RESUMO
Insufficient training data is a common barrier to effectively learn multimodal information interactions and question semantics in existing medical Visual Question Answering (VQA) models. This paper proposes a new Asymmetric Cross Modal Attention network called ACMA, which constructs an image-guided attention and a question-guided attention to improve multimodal interactions from insufficient data. In addition, a Semantic Understanding Auxiliary (SUA) in the question-guided attention is newly designed to learn rich semantic embeddings for improving model performance on question understanding by integrating word-level and sentence-level information. Moreover, we propose a new data augmentation method called Multimodal Augmented Mixup (MAM) to train the ACMA, denoted as ACMA-MAM. The MAM incorporates various data augmentations and a vanilla mixup strategy to generate more non-repetitive data, which avoids time-consuming artificial data annotations and improves model generalization capability. Our ACMA-MAM outperforms state-of-the-art models on three publicly accessible medical VQA datasets (VQA-Rad, VQA-Slake, and PathVQA) with accuracies of 76.14 %, 83.13 %, and 53.83 % respectively, achieving improvements of 2.00 %, 1.32 %, and 1.59 % accordingly. Moreover, our model achieves F1 scores of 78.33 %, 82.83 %, and 51.86 %, surpassing the state-of-the-art models by 2.80 %, 1.15 %, and 1.37 % respectively.
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Aprendizagem , SemânticaRESUMO
In both cancer and infections, diseased cells are presented to human Vγ9Vδ2 T cells through an 'inside out' signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A11-4. Here we show how-in both humans and alpaca-multiple pAgs function as 'molecular glues' to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities. Our structural insights guided mutagenesis experiments that led to disruption of the intracellular BTN3A1-BTN2A1 association, abolishing pAg-mediated Vγ9Vδ2 T cell activation. Analyses using structure-based molecular-dynamics simulations, 19F-NMR investigations, chimeric receptor engineering and direct measurement of intercellular binding force revealed how pAg-mediated BTN2A1 association drives BTN3A1 intracellular fluctuations outwards in a thermodynamically favourable manner, thereby enabling BTN3A1 to push off from the BTN2A1 ectodomain to initiate T cell receptor-mediated γδ T cell activation. Practically, we harnessed the molecular-glue model for immunotherapeutics design, demonstrating chemical principles for developing both small-molecule activators and inhibitors of human γδ T cell function.
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Butirofilinas , Ativação Linfocitária , Fosfoproteínas , Receptores de Antígenos de Linfócitos T gama-delta , Linfócitos T , Animais , Humanos , Antígenos CD/imunologia , Antígenos CD/metabolismo , Butirofilinas/imunologia , Butirofilinas/metabolismo , Camelídeos Americanos/imunologia , Simulação de Dinâmica Molecular , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Cristalografia por Raios X , Ressonância Magnética Nuclear Biomolecular , TermodinâmicaRESUMO
BACKGROUND: Lysosomal cathepsin D (CTSD) can degrade internalized advanced glycation end products (AGEs) in dermal fibroblasts. CTSD expression is decreased in photoaged fibroblasts, which contributes to intracellular AGEs deposition and further plays a role in AGEs accumulation of photoaged skin. The mechanism under downregulated CTSD expression is unclear. OBJECTIVE: To explore possible mechanism of regulating CTSD expression in photoaged fibroblasts. METHODS: Dermal fibroblasts were induced into photoaging with repetitive ultraviolet A (UVA) irradiation. The competing endogenous RNA (ceRNA) networks were constructed to predict candidate circRNAs or miRNAs related with CTSD expression. AGEs-BSA degradation by fibroblasts was studied with flow cytometry, ELISA, and confocal microscopy. Effects of overexpressing circRNA-406918 via lentiviral transduction on CTSD expression, autophagy, AGE-BSA degradation were analyzed in photoaged fibroblasts. The correlation between circRNA-406918 and CTSD expression or AGEs accumulation in sun-exposed and sun-protected skin was studied. RESULTS: CTSD expression, autophagy, and AGEs-BSA degradation were significantly decreased in photoaged fibroblasts. CircRNA-406918 was identified to regulate CTSD expression, autophagy, and senescence in photoaged fibroblasts. Overexpressing circRNA-406918 potently decreased senescence and increased CTSD expression, autophagic flux, and AGEs-BSA degradation in photoaged fibroblasts. Moreover, circRNA-406918 level was positively correlated with CTSD mRNA expression and negatively associated with AGEs accumulation in photodamaged skin. Further, circRNA-406918 was predicted to mediate CTSD expression through sponging eight miRNAs. CONCLUSION: These findings suggest that circRNA-406918 regulates CTSD expression and AGEs degradation in UVA-induced photoaged fibroblasts and might exert a role in AGEs accumulation in photoaged skin.
