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Cholesterol is dynamically transported among organelles, which is essential for multiple cellular functions. However, the mechanism underlying intracellular cholesterol transport has remained largely unknown. We established an amphotericin B-based assay enabling a genome-wide shRNA screen for delayed LDL-cholesterol transport and identified 341 hits with particular enrichment of peroxisome genes, suggesting a previously unappreciated pathway for cholesterol transport. We show dynamic membrane contacts between peroxisome and lysosome, which are mediated by lysosomal Synaptotagmin VII binding to the lipid PI(4,5)P2 on peroxisomal membrane. LDL-cholesterol enhances such contacts, and cholesterol is transported from lysosome to peroxisome. Disruption of critical peroxisome genes leads to cholesterol accumulation in lysosome. Together, these findings reveal an unexpected role of peroxisome in intracellular cholesterol transport. We further demonstrate massive cholesterol accumulation in human patient cells and mouse model of peroxisomal disorders, suggesting a contribution of abnormal cholesterol accumulation to these diseases.
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Colesterol/metabolismo , Lisossomos/metabolismo , Peroxissomos/metabolismo , RNA Interferente Pequeno/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adrenoleucodistrofia/metabolismo , Anfotericina B/farmacologia , Animais , Transporte Biológico , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Transtornos Peroxissômicos/metabolismo , Transtornos Peroxissômicos/patologia , Fosfatidilinositol 4,5-Difosfato/metabolismo , Sinaptotagminas/metabolismo , Peixe-ZebraRESUMO
Cholesterol is an essential lipid and its synthesis is nutritionally and energetically costly1,2. In mammals, cholesterol biosynthesis increases after feeding and is inhibited under fasting conditions3. However, the regulatory mechanisms of cholesterol biosynthesis at the fasting-feeding transition remain poorly understood. Here we show that the deubiquitylase ubiquitin-specific peptidase 20 (USP20) stabilizes HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the cholesterol biosynthetic pathway, in the feeding state. The post-prandial increase in insulin and glucose concentration stimulates mTORC1 to phosphorylate USP20 at S132 and S134; USP20 is recruited to the HMGCR complex and antagonizes its degradation. The feeding-induced stabilization of HMGCR is abolished in mice with liver-specific Usp20 deletion and in USP20(S132A/S134A) knock-in mice. Genetic deletion or pharmacological inhibition of USP20 markedly decreases diet-induced body weight gain, reduces lipid levels in the serum and liver, improves insulin sensitivity and increases energy expenditure. These metabolic changes are reversed by expression of the constitutively stable HMGCR(K248R). This study reveals an unexpected regulatory axis from mTORC1 to HMGCR via USP20 phosphorylation and suggests that inhibitors of USP20 could be used to lower cholesterol levels to treat metabolic diseases including hyperlipidaemia, liver steatosis, obesity and diabetes.
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Colesterol/biossíntese , Ingestão de Alimentos/fisiologia , Hidroximetilglutaril-CoA Redutases/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Ubiquitina Tiolesterase/metabolismo , Animais , Linhagem Celular , Glucose/metabolismo , Humanos , Insulina/metabolismo , Fígado/metabolismo , Masculino , Doenças Metabólicas/genética , Doenças Metabólicas/metabolismo , Metabolismo/genética , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Fosfosserina/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/deficiência , Ubiquitinação , Aumento de PesoRESUMO
Loss of terminal differentiation is a hallmark of cancer and offers a potential mechanism for differentiation therapy. Polycomb repressive complex 2 (PRC2) serves as the methyltransferase for K27 of histone H3 that is crucial in development. While PRC2 inhibitors show promise in treating various cancers, the underlying mechanisms remain incompletely understood. Here, we demonstrated that the inhibition or depletion of PRC2 enhanced adipocyte differentiation in malignant rhabdoid tumors and mesenchymal stem cells, through upregulation of peroxisome proliferator-activated receptor gamma (PPARG) and CEBPA. Mechanistically, PRC2 directly represses their transcription through H3K27 methylation, as both genes exhibit a bivalent state in mesenchymal stem cells. KO of PPARG compromised C/EBPα expression and impeded the PRC2 inhibitor-induced differentiation into adipocytes. Furthermore, the combination of the PPARγ agonist rosiglitazone and the PRC2 inhibitor MAK683 exhibited a higher inhibition on Ki67 positivity in tumor xenograft compared to MAK683 alone. High CEBPA, PLIN1, and FABP4 levels positively correlated with favorable prognosis in sarcoma patients in The Cancer Genome Atlas cohort. Together, these findings unveil an epigenetic regulatory mechanism for PPARG and highlight the essential role of PPARγ and C/EBPα in the adipocyte differentiation of malignant rhabdoid tumors and sarcomas with a potential clinical implication.
