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Kawasaki disease (KD) is a systemic vasculitis with an unknown cause that primarily affects children. The objective of this study was to explore the function and underlying mechanism of mitophagy in Mycoplasma pneumoniae (MP)-induced KD. To create MP-induced KD models, Human coronary endothelial cells (HCAECs) and DBA/2 mice were employed and treated with Mp-Lipid-associated membrane proteins ï¼LAMPsï¼. Lactate dehydrogenase (LDH) levels were tested to determine cellular damage or death. The inflammatory cytokines tumor necrosis factor (TNF)--α and interleukin (IL)-6 were measured using the Enzyme-Linked Immunosorbent Assay (ELISA) method. RT-qPCR and Western blotting were used to determine the expression of Intercellular Adhesion Molecule(ICAM)-1, vascular cell adhesion molecule (VCAM)-1, inducible nitric oxide synthase(iNOS), LC3, p62, PINK1(a mitochondrial serine/threonine-protein kinase), and PARKIN(a cytosolic E3-ubiquitin ligase). The adenosine triphosphate ï¼ATPï¼, reactive oxygen species ï¼ROSï¼, and mitochondrial membrane potentialï¼MMPï¼ levels were measured to determine mitochondrial function. Mitophagy was investigated using immunofluorescence and a mitophagy detection test. Autophagosome and mitochondrial morphology were examined using transmission electron microscopy. To identify inflammatory cell infiltration, hematoxylin and eosin staining was utilized. Mp-LAMPs increased the levels of TNF-α, IL-6, ICAM-1, VCAM-1, and iNOS in an HCAEC cell model, along with LDH release. After Mp-LAMPs exposure, there was a rise in LC3 and a reduction in p62. Meanwhile, the expression of PINK1 and Parkin was increased. Cyclosporin A dramatically increased ATP synthesis and MMP in HCAEC cells treated with Mp-LAMPs, while suppressing ROS generation, demonstrating excessive mitophagy-related mitochondrial dysfunction. Additionally, neither body weight nor artery tissue were affected due to PINK1 and Parkin suppression Cyclosporin A in Mp-LAMPs-treated mice. These findings indicated that PINK1/Parkin-mediated mitophagy inhibition may be a therapeutic target for MP-induced KD.
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Mitofagia , Síndrome Mucocutáneo Linfonodular , Mycoplasma pneumoniae , Proteínas Quinasas , Ubiquitina-Proteína Ligasas , Animales , Síndrome Mucocutáneo Linfonodular/metabolismo , Síndrome Mucocutáneo Linfonodular/patología , Proteínas Quinasas/metabolismo , Humanos , Ratones , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Mycoplasma pneumoniae/patogenicidad , Ratones Endogámicos DBA , Células Endoteliales/metabolismo , Células Endoteliales/patología , Neumonía por Mycoplasma/metabolismo , Neumonía por Mycoplasma/patología , Neumonía por Mycoplasma/microbiología , Mitocondrias/metabolismo , Mitocondrias/patología , Especies Reactivas de Oxígeno/metabolismo , Potencial de la Membrana MitocondrialRESUMEN
BACKGROUND: Nitrogen (N) metabolism-related key genes and conserved amino acid sites in key enzymes play a crucial role in improving N use efficiency (NUE) under N stress. However, it is not clearly known about the molecular mechanism of N deficiency-induced improvement of NUE in the N-sensitive rhizomatous medicinal plant Panax notoginseng (Burk.) F. H. Chen. To explore the potential regulatory mechanism, the transcriptome and proteome were analyzed and the three-dimensional (3D) information and molecular docking models of key genes were compared in the roots of P. notoginseng grown under N regimes. RESULTS: Total N uptake and the proportion of N distribution to roots were significantly reduced, but the NUE, N use efficiency in biomass production (NUEb), the recovery of N fertilizer (RNF) and the proportion of N distribution to shoot were increased in the N0-treated (without N addition) plants. The expression of N uptake- and transport-related genes NPF1.2, NRT2.4, NPF8.1, NPF4.6, AVP, proteins AMT and NRT2 were obviously up-regulated in the N0-grown plants. Meanwhile, the expression of CIPK23, PLC2, NLP6, TCP20, and BT1 related to the nitrate signal-sensing and transduction were up-regulated under the N0 condition. Glutamine synthetase (GS) activity was decreased in the N-deficient plants, while the activity of glutamate dehydrogenase (GDH) increased. The expression of genes GS1-1 and GDH1, and proteins GDH1 and GDH2 were up-regulated in the N0-grown plants, there was a significantly positive correlation between the expression of protein GDH1 and of gene GDH1. Glu192, Glu199 and Glu400 in PnGS1 and PnGDH1were the key amino acid residues that affect the NUE and lead to the differences in GDH enzyme activity. The 3D structure, docking model, and residues of Solanum tuberosum and P. notoginseng was similar. CONCLUSIONS: N deficiency might promote the expression of key genes for N uptake (genes NPF8.1, NPF4.6, AMT, AVP and NRT2), transport (NPF1.2 and NRT2.4), assimilation (proteins GS1 and GDH1), signaling and transduction (genes CIPK23, PLC2, NLP6, TCP20, and BT1) to enhance NUE in the rhizomatous species. N deficiency might induce Glu192, Glu199 and Glu400 to improve the biological activity of GS1 and GDH, this has been hypothesized to be the main reason for the enhanced ability of N assimilation in N-deficient rhizomatous species. The key genes and residues involved in improving NUE provide excellent candidates for the breeding of medicinal plants.
