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MXenes have attracted growing interest in electrochemical energy storage owing to their high electronic conductivity and editable surface chemistry. Besides, rendering MXenes with spectrum defense properties further broadens their versatile applications. However, the development of MXenes suffers from weak van der Waal interaction-driven self-restacking that leads to random alignment and inferior interface microenvironments. Herein, a nacre-inspired MXene film is tailored by dual-filling of 2-ureido-4[1H]-pyrimidinone (UPy)-modified polyvinyl alcohol (PVA-UPy) and carbon nanotubes (CNTs). The dual-nanofillers engineering endows the nanocomposite film with a highly ordered structure (a Herman's order value of 0.838), a high mechanical strength (139.5 MPa), and continuous conductive pathways of both the ab plane and c-axis. As a proof-of-concept, the tailored nanocomposite film achieves a considerable capacitance of 508.2 F cm-3 and long-term cycling stability without performance degradation for 10 000 cycles. It is efficient for spectra defense in radar and infrared bands, displaying a high electromagnetic shielding capacity (19186 dB cm2 g-1) and a super-low infrared (IR) emissivity (0.16), with negligible performance decay after saving in the air for 1 year, responsible for the applications in specific and complex conditions. This interfacial dual-filler engineering concept showcases effective nanotechnology toward sustainable energy applications with a long lifetime and safety.
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BACKGROUND: Cholestasis is a common yet severe complication that occurs during the advancement of liver metastasis. However, how cholestasis impacts the development, treatment, and tumor microenvironment (TME) of liver metastasis remains to be elucidated. METHODS: Extrahepatic and intrahepatic cholestatic mouse models with liver metastasis were established to detect the differential expression levels of genes, infiltration of immune cells and change in bile acid-associated metabolites by using RNA-Sequencing, flowcytometry, and liquid chromatography and mass spectrometry. Western blot was applied to neutrophils under the stimulation of primary bile acids (BAs) in vitro to study the mechanism of phenotypic alteration. In vitro coculture of BA-treated neutrophils with CD8+ T cells were performed to study the immune-suppressive effect of phenotypic-altered neutrophils. Clinical samples collected from colorectal cancer patients with liver metastasis and cholestasis were applied to RNA-Seq. RESULTS: Compared to non-cholestatic mice, the progression of liver metastasis of cholestatic mice was significantly accelerated, which was associated with increased neutrophil infiltration and T-cell exclusion. Both neutrophils and T cells expressed higher immunosuppressive markers in the cholestatic mouse model, further indicating that an immunosuppressive tumor microenvironment was induced during cholestasis. Although neutrophils deletion via anti-Ly6G antibody partially hindered liver metastasis progression, it reduced the overall survival of mice. Tauro-ß-muricholic acid (Tß-MCA) and Glycocholic acid (GCA), the two most abundant cholestasis-associated primary BAs, remarkably promoted the expression of Arg1 and iNOS on neutrophils via p38 MAPK signaling pathway. In addition, BAs-pretreated neutrophils significantly suppressed the activation and cytotoxic effects of CD8+ T cells, indicating that the immunosuppressive phenotype of neutrophils was directly induced by BAs. Importantly, targeting BA anabolism with Obeticholic acid (OCA) under cholestasis effectively suppressed liver metastasis progression, enhanced the efficacy of immune checkpoint blockade, and prolonged survival of mice. CONCLUSIONS: Our study reveals the TME of cholestasis-associated liver metastasis and proposes a new strategy for such patients by targeting bile acid anabolism.