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MicroRNAs , Envelhecimento da Pele , Humanos , Catepsina D/genética , Catepsina D/metabolismo , Catepsina D/farmacologia , Fibroblastos/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , MicroRNAs/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Circular/farmacologia , Pele/metabolismo , Envelhecimento da Pele/genética , Raios Ultravioleta/efeitos adversosRESUMO
Poly(butylene adipate-co-terephthalate) (PBAT), a polyester made of terephthalic acid (TPA), 1,4-butanediol, and adipic acid, is extensively utilized in plastic production and has accumulated globally as environmental waste. Biodegradation is an attractive strategy to manage PBAT, but an effective PBAT-degrading enzyme is required. Here, we demonstrate that cutinases are highly potent enzymes that can completely decompose PBAT films in 48 h. We further show that the engineered cutinases, by applying a double mutation strategy to render a more flexible substrate-binding pocket exhibit higher decomposition rates. Notably, these variants produce TPA as a major end-product, which is beneficial feature for the future recycling economy. The crystal structures of wild type and double mutation of a cutinase from Thermobifida fusca in complex with a substrate analogue are also solved, elucidating their substrate-binding modes. These structural and biochemical analyses enable us to propose the mechanism of cutinase-mediated PBAT degradation.
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Adipatos , Poliésteres , Poliésteres/metabolismoRESUMO
Activation of the T-cell antigen receptor (TCR)-CD3 complex is critical to induce the anti-tumor response of CD8+ T cells. Here, we found that disulfiram (DSF), an FDA-approved drug previously used to treat alcohol dependency, directly activates TCR signaling. Mechanistically, DSF covalently binds to Cys20/Cys23 residues of lymphocyte-specific protein tyrosine kinase (LCK) and enhances its tyrosine 394 phosphorylation, thereby promoting LCK kinase activity and boosting effector T cell function, interleukin-2 production, metabolic reprogramming, and proliferation. Furthermore, our in vivo data revealed that DSF promotes anti-tumor immunity against both melanoma and colon cancer in mice by activating CD8+ T cells, and this effect was enhanced by anti-PD-1 co-treatment. We conclude that DSF directly activates LCK-mediated TCR signaling to induce strong anti-tumor immunity, providing novel molecular insights into the therapeutic effect of DSF on cancer.