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Panax notoginseng , Plantas Medicinales , Nitrógeno/metabolismo , Plantas Medicinales/genética , Plantas Medicinales/metabolismo , Panax notoginseng/genética , Panax notoginseng/metabolismo , Simulación del Acoplamiento Molecular , Fitomejoramiento , Aminoácidos/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Topological defects are widely recognized as effective active sites toward a variety of electrochemical reactions. However, the role of defect curvature is still not fully understood. Herein, carbon nanomaterials with rich topological defect sites of tunable curvature is reported. The curved defective surface is realized by controlling the high-temperature pyrolytic shrinkage process of precursors. Theoretical calculations demonstrate bending the defect sites can change the local electronic structure, promote the charge transfer to key intermediates, and lower the energy barrier for oxygen reduction reaction (ORR). Experimental results convince structural superiority of highly-curved defective sites, with a high kinetic current density of 22.5 mA cm-2 at 0.8 V versus RHE for high-curvature defective carbon (HCDC), ≈18 times that of low-curvature defective carbon (LCDC). Further raising the defect densities in HCDC leads to the dual-regulated products (HCHDC), which exhibit exceptionally outstanding ORR activity in both alkaline and acidic media (half-wave potentials: 0.88 and 0.74 V), outperforming most of the reported metal-free carbon catalysts. This work uncovers the curvature-activity relationship in carbon defect for ORR and provides new guidance to design advanced catalysts via curvature-engineering.
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BACKGROUND: Oxyntic gland neoplasm (OGN) is a rare subtype of gastric cancer. The aim of this study is to evaluate the prevalence, clinicopathological features, effectiveness and safety of endoscopic treatment, as well as the prognosis of OGN. METHODS: We retrospectively analyzed the data of patients pathologically diagnosed with OGN at our hospital from November 1, 2019 to May 1, 2023. RESULTS: A total of 36 patients with 45 lesions were identified, resulting in a disease frequency of 0.047% (36/76,832). The mean age was 55.0 ± 7.5 years, with a male-to-female ratio of about 1:1.12. Most lesions were ≤10 mm in size (84.4%), located in the upper third of the stomach (73.3%), exhibited slight elevation (75.5%), appeared whitish (55%), had dilated blood vessels on the surface (75.5%). 16 and 21 lesions were treated by precutting endoscopic mucosal resection (EMR-P) and endoscopic submucosal dissection (ESD), respectively. No significant differences were found between EMR-P and ESD in terms of en bloc resection rate (100% vs 100%, p = 1.000), complete resection rate (100% vs 90.5%, p = 0.495), and curative resection rate (93.8% vs 90.5%, p = 1.000). No complications such as bleeding and perforation were observed. No recurrence or metastasis was observed during the follow-up period. CONCLUSIONS: OGN is a rare tumor with unique clinical, endoscopic, and pathological characteristics. EMR-P and ESD are deemed safe and effective for treating OGNs. The relatively faster and easier EMR-P seems at least non-inferior to ESD, especially for removal of smaller OGNs. The overall prognosis is favorable.