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Adipócitos , Proteína alfa Estimuladora de Ligação a CCAAT , Diferenciação Celular , PPAR gama , PPAR gama/metabolismo , PPAR gama/genética , Humanos , Adipócitos/metabolismo , Adipócitos/patologia , Adipócitos/citologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Camundongos , Complexo Repressor Polycomb 2/metabolismo , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/antagonistas & inibidores , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Linhagem Celular TumoralRESUMO
Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo-/- mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.
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Colesterol/metabolismo , Proteínas Hedgehog/metabolismo , Transdução de Sinais , Receptor Smoothened/metabolismo , Animais , Células CHO , Cílios/metabolismo , Cricetulus , Regulação da Expressão Gênica no Desenvolvimento , Predisposição Genética para Doença , Células HEK293 , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Proteínas Hedgehog/genética , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Células NIH 3T3 , Receptor Patched-1/genética , Receptor Patched-1/metabolismo , Fenótipo , Processamento de Proteína Pós-Traducional , Interferência de RNA , Receptor Smoothened/genética , TransfecçãoRESUMO
Conversely to canonical splicing, back-splicing connects the upstream 3' splice site (SS) with a downstream 5'SS and generates exonic circular RNAs (circRNAs) that are widely identified and have regulatory functions in eukaryotic gene expression. However, sex-specific back-splicing in Drosophila has not been investigated and its regulation remains unclear. Here, we performed multiple RNA analyses of a variety sex-specific Drosophila samples and identified over ten thousand circular RNAs, in which hundreds are sex-differentially and -specifically back-spliced. Intriguingly, we found that expression of SXL, an RNA-binding protein encoded by Sex-lethal (Sxl), the master Drosophila sex-determination gene that is only spliced into functional proteins in females, promoted back-splicing of many female-differential circRNAs in the male S2 cells, whereas expression of a SXL mutant (SXLRRM) did not promote those events. Using a monoclonal antibody, we further obtained the transcriptome-wide RNA-binding sites of SXL through PAR-CLIP. After splicing assay of mini-genes with mutations in the SXL-binding sites, we revealed that SXL-binding on flanking exons and introns of pre-mRNAs facilitates back-splicing, whereas SXL-binding on the circRNA exons inhibits back-splicing. This study provides strong evidence that SXL has a regulatory role in back-splicing to generate sex-specific and -differential circRNAs, as well as in the initiation of sex-determination cascade through canonical forward-splicing.
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Proteínas de Drosophila , RNA Circular , Proteínas de Ligação a RNA , Animais , Feminino , Masculino , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , RNA/genética , RNA/metabolismo , Splicing de RNA/genética , RNA Circular/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismoRESUMO
Polycomb repressive complex 2 (PRC2) suppresses gene transcription by methylating lysine 27 of histone H3 (H3K27) and plays critical roles in embryonic development. Among the core PRC2 subunits, EZH2 is the catalytic subunit and EED allosterically activates EZH2 upon binding trimethylated H3K27 (H3K27me3). Activating mutations on Y641, A677, and A687 within the enzymatic SET (Su(Var)3 to 9, Enhancer-of-zeste, and Trithorax) domain of EZH2 have been associated with enhanced H3K27me3 and tumorigenicity of many cancers including B-cell lymphoma and melanoma. To tackle the critical residues outside the EZH2 SET domain, we examined EZH2 mutations in lymphoma from cancer genome databases and identified a novel gain-of-function mutation W113C, which increases H3K27me3 in vitro and in vivo and promotes CDKN2A silencing to a similar level as EZH2 Y641F. Different from other gain-of-function mutations, this mutation is located in the SET-activation loop at the EZH2 N terminus, which stabilizes the SET domain and facilitates substrate binding. This may explain how the W113C mutation increases PRC2 activity. Tazemetostat is a Food and Drug Administration-approved EZH2-binding inhibitor for follicular lymphoma treatment. Intriguingly, the W113C mutation leads to tazemetostat resistance in both H3K27 methylation and tumor proliferation. Another class of allosteric PRC2 inhibitor binding EED overcomes the resistance, effectively decreases H3K27me3, and blocks tumor proliferation in cells expressing EZH2 W113C. As this mutation is originally identified from lymphoma samples, our results demonstrated its activating characteristic and the deleterious consequence, provide insights on PRC2 regulation, and support the continued exploration of treatment optimization for lymphoma patients.