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Dissulfiram , Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Animais , Linfócitos T CD8-Positivos , Dissulfiram/farmacologia , Ativação Linfocitária , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Camundongos , Fosforilação , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de SinaisRESUMO
Advanced glycation end product (AGE) accumulation is significantly increased in the dermis of photoaged skin and plays crucial roles in photoaging. Although AGEs have been found to contribute to the yellowish discoloration of photoaged skin, their roles in photoaging-associated hyperpigmentation disorders have not been extensively studied. In this study, we observed that AGEs, NLRP3, and IL-18 were increased in the dermis of sun-exposed skin and lesions of melasma and solar lentigo and that dermal deposition of AGE was positively correlated with epidermal melanin levels. In addition, we found that AGE-BSA potently activated NLRP3 inflammasome and promoted IL-18 production and secretion in cultured fibroblasts, which was mediated by receptor for AGE/NF-κB pathway. Moreover, AGE-BSA significantly promoted melanogenesis by increasing tyrosinase activity and expression of microphthalmia-associated transcription factor and tyrosinase, which was dependent on NLRP3 inflammasome activation and IL-18 secretion in fibroblasts. Notably, AGE-collagen could activate NLRP3 inflammasome in fibroblasts and enhance melanogenesis. Furthermore, we found that IL-18 enhanced melanogenesis by binding to its receptor and activating p38 MAPK and extracellular signalâregulated kinase 1/2 signaling pathways in melanocytes. Importantly, the promelanogenesis of AGE-BSA was verified in ex vivo cultured skin and mouse models. These findings suggest that dermal AGEs stimulate melanogenesis and contribute to the development of photoaging-associated hyperpigmentation disorders.
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Inflamassomos , Lentigo , Animais , Fibroblastos/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Melaninas/metabolismo , Camundongos , Fator de Transcrição Associado à Microftalmia/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Monofenol Mono-Oxigenase/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Background: To explore advanced glycation end products (AGEs)-induced m6A modification in fibroblasts and its potential role in photoaging. Methods: We studied m6A modification in AGEs-bovine serum albumin-treated fibroblasts with m6A-mRNA & lncRNA epitranscriptomic microarray and bioinformatics analysis. The m6A modification level was also investigated in skin samples. Results: m6A methylation microarray analysis revealed m6A modification profiles in AGEs-treated fibroblasts. Gene ontology, Kyoto Encyclopedia of Genes and Genomes, protein-protein interaction and competing endogenous RNA network analysis indicated that the genes of differentially methylated mRNAs and lncRNAs were mainly related to inflammation processes. We also found that AGEs-bovine serum albumin dose-dependently increased the m6A level and METTL14 expression in both fibroblasts and sun-exposed skin. Conclusion: Our study provided novel information regarding alterations of m6A modifications in AGEs-induced dermal fibroblasts and potential targets for treatment of photoaging.
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Produtos Finais de Glicação Avançada , RNA Longo não Codificante , Envelhecimento da Pele , Fibroblastos/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Metiltransferases , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , RNA Mensageiro/genética , Soroalbumina Bovina/metabolismo , Pele/metabolismoRESUMO
Photoreceptor death and neurodegeneration is the leading cause of irreversible vision loss. The inflammatory response of microglia plays an important role in the process of neurodegeneration. In this study, we chose retinal detachment as the model of photoreceptor degeneration. We found Myosin 1f was upregulated after retinal detachment, and it was specifically expressed in microglia. Deficiency of myosin 1f protected against photoreceptor apoptosis by inhibiting microglia activation. The elimination of microglia can abolish the protective effect of myosin 1f deficiency. After stimulation by LPS, microglia with myosin 1f deficiency showed downregulation of the MAPK and AKT pathways. Our results demonstrated that myosin 1f plays a crucial role in microglia-induced neuroinflammation after retinal injury and photoreceptor degeneration by regulating two classic inflammatory pathways and thereby decreasing the expression of inflammatory cytokines. Knockout of myosin 1f reduces the intensity of the immune response and prevents cell death of photoreceptor, suggesting that myosin 1f can be inhibited to prevent a decline in visual acuity after retinal detachment.