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Resección Endoscópica de la Mucosa , Neoplasias Gástricas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/terapia , Neoplasias Gástricas/epidemiología , Prevalencia , Anciano , Resultado del Tratamiento , Adulto , Pronóstico , Gastroscopía , Mucosa Gástrica/patología , Mucosa Gástrica/cirugía , China/epidemiologíaRESUMEN
SR9009 is an activator of REV-ERBs with diverse biological activities, including improving exercise tolerance and controlling skeletal muscle mass. To optimise the carbamate motif of SR9009, analogues of SR9009 were synthesised and evaluated. All of them showed REV-ERB-α agonist activities. Among them, 5a, 5f, 5 g, 5m, and 5p showed potencies equivalent to or slightly higher than the potency of SR9009 in vitro. These data indicate that the halogenated benzyl group is an indispensable active group in these compounds. 5m, 5p and SR9009 improved exercise tolerance in normal mice in vivo. Additionally, in hyperlipidemic mice, 5m and 5p not only improved exercise tolerance but also lowered blood lipid levels. 5m and 5p displayed stronger hypoglycaemic activity than SR9009.
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Glucolípidos , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares , Tiofenos , Animales , Ratones , Tiofenos/farmacología , Tiofenos/química , Tiofenos/síntesis química , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/agonistas , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Glucolípidos/farmacología , Glucolípidos/química , Glucolípidos/síntesis química , Relación Estructura-Actividad , Masculino , Humanos , Estructura Molecular , Ratones Endogámicos C57BL , Pirrolidinas/farmacología , Pirrolidinas/química , Pirrolidinas/síntesis química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Relación Dosis-Respuesta a Droga , Tolerancia al Ejercicio/efectos de los fármacosRESUMEN
BACKGROUND: The role of endoscopic resection (ER) in gastric gastrointestinal stromal tumors (GISTs) has not been fully elucidated. AIMS: The purpose of this work was to evaluate the clinical effectiveness and safety of ER in patients with GISTs originating from the muscularis propria (MP). METHODS: A total of 233 consecutive patients with gastric GISTs originating from the MP layer, who underwent ER between February 2012 and May 2023, were included in this study. Clinical characteristics, tumor features, and outcomes were recorded and compared between patients who underwent en bloc resection and piecemeal resection. RESULTS: Among the 233 patients, the median size of GISTs was 12 mm (range 5-60 mm). Risk assessment categorized 190 patients as very low risk, 26 as low risk, 10 as moderate risk, and 7 as high risk. The procedures performed included endoscopic submucosal excavation (127 cases), endoscopic full-thickness resection (103 cases), and submucosal tunneling endoscopic resection (3 cases). The complete and R0 resection rate was 93.1%. Complications occurred in 4.7% of cases (perioperative perforations 1.7%, perioperative bleeding 1.3%, both 0.9%), resulting in conversion to surgery in 1.3% of cases. Risk factors associated with piecemeal resection were tumor size [odds ratio (OR) 0.402, 95% confidence interval (CI) 0.207-0.783; P = 0.007] and shape (OR 0.045, 95% CI 0.009-0.235; P < 0.001). CONCLUSIONS: ER is proven to be an effective and reasonably safe approach for gastric GISTs originating from the MP. Notably, larger tumor size and irregular shape are identified as risk factors for piecemeal resection during ER procedures.
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Tumores del Estroma Gastrointestinal , Neoplasias Gástricas , Humanos , Tumores del Estroma Gastrointestinal/cirugía , Tumores del Estroma Gastrointestinal/patología , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Anciano , Adulto , Anciano de 80 o más Años , Resección Endoscópica de la Mucosa/métodos , Resección Endoscópica de la Mucosa/efectos adversos , Mucosa Gástrica/cirugía , Mucosa Gástrica/patología , Resultado del Tratamiento , Estudios Retrospectivos , Gastroscopía/métodos , Gastroscopía/efectos adversos , Factores de Riesgo , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
BACKGROUND AND AIM: The incidence of rectal neuroendocrine tumors (R-NETs) has increased in recent years. However, the predictors of lymph node (LN) metastasis and clinical outcomes, particularly following endoscopic treatment, remain unclear. Our study aims to elucidate the potential risk factors for LN metastasis and the clinical outcomes of patients undergoing endoscopic resection in R-NETs. METHODS: A total of 128 patients with R-NETs were retrospectively identified from a single center between June 2012 and December 2021. Risk factors for LN metastasis in R-NETs were analyzed using multivariate analysis. Additionally, the clinical outcomes of endoscopic resections in patients with R-NETs were assessed. RESULTS: In our study, 128 patients with R-NETs were retrospectively analyzed. The risk factors for LN metastasis determined by multivariate analysis were tumor size and patient age at diagnosis. Among the 111 patients treated with endoscopic resection and with tumor margin records available, 92 underwent endoscopic submucosal dissection (ESD) and 19 underwent conventional endoscopic mucosal resection (EMR). There was no significant difference between the two groups regarding the positive rates of basal tumor margin and lateral tumor margin. Furthermore, 64 patients who underwent endoscopic resection for R-NETs were successfully followed up (range, 1.64-76.71 months), during which only one patient developed local recurrence. CONCLUSION: Tumor size and age at diagnosis were predictors for LN metastasis of R-NETs. Both ESD and EMR are alternative techniques with a favorable prognosis for R-NETs, even in cases with positive resection margins. However, due to the relatively small number of patients undergoing EMR and missing data in follow-up protocols, definitive conclusions require further large-scale studies.