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Resistencia a Medicamentos Antineoplásicos , Mutação com Ganho de Função , Linfoma de Células B , Humanos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Histonas/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Mutação , Complexo Repressor Polycomb 2/genéticaRESUMO
Optimal cardiac dose constraints in breast cancer (BC) patients undergoing postoperative intensity-modulated radiation therapy (IMRT) are unclear, although as low as possible is recommended. This trial proposes serial cardiac dose constraint to optimize cardiac safety. Postoperative BC patients eligible for anthracycline/taxanes-based chemotherapy or HER2-targeted therapy were randomized to cardiac safety arm with prespecified mean heart dose (MHD) (≤6 Gy), V30 (≤20%), and V10 (≤50%) constraints, or to a control arm with in-house protocol (mainly MHD ≤8 Gy). The primary endpoint was cumulative incidence of newly onset cardiac events within 1-year post-RT. An exploratory analysis examined the relationship between whole heart dose metrics and those of substructures. Of 199 participants, 93 were in the cardiac safety and 106 in the control arm. The cardiac safety group showed lower MHD, V10, and V30. The 1-year cardiac event incidence was slightly lower in the cardiac safety group (19.4%) compared to controls (24.9%). The LVEF and diastolic dysfunction rates were 0% and 5.4% in the study arm, and 1.9% and 8.8% in the control arm, respectively. The LAD, LV, and RV received the highest doses for left-sided patients. For right-sided patients, RA, RCA, and RV were most irradiated. The MHD, V10, and Dmax of heart significantly correlated with all substructure doses in either laterality. Our study supports the early cardiac safety profile using IMRT in BC patients receiving cardiac-toxic systemic therapy, with serial cardiac dose constraints. Combined constraints on MHD and dose-volume parameters are representative of the cardiac substructure dose.
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PURPOSE: This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma. METHODS AND MATERIALS: Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m2, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS). RESULTS: All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%. CONCLUSIONS: Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.
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Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas , Quimiorradioterapia , Neoplasias do Colo do Útero , Humanos , Feminino , Neoplasias do Colo do Útero/terapia , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Pessoa de Meia-Idade , Quimiorradioterapia/métodos , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Idoso , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: DNA methylation is an important epigenetic modification that plays a crucial role in the development and progression of various tumors. However, the association between methylationdriven genes and diagnosis, prognosis, and immune characteristics of head and neck squamous cell carcinoma (HNSCC) remains unclear. METHODS: We obtained transcriptome, methylation, and clinical data from HNSCC patients in TCGA database, and used MethylMix algorithm to identify methylation-driven genes. A methylation driven gene-related risk model was constructed using Lasso regression analysis, and validated using data from GEO database. Immune infiltration and immune function analysis of the expression profiles were conducted using ssGSEA. Differences in immune checkpoint-related genes were analyzed, and the efficacy of immunotherapy was evaluated using TCIA database. Finally, a series of cell functional experiments were conducted to validate the results. RESULTS: Five methylation-driven genes were identified and utilized to construct a prognostic risk model. Based on the median risk score, all patients were categorized into high-risk and low-risk groups. The K-M analysis revealed that patients in the high-risk group have a worse prognosis. Additionally, the risk model demonstrated better prognostic predictive value as indicated by ROC analysis. GSEA enrichment analysis indicated that gene sets in the high and low-risk groups were primarily enriched in pathways associated with tumor immunity and metabolism. Our subsequent investigations showed that high-risk patients exhibited more immunosuppressive phenotypes, while low-risk patients were more likely to respond positively to immunotherapy. CONCLUSION: These findings of our research have the potential to improve patient stratification, guide treatment decisions, and advance the development of personalized therapies for HNSCC.