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Colestasis , Neoplasias Colorrectales , Neoplasias Hepáticas , Neutrófilos , Animales , Neutrófilos/inmunología , Ratones , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/inmunología , Colestasis/inmunología , Colestasis/metabolismo , Microambiente Tumoral , Masculino , Ratones Endogámicos C57BL , Humanos , Modelos Animales de EnfermedadRESUMEN
The rational design and synthesis of carbon nanocages with highly complex porous structures are continuously facing challenges in the development of high-performance supercapacitors (SCs). The electrochemical performance characteristics of electrodes rely on their compositions and fabrication methods. Here, we propose a universal and efficient approach for the in-situ synthesis of zeolitic imidazolate framework-8 (ZIF-8) on porous carbonized wood, where the selective utilization of hexacarbonyl molybdenum protects the structural integrity of the ZIF-8 precursor, preventing collapse during thermal treatment. The subsequent pyrolysis process leads to the formation of small-sized molybdenum carbide (MoC) which are embedded in carbon nanocages (CN). The composite electrode consists of MoC/CN embedded in a porous carbonized wood (PCW), and it shows area-specific capacity of 9.7F cm-2 and 9.4 F cm-2 at 5 mA cm-2 and 30 mA cm-2, respectively. Subsequently, the symmetric supercapacitor, with two MoC/CN@PCW electrodes exhibits a areal specific capacitance of 2.7 F cm-2 at 5 mA cm-2. Moreover, this supercapacitor maintains an capacitance retention rate of 98.5 % after 12,000 discharge cycles. The supercapacitor exhibits a power density of 6.5 mW cm-2, resulting in an energy density of 0.864 mWh cm-2. Therefore, the utilization of wood-based electrodes holds promise for energy storage systems.
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Lenvatinib is a multi-target inhibitor that exerts anti-tumor effects by inhibiting angiogenesis and is now commonly used as a first-line treatment for hepatocellular carcinoma. However, with the widespread use of lenvatinib, the problem of serious and fatal hepatotoxicity has become increasingly prominent. Currently, the mechanism behind this toxicity is not yet understood, and as a result, there is a lack of safe and effective intervention strategies with minimal side effects. Here, we established the model of lenvatinib-induced liver injury in vivo and in vitro and found that lenvatinib caused hepatotoxicity by inducing apoptosis. Further mechanistic studies in cellular models revealed that lenvatinib upregulated death receptor signaling pathway, which activated the downstream effector Caspase-8, and ultimately led to apoptosis. Meanwhile, lenvatinib-induced apoptosis was associated with ROS generation and DNA damage. In addition, after screening marketed drugs and natural products in combination with cellular modeling, we identified a potential co-administered drug, dabrafenib, which could alleviate lenvatinib-induced hepatotoxicity. Further mechanistic studies revealed that dabrafenib attenuated lenvatinib-induced hepatotoxicity by inhibiting the activation of the death receptor signaling pathway. Subsequently, cancer cell proliferation assays confirmed that dabrafenib did not antagonize the antitumor effects of lenvatinib. In conclusion, our results validate that apoptosis caused by the death receptor signaling pathway is the key cause of lenvatinib-induced hepatotoxicity, and dabrafenib alleviates lenvatinib-induced hepatotoxicity by inhibiting this pathway.
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Apoptosis , Enfermedad Hepática Inducida por Sustancias y Drogas , Imidazoles , Oximas , Compuestos de Fenilurea , Quinolinas , Transducción de Señal , Quinolinas/farmacología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Oximas/farmacología , Oximas/uso terapéutico , Transducción de Señal/efectos de los fármacos , Compuestos de Fenilurea/farmacología , Humanos , Apoptosis/efectos de los fármacos , Imidazoles/farmacología , Ratones , Masculino , Receptores de Muerte Celular/metabolismo , Antineoplásicos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Células Hep G2RESUMEN
Mirabegron and vibegron, both newly identified beta-3 adrenergic agonists, have significantly improved the quality of life for patients suffering from overactive bladder. In order to comprehensively assess the plasma exposure levels of these agents, the development of a rapid and highly sensitive bioanalytical method becomes imperative. The primary objective of this study was to establish a robust high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for the concurrent quantification of mirabegron and vibegron in human plasma. The analytes were extracted from a 100 µL plasma sample through protein precipitation, employing 300 µL of methanol. Subsequently, samples underwent separation and quantification using a Waters XBridge C18 column (2.1 × 100 mm, 3.5 µm), with a mobile phase consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The mass analysis was conducted using positive electrospray ionization (ESI+) operated in a multiple reaction monitoring (MRM) mode. The proposed method was meticulously validated in accordance with the guidelines set forth by the U.S. Food and Drug Administration (FDA) for bioanalytical method validation. The regression equations demonstrated exceptional linearity for both mirabegron (r² ≥ 0.994) and vibegron (r² ≥ 0.996) across the concentration range of 0.5 - 200 ng/mL. Furthermore, the assay exhibited accuracy (inter-day relative error ≤ 6.90%) and precision (inter-day coefficient of variation ≤ 8.88%). The average recoveries of the analytes were found to range from 81.94% to 102.02%, with mean matrix effects falling within the range of 89.77% to 110.58%. As a result, this method was deemed highly suitable for the precise determination of the concentrations of both mirabegron and vibegron in the context of therapeutic drug monitoring and bioequivalence studies.
