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Achieving therapeutic efficacy in protein replacement therapies requires sustaining pharmacokinetic (PK) profiles, while maintaining the bioactivity of circulating proteins. This is often achieved via PEGylation in protein-based therapies, but it remains challenging for proteins produced in vivo in mRNA-based therapies due to the lack of a suitable post-translational modification method. To address this issue, we integrated a genetically encoded zwitterionic polypeptide, EKP, into mRNA constructs to enhance the PK properties of product proteins. Composed of alternating glutamic acid (E), lysine (K), and proline (P), EKP exhibits unique superhydrophilic properties and low immunogenicity. Our results demonstrate that EKP fusion significantly extends the circulation half-life of proteins expressed from mRNA while preserving their bioactivity using human interferon alpha and Neoleukin-2/15 as examples. This EKP fusion technology offers a new approach to overcoming the current limitations in mRNA therapeutics and has the potential to significantly advance the development of mRNA-based protein replacement therapy.
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Péptidos , ARN Mensajero , Humanos , ARN Mensajero/genética , ARN Mensajero/química , Péptidos/química , Péptidos/farmacocinética , Animales , Interferón-alfa/farmacocinética , Interferón-alfa/química , Interferón-alfa/genética , RatonesRESUMEN
BACKGROUND: Peanut (Arachis hypogaea), a vital oil and food crop globally, is susceptible to web blotch which is a significant foliar disease caused by Phoma arachidicola Marasas Pauer&Boerema leading to substantial yield losses in peanut production. Calcium treatment has been found to enhance plant resistance against pathogens. RESULTS: This study investigates the impact of exogenous calcium on peanut resistance to web blotch and explores its mechanisms. Greenhouse experiments revealed that exogenous calcium treatment effectively enhanced resistance to peanut web blotch. Specifically, amino acid calcium and sugar alcohol calcium solutions demonstrated the best induced resistance effects, achieving reduction rates of 61.54% and 60% in Baisha1016, and 53.94% and 50% in Luhua11, respectively. All exogenous calcium treatments reduced malondialdehyde (MDA) and relative electrical conductivity (REC) levels in peanut leaves, mitigating pathogen-induced cell membrane damage. Exogenous calcium supplementation led to elevated hydrogen peroxide (H2O2) content and superoxide anion (O2â-) production in peanut leaves, facilitating the accumulation of reactive oxygen species (ROS) crucial for plant defense responses. Amino acid calcium and sugar alcohol calcium treatments significantly boosted activities of peroxidase (POD), superoxide dismutase (SOD), catalase (CAT), and ascorbate peroxidase (APX) in peanut leaves. Activation of these antioxidant enzymes effectively scavenged excess ROS, maintaining ROS balance and mitigating cellular damage. CONCLUSIONS: In summary, exogenous calcium treatment triggered ROS production, which was subsequently eliminated by the activation of antioxidant enzymes, thereby reducing cell membrane damage and inducing defense responses against peanut web blotch.
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Arachis , Calcio , Membrana Celular , Resistencia a la Enfermedad , Enfermedades de las Plantas , Especies Reactivas de Oxígeno , Arachis/metabolismo , Arachis/fisiología , Especies Reactivas de Oxígeno/metabolismo , Calcio/metabolismo , Membrana Celular/metabolismo , Ascomicetos/fisiología , Hojas de la Planta/metabolismo , Peróxido de Hidrógeno/metabolismoRESUMEN
Photosensitizers (PSs) play a key role in the photodynamic therapy (PDT) of tumors. However, commonly used PSs are prone to intrinsic fluorescence aggregation-caused quenching and photobleaching; this drawback severely limits the clinical application of PDT, necessitating new phototheranostic agents. Herein, a multifunctional theranostic nanoplatform (named TTCBTA NP) is designed and constructed to achieve fluorescence monitoring, lysosome-specific targeting, and image-guided PDT. TTCBTA with a twisted conformation and D-A structure is encapsulated in amphiphilic Pluronic F127 to form nanoparticles (NPs) in ultrapure water. The NPs exhibit biocompatibility, high stability, strong near-infrared emission, and desirable reactive oxygen species (ROSs) production capacity. The TTCBTA NPs also show high-efficiency photo-damage, negligible dark toxicity, excellent fluorescent tracing, and high accumulation in lysosome for tumor cells. Furthermore, TTCBTA NPs are used to obtain fluorescence images with good resolution of MCF-7 tumors in xenografted BALB/c nude mice. Crucially, TTCBTA NPs present a strong tumor ablation ability and image-guided PDT effect by generating abundant ROSs upon laser irradiation. These results demonstrate that the TTCBTA NP theranostic nanoplatform may enable highly efficient near-infrared fluorescence image-guided PDT.
