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Fusobacterium nucleatum (Fn) is a critical colorectal cancer (CRC)-associated bacterium. DNA hunger/stationary phase protective proteins (Dps) are bacterial ferritins that protect DNA from oxidative stress. However, little is known about the regulatory roles of Fn-Dps towards host cellular functions. Here, we identified Fn-Dps from the culture supernatant of Fn by mass spectrometry, and prepared the recombinant of Fn-Dps protein. We show a novel virulence protein of Fn, Fn-Dps, which lyses and disrupts erythrocytes by the competition for iron acquisition. Also, Fn-Dps facilitates intracellular survival of Fn in macrophages by upregulating the expression of the chemokine CCL2/CCL7. In addition, Fn-Dps can elicit a strong humoral immune response, and mucosal immunization with Fn-Dps conferred protection against Fn in the intestinal tract. Moreover, a high level of anti-Fn-Dps antibody was prevalent in populations, and elevated anti-Fn-Dps antibody levels were observed in CRC patients. Furthermore, Fn-Dps promotes the migration of CRC cells via the CCL2/CCL7-induced epithelial-mesenchymal transition (EMT) and promotes CRC metastasis in vivo.
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Neoplasias Colorrectales , Fusobacterium nucleatum , Humanos , Fusobacterium nucleatum/genética , Factores de Virulencia/genética , Intestinos/patología , Eritrocitos/metabolismoRESUMEN
Methylation of cytosine to 5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. Sequential oxidation of 5mC by ten-eleven translocation (TET) dioxygenases results in a cascade of additional epigenetic marks and promotes demethylation of DNA in mammals1,2. However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green alga Chlamydomonas reinhardtii contains a 5mC-modifying enzyme (CMD1) that is a TET homologue and catalyses the conjugation of a glyceryl moiety to the methyl group of 5mC through a carbon-carbon bond, resulting in two stereoisomeric nucleobase products. The catalytic activity of CMD1 requires Fe(II) and the integrity of its binding motif His-X-Asp, which is conserved in Fe-dependent dioxygenases3. However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate4, CMD1 uses L-ascorbic acid (vitamin C) as an essential co-substrate. Vitamin C donates the glyceryl moiety to 5mC with concurrent formation of glyoxylic acid and CO2. The vitamin-C-derived DNA modification is present in the genome of wild-type C. reinhardtii but at a substantially lower level in a CMD1 mutant strain. The fitness of CMD1 mutant cells during exposure to high light levels is reduced. LHCSR3, a gene that is critical for the protection of C. reinhardtii from photo-oxidative damage under high light conditions, is hypermethylated and downregulated in CMD1 mutant cells compared to wild-type cells, causing a reduced capacity for photoprotective non-photochemical quenching. Our study thus identifies a eukaryotic DNA base modification that is catalysed by a divergent TET homologue and unexpectedly derived from vitamin C, and describes its role as a potential epigenetic mark that may counteract DNA methylation in the regulation of photosynthesis.
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5-Metilcitosina/metabolismo , Proteínas Algáceas/metabolismo , Ácido Ascórbico/metabolismo , Biocatálisis , Chlamydomonas reinhardtii/enzimología , ADN/química , ADN/metabolismo , 5-Metilcitosina/química , Dióxido de Carbono/metabolismo , Metilación de ADN , Glioxilatos/metabolismo , Nucleósidos/química , Nucleósidos/metabolismo , FotosíntesisRESUMEN
Solid polymer electrolytes (SPEs) have emerged as promising candidates for sodium-based batteries due to their cost-effectiveness and excellent flexibility. However, achieving high ionic conductivity and desirable mechanical properties in SPEs remains a challenge. In this study, we investigated an AB diblock copolymer, PS-PEA(BuImTFSI), as a potential SPE for sodium batteries. We explored binary and ternary electrolyte systems by combining the polymer with salt and [C3mpyr][FSI] ionic liquid (IL) and analyzed their thermal and electrochemical properties. Differential scanning calorimetry revealed phase separation in the polymer systems. The addition of salt exhibited a plasticizing effect localized to the polyionic liquid (PIL) phase, resulting in an increased ionic conductivity in the binary electrolytes. Introducing the IL further enhanced the plasticizing effect, elevating the ionic conductivity in the ternary system. Spectroscopic analysis, for the first time, revealed that the incorporation of NaFSI and IL influences the conformation of TFSI- and weakens the interaction between TFSI- and the polymer. This establishes correlations between anions and Na+, ultimately enhancing the diffusivity of Na ions. The electrochemical properties of an optimized SPE in Na/Na symmetrical cells were investigated, showcasing stable Na plating/stripping at high current densities up to 0.7 mA cm-2, maintaining its integrity at 70 °C. Furthermore, we evaluated the performance of a Na|NaFePO4 cell cycled at different rates (C/10 and C/5) and temperatures (50 and 70 °C), revealing remarkable high-capacity retention and Coulombic efficiency. This study highlights the potential of solvent-free diblock copolymer electrolytes for high-performance sodium-based energy storage systems, contributing to advanced electrolyte materials.
