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The modulation of inflammation is effective to treat many ocular surface diseases. Thus the low bioavailability of common anti-inflammatory eye-drops urges the development of ocular drug delivery systems to extend the ocular retention and enhance the cellular uptake for improving anti-inflammatory effect of eye-drops. Here we covalently conjugate two molecules of clinically anti-inflammatory drug (i.e., dexamethasone) with a small peptide (i.e., Tyr-Glu-Asn-Pro-Thr-Tyr) to generate an anti-inflammatory hydrogel eye-drop. With a self-assembled ability, the designed supramolecular hydrogel achieves gel-sol-gel transition by varying shearing forces which increases the pre-corneal retention of drug. The fluorescent imaging reveals the efficient cellular uptake of designed conjugate via clathrin-mediated endocytosis. A rodent model of endotoxin-induced uveitis verifies that the supramolecular hydrogel eye-drop suppresses inflammation responses without ocular irritation. As a rational approach to design anti-inflammatory drugs as eye-drops, this work overcomes the frequent instillation of clinical eye-drops and further improves the bioavailability of anti-inflammatory drugs, which may provide an effective and household way to fight ocular surface inflammation.
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The complex pathogenesis of preeclampsia (PE), a significant contributor to maternal and neonatal mortality globally, is poorly understood despite substantial research. This review explores the involvement of exosomal microRNAs (exomiRs) in PE, focusing on their impact on the protein kinase B (AKT)/hypoxia-inducible factor 1-α (HIF1α)/vascular endothelial growth factor (VEGF) signaling pathway as well as endothelial cell proliferation and migration. Specifically, this article amalgamates existing evidence to reveal the pivotal role of exomiRs in regulating mesenchymal stem cell and trophoblast function, placental angiogenesis, the renin-angiotensin system, and nitric oxide production, which may contribute to PE etiology. This review emphasizes the limited knowledge regarding the role of exomiRs in PE while underscoring the potential of exomiRs as non-invasive biomarkers for PE diagnosis, prediction, and treatment. Further, it provides valuable insights into the mechanisms of PE, highlighting exomiRs as key players with clinical implications, warranting further exploration to enhance the current understanding and the development of novel therapeutic interventions.
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MicroRNAs , Pré-Eclâmpsia , Recém-Nascido , Humanos , Gravidez , Feminino , MicroRNAs/genética , MicroRNAs/metabolismo , Placenta/metabolismo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Biomarcadores/metabolismoRESUMO
Arterioles are key determinants of the total peripheral vascular resistance, which, in turn, is a key determinant of arterial blood pressure. However, the amount of protein available from one isolated human arteriole may be less than 5 µg, making proteomic analysis challenging. In addition, obtaining human arterioles requires manual dissection of unfrozen clinical specimens. This limits its feasibility, especially for powerful multicenter clinical studies in which clinical specimens need to be shipped overnight to a research laboratory for arteriole isolation. We performed a study to address low-input, test overnight tissue storage and develop a reference human arteriolar proteomic profile. In tandem mass tag proteomics, use of a booster channel consisting of human induced pluripotent stem cell-derived endothelial and vascular smooth muscle cells (1:5 ratio) increased the number of proteins detected in a human arteriole segment with a false discovery rate of <0.01 from 1051 to more than 3000. The correlation coefficient of proteomic profile was similar between replicate arterioles isolated freshly, following cold storage, or before and after the cold storage (1-way analysis of variance; P = .60). We built a human arteriolar proteomic profile consisting of 3832 proteins based on the analysis of 12 arteriole samples from 3 subjects. Of 1945 blood pressure-relevant proteins that we curated, 476 (12.5%) were detected in the arteriolar proteome, which was a significant overrepresentation (χ2 test; P < .05). These findings demonstrate that proteomic analysis is feasible with arterioles isolated from human adipose tissue following cold overnight storage and provide a reference human arteriolar proteome profile highly valuable for studies of arteriole-related traits.
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Tecido Adiposo , Proteômica , Humanos , Arteríolas/metabolismo , Proteômica/métodos , Tecido Adiposo/metabolismo , Tecido Adiposo/irrigação sanguínea , Proteoma/metabolismo , Proteoma/análise , Feminino , Masculino , Adulto , Pessoa de Meia-IdadeRESUMO
Polymer translocation is a fundamental topic in non-equilibrium physics and is crucially important to many biological processes in life. In the present work, we adopt two-dimensional Langevin dynamics simulations to study the forced and spontaneous translocation dynamics of an active filament. The influence of polymer stiffness on the underlying dynamics is explicitly analyzed. For the forced translocation, the results show a robust stiffness-induced inhibition, and the translocation time exhibits a dual-exponent scaling relationship with the bending modulus. Tension propagation (TP) is also examined, where we find prominent modifications in terms of both activity and stiffness. For spontaneous translocation into a pure solvent, the translocation time is almost independent of the polymer stiffness. However, when the polymer is translocated into a porous medium, an intriguing non-monotonic alteration of translocation time with increasing chain stiffness is demonstrated. The semiflexible chain is beneficial for translocation while the rigid chain is not conducive. Stiffness regulation on the diffusion dynamics of the polymer in porous media shows a consistent scenario. The interplay of activity, stiffness, and porous crowding provides a new mechanism for understanding the non-trivial translocation dynamics of an active filament in complex environments.