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Acetanilidas , Formiatos , Neoplasias , Pirimidinonas , Pirrolidinas , Tiazoles , Vejiga Urinaria Hiperactiva , Humanos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Vejiga Urinaria Hiperactiva/tratamiento farmacológico , Cromatografía Líquida con Espectrometría de Masas , Calidad de Vida , Reproducibilidad de los ResultadosRESUMEN
Background: Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients to reduce the risk of opportunistic fungal infections. Our objective was to investigate whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could change the pharmacokinetics of osimertinib in rats. Methods: The adult male Sprague-Dawley rats were randomly divided into four groups (n = 6): control (0.3% CMC-Na), and voriconazole (20 mg/kg), itraconazole (20 mg/kg), or fluconazole (20 mg/kg) combined with osimertinib (10 mg/kg) group. Tail vein blood samples were collected into heparin tubes at various time points within 0-48 h after osimertinib administration. Osimrtinib's plasma concentration was detected using HPLC-MS/MS system equipped with a Waters XBridge C18 column, with the mobile phase consisting of acetonitrile and 0.2% formic acid water at a flow rate of 0.5 mL/min. Results: Co-administration with voriconazole or fluconazole increased the Cmax of osimertinib by 58.04% and 53.45%, respectively; the AUC0-t increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0-t of osimertinib only increased by 13.91% and 34.80%, respectively. Conclusions: Our results revealed that the pharmacokinetics of osimertinib were significantly changed by voriconazole and fluconazole in rats, whereas it was slightly affected by itraconazole. This work will contribute to a more comprehensive understanding of the pharmacokinetic properties of osimertinib when co-administered with triazole antifungals.
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Itraconazol , Neoplasias Pulmonares , Masculino , Ratas , Animales , Itraconazol/farmacología , Voriconazol/farmacología , Fluconazol/farmacología , Antifúngicos/farmacología , Inhibidores del Citocromo P-450 CYP3A , Espectrometría de Masas en Tándem , Receptores ErbB , Ratas Sprague-Dawley , Neoplasias Pulmonares/tratamiento farmacológico , Inhibidores de Proteínas Quinasas , Mutación , Triazoles/farmacocinéticaRESUMEN
The human ABC transporter ABCC3 (also known as MRP3) transports a wide spectrum of substrates, including endogenous metabolites and exogenous drugs. Accordingly, it participates in multiple physiological processes and is involved in diverse human diseases such as intrahepatic cholestasis of pregnancy, which is caused by the intracellular accumulation of bile acids and estrogens. Here, we report three cryogenic electron microscopy structures of ABCC3: in the apo-form and in complexed forms bound to either the conjugated sex hormones ß-estradiol 17-(ß-D-glucuronide) and dehydroepiandrosterone sulfate. For both hormones, the steroid nuclei that superimpose against each other occupy the hydrophobic center of the transport cavity, whereas the two conjugation groups are separated and fixed by the hydrophilic patches in two transmembrane domains. Structural analysis combined with site-directed mutagenesis and ATPase activity assays revealed that ABCC3 possesses an amphiphilic substrate-binding pocket able to hold either conjugated hormone in an asymmetric pattern. These data build on consensus features of the substrate-binding pocket of MRPs and provide a structural platform for the rational design of inhibitors.
