. Post-treatment,a slight increase in DPOAE was observeds,followed by a recovery trend at 2 months post-treatment. Conclusion:Gene therapy significantly restored hearing in adult Otofî-/- mice, though the surgical delivery may cause transient hearing damage. Precise and gentle surgical techniques are essential to maximize gene therapy's efficacy.
Asunto(s)
Oído Interno , Pérdida Auditiva , Ratones , Animales , Emisiones Otoacústicas Espontáneas/fisiología , Audición/fisiología , Pérdida Auditiva/genética , Pérdida Auditiva/terapia , Terapia Genética , Umbral Auditivo/fisiología , Potenciales Evocados Auditivos del Tronco Encefálico/fisiología , Proteínas de la MembranaRESUMEN
Adeno-associated viral (AAV) vectors are increasingly used as vehicles for gene delivery to treat hearing loss. However, lack of specificity of the transgene expression may lead to overexpression of the transgene in nontarget tissues. In this study, we evaluated the expression efficiency and specificity of transgene delivered by AAV-PHP.eB under the inner ear sensory cell-specific Myo15 promoter. Compared with the ubiquitous CAG promoter, the Myo15 promoter initiates efficient expression of the GFP fluorescence reporter in hair cells, while minimizing non-specific expression in other cell types of the inner ear and CNS. Furthermore, using the Myo15 promoter, we constructed an AAV-mediated therapeutic system with the coding sequence of OTOF gene. After inner ear injection, we observed apparent hearing recovery in Otof-/- mice, highly efficient expression of exogenous otoferlin, and significant improvement in the exocytosis function of inner hair cells. Overall, our results indicate that gene therapy mediated by the hair cell-specific Myo15 promoter has potential clinical application for the treatment of autosomal recessive deafness and yet for other hereditary hearing loss related to dysfunction of hair cells.