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Microglia/metabolismo , Microglia/patologia , Miosina Tipo I/metabolismo , Miosinas/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Degeneração Retiniana/metabolismo , Descolamento Retiniano/metabolismo , Aminopiridinas/farmacologia , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Luz , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Modelos Biológicos , Células Fotorreceptoras de Vertebrados/efeitos dos fármacos , Células Fotorreceptoras de Vertebrados/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/farmacologia , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Descolamento Retiniano/genética , Descolamento Retiniano/patologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Seedless fruit is a feature appreciated by consumers. The ovule abortion process is highly orchestrated and controlled by numerous environmental and endogenous signals. However, the mechanisms underlying ovule abortion in pear remain obscure. Here, we found that gibberellins (GAs) have diverse functions during ovules development between seedless pear '1913' and seeded pear, and that GA4+7 activates a potential programmed cell death process in '1913' ovules. After hormone analyses, strong correlations were determined among jasmonic acid (JA), ethylene and salicylic acid (SA) in seedless and seeded cultivars, and GA4+7 treatments altered the hormone accumulation levels in ovules, resulting in significant correlations between GA and both JA and ethylene. Additionally, SA contributed to ovule abortion in '1913'. Exogenously supplying JA, SA or the ethylene precursor 1-aminocyclopropane-1-carboxylic acid promoted 'Bartlett' seed death. The regulatory mechanism in which ethylene controls ovule death has been demonstrated; therefore, JA's role in regulating '1913' ovule abortion was investigated. A further study identified that the JA signaling receptor MYC2 bound the SENESCENCE-ASSOCIATED 39 promoter and triggered its expression to regulate ovule abortion. Thus, we established ovule abortion-related relationships between GA and the hormones JA, ethylene and SA, and we determined their synergistic functions in regulating ovule death.
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Apoptose/efeitos dos fármacos , Ciclopentanos/farmacologia , Etilenos/farmacologia , Giberelinas/farmacologia , Óvulo Vegetal/metabolismo , Oxilipinas/farmacologia , Pyrus/metabolismo , Ciclopentanos/metabolismo , Etilenos/metabolismo , Giberelinas/metabolismo , Oxilipinas/metabolismoRESUMO
BACKGROUND: From the perspective of information processing, an integrated understanding of the structural and functional connectomes in depression patients is important, a multimodal meta-analysis is required to detect the robust alterations in graph metrics across studies. METHODS: Following a systematic search, 952 depression patients and 1447 controls in nine diffusion magnetic resonance imaging (dMRI) and twelve rest state functional MRI (rs-fMRI) studies with high methodological quality met the inclusion criteria and were included in the meta-analysis. RESULTS: Regarding the dMRI results, no significant differences of meta-analytic metrics were found; regarding the rs-fMRI results, the modularity and local efficiency were found to be significantly lower in the depression group than in the controls (Hedge's g = -0.330 and -0.349, respectively). CONCLUSION: Our findings suggested a lower modularity and network efficiency in the rs-fMRI network in depression patients, indicating that the pathological imbalances in brain connectomes needs further exploration. LIMITATIONS: Included number of trials was low and heterogeneity should be noted.
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Conectoma , Benchmarking , Encéfalo/diagnóstico por imagem , Depressão , Humanos , Imageamento por Ressonância MagnéticaRESUMO
The massive accumulation of polyethylene terephthalate (PET) in the global ecosystem is a growing environmental crisis. Development of environmental friendly strategies to achieve enzyme-catalyzed PET degradation has attracted tremendous attention. In this study, we demonstrated the synergistic effects of combining a specific PET-degrading enzyme IsPETaseEHA variant from PET-assimilating bacterium Ideonella sakaiensis and a lytic polysaccharide monooxygenase from a white-rot fungus Pycnoporus coccineus (PcAA14A) in PET degradation. We found that the presence of PcAA14A alone did not result in PET hydrolysis, but its presence could stimulate IsPETaseEHA-mediated hydrolytic efficiency by up to 1.3-fold. Notably, the stimulatory effects of PcAA14A on IsPETaseEHA-catalyzed PET hydrolysis were found to be independent of monooxygenase activity. Dose-effects of IsPETaseEHA and PcAA14A on PET hydrolysis were observed, with the optimal concentrations being determined to 25 µg/mL and 0.25 µg/mL, respectively. In the 5-day PET hydrolysis experiment, 1097 µM hydrolysis products were produced by adding the optimized concentrations of IsPETaseEHA and PcAA14A, which was 27.7% higher than those were produced by IsPETaseEHA alone. Our study reports the first time that PcAA14A could stimulate the IsPETaseEHA-mediated PET hydrolysis through a monooxygenase activity independent manner.
