RESUMEN
Tn3 family transposons are a widespread group of replicative transposons, notorious for contributing to the dissemination of antibiotic resistance, particularly the global prevalence of carbapenem resistance. The transposase (TnpA) of these elements catalyzes DNA breakage and rejoining reactions required for transposition. However, the molecular mechanism for target site selection with these elements remains unclear. Here, we identify a QLxxLR motif in N-terminal of Tn3 TnpAs and demonstrate that this motif allows interaction between TnpA of Tn3 family transposon Tn1721 and the host ß-sliding clamp (DnaN), the major processivity factor of the DNA replication machinery. The TnpA-DnaN interaction is essential for Tn1721 transposition. Our work unveils a mechanism whereby Tn3 family transposons can bias transposition into certain replisomes through an interaction with the host replication machinery. This study further expands the diversity of mobile elements that use interaction with the host replication machinery to bias integration.
RESUMEN
Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell-driven malignancies. However, approved covalent BTK inhibitors (cBTKis) are associated with treatment limitations because of off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here, we describe the preclinical profile of pirtobrutinib, a potent, highly selective, noncovalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate binding region and shows no direct interaction with C481. Consequently, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKis, prevented Y551 phosphorylation in the activation loop. These data suggest that pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines, and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed that pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest that pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical, and structural attributes with the potential to treat B-cell-driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa , Linfoma , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Humanos , Animales , Ensayos Antitumor por Modelo de Xenoinjerto , Linfoma/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Línea Celular Tumoral , Ratones Endogámicos NOD , Masculino , Ratones SCID , Conformación Molecular , RatonesRESUMEN
BACKGROUND: 8-Oxoguanine DNA glycosylase (OGG1), a well-known DNA repair enzyme, has been demonstrated to promote lung fibrosis, while the specific regulatory mechanism of OGG1 during pulmonary fibrosis remains unclarified. METHODS: A bleomycin (BLM)-induced mouse pulmonary fibrosis model was established, and TH5487 (the small molecule OGG1 inhibitor) and Mitochondrial division inhibitor 1 (Mdivi-1) were used for administration. Histopathological injury of the lung tissues was assessed. The profibrotic factors and oxidative stress-related factors were examined using the commercial kits. Western blot was used to examine protein expression and immunofluorescence analysis was conducted to assess macrophages polarization and autophagy. The conditional medium from M2 macrophages was harvested and added to HFL-1 cells for culture to simulate the immune microenvironment around fibroblasts during pulmonary fibrosis. Subsequently, the loss- and gain-of function experiments were conducted to further confirm the molecular mechanism of OGG1/PINK1. RESULTS: In BLM-induced pulmonary fibrosis, OGG1 was upregulated while PINK1/Parkin was downregulated. Macrophages were activated and polarized to M2 phenotype. TH5487 administration effectively mitigated pulmonary fibrosis, M2 macrophage polarization, oxidative stress and mitochondrial dysfunction while promoted PINK1/Parkin-mediated mitophagy in lung tissues of BLM-induced mice, which was partly hindered by Mdivi-1. PINK1 overexpression restricted M2 macrophages-induced oxidative stress, mitochondrial dysfunction and mitophagy inactivation in lung fibroblast cells, and OGG1 knockdown could promote PINK1/Parkin expression and alleviate M2 macrophages-induced mitochondrial dysfunction in HFL-1 cells. CONCLUSION: OGG1 inhibition protects against pulmonary fibrosis, which is partly via activating PINK1/Parkin-mediated mitophagy and retarding M2 macrophage polarization, providing a therapeutic target for pulmonary fibrosis.