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Transportadoras de Casetes de Unión a ATP , Estradiol , Humanos , Transportadoras de Casetes de Unión a ATP/genética , Estradiol/farmacología , Estradiol/metabolismo , Mutagénesis Sitio-DirigidaRESUMEN
BACKGROUND/AIM: Recently, an increase in the number of asymptomatic rare benign liver tumors (BLTs) has been reported during health check-ups. It is difficult to determine the nature of partial rare BLTs and not easy to distinguish from malignant liver tumors. This study aimed to analysis clinical features, diagnosis and treatment of rare BLTs to reduce misdiagnosis and provide reference for clinical practice. METHODS: From January 2012 to January 2021, we treated 112 rare BLTs by hepatectomy, including 54 focal nodular hyperplasias, 14 hepatocellular adenomas, 28 hepatic angiomyolipomas, 3 hepatic granulomas, 2 inflammatory pseudotumors of the liver, 2 nodular regenerative hyperplasia, 2 hepatic lipomas, 1 solitary fibrous tumor of the liver, 1 hepatic schwannoma and 1 hepatic myelolipoma. RESULTS: The majority of patients were middle-aged female and asymptomatic. Single tumors were dominant. The diagnostic accuracies of computed tomography (CT) and magnetic resonance imaging (MRI) were 32.5% and 44.2%, respectively. The majority of tumors were likely to be misdiagnosed as hepatocellular carcinoma (HCC) or difficult to distinguish from HCC. All patients underwent surgical treatment. Postoperative pathological and immunohistochemical examination can confirm the diagnosis. No patients without tumor recurrence or metastasis during follow-up period. CONCLUSION: Altogether, the clinical symptoms of rare BLTs lack specificity, and their preoperative diagnosis largely depends on imaging examination, with a low diagnostic accuracy rate and high chances of misdiagnosis as HCC. Diagnosis is confirmed by pathological and immunohistochemical examination. Surgical resection for rare BLT is safe and effective, regular postoperative follow-up is necessary.
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Carcinoma Hepatocelular , Hiperplasia Nodular Focal , Neoplasias Hepáticas , Persona de Mediana Edad , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/cirugía , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/cirugía , Recurrencia Local de Neoplasia/cirugía , Hígado/patología , Hiperplasia Nodular Focal/diagnóstico , Hiperplasia Nodular Focal/cirugía , HepatectomíaRESUMEN
Artificial intelligence (AI)-assisted diagnosis and treatment could expand the medical scenarios and augment work efficiency and accuracy. However, factors influencing healthcare workers' adoption intention of AI-assisted diagnosis and treatment are not well-understood. This study conducted a cross-sectional study of 343 dental healthcare workers from tertiary hospitals and secondary hospitals in Anhui Province. The obtained data were analyzed using structural equation modeling. The results showed that performance expectancy and effort expectancy were both positively related to healthcare workers' adoption intention of AI-assisted diagnosis and treatment. Social influence and human-computer trust, respectively, mediated the relationship between expectancy (performance expectancy and effort expectancy) and healthcare workers' adoption intention of AI-assisted diagnosis and treatment. Furthermore, social influence and human-computer trust played a chain mediation role between expectancy and healthcare workers' adoption intention of AI-assisted diagnosis and treatment. Our study provided novel insights into the path mechanism of healthcare workers' adoption intention of AI-assisted diagnosis and treatment.
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Intención , Confianza , Humanos , Inteligencia Artificial , Estudios Transversales , Personal de Salud , Computadores , InteligenciaRESUMEN
AIM: The aim of this work is to investigate the influence of leaders' innovation expectation on nurses' innovation behaviour in conjunction with artificial intelligence, as well as explore the chain mediating effect of job control and creative self-efficacy between leaders' innovation expectation and nurses' innovation behaviour. BACKGROUND: The nurses' innovation behaviour is crucial in promoting medical artificial intelligence. Thus, clarifying the influencing factors of nurses' innovation behaviour has become a priority. METHODS: A cross-sectional survey was conducted with 263 Chinese nurses from tertiary hospitals and secondary hospitals in Hefei, Anhui province. RESULTS: Leaders' innovation expectation was positively related to nurses' innovation behaviour. Creative self-efficacy and job control respectively mediated the relationship between leaders' innovation expectation and nurses' innovation behaviour. Furthermore, creative self-efficacy and job control played a chain mediation role between leaders' innovation expectation and nurses' innovation behaviour. CONCLUSION: Leaders' innovation expectation helps to enhance nurses' creative self-efficacy and job control, thereby enhancing nurses' enthusiasm for innovation. IMPLICATIONS FOR NURSING MANAGEMENT: Hospital managers and leaders formulate intervention measures to increase leaders' innovation expectation, nurses' creative self-efficacy and job control, and encourage nurses' innovation behaviour.