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The high expression of Spermidine/spermine N1-acetyltransferase (SSAT-1) is an important indicator in early cancer diagnosis. Here, we developed a nanopore-based methodology with γ-cyclodextrin as an adaptor to detect and quantify acetylamantadine, the specific SSAT-1-catalyzed product from amantadine, to accordingly reflect the activity of SSAT-1. We employ γ-cyclodextrin and report that amantadine cannot cause any secondary signals in γ-cyclodextrin-assisted α-HL nanopore, while its acetylation product, acetylamantadine, does. This allows γ-cyclodextrin to practically detect acetylamantadine in the interference of excessive amantadine, superior to the previously reported ß-cyclodextrin. The quantification of acetylamantadine was not interfered with even a 50-fold amantadine and displayed no interference in artificial urine sample analysis, which indicates the good feasibility of this nanopore-based methodology in painless cancer prediagnosis. In addition, the discrimination mechanism is also explored by 2-D nuclear magnetic resonance (NMR) and nanopore experiments with a series of adamantane derivatives with different hydrophilic and hydrophobic groups. We found that both the hydrophobic region matching effect and hydrophilic interactions play a synergistic effect in forming a host-guest complex to further generate the characteristic signals, which may provide insights for the subsequent design and study of drug-cyclodextrin complexes.
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Amantadina , Nanoporos , gamma-Ciclodextrinas , gamma-Ciclodextrinas/química , Humanos , Amantadina/química , Amantadina/análisis , NeoplasiasRESUMEN
Atomic force microscope (AFM) videos reveal the near-surface nanostructure and dynamics of the ionic liquids (ILs) 1-butyl-3-methylimidazolium dicyanamide (BMIM DCA) and 1-hexyl-3-methylimidazolium dicyanamide (HMIM DCA) above highly oriented pyrolytic graphite (HOPG) electrodes as a function of surface potential. Molecular dynamics (MD) simulations reveal the molecular-level composition of the nanostructures. In combination, AFM and MD show that the near-surface aggregates form via solvophobic association of the cation alkyl chains at the electrode interface. The diffusion coefficients of interfacial nanostructures are ≈0.01 nm2 s-1 and vary with the cation alkyl chain length and the surface potential. For each IL, the nanostructure diffusion coefficients are similar at open-circuit potential (OCP) and OCP + 1V, but BMIM DCA moves about twice as fast as HMIM DCA. At negative potentials, the diffusion coefficient decreases for BMIM DCA and increases for HMIM DCA. When the surface potential is switched from negative to positive, a sudden change in the direction of the nanostructure motion is observed for both BMIM DCA and HMIM DCA. No transient dynamics are noted following other potential jumps. This study provides a new fundamental understanding regarding the dynamics of electrochemically stable ILs at electrodes vital for the rational development of IL-based electrochemical devices.
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It's challenging work to identify disease-causing genes from the next-generation sequencing (NGS) data of patients with Mendelian disorders. To improve this situation, researchers have developed many phenotype-driven gene prioritization methods using a patient's genotype and phenotype information, or phenotype information only as input to rank the candidate's pathogenic genes. Evaluations of these ranking methods provide practitioners with convenience for choosing an appropriate tool for their workflows, but retrospective benchmarks are underpowered to provide statistically significant results in their attempt to differentiate. In this research, the performance of ten recognized causal-gene prioritization methods was benchmarked using 305 cases from the Deciphering Developmental Disorders (DDD) project and 209 in-house cases via a relatively unbiased methodology. The evaluation results show that methods using Human Phenotype Ontology (HPO) terms and Variant Call Format (VCF) files as input achieved better overall performance than those using phenotypic data alone. Besides, LIRICAL and AMELIE, two of the best methods in our benchmark experiments, complement each other in cases with the causal genes ranked highly, suggesting a possible integrative approach to further enhance the diagnostic efficiency. Our benchmarking provides valuable reference information to the computer-assisted rapid diagnosis in Mendelian diseases and sheds some light on the potential direction of future improvement on disease-causing gene prioritization methods.