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Neoplasias , Fotoquimioterapia , Animales , Ratones , Fotoquimioterapia/métodos , Medicina de Precisión , Fluorescencia , Ratones Desnudos , Fármacos Fotosensibilizantes/química , Neoplasias/terapia , OrgánulosRESUMEN
Inkjet printing technology is widely used in the textile digital printing application today though the current technology still requires pretreatment and postwashing procedures before and after printing. Additional chemical treatment generates a large amount of wastewater and complicates the process. Among the many potential approaches for reducing chemical waste, pigments with self-dispersing capability were prepared and formulated into binder-free inkjet inks that require no pretreatment or after-washing process when printing cotton fabrics. The new self-dispersing pigment inks were tested and evaluated on cotton fabrics. The distribution of particles was between 122.2 and 188.5 nm, and inks have excellent storage capability. Printed fabrics' light fastness and acid/alkali resistance are about grade 5, and printed cotton's washing and rubbing fastness are above grade 3. The mechanism and performance of ink drops were investigated by LF-NMR and ink-drop observation methods. This work provides a possible solution for reducing wastewater in the textile industry.
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Secondary lymphoid organs (SLOs) are an important target for mRNA delivery in various applications. While the current delivery method relies on the drainage of nanoparticles to lymph nodes by intramuscular (IM) or subcutaneous (SC) injections, an efficient mRNA delivery carrier for SLOs-targeting delivery by systemic administration (IV) is highly desirable but yet to be available. In this study, we developed an efficient SLOs-targeting carrier using phosphatidylserine (PS), a well-known signaling molecule that promotes the endocytic activity of phagocytes and cellular entry of enveloped viruses. We adopted these biomimetic strategies and added PS into the standard four-component MC3-based LNP formulation (PS-LNP) to facilitate the cellular uptake of immune cells beyond the charge-driven targeting principle commonly used today. As a result, PS-LNP performed efficient protein expression in both lymph nodes and the spleen after IV administration. In vitro and in vivo characterizations on PS-LNP demonstrated a monocyte/macrophage-mediated SLOs-targeting delivery mechanism.
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Nanopartículas , Fosfatidilserinas , Nanopartículas/química , ARN Interferente Pequeño/genética , ARN Mensajero/genéticaRESUMEN
Much heat is released in aerobic landfills, which leads to temperature change. Quantitative prediction of temperature change with time and space is essential for the safe aerobic operation of landfill. In this article, based on the theory of porous media seepage mechanics and heat transfer, a seepage-temperature coupling model considering aeration, recirculation and degradation was established, which included internal energy change, heat conduction, convection and heat transfer. Moreover, combined with the long-time on-site monitoring temperature data from Wuhan Jinkou Landfill, the model's reliability was preliminarily verified. Sensitivity analysis was carried out for aeration intensity, aeration temperature, recirculation intensity and recirculation temperature. Among the four factors, recirculation intensity influences the peak temperature most with a decrease of 20.11%. Compared with Borglin's and Hao's models, it is found that waste should not be assumed as a cell for temperature prediction. By comparing the results of Non-linear Ascent Stage model, Linear Ascent Stage model and Absent Ascent Stage model, it showed that the temperature difference of the three models decreases with the increase of operation time. In addition, the time point of peak temperature, t0, affects the temperature distribution. The above results provide a reference for predicting the spatial and temporal distribution of temperature and regulations for long-term aerobic landfill operations.
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Eliminación de Residuos , Contaminantes Químicos del Agua , Eliminación de Residuos/métodos , Temperatura , Reproducibilidad de los Resultados , Contaminantes Químicos del Agua/análisis , Instalaciones de Eliminación de Residuos , Reactores BiológicosRESUMEN
The key to upgrade the efficiency of aerobic remediation of landfills is to determine the distribution characteristics of oxygen concentration during aerobic ventilation. This study discusses the distribution law of oxygen concentration with time and radial distance based on a single-well aeration test at an old landfill site. The transient analytical solution of the radial oxygen concentration distribution was deduced using the gas continuity equation and approximation of calculus and logarithmic functions. Oxygen concentration data from the field monitoring were compared with the results predicted by the analytical solution. The results indicated that the oxygen concentration initially increased and then decreased with prolonged aeration time. With an increase in radial distance, the oxygen concentration rapidly declined, followed by a gradual decrease. The influence radius of the aeration well increased slightly when the aeration pressure increased from 2 to 20 kPa. The field test data agreed with the analytical solution prediction results, preliminarily verifying the reliability of the oxygen concentration prediction model. Results from this study provide a basis of guidelines for the design, operation and maintenance management of a landfill aerobic restoration project.