Assuntos
Biocatálise , Oxigenases de Função Mista/metabolismo , Polietilenotereftalatos/metabolismo , Polissacarídeos/metabolismo , Fungos/enzimologia , Hidrólise , Proteínas Recombinantes/metabolismo , Fatores de TempoRESUMO
Anthocyanins are common secondary metabolites in plants that impart red coloration to fruits and flowers. The important WRKY transcription factor family plays multifaceted roles in plant growth and development. In this study, we found a WRKY family gene, Pyrus bretschneideri WRKY75, that may be involved in anthocyanin synthesis in pear. Unlike Arabidopsis thaliana WRKY75, PbWRKY75 may be a positive regulator of anthocyanin synthesis. A transient expression assay indicated that PbWRKY75 promoted pear anthocyanin synthesis. The structural genes (PbANS, PbDFR, and PbUFGT) and positive regulators (PbMYB10 and PbMYB10b) of anthocyanin synthesis were significantly upregulated in the fruitlet skins of PbWRKY75-overexpressing "Zaosu" pears. Subsequently, yeast one-hybrid and dual-luciferase assays indicated that PbWRKY75 promoted PbDFR, PbUFGT, and PbMYB10b expression by activating their promoters. These results revealed that PbWRKY75 may promote the expression of both PbMYB10b and anthocyanin late biosynthetic genes (PbDFR and PbUFGT) by activating their promoters, thereby inducing anthocyanin synthesis in pear. This study enhanced our understanding of the mechanism of pear anthocyanin synthesis, which will be beneficial in the improvement of pear peel color.
Assuntos
Pyrus , Antocianinas , Frutas/genética , Frutas/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Pyrus/genética , Pyrus/metabolismoRESUMO
It is still a challenge to realize the absolute optical path difference (OPD) demodulation of multi-interference systems with a narrow spectral interval and small OPD interval. In this paper, an iterative normalized cross-correlation algorithm is firstly proposed for demodulating the multiple absolute OPDs of a dual-interference system and applied to optical fiber sensing system. By constructing a template function in combined form, the optimal solutions of its components and OPDs are solved iteratively based on the reconstruction matrix method and cross-correlation algorithm, respectively. The simulation and experiment show that the demodulation accuracies near the OPDs of 560 µm and 660 µm are both up to 5â nm in different spectral intervals from 45 to 80â nm. The simulation results show that all demodulation precisions at the spectral interval of 55â nm do not exceed 4â nm when the OPD changes in the range of 650-670 µm. Besides, the experimental verification shows the temperature accuracy (0.125 °C) with 95% confidence of T-distribution is very close to the control accuracy (0.1 °C). The proposed algorithm can improve the multiplexing capability of optical fiber sensor system and reduce its cost.