Asunto(s)
Bleomicina , ADN Glicosilasas , Modelos Animales de Enfermedad , Macrófagos , Mitofagia , Proteínas Quinasas , Fibrosis Pulmonar , Animales , Mitofagia/efectos de los fármacos , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/patología , ADN Glicosilasas/metabolismo , ADN Glicosilasas/genética , Ratones , Macrófagos/metabolismo , Proteínas Quinasas/metabolismo , Bleomicina/efectos adversos , Masculino , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Estrés Oxidativo/efectos de los fármacos , Ratones Endogámicos C57BL , Activación de Macrófagos , Humanos , QuinazolinonasRESUMEN
As a key regulator of plant photosynthesis, water use efficiency and immunity, stomata are specialized cellular structures that adopt defined shapes. However, our knowledge about the genetic players of stomatal pore formation and stomatal morphogenesis remains limited. Forward genetic screening, positional cloning, confocal and electron microscopy, physiological and pharmacological assays were employed for isolation and characterization of mutants and genes. We identified a mutant, dsm1, with impaired cytokinesis and deformed stomata. DSM1 is highly expressed in guard mother cells and guard cells, and encodes COBRA-LIKE 7 (COBL7), a plant-specific glycosylphosphatidylinositol (GPI)-anchored protein. COBRA-LIKE 7 and its closest homologue, COBL8, are first enriched on the forming cell plates during cytokinesis, and then their subcellular distribution and abundance change are correlated with the progressive stages of stomatal pore formation. Both COBL7 and COBL8 possess an ability to bind cellulose. Perturbing the expression of COBL7 and COBL8 leads to a decrease in cellulose content and inhibition of stomatal pore development. Moreover, we found that COBL7, COBL8 and CSLD5 have synergistic effects on stomatal development and plant growth. Our findings reveal that COBL7 plays a predominant and functionally redundant role with COBL8 in stomatal formation through regulating cellulose deposition and ventral wall modification in Arabidopsis.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Celulosa/metabolismo , Regulación de la Expresión Génica de las Plantas , Fotosíntesis , Estomas de Plantas/metabolismoRESUMEN
Legume nodulation requires the detection of flavonoids in the rhizosphere by rhizobia to activate their production of Nod factor countersignals. Here we investigated the flavonoids involved in nodulation of Medicago truncatula. We biochemically characterized five flavonoid-O-methyltransferases (OMTs) and a lux-based nod gene reporter was used to investigate the response of Sinorhizobium medicae NodD1 to various flavonoids. We found that chalcone-OMT 1 (ChOMT1) and ChOMT3, but not OMT2, 4, and 5, were able to produce 4,4'-dihydroxy-2'-methoxychalcone (DHMC). The bioreporter responded most strongly to DHMC, while isoflavones important for nodulation of soybean (Glycine max) showed no activity. Mutant analysis revealed that loss of ChOMT1 strongly reduced DHMC levels. Furthermore, chomt1 and omt2 showed strongly reduced bioreporter luminescence in their rhizospheres. In addition, loss of both ChOMT1 and ChOMT3 reduced nodulation, and this phenotype was strengthened by the further loss of OMT2. We conclude that: the loss of ChOMT1 greatly reduces root DHMC levels; ChOMT1 or OMT2 are important for nod gene activation in the rhizosphere; and ChOMT1/3 and OMT2 promote nodulation. Our findings suggest a degree of exclusivity in the flavonoids used for nodulation in M. truncatula compared to soybean, supporting a role for flavonoids in rhizobial host range.
Asunto(s)
Chalconas , Medicago truncatula , Nodulación de la Raíz de la Planta , Rizosfera , Medicago truncatula/genética , Medicago truncatula/microbiología , Medicago truncatula/metabolismo , Chalconas/metabolismo , Nodulación de la Raíz de la Planta/genética , Regulación de la Expresión Génica de las Plantas , Mutación/genética , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Flavonoides/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Sinorhizobium/fisiología , Sinorhizobium/genética , Metiltransferasas/metabolismo , Metiltransferasas/genéticaRESUMEN
This research proposed a novel pulse-shaping design for directly shaping distorted pulses after the amplification. Based on the principle of the design we made a pulse shaper. With this pulse shaper, we successfully manipulate the pulse's leading edge and width to achieve an 'M'-shaped waveform in an amplification system. Comparative experiments were conducted within this system to compare the output with and without the integration of the pulse shaper. The results show a significant suppression of the nonlinear effect upon adding the pulse shaper. This flexible and effective pulse shaper can be easily integrated into a high-power all-fiber system, supplying the capability to realize the desired output waveform and enhance the spectral quality.