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Eliminación de Residuos , Eliminación de Residuos/métodos , Oxígeno , Reproducibilidad de los Resultados , Instalaciones de Eliminación de Residuos , Reactores BiológicosRESUMEN
Although recombinant adeno-associated viruses (AAVs) are considered low immunogenic and safe for gene delivery, the immunogenicity of capsids still represents a major obstacle to the readministration of AAV vectors. Here, we design an immunosuppressive zwitterionic phosphoserine (PS)-containing polypeptide to induce AAV-specific immune tolerance and eradicate the immunological response. AAVs modified with the zwitterionic PS polypeptide maintain their transduction activity and tissue tropism but suppress the induction of AAV-specific antibodies. In a hemophilia A mouse model (FVIII knockout mice), the readministration of zwitterionic PS polypeptide-modified AAV8-FVIII vectors successfully evades immunological response, corrects blood FVIII levels, and stops blood loss in tail-bleeding experiments. This potent and safe technology mimics the natural tolerance of apoptotic cells and controls the immunosuppressive, zwitterionic, and degradable polypeptide precisely, reducing the concern of toxicities upon readministrations. This work presents a new concept and a platform of engineered viral vectors by chemically linking immunosuppressive materials to AAV vectors, enabling the readministration of AAV vectors while maintaining their transduction efficiency to a considerable degree.
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Dependovirus , Terapia Genética , Animales , Ratones , Fosfoserina , Dependovirus/genética , Vectores Genéticos , Ratones Noqueados , Péptidos/genéticaRESUMEN
Novel functional AIEgen based on three compact bound aryl skeletons is designed and synthesized. This tri-aryl type luminogen (TA-Catechol) embedded with catechol moiety responds rapidly to series of boronic acids. Real-time visual and quantitative dual-mode detection method is established for the first time with modest precision and low detection limit (8.0â µM). Detailed mechanistic discussion identifies tetra-coordinated boronic species as the key intermediate within sensing procedure. Wide range of organic boronic acids compatible with this strategy is displayed which is promising in high throughput screening technology. Furthermore, solid-state sensing capability of TA-Catechol is also demonstrated.
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Ácidos Borónicos , Catecoles , BoroRESUMEN
We describe the efficient synthesis of a series of new simplified hamigeran B and 1-hydroxy-9-epi-hamigeran B norditerpenoid analogs (23 new members in all), structurally related to cyathane diterpenoid scaffold, and their anti-neuroinflammatory and neurite outgrowth-stimulating (neurotrophic) activity. Compounds 9a, 9h, 9o, and 9q exhibited moderate nerve growth factor (NGF)-mediated neurite-outgrowth promoting effects in PC-12 cells at the concentration of 20 µm. Compounds 9b, 9c, 9o, 9q, and 9t showed significant nitric oxide (NO) production inhibition in lipopolysaccharide (LPS)-activated BV-2 microglial cells, of which 9c and 9q were the most potent inhibitors, with IC50 values of 5.85 and 6.31 µm, respectively. Two derivatives 9q and 9o as bifunctional agents displayed good activities as NO production inhibitors and neurite outgrowth-inducers. Cytotoxicity experiments, H2O2-induced oxidative injury assay, and ELISA reaction speculated that compounds may inhibit the TNF-α pathway to achieve anti-inflammatory effects on nerve cells. Moreover, molecular docking studies provided a better understanding of the key structural features affecting the anti-neuroinflammatory activity and displayed significant binding interactions of some derivatives (like 9c, 9q) with the active site of iNOS protein. The structure-activity relationships (SARs) were also discussed. These results demonstrated that this structural class compounds offered an opportunity for the development of a new class of NO inhibitors and NGF-like promotors.
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Naftoquinonas/química , Proyección Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Concentración 50 Inhibidora , Fármacos Neuroprotectores/química , Relación Estructura-ActividadRESUMEN
This study synthesized 20 sclareol derivatives. The antifungal activities of these derivatives were evaluated in vitro against five phytopathogenic fungi using the mycelium growth rate method. Among all the tested compounds, compound 16 with one iodine atom and three hydroxyl groups displayed higher fungicidal activities against all the tested phytopathogenic fungi than precursor sclareol. Compound 16 also showed more pronounced antifungal activities against Curvularia lunata (IC50=12.09 µg/mL) and Alternaria brassicae (IC50=14.47 µg/mL) than the positive control, a commercial agricultural fungicide thiabendazole.