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ETHNOPHARMACOLOGICAL RELEVANCE: Cinnamomum cassia Presl (Rougui) has character of xinãganãwen, belongs to Jing of heartãlungãbladder, and has the effect of dispersing cold and relieving pain. It is widely used to resolve the exterior and dissipate cold in Treatise on Febrile Diseases (Shang Han Lun), such as Chaihu Guizhi Ganjiang Tang and Guizhi Renshen Tang. Both these two prescriptions contain Cinnamomum cassia Presl and Zingiber officinale Rosc (Ganjiang). Rougui-Ganjiang herb-pair (RGHP) can warm viscera and remove cold, which is widely used in Shang Han Lun. And in modern times, recent studies have showed that cinnamon and ginger also have the effect of thermogenesis and regulating the body temperature, respectively. AIM OF THE STUDY: To maintain the body thermal homeostasis and prevent cold invasion of main organs, in this study, we assessed the underlying physiological changes induced by RGHP in mice exposed to -20 °C and explored the mechanisms for the thermogenic actions of RGHP in brown adipose tissue (BAT) by network pharmacology and molecular docking. MATERIALS AND METHODS: Male Kunming (KM) mice were fed normal diet with orally administration of distilled water or ethanol RGHP extract (three doses: 375,750 and 1500 mg/kg) for 21 days, once per day and then exposed to -20 °C for 2 h. The core temperature, activity ability and the degree of frostbite in mice, morphological and ATP content of adipocytes were measured. In addition, the network pharmacology was employed to predict the targets of RGHP' s thermogenesis effect on BAT. Pathway analysis and biological process with key genes was carried out through KEGG and GO analysis, respectively. Furthermore, the core ingredients and targets obtained by network pharmacology were verified by molecular docking and Western blot assays. RESULTS: RGHP can significantly increase the core body temperature, reduce the degree of frostbite and enhance the activity ability of mice after cold exposure. Meanwhile, it can also improve the lipid morphology and decrease ATP production in BAT. A network pharmacology-based analysis identified 246 ingredients from RGHP (two herbs), which related to 222 target genes. There were 8 common genes between 222 compounds target genes and 62 thermogenesis associated target genes, which linked to 49 potential compounds. There are 24 ingredients which degree are greater than the average. Among them, we found that oleic acid, EIC, 6-gingerol, eugenol, isohomogenol and sitogluside could be detected in mice plasma. The cAMP-PPAR signaling pathway was enriched for thermogenesis after KEGG analysis with 8 genes. Molecular docking analysis and Western blot assay further confirmed that oleic acid, 6-gingerol, eugenol and isohomogenol were potential active ingredients for RGHP's heat production effect. And UCP1, PGC-1α, PPARα and PPARγ are key thermogenesis proteins. CONCLUSIONS: RGHP treatment can significantly maintain the rectal temperature of mice by enhancing the BAT heat production. RGHP exhibited the heat production effect, which might be mainly attributed to increasing thermogenesis through the cAMP-PPAR signaling pathway in cold exposure mice. Oleic acid, 6-gingerol, eugenol and isohomogenol might be considered the potential therapeutic ingredients which affect the key targets of thermogenesis effect.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Cinnamomum aromaticum/química , Medicamentos de Ervas Chinesas/farmacologia , Farmacologia em Rede/métodos , Administração Oral , Animais , Sobrevivência Celular/efeitos dos fármacos , Temperatura Baixa , Medicamentos de Ervas Chinesas/administração & dosagem , Metabolismo Energético/efeitos dos fármacos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Distribuição Aleatória , TermogêneseRESUMO
The large amounts of polyethylene terephthalate (PET) that enter and accumulate in the environment have posed a serious threat to global ecosystems and human health. A PET hydrolase from PET-assimilating bacterium Ideonella sakaiensis (IsPETase) that exhibits superior PET hydrolytic activity at mild conditions is attracting enormous attention in development of plastic biodegrading strategies. In order to enhance the PET hydrolysis capacity of IsPETase, we selected several polymer-binding domains that can adhere to a hydrophobic polymer surface and fused these to a previously engineered IsPETaseS121E/D186H/R280A (IsPETaseEHA) variant. We found that fusing a cellulose-binding domain (CBM) of cellobiohydrolase I from Trichoderma reesei onto the C-terminus of IsPETaseEHA showed a stimulatory effect on enzymatic hydrolysis of PET. Compared to the parental enzyme, IsPETaseEHA_CBM exhibited 71.5 % and 44.5 % higher hydrolytic activity at 30 â and 40 â, respectively. The catalytic activity of IsPETaseEHA_CBM was increased by 86 % when the protein concentration was increased from 2.5 µg/mL to 20 µg/mL. These findings suggest that the fusion of polymer-binding module to IsPETase is a promising strategy to stimulate the enzymatic hydrolysis of PET.