RESUMEN
ABSTRACTSIn recent years, the demand for gluten-free (GF) bakery products has grown rapidly due to the remarkable rising number of celiac patients and the increasing health awareness of GF products. However, GF products generally suffer from defects such as poor sensorial level, low nutritional value, high prices and short shelf life. Sourdough is the important starter culture applied in bakery field, and it has been proven to be ideal for enhancing the overall quality of bakery products. This review aims to systematically reviewed the application of sourdough in GF bakery products and its improvement to GF bakery products in terms of texture, shelf life, nutrition and flavor. Its positive effects derive from the complex metabolic activities of sourdough microorganisms, such as acidification, proteolysis, production of exopolysaccharides (EPS), activation of endogenous enzymes, and production of antibacterial substances. Finally, researchers are encouraged to expand the use of sourdough in GF bakery products to increase the variety of GF products. And the technical and nutritional potential of sourdough should be developed more widely.
RESUMEN
PURPOSE: The objective of this multicenter study was to compare the diagnostic performance of lateral flow assay (LFA) and enzyme-linked immunosorbent assay (ELISA) to detect the Dynamiker Aspergillus Galactomannan levels in serum and bronchoalveolar lavage fluid (BALF) samples for I. METHODS: We registered 310 clinically suspected Aspergillus infection patients from December 2021 to February 2023 and classified them into subgroups as the "IA group" and "non-IA group" based on the latest EORTC/MSG guidelines. The immunoassays were analyzed by LFA and ELISA respectively. RESULTS: Galactomannan was examined using LFA, and serum and BALF samples demonstrated sensitivities of 82.57% and 89.47%, specificities of 90.76% and 92.00%, PPVs of 89.11% and 96.23%, and NPVs of 85.04% and 79.31%, respectively. Galactomannan was observed using two assays in serum and BALF samples and showed PPAs of 95.11% and 93.33%, NPAs of 89.19% and 96.30%, and TPAs of 92.47% and 94.25%, respectively. The ROC curve demonstrated that LFA had optimum diagnostic value when the index value (I value) = 0.5, the sensitivity was 84.94%, and the specificity was 90.97%. CONCLUSION: Compared to the ELISA method, the LFA has shown excellent performance for the diagnosis of IA in serum and BALF sample and can be used as an assay for the early diagnosis of patients with IA. The dynamic change in galactomannan levels may be useful for assessing treatment response.
Asunto(s)
Aspergilosis , Galactosa/análogos & derivados , Infecciones Fúngicas Invasoras , Humanos , Sensibilidad y Especificidad , Aspergilosis/diagnóstico , Aspergillus , Mananos/análisis , Líquido del Lavado Bronquioalveolar/microbiologíaRESUMEN
BACKGROUND: Sensitive skin is hypersensitive to various external stimuli and a defective epidermal permeability barrier is an important clinical feature of sensitive skin. Claudin-5 (CLDN5) expression levels decrease in sensitive skin. This study aimed to explore the impact of CLDN5 deficiency on the permeability barrier in sensitive skin and the regulatory role of miRNAs in CLDN5 expression. MATERIALS AND METHODS: A total of 26 patients were retrospectively enrolled, and the CLDN5 expression and permeability barrier dysfunction in vitro were assessed. Then miRNA-224-5p expression was also assessed in sensitive skin. RESULTS: Immunofluorescence and electron microscopy revealed reduced CLDN5 expression, increased miR-224-5p expression, and disrupted intercellular junctions in sensitive skin. CLDN5 knockdown was associated with lower transepithelial electrical resistance (TEER) and Lucifer yellow penetration in keratinocytes and organotypic skin models. The RNA-seq and qRT-PCR results indicated elevated miR-224-5p expression in sensitive skin; MiR-224-5p directly interacted with the 3`UTR of CLDN5, resulting in CLDN5 deficiency in the luciferase reporter assay. Finally, miR-224-5p reduced TEER in keratinocyte cultures. CONCLUSION: These results suggest that the miR-224-5p-induced reduction in CLDN5 expression leads to impaired permeability barrier function, and that miR-224-5p could be a potential therapeutic target for sensitive skin.
Asunto(s)
Claudina-5 , MicroARNs , Permeabilidad , Piel , Adulto , Femenino , Humanos , Masculino , Claudina-5/genética , Claudina-5/metabolismo , Queratinocitos/metabolismo , MicroARNs/metabolismo , MicroARNs/genética , Estudios Retrospectivos , Piel/metabolismoRESUMEN
The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.