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Resección Endoscópica de la Mucosa , Metástasis Linfática , Tumores Neuroendocrinos , Neoplasias del Recto , Humanos , Masculino , Neoplasias del Recto/patología , Neoplasias del Recto/cirugía , Estudios Retrospectivos , Femenino , Tumores Neuroendocrinos/cirugía , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/secundario , Persona de Mediana Edad , Resección Endoscópica de la Mucosa/métodos , Anciano , Adulto , Factores de Riesgo , Resultado del Tratamiento , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/patología , Márgenes de EscisiónRESUMEN
AIM: To measure the association of leader-member exchange and team-member exchange with nurses' innovative behaviours through social exchange theory. BACKGROUND: The field of nursing is actively advocating innovation. Other fields have proven that leader-member exchange and team-member exchange can promote innovative behaviour, but such an association is not clear in nursing. DESIGN: A cross-sectional study. METHODS: A total of 560 nurses were selected from five tertiary hospitals in Henan Province (China) by multistage sampling. Data were collected from a self-report questionnaire. Thirty nurses in the pre-survey were used to verify the validity of the questionnaire. SPSS PROCESS macro was used to verify the association of leader-member exchange and team-member exchange with nurses' innovative behaviours. RESULTS: Leader-member exchange and team-member exchange were significantly associated with nurses' innovative behaviours, and team-member exchange had a mediating effect on the relationship between leader-member exchange and innovative behaviour. CONCLUSIONS: Leader-member exchange and team-member exchange positively affect nurses' innovative behaviours. Leader-member exchange can promote nurses' innovative behaviours through the mediating role of team-member exchange. IMPACT: This study indicated that leader-member exchange and team-member exchange should be given more attention in promoting nurses' innovative behaviours. This finding has implications for the promotion of innovative behaviours in nurses. Leaders need to focus on the innovative needs of nurses and offer support. Meanwhile, leadership training programs are necessary for managers to create positive team relationships. PATIENT OR PUBLIC CONTRIBUTION: No patient or public involvement.
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Liderazgo , Personal de Enfermería en Hospital , Humanos , Estudios Transversales , Adulto , Femenino , Masculino , China , Encuestas y Cuestionarios , Personal de Enfermería en Hospital/psicología , Relaciones Interprofesionales , Persona de Mediana Edad , Actitud del Personal de SaludRESUMEN
Dermatophyte biofilms frequently count for inadequate responses and resistance to standard antifungal treatments, resulting in refractory chronic onychomycosis infection. Although antimicrobial photodynamic therapy (aPDT) has clinically proven to exert significant antifungal effects or even capable of eradicating dermatophyte biofilms, considerably less is known about the molecular mechanisms underlying aPDT and the potential dysregulation of signaling networks that could antagonize its action. The aim of this study is to elucidate the molecular mechanisms underlining aPDT combat against dermatophyte biofilm in recalcitrant onychomycosis and to decipher the potential detoxification processes elicited by aPDT, facilitating the development of more effective photodynamic interventions. We applied genome-wide comparative transcriptome analysis to investigate how aPDT disrupting onychomycosis biofilm formed by three distinct dermatophytes, including Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum gypseum, the most frequently occurring pathogenic species. In total, 352.13 Gb of clean data were obtained for the transcriptomes of dermatophyte biofilms with or without aPDT treatment, resulting in 2,422.42 million reads with GC content of 51.84%, covering 99.9%, 98.5% and 99.4% of annotated genes of T. rubrum, T. mentagrophytes, and M. gypseum, respectively. The genome-wide orthologous analysis identified 6624 transcribed single-copy orthologous genes in all three species, and 36.5%, 6.8% and 17.9% of which were differentially expressed following aPDT treatment. Integrative orthology analysis demonstrated the upregulation of oxidoreductase activities is a highly conserved detoxification signaling alteration in response to aPDT across all investigated dermatophyte biofilms. This study provided new insights into the molecular mechanisms underneath anti-dermatophyte biofilm effects of aPDT and successfully identified a conserved detoxification regulation upon the aPDT application.