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Biología Computacional , Secuenciación de Nucleótidos de Alto Rendimiento , Biología Computacional/métodos , Genotipo , Humanos , Fenotipo , Estudios RetrospectivosRESUMEN
Excessive inflammation is a major cause of morbidity and mortality in many viral infections including influenza. Therefore, there is a need for therapeutic interventions that dampen and redirect inflammatory responses and, ideally, exert antiviral effects. Itaconate is an immunomodulatory metabolite which also reprograms cell metabolism and inflammatory responses when applied exogenously. We evaluated effects of endogenous itaconate and exogenous application of itaconate and its variants dimethyl- and 4-octyl-itaconate (DI, 4OI) on host responses to influenza A virus (IAV). Infection induced expression of ACOD1, the enzyme catalyzing itaconate synthesis, in monocytes and macrophages, which correlated with viral replication and was abrogated by DI and 4OI treatment. In IAV-infected mice, pulmonary inflammation and weight loss were greater in Acod1-/- than in wild-type mice, and DI treatment reduced pulmonary inflammation and mortality. The compounds reversed infection-triggered interferon responses and modulated inflammation in human cells supporting non-productive and productive infection, in peripheral blood mononuclear cells, and in human lung tissue. All three itaconates reduced ROS levels and STAT1 phosphorylation, whereas AKT phosphorylation was reduced by 4OI and DI but increased by itaconate. Single-cell RNA sequencing identified monocytes as the main target of infection and the exclusive source of ACOD1 mRNA in peripheral blood. DI treatment silenced IFN-responses predominantly in monocytes, but also in lymphocytes and natural killer cells. Ectopic synthesis of itaconate in A549 cells, which do not physiologically express ACOD1, reduced infection-driven inflammation, and DI reduced IAV- and IFNγ-induced CXCL10 expression in murine macrophages independent of the presence of endogenous ACOD1. The compounds differed greatly in their effects on cellular gene homeostasis and released cytokines/chemokines, but all three markedly reduced release of the pro-inflammatory chemokines CXCL10 (IP-10) and CCL2 (MCP-1). Viral replication did not increase under treatment despite the dramatically repressed IFN responses. In fact, 4OI strongly inhibited viral transcription in peripheral blood mononuclear cells, and the compounds reduced viral titers (4OI>Ita>DI) in A549 cells whereas viral transcription was unaffected. Taken together, these results reveal itaconates as immunomodulatory and antiviral interventions for influenza virus infection.
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Virus de la Influenza A/inmunología , Macrófagos/inmunología , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Succinatos/farmacología , Células A549 , Animales , Carboxiliasas/deficiencia , Carboxiliasas/inmunología , Citocinas/genética , Citocinas/inmunología , Humanos , Macrófagos/virología , Ratones , Ratones Noqueados , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/inmunología , Células THP-1RESUMEN
[This corrects the article DOI: 10.1371/journal.ppat.1010219.].
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(+)-Nootkatone is a natural sesquiterpene ketone widely used in food, cosmetics, pharmaceuticals, and agriculture. It is also regarded as one of the most valuable terpenes used commercially. However, plants contain trace amounts of (+)-nootkatone, and extraction from plants is insufficient to meet market demand. Alpinia oxyphylla is a well-known medicinal plant in China, and (+)-nootkatone is one of the main components within the fruits. By transcriptome mining and functional screening using a precursor-providing yeast chassis, the complete (+)-nootkatone biosynthetic pathway in Alpinia oxyphylla was identified. A (+)-valencene synthase (AoVS) was identified as a novel monocot-derived valencene synthase; three (+)-valencene oxidases AoCYP6 (CYP71BB2), AoCYP9 (CYP71CX8), and AoCYP18 (CYP701A170) were identified by constructing a valencene-providing yeast strain. With further characterisation of a cytochrome P450 reductase (AoCPR1) and three dehydrogenases (AoSDR1/2/3), we successfully reconstructed the (+)-nootkatone biosynthetic pathway in Saccharomyces cerevisiae, representing a basis for its biotechnological production. Identifying the biosynthetic pathway of (+)-nootkatone in A. oxyphylla unravelled the molecular mechanism underlying its formation in planta and also supported the bioengineering production of (+)-nootkatone. The highly efficient yeast chassis screening method could be used to elucidate the complete biosynthetic pathway of other valuable plant natural products in future.