RESUMEN
Aspergillus species is a widespread environmental mould that can cause aspergillosis. The purpose of this study was to investigate the antifungal susceptibility profile and genotypic characterization of clinical Aspergillus isolates from different provinces in Eastern China. The data included the antifungal susceptibility distributions with eight common antifungal drugs, cyp51A gene mutations of triazole-resistant Aspergillus fumigatus sensu stricto, and the genotypic relationships among the A. fumigatus sensu stricto isolates based on microsatellite typing. A. fumigatus sensu lato was the most common clinical Aspergillus species (n = 252), followed by A. flavus (n = 169), A. terreus (n = 37), A. niger (n = 29), and A. nidulans (n = 4). The modal minimum effective concentration values of micafungin and anidulafungin were lower than those of caspofungin for all Aspergillus species. The in vitro efficacy of isavuconazole was similar to that of voriconazole against most Aspergillus species. Sequencing revealed cyp51A gene mutations TR34/L98H, TR34/L98H/S297T/F495I, and TR46/Y121F/T289A in four triazole-resistant A. fumigatus sensu stricto. Phylogenetic analyses using microsatellite markers of A. fumigatus sensu stricto revealed that 211 unique genotypes clustered into two clades. The data demonstrate the diversity of clinically relevant Aspergillus species in Eastern China. Routine antifungal susceptibility testing should be performed to monitor the antifungal resistance and guide clinical therapy.
The 6-year multicenter study collected a total of 491 Aspergillus isolates from Eastern China to investigate the in vitro antifungal susceptibility to eight antifungal drugs, the cyp51A gene mutations of triazole-resistant A. fumigatus sensu stricto, and the genetic relatedness through microsatellite typing.
Asunto(s)
Antifúngicos , Infecciones Fúngicas Invasoras , Animales , Antifúngicos/farmacología , Aspergillus fumigatus , Filogenia , Proteínas Fúngicas/genética , Azoles/farmacología , Farmacorresistencia Fúngica/genética , Aspergillus , Triazoles/farmacología , Genotipo , Infecciones Fúngicas Invasoras/veterinaria , Pruebas de Sensibilidad Microbiana/veterinariaRESUMEN
AIM: To investigate the seizure course of PCDH19 clustering epilepsy (PCDH19-CE) in a cohort of female children in China. METHOD: This ambidirectional cohort study examined 113 female patients with PCDH19-CE through multicentre collaboration. Prognostic factors for seizure freedom were evaluated by multivariate Cox regression analysis. RESULTS: The median seizure course period from seizure onset was 6 years 6 months. Of 113 patients, 78% and 56% experienced seizure freedom for at least 1 year and at least 2 years respectively. In patients younger than 5 years (n = 30), 5 to 10 years (n = 52), and older than 10 years (n = 31), 57%, 81%, and 94% experienced at least 1 year of seizure freedom, and 32%, 52%, and 84% experienced at least 2 years of seizure freedom, respectively. However, 58% (65 out of 113) relapsed at least once after more than 1 year of seizure freedom without trigger exposure (40%) or because of common triggers, including fever (43%) and antiseizure medication (ASM) reduction (29%). There was an 84% risk of seizure relapse after ASM reduction attempts. The likelihood of seizure freedom decreased with early age at seizure onset and developmental delay. INTERPRETATION: Patients with PCDH19-CE exhibit increasing seizure freedom with age, but there is a risk of relapse. ASM reduction in children younger than 10 years old requires caution. Patients with early seizure onset and developmental delay have a reduced chance of seizure freedom.