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Arthrodermataceae , Biopelículas , Perfilación de la Expresión Génica , Fotoquimioterapia , Biopelículas/efectos de los fármacos , Arthrodermataceae/efectos de los fármacos , Arthrodermataceae/genética , Microsporum/efectos de los fármacos , Microsporum/genética , Humanos , Antifúngicos/farmacología , Onicomicosis/microbiología , Onicomicosis/tratamiento farmacológico , TranscriptomaRESUMEN
Metasurface-based structural color with high resolution is promising for color printing and encryption. However, achieving tunable structural colors in practical applications is challenging owing to the immutability after the fabrication of metasurfaces. Herein, we proposed the polarization-switchable dielectric metasurfaces with full colors. The colorful images can be switched on/off by controlling the polarization of incident light. For the nanorods metasurfaces, all colors turned to black in the "off" mode because of the near-zero reflection, and the uniform black was advantageous for designing encryption applications. For the nanocrosses metasurfaces, colors reversed in two different "on" modes and images hidden in the "off" mode. With the polarization-sensitive metasurfaces, a fish-bird image, an overlapped dual-channel image, and a green-red heart image were obtained, respectively. The demonstrations can be applied to dynamic displays, optical cryptography, multichannel imaging, and optical data storage.
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The global prevalence of RNA virus infections has presented significant challenges to public health in recent years, necessitating the expansion of its alternative therapeutic library. Due to its evolutional conservation, RNA-dependent RNA polymerase (RdRp) has emerged as a potential target for broad-spectrum antiviral nucleoside analogues. However, after over half a century of structural modification, exploring unclaimed chemical space using frequently-used structural substitution methods to design new nucleoside analogues is challenging. In this study, we explore the use of the "ring-opening" strategy to design new base mimics, thereby using these base mimics to design new nucleoside analogues with broad-spectrum antiviral activities. A total of 29 compounds were synthesized. Their activity against viral RdRp was initially screened using an influenza A virus RdRp high-throughput screening model. Then, the antiviral activity of 38a was verified against influenza virus strain A/PR/8/34 (H1N1), demonstrating a 50% inhibitory concentration (IC50) value of 9.95 µM, which was superior to that of ribavirin (the positive control, IC50 = 11.43 µM). Moreover, 38a also has inhibitory activity against coronavirus 229E with an IC50 of 30.82 µM. In addition, compounds 42 and 46f exhibit an 82% inhibition rate against vesicular stomatitis virus at a concentration of 20 µM and hardly induce cytotoxicity in host cells. This work demonstrates the feasibility of designing nucleoside analogues with "ring-opening" bases and suggests the "ring-opening" nucleosides may have greater polarity, and designing prodrugs is an important aspect of optimizing their antiviral activity. Future research should focus on enhancing the conformational restriction of open-loop bases to mimic Watson-Crick base pairing better and improve antiviral activity.
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Antivirales , Diseño de Fármacos , Nucleósidos , ARN Polimerasa Dependiente del ARN , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Nucleósidos/química , Nucleósidos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Subtipo H1N1 del Virus de la Influenza A/efectos de los fármacos , Humanos , Animales , Células de Riñón Canino Madin Darby , Perros , Relación Estructura-ActividadRESUMEN
The antibacterial agents deoxynybomycin (DNM) and nybomycin (NM) have a unique tetracyclic structure featuring an angularly fused 4-oxazoline ring. Here, we report the identification of key enzymes responsible for forming the 4-oxazoline ring in Embleya hyalina NBRC 13850 by comparative bioinformatics analysis of the biosynthetic gene clusters encoding structurally similar natural products DNM, deoxynyboquinone (DNQ), and diazaquinomycins (DAQs). The N-methyltransferase DnmS plays a crucial role in catalyzing the N-dimethylation of a tricyclic precursor prenybomycin to generate NM D; subsequently, the Fe(II)/α-ketoglutarate-dependent dioxygenase (Fe/αKGD) DnmT catalyzes the formation of a 4-oxazoline ring from NM D to produce DNM; finally, a second Fe/αKGD DnmU catalyzes the C-12 hydroxylation of DNM to yield NM. Strikingly, DnmT is shown to display unexpected functions to also catalyze the decomposition of the 4-oxazoline ring and the N-demethylation, thereby converting DNM back to prenybomycin, to putatively serve as a manner to control the intracellular yield of DNM. Structure modeling, site-directed mutagenesis, and quantum mechanics calculations provide mechanistic insights into the DnmT-catalyzed reactions. This work expands our understanding of the functional diversity of Fe/αKGDs in natural product biosynthesis.