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Enfermeras y Enfermeros , Personal de Enfermería en Hospital , Humanos , Autoeficacia , Estudios Transversales , Inteligencia Artificial , Motivación , Encuestas y Cuestionarios , Satisfacción en el TrabajoRESUMEN
Human ABC transporter ABCD1 transports very long-chain fatty acids from cytosol to peroxisome for ß-oxidation, dysfunction of which usually causes the X-linked adrenoleukodystrophy (X-ALD). Here, we report three cryogenic electron microscopy structures of ABCD1: the apo-form, substrate- and ATP-bound forms. Distinct from what was seen in the previously reported ABC transporters, the two symmetric molecules of behenoyl coenzyme A (C22:0-CoA) cooperatively bind to the transmembrane domains (TMDs). For each C22:0-CoA, the hydrophilic 3'-phospho-ADP moiety of CoA portion inserts into one TMD, with the succeeding pantothenate and cysteamine moiety crossing the inter-domain cavity, whereas the hydrophobic fatty acyl chain extends to the opposite TMD. Structural analysis combined with biochemical assays illustrates snapshots of ABCD1-mediated substrate transport cycle. It advances our understanding on the selective oxidation of fatty acids and molecular pathology of X-ALD.
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Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP , Adrenoleucodistrofia , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/metabolismo , Adrenoleucodistrofia/metabolismo , Coenzima A/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Humanos , Peroxisomas/metabolismoRESUMEN
SignificanceATP8B1 is a P4 ATPase that maintains membrane asymmetry by transporting phospholipids across the cell membrane. Disturbance of lipid asymmetry will lead to the imbalance of the cell membrane and eventually, cell death. Thus, defects in ATP8B1 are usually associated with severe human diseases, such as intrahepatic cholestasis. The present structures of ATP8B1 complexed with its auxiliary noncatalytic partners CDC50A and CDC50B reveal an autoinhibited state of ATP8B1 that could be released upon substrate binding. Moreover, release of this autoinhibition could be facilitated by the bile acids, which are key factors that alter the membrane asymmetry of hepatocytes. This enabled us to figure out a feedback loop of bile acids and lipids across the cell membrane.
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Adenosina Trifosfatasas , Colestasis Intrahepática , Adenosina Trifosfatasas/metabolismo , Ácidos y Sales Biliares/metabolismo , Membrana Celular/metabolismo , Colestasis Intrahepática/metabolismo , Humanos , Proteínas de Transferencia de Fosfolípidos/metabolismo , Fosfolípidos/metabolismoRESUMEN
Collaborative problem-solving (CPS) engages students in solving ill-structured problems, creating group knowledge, and developing self-regulation and collaboration skills. Different scaffoldings, such as minimal-guided, task-oriented, and idea-oriented, can be used to facilitate students' CPS activities, but their effects have not been comprehensively explored. In this research, we use minimally-guided, task-oriented, and idea-oriented scaffoldings to promote Chinese university students' online CPS activities and use a multi-method approach to analyze the effects of three scaffolding on collaboration. The results indicate relatively complicated collaborative processes and outcomes supported by three scaffoldings. It is initially shown that the idea-centered scaffolding strengthens students' connections between idea contribution, metacognitive regulation, and knowledge artifact behaviors, which are critical factors for improving the CPS quality. Based on the empirical research results, we conclude that future instructional design should carefully consider the educational culture, time constraint, and student regulation to better facilitate CPS practices.
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Recent studies have been found that polyphenols from plums fruits can inhibit the proliferation of multiple cancer cells, while the molecular mechanism was unclear. This study aimed to investigate the molecular mechanism underlying the pro-apoptotic effect of purified plum polyphenols (PPP) on human lung cancer A549 cells. Quercitrin (quercetin-3-O-glucoside, 814.19 ± 40.71 mg/g) was identified as the primary polyphenol in PPP via ultra high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS). PPP showed a strong capacity for inhibiting the proliferation of the A549 cells by inducing apoptosis, which was reflected by an increase in the Bax/Bcl-2 ratio. Additionally, the inhibitory rate of PPP on the A549 cells were higher than that of vitamin C when the treatment dose exceeded 160 µg/mL. Transcriptome analysis suggested that PPP-induced apoptosis was closely associated with regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/forkhead box protein O 1 (FOXO1) pathway in the A549 cells. Subsequently, as an activator of AKT, SC79 was applied to confirm that the inhibition of AKT phosphorylation play an important role in the PPP-induced apoptosis of the A549 cells. These results illustrated the potential of PPP as a dietary compound for the prevention of cancer or for use during chemotherapy.