RESUMEN
BACKGROUND: Chronic actinic dermatitis (CAD) is an immune-mediated photodermatosis characterized by a high eosinophil count and total immunoglobulin E (IgE) in the peripheral blood of patients. At present, however, the reasons for their elevation remain unclear. OBJECTIVE: The current study aimed to detect changes in inflammatory cytokines in CAD and explore their role in this disease. METHODS: Enzyme-linked immunosorbent assay and Luminex assay were conducted to measure inflammatory factor levels. Immunohistochemical analysis and quantitative real-time polymerase chain reaction were performed to evaluate the expression levels of interleukin-36γ (IL-36γ), IL-8, chemokine (C-C motif) ligand 17 (CCL17), and CCL18. CCK8 kits were used to assess cell proliferation. Immunofluorescence was used to detect nuclear factor κB (NF-κB) p65 nuclear translocation. Western blot analysis was performed to detect the protein expression level of phosphorylated NF-κB (p-NF-κB) p65. Hematoxylin and eosin and Masson trichrome staining were applied to observe histological changes in a chronic photo-damaged mouse model. RESULTS: Eosinophils, total IgE, IL-36γ, IL-8, tumor necrosis factor α, CCL17, and CCL18 were elevated in CAD. Of note, IL-36γ promoted the proliferation of eosinophilic cells (EOL-1) and the production of IgE in peripheral blood mononuclear cells. IL-36γ also promoted the production of IL-8 and CCL18 in immortalized human keratinocytes (HaCaT cells), while ultraviolet radiation (UVR)-induced IL-36γ via activation of the NF-κB signaling pathway. CONCLUSIONS: IL-36γ was involved in the pathogenesis of CAD and UVR contributed to the production of IL-36γ, which may provide a novel therapeutic target for CAD.
Asunto(s)
Trastornos por Fotosensibilidad , Rayos Ultravioleta , Animales , Ratones , Humanos , Rayos Ultravioleta/efectos adversos , FN-kappa B/metabolismo , Interleucina-8 , Leucocitos Mononucleares , Interleucinas , Factor de Necrosis Tumoral alfa/farmacología , Inmunoglobulina ERESUMEN
BACKGROUND: Due to the inadequacy of published evidence, association of telomere length (TL), obesity and tobacco smoking with idiopathic pulmonary fibrosis (IPF) remains unclear. The aim of the study was to explore whether these exposures genetically affected the risk of the disease. METHODS: Genetic variants from genome-wide association studies for TL, body mass index (BMI), body fat percentage (BFP) and tobacco smoking (including maternal smoking) were used as instrumental variables. Inverse-variance weighted were mainly adopted to determine the genetic association of these exposures with IPF. All analyses were conducted by R-software (version 3.6.1). RESULTS: Firstly, longer TL was associated with the decreased risk of IPF (OR = 0.475 per SD increase in TL, 95%CI = 0.336 ~ 0.670, P<0.001). Secondly, higher levels of BMI and BFP were related to the increased risk of the disease (OR = 1.425 per SD increase in BMI level, 95%CI = 1.114 ~ 1.823, P = 0.005; OR = 1.702 per SD increase in BFP level, 95%CI = 1.202 ~ 2.409, P = 0.003). Thirdly, maternal smoking was implicated in the increased risk of the disease (OR = 13.183 per SD increase in the prevalence of maternal smoking, 95%CI = 1.820 ~ 95.484, P = 0.011). CONCLUSION: TL should be a genetic risk factor for IPF. Obesity and exposure to tobacco smoking as a fetus might also contribute to the development of this fibrotic diseases. These findings should be verified by future studies.
Asunto(s)
Estudio de Asociación del Genoma Completo , Fibrosis Pulmonar Idiopática , Humanos , Obesidad/epidemiología , Obesidad/genética , Fibrosis Pulmonar Idiopática/epidemiología , Fibrosis Pulmonar Idiopática/genética , Fumar/efectos adversos , Fumar/epidemiología , Fumar Tabaco , Telómero/genética , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: There are few reports on the timing of onset and the symptoms of enterovirus A71 (EV-A71) infection, which can easily be misdiagnosed. This study aimed to explore the clinical characteristics of children with severe EV-A71 infection. METHODS: This retrospective observational study included children with severe EV-A71 infection admitted to Hebei Children's Hospital between January 2016 and January 2018. RESULTS: A total of 101 patients were included: 57 males (56.4%) and 44 females (43.6%). They were 1-13 years of age. The symptoms were fever in 94 patients (93.1%), rash in 46 (45.5%), irritability in 70 (69.3%), and lethargy in 56 (55.4%). There were 19 (59.3%) patients with abnormal neurological magnetic resonance imaging [pontine tegmentum (n = 14, 43.8%), medulla oblongata (n = 11, 34.4%), midbrain (n = 9, 28.1%), cerebellum and dentate nucleus (n = 8, 25.0%), basal ganglia (n = 4, 12.5%), cortex (n = 4, 12.5%), spinal cord (n = 3, 9.3%), and meninges (n = 1, 3.1%)]. There was a positive correlation between the ratio of neutrophil count and white blood cell count in cerebrospinal fluid in the first 3 days of the disease (r = 0.415, P < 0.001). CONCLUSION: The clinical symptoms of EV-A71 infection are fever and/or skin rash, irritability, and lethargy. Some patients have abnormal neurological magnetic resonance imaging. The white blood cell count in the cerebrospinal fluid of children with EV-A71 infection may increase alongside neutrophil counts.