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Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato , Quinolonas , Catálisis , Compuestos Ferrosos/químicaRESUMEN
The practical catalytic enantioselective cis-dihydroxylation of olefins that utilize earth-abundant first-row transition metal catalysts under environmentally friendly conditions is an important yet challenging task. Inspired by the cis-dihydroxylation reactions catalyzed by Rieske dioxygenases and non-heme iron models, we report the biologically inspired cis-dihydroxylation catalysis that employs an inexpensive and readily available mononuclear non-heme manganese complex bearing a tetradentate nitrogen-donor ligand and aqueous hydrogen peroxide (H2O2) and potassium peroxymonosulfate (KHSO5) as terminal oxidants. A wide range of olefins are efficiently oxidized to enantioenriched cis-diols in practically useful yields with excellent cis-dihydroxylation selectivity and enantioselectivity (up to 99% ee). Mechanistic studies, such as isotopically 18O-labeled water experiments, and density functional theory (DFT) calculations support that a manganese(V)-oxo-hydroxo (HO-MnVâO) species, which is formed via the water-assisted heterolytic O-O bond cleavage of putative manganese(III)-hydroperoxide and manganese(III)-peroxysulfate precursors, is the active oxidant that effects the cis-dihydroxylation of olefins; this is reminiscent of the frequently postulated iron(V)-oxo-hydroxo (HO-FeVâO) species in the catalytic arene and alkene cis-dihydroxylation reactions by Rieske dioxygenases and synthetic non-heme iron models. Further, DFT calculations for the mechanism of the HO-MnVâO-mediated enantioselective cis-dihydroxylation of olefins reveal that the first oxo attack step controls the enantioselectivity, which exhibits a high preference for cis-dihydroxylation over epoxidation. In this study, we are able to replicate both the catalytic function and the key chemical principles of Rieske dioxygenases in mononuclear non-heme manganese-catalyzed enantioselective cis-dihydroxylation of olefins.
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Dioxigenasas , Peróxido de Hidrógeno/química , Manganeso , Oxidación-Reducción , Alquenos/química , Estereoisomerismo , Hierro/química , Oxidantes , Catálisis , AguaRESUMEN
Mononuclear nonheme iron enzymes catalyze a large variety of oxidative transformations responsible for various biosynthesis and metabolism processes. Unlike their P450 counterparts, non-heme enzymes generally possess flexible and variable coordination architecture, which can endow rich reactivity for non-heme enzymes. This Concept highlights that the coordination dynamics of iron can be a key player in controlling the activity and selectivity of non-heme enzymes. In ergothioneine synthase EgtB, the coordination switch of the sulfoxide radical species enables the efficient and selective C-S coupling reaction. In iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenases, the conformational flip of ferryl-oxo intermediate can be extensively involved in selective oxidation reactions. Especially, the five-coordinate ferryl-oxo species may allow the substrate coordination via O or N atom, which may facilitate the C-O or C-N coupling reactions via stabilizing the transition states and inhibiting the unwanted hydroxylation reactions.