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Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Transcriptoma , Humanos , Metilação de DNA/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Prognóstico , Transcriptoma/genética , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/diagnóstico , Biomarcadores Tumorais/genética , Masculino , Feminino , Imunoterapia , Perfilação da Expressão Gênica , Epigênese Genética , Bases de Dados GenéticasRESUMO
Background Preoperative recognition of irreversible bowel necrosis is important, as it provides valuable guidance for surgical strategy selection but also may inform perioperative risk assessment and communication. Few studies have focused on the association between CT signs and bowel necrosis. Purpose To assess the diagnostic accuracy of CT signs to predict bowel necrosis in patients with closed-loop small bowel obstruction (CL-SBO). Materials and Methods This retrospective single-center study included patients who were surgically confirmed to have CL-SBO caused by adhesion or internal hernia between January 2016 and May 2022. Necrosis was determined based on surgical exploration and postoperative pathologic examination. Two radiologists independently reviewed CT signs by both subjective visual assessment and objective measurement. Disagreements were resolved in consensus with a third gastrointestinal radiologist. Univariable and multivariable analyses were used to assess the association between CT signs and bowel necrosis, and Cohen κ was used to assess interobserver agreement. Sensitivity and specificity were calculated for each CT sign. Results This study included 145 patients: 61 (42.1%) in the necrotic group (median age, 62 years [IQR, 51-71.5 years]; 37 [60.7%] women) and 84 (57.9%) in the nonnecrotic group (median age, 61.5 years [IQR, 51-68.8 years]; 51 [60.7%] women). Univariable analysis and multivariable analysis showed that increased attenuation of intestinal contents and increased attenuation of intestinal wall were independent predictors for bowel necrosis (odds ratio = 45.3 and 15.1; P = .001 and P < .001, respectively). Increased attenuation of intestinal contents and increased attenuation of intestinal wall had similar sensitivity (64% and 67%, respectively) and specificity (99% and 92%, respectively) for predicting bowel necrosis. However, interobserver agreement was better for assessing the contents than the wall (κ = 0.84 and 0.59, respectively). Conclusion Increased attenuation of intestinal contents was a highly specific CT sign with good reproducibility to predict bowel necrosis in CL-SBO. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Taourel and Zins in this issue.
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Conteúdo Gastrointestinal , Obstrução Intestinal , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Reprodutibilidade dos Testes , Estudos Retrospectivos , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , Necrose/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Borocarbonitride (BCN) catalysts, boasting multiple redox sites, have shown considerable potential in alkane oxidative dehydrogenation (ODH) to olefin molecules. However, their catalytic efficiency still lags behind that of leading commercial catalysts, primarily due to the limited reactivity of oxygen functional groups. In this study, a groundbreaking hybrid catalyst is developed, featuring BCN nanotubes (BCNNTs) encapsulated with manganese (Mn) clusters, crafted through a meticulous supramolecular self-assembly and postcalcination strategy. This novel catalyst demonstrates a remarkable enhancement in activity, achieving 30% conversion and ≈100% selectivity toward styrene in ethylbenzene ODH reactions. Notably, its performance surpasses both pure BCNNTs and those hosting Mn nanoparticles. Structural and kinetic analyses unveil a robust interaction between BCNNTs and the Mn component, substantially boosting the catalytic activity of BCNNTs. Furthermore, density functional theory (DFT) calculations elucidate that BCNNTs encapsulated with Mn clusters not only stabilize key intermediates (âBâOâOâBâ) but also enhance the nucleophilicity of active sites through electron transfer from the Mn cluster to the BCNNTs. This electron transfer mechanism effectively lowers the energy barrier for âCâH cleavage, resulting in a 13% improvement in catalytic activity compared to pure BCNNTs.
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Fibrillated cellulose-based nanocomposites can improve energy efficiency of building envelopes, especially windows, but efficiently engineering them with a flexible ability of lighting and thermal management remains highly challenging. Herein, a scalable interfacial engineering strategy is developed to fabricate haze-tunable thermal barrier films tailored with phosphorylated cellulose nanofibrils (PCNFs). Clear films with an extremely low haze of 1.6% (glass-scale) are obtained by heat-assisted surface void packing without hydrophobization of nanocellulose. PCNF gel cakes serve here as templates for surface roughening, thereby resulting in a high haze (73.8%), and the roughened films can block heat transfer by increasing solar reflection in addition to a reduced thermal conduction. Additionally, obtained films can tune distribution of light from visible to near-infrared spectral range, enabling uniform colored lighting and inhibiting localized heating. Furthermore, an integrated simulation of lighting and cooling energy consumption in the case of office buildings shows that the film can reduce the total energy use by 19.2-38.1% under reduced lighting levels. Such a scalable and versatile engineering strategy provides an opportunity to endow nanocellulose-reinforced materials with tunable optical and thermal functionalities, moving their practical applications in green buildings forward.