Asunto(s)
Enterovirus Humano A , Infecciones por Enterovirus , Enterovirus , Exantema , Masculino , Femenino , Humanos , Niño , Letargia , Infecciones por Enterovirus/diagnóstico , Estudios Retrospectivos , Exantema/etiología , Antígenos Virales , Fiebre/etiologíaRESUMEN
BACKGROUND: Chronic actinic dermatitis (CAD) is an immune-mediated photo-allergic skin disease. In the clinic, the treatment of this disease is hampered by the lack of proper understanding of the skin barrier dysfunction mechanism. OBJECTIVE: To illuminate the mechanism of skin barrier dysfunction in CAD. METHODS: Transcriptome sequencing and protein profiling were used to detect skin barrier injury-related genes. RNA pull down, a promoter-reporter gene assay, and chromatin isolation by RNA purification-sequencing were used to elucidate the effect of WAKMAR2 in skin barrier functionality. RESULTS: Transcriptome sequencing from patient's tissues showed a significantly decreased expression of WAKMAR2. Down-regulation of WAKMAR2 destroyed the keratinocyte barrier. Moreover, WAKMAR2 can directly bind to the c-Fos protein. This novel long non-coding RNA (LncRNA)-protein complexes were targeted to the CLDN1 promotor. Overexpression of WAKMAR2 enhanced the promoter activity of CLDN1, while the addition of AP-1 inhibitor could reverse this phenomenon. Furthermore, our in vivo results suggested that expression of WAKMAR2 was required for the repair of skin damage in mice induced by ultraviolet irradiation. CONCLUSIONS: We identified a crucial LncRNA (WAKMAR2) for the protection of the skin barrier in vitro and in vivo. Mechanically, it can specifically interact with c-Fos protein for the regulation of CLDN1, a finding which could be applied for CAD treatment.
Asunto(s)
Dermatitis Alérgica por Contacto , Dermatitis Atópica , ARN Largo no Codificante , Animales , Ratones , Dermatitis Alérgica por Contacto/metabolismo , Dermatitis Atópica/metabolismo , Queratinocitos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , ARN Largo no Codificante/farmacología , HumanosRESUMEN
3D nanocake-like Au-MXene and Au pallet (Au-MXene/AuP) nanocomposite-modified screen-printed carbon electrodes (SPCEs) were utilized to construct an ultrasensitive label-free electrochemical aptasensor through a self-assembly procedure for trace paraquat (PQ) residue detection. Benefiting from the excellent electrochemical (EC) performances (e.g., high conductivity and large surface area) of Au-MXene nanocomposites and AuP substrate, the developed Apt/Au-MXene/AuP/SPCE-based EC aptasensor displayed excellent specificity and anti-interference ability, good repeatability, and stability. A linear relationship between the log value of the change in current intensity [lg (ΔI)] and the log value of the concentration of PQ [lg (CPQ)] was obtained in the range 0.05-1000 ng/mL. The limit of detection was 0.028 ng/mL, and the sensitivity was 255.5 µA/(µM·cm2). Practical applications in malt and mint samples confirmed the accuracy of the EC aptasensor in complex matrices for PQ detection, providing a universal analytical tool for other trace pesticides in different food samples by simply replacing the corresponding aptamers.