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Alpinia , Plantas Medicinales , Sesquiterpenos , Alpinia/metabolismo , Saccharomyces cerevisiae/metabolismo , Sesquiterpenos/metabolismo , Plantas Medicinales/metabolismoRESUMEN
Many chlorophyll-a (Chl-a) remote sensing estimation algorithms have been developed for inland water, and they are proposed always based on some ideal assumptions, which are difficult to meet in complex inland waters. Based on MIE scattering theory, this study calculated the optical properties of mineral particles under different size distribution and refractive index conditions, and the Hydrolight software was employed to simulate remote sensing reflectance in the presence of different mineral particles. The findings indicated that the reflectance is significantly influenced by the slope (j) of particle size distribution function and the imaginary part (n') of the refractive index, with the real part (n) having a comparatively minor impact. Through both a simulated dataset containing 18,000 entries and an in situ measured dataset encompassing 2183 data from hundreds of lakes worldwide, the sensitivities of band ratio (BR), fluorescence baseline height (FLH), and three-band algorithms (TBA) to mineral particles were explored. It can be found that BR showed the best tolerance to mineral particles, followed by TBA. However, when the ISM concentration is less than 30â g m-3, the influence of CDOM cannot be ignored. Additionally, a dataset of over 400 entries is necessary for developing the BR algorithm to mitigate the incidental errors arising from differences in data magnitude. And if the amount of developing datasets is less than 400 but greater than 200, the TBA algorithm is more likely to obtain more stable accuracy.
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BACKGROUND: Celastrol is a natural triterpene exhibiting significant and extensive antitumor activity in a wide range of cancer. Due to unfavorable toxicity profile and undefined mechanism, Celastrol's application in clinical cancer therapy remains limited. Herein, we elucidate the pharmacological mechanism of Celastrol's anticancer effects, with a fucus on STAT3 signaling pathway in cancers with high incidence of metastasis. METHODS: The safety profile of Celastrol were assessed in mice. In vitro analysis was performed in gastric cancer and ovarian cancer to assess the cytotoxicity, induction of reactive oxygen species (ROS) of Celastrol using STAT3 knockout cancer cells. Effects of Celastrol on STAT3 activation and transcription activity, JAK2/STAT3 signaling protein expression were assessed. Additionally, proteomic contrastive analysis was performed to explore the molecular association of Celastrol with STAT3 deletion in cancer cells. RESULTS: Celastrol has no obvious toxic effect at 1.5â¯mg/kg/day in a 1â¯5â¯days' administration. Celastrol inhibits tumor growth and increases ROS in a STAT3 dependent manner in gastric and ovarian cancer celllines. On molecular level, it downregulates IL-6 level and inhibits the JAK2/STAT3 signaling pathway by suppressing STAT3' activation and transcription activity. Proteomic contrastive analysis suggests a similar cellular mechanism of action between Celastrol and STAT3 deletion on regulating cancer progression pathways related to migration and invasion. CONCLUSION: Our research elucidates the anti-cancer mechanism of Celastrol through targeting the JAK2/STAT3 signaling pathway in cancer with high incidence of metastasis. This study provides a solid theoretical basis for the application of Celastrol in cancer therapy.
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The application of a liquid crystal (LC) in displays has driven the development of novel LC elements. In this Letter, polarization variable line-space (PVLS) gratings based on photoalignment are fabricated, and their variable-spacing properties are derived using the vector diffraction theory. Both transmissive and reflective PVLS gratings are fabricated to validate the correctness of the derivation. Experimental results indicate that PVLS gratings have a wider wavelength response bandwidth than that of polarization volume grating (PVG). PVLS gratings have angle selectivity, and a large incident angle causes wavelength blueshift. Additionally, the relationship between wavelength and focal length indicates its anomalous dispersion as a diffractive optical element. These results of photoalignment-based PVLS gratings provide valuable insights for the advancement of displays and have the potential to improve visual experiences.