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This paper examined Chinese undergraduate students' perceptions of using videoconferencing in learning English as a foreign language (EFL) during the COVID-19 pandemic. The data were collected among 348 Chinese university students who attended sixteen-week learning of Integrated English Course through Tencent Meeting, the most widely used videoconferencing application in China. We adopted voluntary response sampling method in this cross-sectional study. Students completed an online survey on "Wenjuanxing", China's biggest online questionnaire distribution platform. A structural equation model (SEM) was constructed and analyses revealed that perceived ease of use and perceived usefulness were significant predictors of students' satisfaction and participation intention. Students' computer self-efficacy had a positive effect on their perceived ease of use, perceived usefulness, and participation intention while their frequency of using videoconferencing did not influence these variables. This study contributes to the existing literature on the acceptance of videoconferencing in the context of EFL learning and offers insights for developing up-to-date videoconferencing teaching strategies.
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Recently, the increasing demand for data-centric applications is driving the elimination of image sensing, memory and computing unit interface, thus promising for latency- and energy-strict applications. Although dedicated electronic hardware has inspired the development of in-memory computing and in-sensor computing, folding the entire signal chain into one device remains challenging. Here an in-memory sensing and computing architecture is demonstrated using ferroelectric-defined reconfigurable two-dimensional photodiode arrays. High-level cognitive computing is realized based on the multiplications of light power and photoresponsivity through the photocurrent generation process and Kirchhoff's law. The weight is stored and programmed locally by the ferroelectric domains, enabling 51 (>5 bit) distinguishable weight states with linear, symmetric and reversible manipulation characteristics. Image recognition can be performed without any external memory and computing units. The three-in-one paradigm, integrating high-level computing, weight memorization and high-performance sensing, paves the way for a computing architecture with low energy consumption, low latency and reduced hardware overhead.
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Preeclampsia (PE) is usually associated with the accumulation of reactive oxygen species (ROS) resulting from heightened oxidative stress (OS). Ferroptosis is a unique type of lipid peroxidation-induced iron-dependent cell death distinct from traditional apoptosis, necroptosis, and pyroptosis and most likely contributes considerable to PE pathogenesis. At approximately 10-12 weeks of gestation, trophoblasts create an environment rich in oxygen and iron. In patients with PE, ferroptosis-related genes such as HIF1 and MAPK8 are downregulated, whereas PLIN2 is upregulated. Furthermore, miR-30b-5p overexpression inhibits solute carrier family 11 member 2, resulting in a decrease in glutathione levels and an increase in the labile iron pool. At the maternal-fetal interface, physiological hypoxia/reperfusion and excessive iron result in lipid peroxidation and ROS production. Owing to the high expression of Fpn and polyunsaturated fatty acid-containing phospholipid-related enzymes, including acyl-CoA synthetase long-chain family member 4, lysophosphatidylcholine acyl-transferase 3, and spermidine/spermine N1-acetyltransferase 1, trophoblasts become more susceptible to OS and ROS damage. In stage 1, the injured trophoblasts exhibit poor invasion and incomplete uterine spiral artery remodeling caused by ferroptosis, leading to placental ischemia and hypoxia. Subsequently, ferroptosis marked by OS occurs in stage 2, eventually causing PE. We aimed to explore the new therapeutic target of PE through OS in ferroptosis.
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Mendelian randomization is a technique used to examine the causal effect of a modifiable exposure on a trait using an observational study by utilizing genetic variants. The use of many instruments can help to improve the estimation precision but may suffer bias when the instruments are weakly associated with the exposure. To overcome the difficulty of high-dimensionality, we propose a model average estimator which involves using different subsets of instruments (single nucleotide polymorphisms, SNPs) to predict the exposure in the first stage, followed by weighting the submodels' predictions using penalization by common penalty functions such as least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD) and minimax concave penalty (MCP). The model averaged predictions are then used as a genetically predicted exposure to obtain the estimation of the causal effect on the response in the second stage. The novelty of our model average estimator also lies in that it allows the number of submodels and the submodels' sizes to grow with the sample size. The practical performance of the estimator is examined in a series of numerical studies. We apply the proposed method on a real genetic dataset investigating the relationship between stature and blood pressure.