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Hierro , Oxigenasas , Hierro/química , Oxidación-Reducción , Oxigenasas/química , Catálisis , Conformación MolecularRESUMEN
OBJECTIVES: To evaluate the humoral immunogenicity for 6 months after the two-dose coronavirus disease 2019 (COVID-19) mRNA vaccination in adolescents and young adults (AYAs) with childhood-onset rheumatic diseases (cRDs). METHODS: This monocentric observational study was conducted between August 2020 and March 2022. Humoral immunogenicity was assessed at 2-3 weeks after first vaccine dose and 1, 3 and 6 months after the second dose by the cPass™ severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralization antibody (nAb) assay. An inhibition signal of ≥30% defined the seroconversion threshold and the readings were calibrated against the World Health Organization International Standard for SARS-CoV-2 antibodies. RESULTS. ONE HUNDRED AND SIXTY-NINE: AYAs with cRDs were recruited [median age 16.8 years (interquartile range, IQR 14.7-19.5), 52% female, 72% Chinese]. JIA (58%) and SLE (18%) comprised the major diagnoses. After second vaccine dose, 99% seroconverted with a median nAb titre of 1779.8 IU/ml (IQR 882.8-2541.9), declining to 935.6 IU/ml (IQR 261.0-1514.9) and 683.2 IU/ml (IQR 163.5-1400.5) at the 3- and 6-month timepoints, respectively. The diagnosis of JIA [odds ratio (OR) 10.1, 95% CI 1.8-58.4, P = 0.010] and treatment with anti-TNF-α (aTNF) (OR 10.1, 95% CI 1.5-70.0, P = 0.019) were independently associated with a >50% drop of nAb titres at 6 months. Withholding MTX or MMF did not affect the vaccine response or decay rate. The COVID-19 breakthrough infection was estimated at 18.2 cases/1000 patient-months with no clinical risk factors identified. CONCLUSION: Over half of AYAs with cRDs had a significant drop in SARS-CoV-2 nAb at 6-month despite an initial robust humoral response. JIA and aTNF usage are predictors of a faster decay rate.
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COVID-19 , Enfermedades Reumáticas , Niño , Adolescente , Femenino , Humanos , Adulto Joven , Masculino , Vacunas contra la COVID-19 , COVID-19/epidemiología , COVID-19/prevención & control , Inmunogenicidad Vacunal , Inhibidores del Factor de Necrosis Tumoral , SARS-CoV-2 , Anticuerpos Antivirales , Enfermedades Reumáticas/tratamiento farmacológicoRESUMEN
BACKGROUND: Underwater endoscopic mucosal resection (UEMR) is increasingly applied in the treatment of superficial non-ampullary duodenal epithelial tumors (SNADETs). This meta-analysis aimed to assess the efficacy and safety of UEMR for SNADETs ≤20 mm in comparison with conventional endoscopic mucosal resection (CEMR). METHODS: The following electronic databases were searched from 2012 until November 20, 2021: PubMed, Embase, Scopus, Web of Science databases, and Cochrane Library. The primary outcomes were the rates of en bloc resection and complete (R0) resection, and the secondary outcomes were procedure time, adverse events (delayed bleeding and delayed perforation), and recurrence rate. RESULTS: A total of 6 studies with 679 lesions (331 underwent UEMR and 348 CEMR) were included in this study. The pooled analysis showed that UMER achieves a similar en bloc resection rate (87.6 vs. 89.9%; odds ratio [OR], 1.29; 95% confidence interval [CI], 0.45 to 3.73; P =0.64; I2 =74%), a similar R0 resection rate (67.3 vs. 73.6%; OR, 1.11; 95% CI, 0.55 to 2.23; P =0.78; I2 =59%), a shorter procedure time (min) (mean difference [MD], -4.05, 95% CI: -6.40 to -1.71; P =0.0007; I2 =70%) compared with CEMR. There were no significant differences in the rates of delayed bleeding, delayed perforation, and recurrence (2.4 vs. 1.7%, 0 vs. 0.6%, 2.2 vs. 4.4%, respectively). CONCLUSION: This meta-analysis demonstrated that UEMR appears to be an effective and safe alternative to CEMR for SNADETs ≤20 mm.