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OBJECTIVE: This study is part of a programmatic investigation of rural disparities in cigarette smoking examining disparities in smoking prevalence and for the first-time quit ratios among adult women of reproductive age (18-44 years), a highly vulnerable population due to risk for multigenerational adverse effects. METHODS: Data came from 18 years (2002-2019) of the U.S. National Survey on Drug Use and Health (NSDUH) among women (n = 280,626) categorized by rural-urban residence, pregnancy status, using weighted logistic regression models testing time trends and controlling for well-established sociodemographic predictors of smoking (race/ethnicity, education, income). Concerns regarding changes in survey methods used before 2002 and after 2019 precluded inclusion of earlier and more recent survey years in the present study. RESULTS: Overall smoking prevalence across years was greater in rural than urban residents (adjusted odds ratio [AOR] = 1.11; 95%CI, 1.07-1.15; P < .001) including those not-pregnant (AOR = 1.10; 1.07-1.14; P < .001) and pregnant (AOR = 1.29; 1.09-1.52; P < .001). Overall quit ratios across years were lower in rural than urban residents (AOR = 0.93; 0.87-0.99; P < .001) including those not-pregnant (AOR = 0.93; 0.88-1.00, P = .035) and pregnant (AOR = 0.78; 0.62-0.99; P = .039). Interactions of rural versus urban residence with study years for prevalence and quit ratios overall and by pregnancy status are detailed in the main text. CONCLUSIONS: These results support a longstanding and robust rural disparity in smoking prevalence among women of reproductive age including those currently pregnant and provides novel evidence that differences in smoking cessation contribute to this disparity further underscoring a need for greater access to evidence-based tobacco control and regulatory interventions in rural regions.
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OBJECTIVE: This study is part of a programmatic investigation of rural disparities in cigarette smoking examining disparities in smoking prevalence and for the first-time quit ratios among adult women of reproductive age (18-44 years), a highly vulnerable population due to risk for multigenerational adverse effects. METHODS: Data came from 18 years (2002-2019) of the U.S. National Survey on Drug Use and Health (NSDUH) among women (n = 280,626) categorized by rural-urban residence, pregnancy status, using weighted logistic regression models testing time trends and controlling for well-established sociodemographic predictors of smoking (race/ethnicity, education, income). Concerns regarding changes in survey methods used before 2002 and after 2019 precluded inclusion of earlier and more recent survey years in the present study. RESULTS: Overall smoking prevalence across years was greater in rural than urban residents (adjusted odds ratio [AOR] = 1.11; 95%CI, 1.07-1.15; P < .001) including those not-pregnant (AOR = 1.10; 1.07-1.14; P < .001) and pregnant (AOR = 1.29; 1.09-1.52; P < .001). Overall quit ratios across years were lower in rural than urban residents (AOR = 0.93; 0.87-0.99; P < .001) including those not-pregnant (AOR = 0.93; 0.88-1.00, P = .035) and pregnant (AOR = 0.78; 0.62-0.99; P = .039). Interactions of rural versus urban residence with study years for prevalence and quit ratios overall and by pregnancy status are detailed in the main text. CONCLUSIONS: These results support a longstanding and robust rural disparity in smoking prevalence among women of reproductive age including those currently pregnant and provides novel evidence that differences in smoking cessation contribute to this disparity further underscoring a need for greater access to evidence-based tobacco control and regulatory interventions in rural regions.
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Población Rural , Población Urbana , Humanos , Femenino , Adulto , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricos , Estados Unidos/epidemiología , Adolescente , Prevalencia , Adulto Joven , Embarazo , Fumar/epidemiología , Fumar/tendencias , Encuestas Epidemiológicas , Disparidades en el Estado de Salud , Cese del Hábito de Fumar/estadística & datos numéricosRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) is an evolving global pandemic, and nanobodies, as well as other single-domain antibodies (sdAbs), have been recognized as a potential diagnostic and therapeutic tool for infectious diseases. High-throughput screening techniques such as phage display have been developed as an alternative to in vivo immunization for the discovery of antibody-like target-specific binders. METHODS: We designed and constructed a highly diverse synthetic phage library sdAb-U (single-domain Antibody - Universal library ) based on a human framework. The SARS-CoV-2 receptor-binding domain (RBD) was expressed and purified. The universal library sdAb-U was panned against the RBD protein target for two rounds, followed by monoclonal phage ELISA (enzyme-linked immunosorbent assay) to identify RBD-specific binders (the first stage). High-affinity binders were sequenced and the obtained CDR1 and CDR2 sequences were combined with fully randomized CDR3 to construct a targeted (focused) phage library sdAb-RBD, for subsequent second-stage phage panning (also two rounds) and screening. Then, sequences with high single-to-background ratios in phage ELISA were selected for expression. The binding affinities of sdAbs to RBD were measured by an ELISA-based method. In addition, we conducted competition ELISA (using ACE2 ectodomain S19-D615) and SARS-CoV-2 pseudovirus neutralization assays for the high-affinity RBD-binding sdAb39. RESULTS: Significant enrichments were observed in both the first-stage (universal library) and the second-stage (focused library) phage panning. Five RBD-specific binders were identified in the first stage with high ELISA signal-to-background ratios. In the second stage, we observed a much higher possibility of finding RBD-specific clones in phage ELISA. Among 45 selected RBD-positive sequences, we found eight sdAbs can be well expressed, and five of them show high-affinity to RBD (EC50 < 100nM). We finally found that sdAb39 (EC50 ~ 4nM) can compete with ACE2 for binding to RBD. CONCLUSION: Overall, this two-stage strategy of synthetic phage display libraries enables rapid selection of SARS-CoV-2 RBD sdAb with potential therapeutic activity, and this two-stage strategy can potentially be used for rapid discovery of sdAbs against other targets.