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Alternaria/efectos de los fármacos , Antifúngicos/química , Antifúngicos/farmacología , Diterpenos/química , Diterpenos/farmacología , Alcoholes/química , Alcoholes/farmacología , Antifúngicos/síntesis química , Ascomicetos/efectos de los fármacos , Cristalografía por Rayos X , Diterpenos/síntesis química , Éteres/química , Éteres/farmacología , Conformación Molecular , Relación Estructura-Actividad , Tiabendazol/química , Tiabendazol/farmacologíaRESUMEN
Energy performance contracting (EPC) as a market instrument has been effective in promoting energy efficiency worldwide, but it has encountered many insurmountable obstacles in rural energy management. In this study, based on the characteristics of energy management in rural areas, three EPC modes are designed and tested in 24,000 rural households. The test results show that two adapted EPC modes of local government involvement and energy payment directly from the national grid can effectively overcome the barriers encountered in the traditional EPC modes and work well under the economic and social environmental conditions in rural areas. The key to the adaptation of the traditional EPC modes is the introduction of the local government as the third party. Participation of the third party can effectively reduce and remove the barriers and risks and increase the mutual trust between the clients (households) and the energy service companies (ESCOs). Based on the testing results, this study suggests that governmental departments should formulate relevant EPC policies and technical guidelines within the rural context. This research recommends that farmers should not manage their energy services by themselves and it is suggested to out-contracting ESCOs by applying the modes developed and tested by this paper.
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One of the greenest and promising ways to solve the problem of freshwater crisis is surface solar steam generation from seawater. A great number of photothermal materials with multi-component and multi-layered delicate yet complex structures often suffer from either low evaporation rate or high energy loss. Here, this work presents a single component foam evaporator with steam generation rate of up to 4.32 kg m-2 h-1 under 1 sun irradiation. The evaporator is constructed from an aniline oligomer as a single light-absorbing component, covalent linked with polyethylene glycol to form a monolithic polymer foam. Floating on the seawater, the foam has absorbance of 99.5% over the entire solar spectral range and low thermal conductivity (0.0077 W K-1m-1) that effectively retains heat in the material and at the interface. After 3 months of continuous outdoor natural sunlight irradiation, the evaporator maintains a stable and durable evaporation rate. Moreover, the materials have good mechanical properties (7.48 MPa young's modulus and 57.38% elongation at break) and excellent chemical resistance in 10 common organic solvents and aqueous solutions of pH = 1 to 14. This study provides a new system and strategy for desalination, steam power generation, treatment of polluted water and sewage, etc.
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In this study, three distinct bioretention setups incorporating fillers, plants, and earthworms were established to evaluate the operational efficiency under an ecosystem concept across varying time scales. The results revealed that under short-term operating conditions, extending the drying period led to a notable increase in the removal of NO3--N, total phosphorus (TP), and chemical oxygen demand (COD) by 5 %-7%, 4 %-12 %, and 5 %-10 %, respectively. Conversely, under long-time operating conditions, the introduction of plants resulted in a significant boost in COD removal by 10 %-20 %, while the inclusion of earthworms improved NH4+-N and NO3--N removal, especially TP removal by 9 %-16 %. Microbial community analysis further indicated the favorable impact of the bioretention system on biological nitrogen and phosphorus metabolism, particularly with the incorporation of plants and earthworms. This study provides a reference for the operational performance of bioretention systems on different time scales.
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Biodegradación Ambiental , Ecosistema , Nitrógeno , Oligoquetos , Fósforo , Animales , Oligoquetos/metabolismo , Análisis de la Demanda Biológica de Oxígeno , Contaminantes Químicos del Agua , LluviaRESUMEN
Neural networks such as variational autoencoders (VAE) perform dimensionality reduction for the visualization and analysis of genomic data, but are limited in their interpretability: it is unknown which data features are represented by each embedding dimension. We present siVAE, a VAE that is interpretable by design, thereby enhancing downstream analysis tasks. Through interpretation, siVAE also identifies gene modules and hubs without explicit gene network inference. We use siVAE to identify gene modules whose connectivity is associated with diverse phenotypes such as iPSC neuronal differentiation efficiency and dementia, showcasing the wide applicability of interpretable generative models for genomic data analysis.