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Celulose 1,4-beta-Celobiosidase , Polietilenotereftalatos/metabolismo , Trichoderma , Burkholderiales , Celulose , Celulose 1,4-beta-Celobiosidase/genética , Ecossistema , Hidrólise , Hypocreales , Trichoderma/enzimologiaRESUMO
Selenomethionine (SeMet) is a widely used food supplement. However, the research on the effect of SeMet on intestinal immune function is not enough. Therefore, in this experiment, SeMet was added to the diet of chickens, and lipopolysaccharide (LPS) was used as harmful stimulation to study the effect of SeMet on intestinal immune function in chickens. We chose chicken jejunum as the research object. The results showed that LPS treatment decreased the expressions of selenoproteins and induced inflammatory reaction, cytokine disorder, decreases of immunoglobulin levels, heat shock protein expression disorder, and decreases of defensin expression levels in jejunum. However, dietary SeMet can effectively alleviate the above injury caused by LPS. Our results showed that SeMet could improve the intestinal immunity in chickens, and feeding SeMet could alleviate the intestinal immune dysfunction caused by LPS. The application range of SeMet in feed can be roughly given through our experiment; i.e. 0.35-0.5 mg/kg SeMet was effective. We speculated that dietary SeMet could effectively alleviate the intestinal immune dysfunction caused by harmful stimulation and help to resist the further damage caused by harmful stimulation.
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Dieta/veterinária , Inflamação/imunologia , Intestinos/imunologia , Jejuno/imunologia , Lipopolissacarídeos/toxicidade , Selenometionina/farmacologia , Animais , Antioxidantes/metabolismo , Galinhas , Suplementos Nutricionais , Inflamação/patologia , Inflamação/prevenção & controle , Intestinos/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Selenoproteínas/metabolismoRESUMO
The wide application of plastics led to the wide exposure of plasticizers to the environment. As a new environmental pollutant, plasticizers' toxicity researches were far from enough in fish. To further explore these mechanisms, we used two common plasticizers (Diethylhexyl phthalate (DEHP) and dibutyl phthalate (DBP) expose to grass carp hepatocytes (L8824). The results showed that the mRNA levels of NOD2-RIP2-NF-κB signal pathway and its downstream inflammatory genes were significantly increased compared to those in control group. Then, the levels of mRNAs and proteins of apoptosis markers were changed, and hepatocytes apoptosis was induced. After DBP and DEHP exposure together, there were higher levels of inflammatory factors and the proportion of apoptotic cells. After NOD2 inhibitor treatment, the phenomena mentioned above were obviously alleviated. We conclude that DBP and DEHP exposure at least partially activated the NOD2-RIP2-NF-κB signal pathway in grass carp hepatocytes, and caused inflammation and apoptosis. In terms of hepatotoxicity, there was synergistic relationship between DBP and DEHP. In addition, we put forward new views on the use of plasticizers: select low toxicity plasticizers, then reduce the types of plasticizers used and reduce the high toxicity level of mixed plasticizers.