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Developing a facile strategy for constructing oriented mixed matrix membranes (MMMs) with uniformly dispersed and high-loading metal-organic frameworks (MOFs) is a crucial scientific challenge in probing the enhanced capability and potential applications of MOF-polymer MMMs. Herein, a novel synchronous synthetic method for constructing oriented CuBDC/poly(m-phenylenediamine) (CuBDC/PmPD) MMM with uniform MOF dispersion at high loading at the air-solution interface via the dual function of metal ions is reported. The resulting MMM exhibits excellent separation performance in ion sieving and seawater desalination due to the structural integrity of the proposed membrane and the highly interconnected channels created through the oriented distribution of MOF in a polymer matrix. Such a cutting-edge approach may provide promising insights into the development of advanced MMMs with optimized structure and superior performances.
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Amino acids are not only the building blocks of proteins but also lead to the development of novel nanomaterials with unique properties. Herein, we proposed a simple strategy to produce gold nanoparticles (Au NPs) with peroxidase-like (POD-like) activities by using a series of amino acids as reducing agents, named Au NPs@M (M represents different amino acids). The Au NPs@His was identified as the nanozyme with the most potent catalytic performance, which was used in combination with smartphones to achieve rapid detection of hydrogen peroxide with a detection limit of 0.966â µM. It also enables rapid detection of glucose with a detection limit of 2.904â µM, highlighting the significant contribution of Au NPs@His in expediting the detection of critical biomolecules. This work not only provides a convenient and highly efficient method to identify glucose but also shows the potential of histidine as a reducing agent in constructing Au nanomaterials exerting enzyme-like catalysis.
Assuntos
Aminoácidos , Glucose , Ouro , Peróxido de Hidrogênio , Nanopartículas Metálicas , Smartphone , Ouro/química , Nanopartículas Metálicas/química , Peróxido de Hidrogênio/análise , Peróxido de Hidrogênio/química , Aminoácidos/química , Aminoácidos/análise , Glucose/análise , Técnicas Biossensoriais , Catálise , Limite de Detecção , Histidina/análise , Histidina/químicaRESUMO
Modulating the assembly pathway is an indispensable strategy for optimizing the performance of optical materials. However, implementing this strategy is nontrivial for metal nanocluster building blocks, due to the limited functional modification of nanoclusters and complexity of their emission mechanism. In this report, we demonstrate that a gold nanocluster modified by 4,6-diamino-2-pyrimidinethiol (DPT-AuNCs) self-assembles into two distinct aggregation structures in methanol (MeOH)/water mixed solvent, thus exhibiting pathway complexity. Kinetic studies show that DPT-AuNCs firstly assembles into non-luminescent nanofibers (kinetically controlled), which further transforms into strongly luminescent microflowers (thermodynamically controlled). In-depth analysis of the assembly mechanism reveals that the transformation of aggregation structures involves the disassembly of nanofibers and a subsequent nucleation-growth process. Temperature-dependent photoluminescence (PL) spectroscopy and infrared (IR) measurements reveal that inter-cluster hydrogen bonding bridged by solvent molecules and C-Hâ â â π interaction are the key factors for emission enhancement. The photoluminescent property of DPT-AuNCs can be controlled by varying the cosolvent in water, enabling DPT-AuNCs to distinguish different kind of alcohols, particularly the isomerism n-propanol (NPA) and isopropanol (IPA). Additionally, the addition of seeds effectively regulate the assembly kinetics of DPT-AuNCs. This study advances our understanding of assembly pathways and improves the luminescent performance of nanoclusters (NCs).
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Band gap engineering based on doped two-dimensional (2D) transition metal dichalcogenides (TMDs) has shown great potential in the design and development of new nano photoelectronic devices and their application in photoelectrocatalysis. However, there are two key issues that are difficult to take into account, namely the impurity levels induced by dopant atoms appear in the forbidden band of the doping system, which can become the recombination center of photogenerated carriers, thereby reducing the photocatalytic efficiency. Compared with the carrier mobility of the corresponding doped systems, that of intrinsic 2D TMDs is too low. Understanding the doping mechanism of heteroatoms in these systems and designing corresponding crystal structures rationally is important for solving these problems. In this study, the crystal structures of co-doped monolayer WS2 with Nb and Re atoms were designed using density functional theory, and doping systems with graphene (high carrier mobility) were assembled into a heterostructure using the concept of heterorecombination. The N-P type co-doping of Nb and Re atoms retained the continuous band characteristics of the original monolayer WS2 while also providing the high carrier mobility of graphene, yielding an excellent multipurpose material for manufacturing high-speed Schottky devices and efficient water-splitting H evolution catalysts.