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Neoplasias Duodenales , Resección Endoscópica de la Mucosa , Neoplasias Glandulares y Epiteliales , Neoplasias Pancreáticas , Humanos , Resección Endoscópica de la Mucosa/efectos adversos , Resección Endoscópica de la Mucosa/métodos , Mucosa Intestinal/cirugía , Mucosa Intestinal/patología , Resultado del Tratamiento , Duodeno/patología , Neoplasias Duodenales/cirugía , Neoplasias Duodenales/patología , Neoplasias Pancreáticas/patología , Neoplasias Glandulares y Epiteliales/etiología , Neoplasias Glandulares y Epiteliales/patología , Estudios RetrospectivosRESUMEN
The epidemiological characteristics of New Delhi Metallo-ß-Lactamase-Producing (NDM) Enterobacteriaceae were analyzed to provide theoretical support for clarifying the distribution characteristics of carbapenem-resistant Enterobacteriaceae (CRE) in the hospital environment and early identification of susceptible patients. From January 2017 to December 2021,42 strains of NDM-producing Enterobacteriaceae were gathered from the Fourth Hospital of Hebei Medical University, primarily Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. The micro broth dilution method combined with the Kirby-Bauer method was used to determine the minimal inhibitory concentrations (MICs) of antibiotics. The carbapenem phenotype was detected by the modified carbapenem inactivation method (mCIM) and EDTA carbapenem inactivation method (eCIM). Carbapenem genotypes were detected by colloidal gold immunochromatography and real-time fluorescence PCR. The results of antimicrobial susceptibility testing showed that all NDM-producing Enterobacteriaceae were multiple antibiotic resistant, but the sensitivity rate to amikacin was high. Invasive surgery prior to culture, the use of excessive amounts of different antibiotics, the use of glucocorticoids, and ICU hospitalization were clinical characteristics of NDM-producing Enterobacteriaceae infection. Molecular typing of NDM-producing Escherichia coli and Klebsiella pneumoniae was carried out by Multilocus Sequence Typing (MLST), and the phylogenetic trees were constructed. Eight sequence types (STs) and two NDM variants were detected in 11 strains of Klebsiella pneumoniae, primarily ST17, and NDM-1. A total of 8 STs and 4 NDM variants were detected in 16 strains of Escherichia coli, mainly ST410, ST167, and NDM-5. For high-risk patients who have CRE infection, CRE screening should be done as soon as feasible to adopt prompt and efficient intervention measures to prevent outbreaks in the hospital.
Asunto(s)
Enterobacteriaceae Resistentes a los Carbapenémicos , Infecciones por Enterobacteriaceae , Humanos , Enterobacteriaceae/genética , Tipificación de Secuencias Multilocus , Filogenia , Universidades , beta-Lactamasas/genética , Infecciones por Enterobacteriaceae/epidemiología , Escherichia coli , Antibacterianos/farmacología , Klebsiella pneumoniae/genética , Carbapenémicos/farmacología , Pruebas de Sensibilidad Microbiana , HospitalesRESUMEN
Extracellular vesicles (EVs) are a class of nanoparticles that mediate signaling molecules delivery between donor and recipient cells. Heterogeneity in the content of EVs and their membrane surface proteins determines their unique targetability. Their low immunogenicity, capability to cross various biological barriers, and superior biocompatibility enable engineering-modified EVs to be ideal drug delivery carriers. In addition, the engineered EVs that emerge in recent years have become a powerful tool for cancer treatment through the selective delivery of bioactive molecules to therapeutic targets, such as tumor cells and stroma. Our review focuses on the various types of EV modifications and their promoting therapeutic capabilities, which provide an innovative means for cancer precision therapy.
Asunto(s)
Vesículas Extracelulares , Nanopartículas , Neoplasias , Vesículas Extracelulares/metabolismo , Sistemas de Liberación de Medicamentos , Portadores de Fármacos/metabolismo , Transducción de Señal , Proteínas de la Membrana/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismoRESUMEN
Six new phloroglucinol derivatives, xanchryones I-N (1-6), were isolated from the leaves of Xanthostemon chrysanthus. Compounds 1-6 are unusual phloroglucinol-amino acid hybrids constructed through C2 -N and O-C1 ' bonds forming a peculiar oxazole ring. The structures and absolute configurations of compounds 1-6 were determined by MS, NMR, and single-crystal X-ray diffraction. Moreover, the anti-inflammatory and antibacterial activities of these compounds were evaluated.
Asunto(s)
Myrtaceae , Floroglucinol , Estructura Molecular , Floroglucinol/química , Aminoácidos/análisis , Myrtaceae/química , Antibacterianos/química , Hojas de la Planta/químicaRESUMEN
Plasmonic nanostructure biosensors based on metal are a powerful tool in the biosensing field. Surface plasmon resonance (SPR) can be classified into localized surface plasmon resonance (LSPR) and propagating surface plasmon polariton (PSPP), based on the transmission mode. Initially, the physical principles of LSPR and PSPP are elaborated. In what follows, the recent development of the biosensors related to SPR principle is summarized. For clarity, they are categorized into three groups according to the sensing principle: (i) inherent resonance-based biosensors, which are sensitive to the refractive index changes of the surroundings; (ii) plasmon nanoruler biosensors in which the distances of the nanostructure can be changed by biomolecules at the nanoscale; and (iii) surface-enhanced Raman scattering biosensors in which the nanostructure serves as an amplifier for Raman scattering signals. Moreover, the advanced application of single-molecule detection is discussed in terms of metal nanoparticle and nanopore structures. The review concludes by providing perspectives on the future development of plasmonic nanostructure biosensors.