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Redes Neurales de la Computación , TranscriptomaRESUMEN
Thermally expandable microspheres (TEMs) are hollow polymeric particles in which a blowing gas has been encapsulated. This property makes them excellent for thermal insulation applications, such as lightweight fillers. This study has developed a viable technology for further improving thermal insulation properties in the field that needs excellent thermal insulation of textile fabrics. The ATO/TEMs composites were designed and prepared to reduce sunlight radiation by the charge gravity method. The test results showed that the ATO-coated TEMs effectively block thermal radiation from sunlight. The temperature difference between ATO/TEMs treated cotton and the uncoated cotton fabric was 9 °C, and the thermal conductivity coatings were 0.0432â W/mâ K. The UPF value of ATO/TEMs (ILs) coated cotton fabric is 440, significantly higher than pure cotton. This approach can provide insight into the design of high-performance solar insulation composite structures.
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A catalytic asymmetric nucleophilic reverse prenylation of indol-2-ones in situ generated from 3-bromooxindoles with prenyltributylstannane promoted by Ni(II)/chiral N,N'-dioxide was developed. This reaction provides facile access to C3 reverse-prenylated oxindoles in good to excellent enantioselectivities, which enabled the asymmetric synthesis of debromoflustramine A in five steps.
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Solar-driven desalination systems have been recognized as an effective technology to address the water crisis. Recently, evaporators prepared based on advanced manufacturing technologies have emerged as a promising tool in enhancing ocean energy utilization. In this review, we discussed the thermal conversion, energy flow, salt deposition mechanisms, and design strategies for solar-driven desalination systems, and explored how to improve the desalination performance and energy use efficiency of the systems through advanced manufacturing technologies. In future perspectives, we determined the feasibility of coupling solar-driven solar desalination systems with multi-stage energy utilization systems and emerging artificial intelligence technologies, for which conclusions are given and new directions for future desalination system development are envisioned. Finally, exciting opportunities and challenges in the face of basic research and practical implementation are discussed, providing promising solutions and blueprints for green and novel desalination technologies while achieving sustainable development.
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INTRODUCTION: Previous studies have documented that rhynchophylline exerts antioxidative and anti-inflammatory effects on ischemic neuronal damage in vitro or in vivo. There is a considerable lack of direct evidence for its role in neural function and neuroplasticity after ischemic stroke. AIMS: This study aims to explore the role of rhynchophylline in middle cerebral artery occlusion (MCAO) induced ischemic stroke model and the potential mechanisms. METHODS: Mice were randomly divided into the following three groups: Sham, MCAO + ddH2O, and MCAO + Rhy(40 mg/kg by oral gavage) groups. Cerebral ischemia was induced by MCAO. Cerebral blood flow was monitored to indicate the success of the ischemic model. The neurological severity score and a series of related behavior tests were performed(after MCAO 3d,7d,14d,21d,28d). Golgi staining and Sholl analysis were used to evaluate the complexity of dendrites and the density of dendritic spines. Immunohistochemistry was used to detect the expression of synapsin I and NeuN. RESULTS: Administration of rhynchophylline for 7 consecutive days after the onset of cerebral ischemia alleviated the sensory-motor functional defects and ameliorated hippocampus-dependent spatial memory injury as well as reduced the infarct volume induced by MCAO. However, golgi staining and sholl analysis showed that rhynchophylline improved dendritic complexity and spine density as well as the synaptic plasticity. Furthermore,the expression of synapsin I and Neun was significantly reduced after cerebral ischemia and rhynchophylline administration ameliorated the loss of synapsin I. CONCLUSION: Rhynchophylline is a promising treatment for ischemic stroke via improving synaptic plasticity and ameliorating the sensory-motor function.
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Isquemia Encefálica , Accidente Cerebrovascular Isquémico , Ratones , Animales , Infarto de la Arteria Cerebral Media/complicaciones , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Sinapsinas , Isquemia Encefálica/complicaciones , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Plasticidad Neuronal/fisiología , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/tratamiento farmacológicoRESUMEN
Tumor-associated adipocytes (TAAs) recruit monocytes and promote their differentiation into tumor-associated macrophages (TAMs) that support tumor development. Here, TAAs are engineered to promote the polarization of TAMs to the tumor suppressive M1 phenotype. Telratolimod, a toll-like receptor 7/8 agonist, is loaded into the lipid droplets of adipocytes to be released at the tumor site upon tumor cell-triggered lipolysis. Locally administered drug-loaded adipocytes increased tumor suppressive M1 macrophages in both primary and distant tumors and suppressed tumor growth in a melanoma model. Furthermore, drug-loaded adipocytes improved CD8+ T cell-mediated immune responses within the tumor microenvironment and favored dendritic cell maturation in the tumor draining lymph nodes.