Asunto(s)
Aptámeros de Nucleótidos , Técnicas Biosensibles , Límite de Detección , Técnicas Electroquímicas/métodos , Paraquat , Aptámeros de Nucleótidos/química , Técnicas Biosensibles/métodos , Oro/químicaRESUMEN
INTRODUCTION: The aim of the study was to retrospectively identify the metastatic influence factors and predict the prognosis and develop an individualized prognostic prediction model for patients with N3-stage nasopharyngeal carcinoma (NPC). METHODS: The study collected 446 NPC patients with N3 stage from the Surveillance, Epidemiology, and End Results database between 2010 and 2015. The patients were classified into subgroups based on the histological types and metastatic status. Multivariable logistic, Cox regression, and Kaplan-Meier method with the log-rank test were performed. The nomogram model was created using the prognostic factors identified from Cox regression analysis. The predictive accuracy was determined based on the concordance index (c-index) and calibration curves. RESULTS: The 5-year overall survival (OS) of the NPC patients with N3 stage was 43.9%, and the prognosis of patients without any distant metastases was largely longer than that with metastases. No difference was observed between different pathological types in the entire cohort. However, patients with non-keratinized squamous cell carcinoma had a better OS than that of the patients with keratinized squamous cell carcinoma in a nonmetastatic subgroup. Using the Cox regression analysis results, the nomogram successfully classified these patients into low- and high-risk subgroups and presented the survival difference. The c-index of the nomogram for predicting the prognosis was satisfactory. CONCLUSION: This study identified metastatic risk factors and developed a convenient clinical tool for the prognosis of NPC patients. This tool can be used for individualized risk classification and decision-making regarding treatment of NPC patients with N3 stage.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias Nasofaríngeas , Humanos , Nomogramas , Pronóstico , Carcinoma Nasofaríngeo/patología , Estadificación de Neoplasias , Estudios Retrospectivos , Carcinoma de Células Escamosas/patología , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patologíaRESUMEN
As a natural polymer, lignin is only less abundant in nature than cellulose. It has the form of an aromatic macromolecule, with benzene propane monomers connected by molecular bonds such as C-C and C-O-C. One method to accomplish high-value lignin conversion is degradation. The use of deep eutectic solvents (DESs) to degrade lignin is a simple, efficient and environmentally friendly degradation method. After degradation, the lignin is broken due to ß-O-4 to produce phenolic aromatic monomers. In this work, lignin degradation products were evaluated as additives for the preparation of polyaniline conductive polymers, which not only avoids solvent waste but also achieves a high-value use of lignin. The morphological and structural characteristics of the LDP/PANI composites were investigated using 1H NMR, Fourier-transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, thermogravimetric analysis and elemental analysis. The LDP/PANI nanocomposite provides a specific capacitance of 416.6 F/g at 1 A/g and can be used as a lignin-based supercapacitor with good conductivity. Assembled as a symmetrical supercapacitor device, it provides an energy density of 57.86 Wh/kg, an excellent power density of 952.43 W/kg and, better still, a sustained cycling stability. Thus, the combination of polyaniline and lignin degradate, which is environmentally friendly, amplifies the capacitive function on the basis of polyaniline.
Asunto(s)
Lignina , Fenol , Fenoles , Conductividad Eléctrica , PolímerosRESUMEN
Lignosulfonate/polyaniline (LS/PANI) nanocomposite adsorbent materials were prepared by the chemical polymerization of lignosulfonate with an aniline monomer as a dopant and structure-directing agent, and the adsorption behavior of dyes as well as heavy metal ions was investigated. LS/PANI composites were used as dye adsorbents for the removal of different cationic dyes (malachite green, methylene blue, and crystal violet). The adsorption behavior of LS/PANI composites as dye adsorbents for malachite green was investigated by examining the effects of the adsorbent dosage, solution pH, initial concentration of dye, adsorption time, and temperature on the adsorption properties of this dye. The following conclusions were obtained. The optimum adsorption conditions for the removal of malachite green dye when LS/PANI composites were used as malachite green dye adsorbents were as follows: an adsorbent dosage of 20 mg, an initial concentration of the dye of 250 mg/L, an adsorption time of 300 min, and a temperature of 358 K. The LS/PANI composite adsorbed malachite green dye in accordance with the Langmuir adsorption model and pseudo-second-order kinetic model, which belongs to chemisorption-based monomolecular adsorption, and the equilibrium adsorption amount was 245.75 mg/g. In particular, the adsorption of heavy metal ion Pb2+ was investigated, and the removal performance was also favorable for Pb2+.