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Neoplasias Pulmonares , Prunus domestica , Células A549 , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Proteína Forkhead Box O1/genética , Frutas/metabolismo , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Polifenoles/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Prunus domestica/metabolismo , Transducción de Señal , Espectrometría de Masas en TándemRESUMEN
BACKGROUND: Electromagnetic hypersensitivity refers to health effects attributed to electromagnetic fields (EMF) exposure and has been formally named "idiopathic environmental intolerance attributed to electromagnetic fields" (IEI-EMF) by the World Health Organization. Because of the growing use of cell phones, IEI-EMF has become a global public health concern. A survey in 2007 in Taiwan showed that the prevalence rate of IEI-EMF was 13.3%, which is higher than rates in studies conducted previously. The survey also found that the rate was higher in women. METHODS: To evaluate whether the prevalence rate of IEI-EMF is increasing and to verify the higher risk in women, we conducted a nationwide questionnaire survey using the same methods as the 2007 survey to assess the change in the prevalence rate of IEI-EMF in Taiwan. We also conducted a review of the literature and a meta-analysis to evaluate the changes in the prevalence rate around the world. RESULTS: On the basis of the representative sample of 3303 participants, we found that the prevalence rate of IEI-EMF in Taiwan declined from 13.3% to 4.6% over a period of 5 years. The literature review also found the prevalence rates in other countries to be decreasing, instead of increasing as predicted previously. The meta-analysis of the data from the literature showed that women are more likely to have IEI-EMF than men, with an odds ratio of 1.19 (95% confidence interval: 1.01-1.40). CONCLUSIONS: We found the prevalence rate of IEI-EMF has been declining, instead of increasing as predicted previously. Women are more likely to report having IEI-EMF than men. Further studies to explore the causes leading to the declines may help the public, scientific community, and government deal with idiopathic intolerance to other environmental exposures.
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Campos Electromagnéticos/efectos adversos , Exposición a Riesgos Ambientales , Sensibilidad Química Múltiple/epidemiología , Adulto , Anciano , Teléfono Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad Química Múltiple/etiología , Prevalencia , Encuestas y Cuestionarios , Taiwán/epidemiología , Adulto JovenRESUMEN
The spr0693-spr0694-spr0695 operon of Streptococcus pneumoniae encodes a putative ATP-binding cassette (ABC)-type efflux pump involved in the resistance of antibiotics and antimicrobial peptides. Here we report the crystal structures of Spr0694-0695 at 3.3 Å and Spr0693 at 3.0 Å resolution, revealing a MacAB-like efflux pump. The dimeric Spr0694-0695 adopts a non-canonical fold of ABC transporter, the transmembrane domain of which consists of eight tightly packed transmembrane helices with an insertion of extracellular domain between the first and second helices, whereas Spr0693 forms a nanotube channel docked onto the ABC transporter. Structural analyses combined with ATPase activity and antimicrobial susceptibility assays, enable us to propose a putative substrate-entrance tunnel with a lateral access controlled by a guard helix. Altogether, our findings provide structural insights and putative transport mechanism of a MacAB-like efflux pump in Gram-positive bacteria.
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Transportadoras de Casetes de Unión a ATP/química , Proteínas Bacterianas/química , Streptococcus pneumoniae/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Bacterias Grampositivas/química , Bacterias Grampositivas/clasificación , Bacterias Grampositivas/genética , Bacterias Grampositivas/metabolismo , Modelos Moleculares , Operón , Filogenia , Unión Proteica , Conformación Proteica , Dominios Proteicos , Streptococcus pneumoniae/química , Streptococcus pneumoniae/genéticaRESUMEN
Visceral adiposity is of greater risk than obesity in s.c. adipose tissue for diabetes and cardiovascular disease. Its pathogenesis remains unclear, but it is associated with extracellular matrix (ECM) remodeling. A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) are a family of secreted zinc-dependent metalloproteinases that play crucial roles in development and various diseases because of their ECM remodeling activity. ADAMTS18 is an orphan ADAMTS whose function and substrate remain unclear. Herein, we showed that Adamts18 mRNA was abundantly expressed in visceral (gonadal) white adipose tissue (vWAT) during the early stage of development after birth. Adamts18 knockout (KO) mice showed increased body fat percentage and larger adipocyte size in vWAT relative to wild-type littermates. These findings may be partly attributed to ECM remodeling, especially increased expression of laminin 1 and adipokine thrombospondin 1 in vWAT. Attenuated extracellular signal-regulated kinase 1 and 2 activity, along with increased expression of adipocyte-specific transcription factors peroxisome proliferator-activated receptor-γ, CCAAT/enhancer binding protein ß, and marker gene Fabp4, was detected in vWAT of Adamts18 KO mice. Furthermore, Adamts18 KO mice showed early metabolic syndrome, including hyperlipidemia, blood glucose metabolic disorder, and hypertension. ADAMTS18 deficiency promotes atherosclerosis in apolipoprotein E-deficient mice. These results indicate a novel function of ADAMTS18 in vWAT development and associated metabolic disorders.