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BACKGROUND: To compare the difference of postoperative anastomotic leakage (AL) rate between neoadjuvant chemoradiotherapy (NCRT) with pembrolizumab and NCRT group, and investigate the risk factors of developing AL for locally advanced esophageal squamous cell cancer (ESCC). MATERIALS AND METHODS: The GF was contoured on the pretreatment planning computed tomography and dosimetric parameters were retrospectively calculated. Univariate and multivariate logistic regression analysis was performed to determine the independent risk predictors for the entire cohort. A nomogram risk prediction model for postoperative AL was established. RESULTS: A total of 160 ESCC patients were included for analysis. Of them, 112 were treated with NCRT with pembrolizumab and 44 patients with NCRT. Seventeen (10.6%) patients experienced postoperative AL with a rate of 10.7% (12/112) in NCRT with pembrolizumab and 11.4% (5/44) in NCRT group. For the entire cohort, mean, D50, Dmax, V5, V10 and V20 GF dose were statistically higher in those with AL (all p < 0.05). Multivariate logistic regression analysis indicated that tumor length (p = 0.012), volume of GF (p = 0.003) and mean dose of GF (p = 0.007) were independently predictors for postoperative AL. Using receiver operating characteristics analysis, the mean dose limit on the GF was defined as 14 Gy. CONCLUSION: Based on our prospective database, no significant difference of developing AL were observed between NCRT with pembrolizumab and NCRT group. We established an individualized nomograms based on mean GF dose combined with clinical indicators to predict AL in the early postoperative period.
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Fístula Anastomótica , Anticorpos Monoclonais Humanizados , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Terapia Neoadjuvante , Humanos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Fístula Anastomótica/etiologia , Fístula Anastomótica/epidemiologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Estudos Prospectivos , Idoso , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Nomogramas , Fatores de Risco , Estudos Retrospectivos , Adulto , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologiaRESUMO
Invasive Aspergillosis is a high-risk illness with a high death rate in immunocompromised people due to a lack of early detection and timely treatment. Based on immunology study, we achieved an efficient production of anti-galactomannan antibody by Chinese hamster ovary (CHO) cells and applied it to time-resolved fluoroimmunoassay for Aspergillus galactomannan detection. We first introduced dual promoter expression vector into CHO host cells, and then applied a two-step screening strategy to screen the stable cell line by methionine sulfoximine pressurization. After amplification and fermentation, antibody yield reached 4500 mg/L. Then we conjugated the antibodies with fluorescent microspheres to establish a double antibody sandwich time-resolved fluoroimmunoassay, which was compared with the commercial Platelia™ Aspergillus Ag by clinical serum samples. The preformed assay could obtain the results in less than 25 min, with a limit of detection for galactomannan of approximately 1 ng/mL. Clinical results of the two methods showed that the overall percent agreement was 97.7% (95% CI: 96.6%-98.4%) and Cohen's kappa coefficient was 0.94. Overall, the assay is highly consistent with commercial detection, providing a more sensitive and effective method for the rapid diagnosis of invasive aspergillosis.
Assuntos
Aspergilose , Aspergillus , Galactose/análogos & derivados , Animais , Cricetinae , Humanos , Células CHO , Cricetulus , Aspergilose/diagnóstico , Mananas , Fluorimunoensaio , Anticorpos MonoclonaisRESUMO
A series of analogous chain selenite chlorides Ba2M(SeO3)2Cl2 (M = Cu 1, Ni 2, Co 3, Mn 4) and Pb2Cu(SeO3)2Cl2 5 with tunable spin S from S = 1/2 to S = 5/2 have been hydrothermally synthesized and characterized. These analogues crystallized in the orthorhombic Pnnm space group (monoclinic P21/n space group for 5) all containing M2+-SeO3-M2+ spin chains, which are further separated by the Ba2+ ions (Pb2+ for 5). The magnetic susceptibility results of 1, 2, and 5 show broad maxima around 80.0, 18.9, and 78.0 K, respectively, indicating good one-dimensional (1D) magnetism. Meanwhile, no long-range order (LRO) is observed down to 2 K for both 1 and 5, while the isostructural compounds 2, 3, and 4 exhibit LRO at 3.4 K, 10.8 K, and 5.7 K, respectively, which are further confirmed by the heat capacity and electron spin resonance results, as well as the observed spin-flop transitions in the M-H curves measured at 2 K below TN. The magnetizations of 1-5 at 7 T are still far from saturation. In addition, thermal stability and FT-IR and UV-vis-NIR spectroscopy of 1-5 are reported.