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Variação Genética , Análise da Randomização Mendeliana , Humanos , Análise da Randomização Mendeliana/métodos , Causalidade , Fenótipo , Pressão Sanguínea/genética , Polimorfismo de Nucleotídeo Único , Estudo de Associação Genômica AmplaRESUMO
The present study aimed to explore the chemical constituents from the stems and leaves of Cephalotaxus fortunei. Seven lignans were isolated from the 75% ethanol extract of C. fortunei by various chromatographic methods, including silica gel, ODS column chromatography, and HPLC. The structures of the isolated compounds were elucidated according to physicochemical properties and spectral data. Compound 1 is a new lignan named cephalignan A. The known compounds were identified as 8-hydroxy-conidendrine(2), isolariciresinol(3), leptolepisol D(4), diarctigenin(5), dihydrodehydrodiconiferyl alcohol 9'-O-ß-D-glucopyranoside(6), and dihydrodehydrodiconiferyl alcohol 4-O-ß-D-glucopyranoside(7). Compounds 2 and 5 were isolated from the Cephalotaxus plant for the first time.
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Cephalotaxus , Lignanas , Lignanas/análise , Folhas de Planta/química , Etanol , Cromatografia Líquida de Alta PressãoRESUMO
The structural and dynamical properties of active filamentous objects under macromolecular crowding have a great relevance in biology. By means of Brownian dynamics simulations, we perform a comparative study for the conformational change and diffusion dynamics of an active chain in pure solvents and in crowded media. Our result shows a robust compaction-to-swelling conformational change with the augment of the Péclet number. The presence of crowding facilitates self-trapping of monomers and, thus, reinforces the activity mediated compaction. In addition, the efficient collisions between the self-propelled monomers and crowders induce a coil-to-globulelike transition, indicated by a marked change of the Flory scaling exponent of the gyration radius. Moreover, the diffusion dynamics of the active chain in crowded solutions demonstrates activity-enhanced subdiffusion. The center of mass diffusion manifests rather new scaling relations with respect to both the chain length and Péclet number. The interplay of chain activity and medium crowding provides a new mechanism to understand the non-trivial properties of active filaments in complex environments.
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Artificial intervention combined with stress acclimation was used to screen a heterotrophic nitrifying-aerobic denitrifying (HN-AD) bacterial, strain Rhodococcus SY24, resistant to linear alkylbenzenesulfonic acid (LAS) stress. When LAS was<15 mg/L, strain SY24 performed better cell growth and carbon source metabolism activity. The maximum nitrification and denitrification rates of SY24 under LAS stress could reach 1.18 mg/L/h and 1.05 mg/L/h, respectively, which were 13.80 % and 8.81 % higher than those of the original strain CPZ24. Higher LAS tolerance was seen in the functional genes (amoA, nxrA, napA, narG, nirK, nirS, norB, and nosZ). Response surface modeling revealed that 2 mg/L LAS, sodium succinate as a carbon source, 190 rams, and carbon/nitrogen 11 were the ideal culture conditions for SY24 to nitrogen removal under the LAS environment. This study offered a new screening strategy for the functional species, and strain SY24 showed significant LAS tolerance and HN-AD potential.
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Nitrogênio , Rhodococcus , Animais , Masculino , Ovinos , Carbono , Cinética , Desnitrificação , Radioisótopos de CarbonoRESUMO
Valley pseudospin is an electronic degree of freedom that promises highly efficient information processing applications. However, valley-polarized excitons usually have short pico-second lifetimes, which limits the room-temperature applicability of valleytronic devices. Here, we demonstrate room-temperature valley transistors that operate by generating free carrier valley polarization with a long lifetime. This is achieved by electrostatic manipulation of the non-trivial band topology of the Weyl semiconductor tellurium (Te). We observe valley-polarized diffusion lengths of more than 7 µm and fabricate valley transistors with an ON/OFF ratio of 105 at room temperature. Moreover, we demonstrate an ion insertion/extraction device structure that enables 32 non-volatile memory states with high linearity and symmetry in the Te valley transistor. With ultralow power consumption (~fW valley contribution), we enable the inferring process of artificial neural networks, exhibiting potential for applications in low-power neuromorphic computing.
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Cognição , Meio Ambiente , Temperatura , Difusão , Eletrônica , TelúrioRESUMO
OBJECTIVE: To explore the genetic basis for a child with metachromatic leukodystrophy (MLD). METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members. Potential variant was screened by whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. The pathogenicity the variant was analyzed by multiple sequence alignment of the amino acid sequence and three-dimensional model prediction of its protein product. RESULTS: The child was found to harbor compound heterozygous variants c.257G>A (p.R86Q) and c.467del (p.G156Afs*6) of the ARSA gene, among which the c.467del (p.G156Afs*6) frameshift variation was unreported previously. Multiple sequence alignment showed that the site of the c.257G>A (p.R86Q) missense variant is highly conserved. Three-dimensional structure modeling analysis showed that the partial deletion due to the p.G156Afs*6 variant may cause significant alteration of the structure of ARSA protein. CONCLUSION: The discovery of novel variant in ARSA has enriched the mutational spectrum of MLD and may facilitate the understanding of the genotype-phenotype correlation of MLD.