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Bacteriófagos , COVID-19 , Anticuerpos de Dominio Único , Humanos , SARS-CoV-2/genética , Anticuerpos de Dominio Único/genética , Anticuerpos de Dominio Único/química , Enzima Convertidora de Angiotensina 2 , COVID-19/diagnóstico , Anticuerpos Antivirales , Anticuerpos NeutralizantesRESUMEN
Government health messaging is significant to the containment of public health crises. Such communication may benefit from using fear appeal, a message strategy for promoting health and preventing diseases. Yet little scholarly attention has been paid to how fear appeal is employed in government messaging to promote social media engagement through online actions including likes, shares, and comments. These actions play a meaningful role in addressing communication exigencies within the context of health crises. In this study, quantitative content analysis and corpus linguistics methods were employed to analyze fear appeal-related elements in COVID-19 messages sent by a state-owned media outlet on social media. The results show that when compared to messages without threat, messages conveying threat elicited significantly more comments, in which emotions and perceptions to threat and efficacy were exhibited, while messages containing both threat and efficacy generated more engagement in comparison to messages with threat alone. Moreover, while subdimensions under efficacy were positive predictors of engagement, those under threat were primarily found to have exerted negative effects. The findings provide insights into how fear appeal elements can be employed in government health crisis communication to engage the public.
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COVID-19 , Miedo , Comunicación en Salud , Medios de Comunicación Sociales , Humanos , COVID-19/prevención & control , Medios de Comunicación Sociales/estadística & datos numéricos , Comunicación en Salud/métodos , Gobierno Estatal , Comunicación Persuasiva , Estados UnidosRESUMEN
Alterations in the microbiota composition, or ecological dysbiosis, have been implicated in the development of various diseases, including allergic diseases and asthma. Examining the relationship between microbiota alterations in the host and cough variant asthma (CVA) may facilitate the discovery of novel therapeutic strategies. To elucidate the diversity and difference of microbiota across three ecological niches, we performed 16S rDNA amplicon sequencing on lung, ileum, and colon samples. We assessed the levels of interleukin-12 (IL-12) and interleukin-13 (IL-13) in guinea pig bronchoalveolar lavage fluid using the enzyme-linked immunosorbent assay (ELISA). We applied Spearman's analytical method to evaluate the correlation between microbiota and cytokines. The results demonstrated that the relative abundance, α-diversity, and ß-diversity of the microbial composition of the lung, ileum, and colon varied considerably. The ELISA results indicated a substantial increase in the level of IL-13 and a decreasing trend in the level of IL-12 in the CVA guinea pigs. The Spearman analysis identified a correlation between Mycoplasma, Faecalibaculum, and Ruminococcus and the inflammatory factors in the CVA guinea pigs. Our guinea pig model showed that core microorganisms, such as Mycoplasma in the lung, Faecalibaculum in the ileum, and Ruminococcus in the colon, may play a crucial role in the pathogenesis of CVA. The most conspicuous changes in the ecological niche were observed in the guinea pig ileum, followed by the lung, while relatively minor changes were observed in the colon. Notably, the microbial structure of the ileum niche approximated that of the colon niche. Therefore, the results of this study suggest that CVA development is closely related to the dysregulation of ileal, lung, and colon microbiota and the ensuing inflammatory changes in the lung.