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Proteínas ADAMTS/fisiología , Adiposidad/fisiología , Grasa Intraabdominal/metabolismo , Síndrome Metabólico/metabolismo , Proteínas ADAMTS/deficiencia , Proteínas ADAMTS/genética , Adipocitos/patología , Animales , Aterosclerosis/metabolismo , Aterosclerosis/fisiopatología , Células Cultivadas , Matriz Extracelular/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Grasa Intraabdominal/patología , Lípidos/sangre , Masculino , Síndrome Metabólico/patología , Ratones Noqueados , ARN Mensajero/genéticaRESUMEN
ADAMTS18 is a member of a secreted Zn-metalloproteinase ADAMTS family, and has been implicated in development, hemostasis, and various malignancies. It has thus far proven difficult to resolve its post-translational modification status, cleaved forms, and splice variants in living organisms due to the lack of specific antibodies available to characterize this enzyme. In this study, we develop six murine monoclonal antibodies (mAbs) against different functional regions of ADAMTS18 using hybridoma technology. These mAbs exhibit cross-recognition between ADAMTS18 and the homology domain of its family members. Using the tissues from Adamts18 knockout (KO) mice, we find that two of these mAbs (N-3 and C-5) precisely identify five significantly attenuated bands located at 180, 135, 95, 72, and 45 kDa. These bands represent the forms of ADAMTS18 that potentially exist in the tissues. These mAbs will provide a useful tool to investigate the ADAMTS18's biologic significance in the tissues.
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Proteínas ADAMTS/inmunología , Proteínas ADAMTS/metabolismo , Anticuerpos Monoclonales/inmunología , Procesamiento Proteico-Postraduccional , Proteínas ADAMTS/química , Proteínas ADAMTS/deficiencia , Animales , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Moleculares , Reproducibilidad de los ResultadosRESUMEN
Potassium homeostasis plays an essential role in the control of blood pressure. It is unknown, however, whether potassium balance is involved in the gender-associated blood pressure differences. We therefore investigated the possible mechanism of sexual dimorphism in blood pressure regulation by measuring the blood pressure, plasma potassium, renal actions of potassium channels and upstream regulator in male and female mice. Here we found that female mice exhibited lower blood pressure and higher plasma K+ level as compared to male littermates. Western blot analyses of mouse kidney extract revealed a significant decrease in renal outer medullary potassium (ROMK) channel expression, while large-conductance Ca2+-activated K+ (BK) channel and Na-K-2Cl cotransporter (NKCC2) as well as the upstream regulator with-no-lysine kinase 1 (WNK1) enhanced in female mice under normal condition. Surprisingly, both dietary K+ loading and K+ depletion eliminated the differences in plasma K+ and blood pressure between females and males, and the differences of renal K+ channels and WNK1 also attenuated in both groups of mice. These findings indicated the existence of a close correlation between K+ homeostasis and sex-associated blood pressure. Moreover, the differential regulation of ROMK, BK-α and NKCC2 between female and male mice, at least, were partly mediated via WNK1 pathway, which may contribute to the sexual dimorphism of plasma K+ and blood pressure control.
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Presión Sanguínea , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/metabolismo , Antígenos de Histocompatibilidad Menor/metabolismo , Canales de Potasio de Rectificación Interna/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Caracteres Sexuales , Miembro 1 de la Familia de Transportadores de Soluto 12/metabolismo , Animales , Femenino , Riñón/metabolismo , Masculino , Ratones Endogámicos C57BL , Potasio/sangre , Potasio/metabolismo , Proteína Quinasa Deficiente en Lisina WNK 1RESUMEN
Graphene oxide nanoribbons (GONRs) were covalently functionalized with an antibody using polyethylene glycol (PEG) as a linker to produce a novel probe for surface enhanced laser desorption/ionization mass spectrometry (SELDI MS). This probe provides a highly sensitive and selective platform for enrichment and MS detection of small molecules in complex media.