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Cerebrosídeo Sulfatase , Leucodistrofia Metacromática , Cerebrosídeo Sulfatase/genética , DNA , Estudos de Associação Genética , Humanos , Leucodistrofia Metacromática/genética , MutaçãoRESUMO
BACKGROUND: As a rare mitochondrial disease, combined oxidative phosphorylation deficiency 14 (COXPD14) is caused by biallelic variants in the phenylalanyl-tRNA synthetase 2, mitochondrial gene (FARS2) with clinical features of developmental delay, an elevated lactate level, early-onset encephalopathy, liver failure, and hypotonia. The objectives of this study were to analyze the clinical and molecular features of two Chinese siblings affected with COXPD14, and to review relevant literature. METHODS: Mutation screening was performed by whole exome sequencing (WES) in combination with Sanger sequencing validation to identify the disease-causing variants of the two patients. RESULTS: The two siblings presented with severe clinical features and both progressed aggressively and failed to survive after treatment abandonment. We identified two compound heterozygous FARS2 variants c.925G>A p.Gly309Ser and c.943G>C p.Gly315Arg in this proband, which were inherited from the unaffected father and mother, respectively. In addition, Sanger sequencing confirmed that the elder affected sister carried the same compound heterozygous variants. The c.925G>A p.Gly309Ser variant is known and commonly reported in COXPD14 patients, while c.943G>C p.Gly315Arg is a novel one. Neither of the variants was found in 100 Chinese healthy controls. Both variants were classified as "deleterious" and were located in the highly conserved regions of the protein. The above results suggested that the two variants were likely causative in this COXPD14-affected pedigree. CONCLUSIONS: Our study expands the mutation spectrum of FARS2 and highlights the importance of genetic testing in the diagnosis of diseases with a wide variety of phenotypes, especially in the differential diagnosis of diseases.
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Doenças Mitocondriais , Fenilalanina-tRNA Ligase , China , Humanos , Lactatos , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Mutação/genética , Linhagem , Fenilalanina-tRNA Ligase/genética , IrmãosRESUMO
Enormous production, use, and disposal of plastic goods present great challenges to environmental sustainability. Microplastics (MPs) are added into land which may serve as a larger MP repository than the ocean. Organic solid wastes and their biologically treated products can easily enter the soil and accumulate in soil systems. The current work deals with the extraction, identification, and distribution of MPs in typical organic solid wastes (food waste, livestock manure, and sludge) and their biologically treated products. The ecological risks of MPs were also preliminarily evaluated. The results showed that the abundance of MPs in organic solid wastes was in order of sludge > food waste > livestock manure. The main categories of MPs were fibers and films including PE, PP, and PET. The colors of MPs were mainly black, red, blue, and green. MPs generally exhibited bulges, depressions, cracks, or holes after biological treatment, and would be degraded into smaller fragments with potentially greater ecological risks. It was also found that the polymer risk index (H) of MPs in semi-dynamic composting products, compound fertilizer, and biogas residue of sedimentation tank sludge were higher than 10, reflecting their high ecological risk. Thus, it is recommended that the input of (micro)plastics to organic solid wastes streams should be minimized and related management should be established for the utilization of organic solid wastes and their biologically treated products.
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Eliminação de Resíduos , Poluentes Químicos da Água , Microplásticos , Resíduos Sólidos , Plásticos , Esgotos/química , Fertilizantes , Esterco , Biocombustíveis , Alimentos , Eliminação de Resíduos/métodos , Solo/químicaRESUMO
Objectives: This study aimed to explore the effect of subjective age on loneliness in old adults, and the mediating role of resilience and self-esteem in subjective age and loneliness. Methods: Approximately 450 old adults from Jiangxi, Hunan, Henan provinces completed the third edition of the Loneliness Scale (UCLA-LS III), Age Decade Scale (ADS), Connor-Davidson Resilience Scale (CD-RISC), and Self-Esteem Scale (SES). Results: (1) Subjective age was significantly positively correlated with loneliness. (2) Resilience, self-esteem, and loneliness were significantly negatively correlated. (3) Subjective age affected loneliness through the mediating effects of resilience and self-esteem, respectively. (4) Resilience and self-esteem played a chain mediating role between subjective age and loneliness. Conclusion: Resilience and self-esteem can directly affect the loneliness of the old adults alone and can also affect the loneliness of the old adults through the chain mediating effect of resilience and self-esteem.