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Asma Variante con Tos , Microbiota , Cobayas , Animales , Interleucina-13 , Pulmón/patología , Íleon , Colon , Interleucina-12RESUMEN
Echocardiographic guidance in left atrial appendage (LAA) closure procedures is increasingly recognized for its potential to enhance patient outcomes in atrial fibrillation (AF). This retrospective study assesses its impact on hospital stay duration, readmission rates and surgical site wound complications in 200 AF patients. Divided equally into an echocardiographically guided group (Group E) and a non-guided group (Group N), the analysis focused on detailed patient data encompassing hospital stay, 30-day readmission and wound complications. Findings revealed that Group E experienced a significantly shorter average hospital stay of 3.5 days, compared with 6.5 days in Group N, along with a lower 30-day readmission rate (5% vs. 18% in Group N). Furthermore, Group E showed a considerable reduction in surgical site wound complications, such as infections and hematomas. The study concludes that echocardiographic guidance in LAA closure procedures markedly improves postoperative wound outcomes, underscoring its potential as a standard practice in cardiac surgeries for AF patients. This approach not only optimizes patient safety and postoperative recovery but also enhances healthcare resource utilization.
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Apéndice Atrial , Fibrilación Atrial , Humanos , Estudios Retrospectivos , Cierre del Apéndice Auricular Izquierdo , Resultado del Tratamiento , Ecocardiografía , Fibrilación Atrial/cirugía , Fibrilación Atrial/complicaciones , Complicaciones Posoperatorias/prevención & control , Apéndice Atrial/diagnóstico por imagen , Apéndice Atrial/cirugíaRESUMEN
Nanozymes have demonstrated significant potential in combating malignant tumor proliferation through catalytic therapy. However, the therapeutic effect is often limited by insufficient catalytic performance. In this study, we propose the utilization of strain engineering in metallenes to fully expose the active regions due to their ultrathin nature. Here, we present the first report on a novel tensile strain-mediated local amorphous RhRu (la-RhRu) bimetallene with exceptional intrinsic photothermal effect and photo-enhanced multiple enzyme-like activities. Through geometric phase analysis, electron diffraction profile, and X-ray diffraction, it is revealed that crystalline-amorphous heterophase boundaries can generate approximately 2 % tensile strain in the bimetallene. The ultrathin structure and in-plane strain of the bimetallene induce an amplified strain effect. Both experimental and theoretical evidence support the notion that tensile strain promotes multiple enzyme-like activities. Functioning as a tumor microenvironment (TME)-responsive nanozyme, la-RhRu exhibits remarkable therapeutic efficacy both in vitro and in vivo. This work highlights the tremendous potential of atomic-scale tensile strain engineering strategy in enhancing tumor catalytic therapy.
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Terapia Fototérmica , Humanos , Catálisis , Animales , Ratones , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Resistencia a la Tracción , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacosRESUMEN
Benzylisoquinoline alkaloids (BIAs) are a class of plant secondary metabolites with great pharmacological value. Their biosynthetic pathways have been extensively elucidated in the species from the Ranunculales order, such as poppy and Coptis japonica, in which methylation events play central roles and are directly responsible for BIA chemodiversity. Here, we combined BIA quantitative profiling and transcriptomic analyses to identify novel BIA methyltransferases (MTs) from Liriodendron chinense, a basal angiosperm plant. We identified an N-methyltransferase (LcNMT1) and two O-methyltransferases (LcOMT1 and LcOMT3), and characterized their biochemical functions in vitro. LcNMT1 methylates (S)-coclaurine to produce mono- and dimethylated products. Mutagenesis experiments revealed that a single-residue alteration is sufficient to change its substrate selectivity. LcOMT1 methylates (S)-norcoclaurine at the C6 site and LcOMT3 methylates (S)-coclaurine at the C7 site, respectively. Two key residues of LcOMT3, A115 and T301, are identified as important contributors to its catalytic activity. Compared with Ranunculales-derived NMTs, Magnoliales-derived NMTs were less abundant and had narrower substrate specificity, indicating that NMT expansion has contributed substantially to BIA chemodiversity in angiosperms, particularly in Ranunculales species. In summary, we not only characterized three novel enzymes that could be useful in the biosynthetic production of valuable BIAs but also shed light on the molecular origin of BIAs during angiosperm evolution.