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Carpas , Dietilexilftalato , Animais , Apoptose , Dibutilftalato/toxicidade , Dietilexilftalato/toxicidade , Hepatócitos , NF-kappa B/genética , Plastificantes/toxicidadeRESUMO
BACKGROUND: Eligibility criteria are the main strategy for screening appropriate participants for clinical trials. Automatic analysis of clinical trial eligibility criteria by digital screening, leveraging natural language processing techniques, can improve recruitment efficiency and reduce the costs involved in promoting clinical research. OBJECTIVE: We aimed to create a natural language processing model to automatically classify clinical trial eligibility criteria. METHODS: We proposed a classifier for short text eligibility criteria based on ensemble learning, where a set of pretrained models was integrated. The pretrained models included state-of-the-art deep learning methods for training and classification, including Bidirectional Encoder Representations from Transformers (BERT), XLNet, and A Robustly Optimized BERT Pretraining Approach (RoBERTa). The classification results by the integrated models were combined as new features for training a Light Gradient Boosting Machine (LightGBM) model for eligibility criteria classification. RESULTS: Our proposed method obtained an accuracy of 0.846, a precision of 0.803, and a recall of 0.817 on a standard data set from a shared task of an international conference. The macro F1 value was 0.807, outperforming the state-of-the-art baseline methods on the shared task. CONCLUSIONS: We designed a model for screening short text classification criteria for clinical trials based on multimodel ensemble learning. Through experiments, we concluded that performance was improved significantly with a model ensemble compared to a single model. The introduction of focal loss could reduce the impact of class imbalance to achieve better performance.
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BACKGROUND: Temporal information frequently exists in the representation of the disease progress, prescription, medication, surgery progress, or discharge summary in narrative clinical text. The accurate extraction and normalization of temporal expressions can positively boost the analysis and understanding of narrative clinical texts to promote clinical research and practice. OBJECTIVE: The goal of the study was to propose a novel approach for extracting and normalizing temporal expressions from Chinese narrative clinical text. METHODS: TNorm, a rule-based and pattern learning-based approach, has been developed for automatic temporal expression extraction and normalization from unstructured Chinese clinical text data. TNorm consists of three stages: extraction, classification, and normalization. It applies a set of heuristic rules and automatically generated patterns for temporal expression identification and extraction of clinical texts. Then, it collects the features of extracted temporal expressions for temporal type prediction and classification by using machine learning algorithms. Finally, the features are combined with the rule-based and a pattern learning-based approach to normalize the extracted temporal expressions. RESULTS: The evaluation dataset is a set of narrative clinical texts in Chinese containing 1459 discharge summaries of a domestic Grade A Class 3 hospital. The results show that TNorm, combined with temporal expressions extraction and temporal types prediction, achieves a precision of 0.8491, a recall of 0.8328, and a F1 score of 0.8409 in temporal expressions normalization. CONCLUSIONS: This study illustrates an automatic approach, TNorm, that extracts and normalizes temporal expression from Chinese narrative clinical texts. TNorm was evaluated on the basis of discharge summary data, and results demonstrate its effectiveness on temporal expression normalization.
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BACKGROUND: Catheter-related thrombosis may lead to catheter infections and failure, further deep venous thrombosis, and pulmonary embolism. Recognizing the risk factors for catheter-related thrombosis is extremely important to inform the development of catheter care guidelines. METHODS: Data were collected from a total of 1,532 patients who had undergone venous catheterization, including indwelling catheterization from 19 March 2019 to 30 March 2019 in the Sun Yat-sen Memorial Hospital. The factors for which data were to be collected included the patients' physical characteristics, catheter-related factors, and catheter care-related factors. Logistic regression analysis, the chi-squared test, Fisher's exact test, and the t-test were used to analyze the data. RESULTS: Of the 1,532 patients studied, 28 developed intraductal thrombi, and of the factors analyzed, malignancy, a catheterization history, a history of thrombophilia, surgery during the week before catheterization, the catheterization duration, and anticoagulant therapy were significant risk factors associated with catheter-related thrombosis (all p < 0.05). There were no significant associations between the catheter brand, the number of lumens, the insertion direction, or the factors associated with catheter care and catheter-related thrombosis (all p > 0.05). CONCLUSION: Our study incorporated clear and systematic risk factors associated with catheter-related thrombosis. Malignancy, history of thrombophilia, history of catheterization, surgery during the week before catheterization, and catheterization duration were associated with increased risks of catheter-related thrombosis. Prophylactic anticoagulation was effective for preventing and treating catheter-related thrombosis.