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Heterochromatin is a key feature of eukaryotic genomes and is crucial for maintaining genomic stability. In fission yeast, heterochromatin nucleation is mainly mediated by DNA-binding proteins or the RNA interference (RNAi) pathway. In the filamentous fungus Neurospora crassa, however, the mechanism that causes the initiation of heterochromatin at the relics of repeat-induced point mutation is unknown and independent of the classical RNAi pathway. Here, we show that casein kinase II (CKII) and its kinase activity are required for heterochromatin formation at the well-defined 5-kb heterochromatin of the 5H-cat-3 region and transcriptional repression of its adjacent cat-3 gene. Similarly, mutation of the histone H3 phosphorylation site T11 also impairs heterochromatin formation at the same locus. The catalytic subunit CKA colocalizes with H3T11 phosphorylation (H3pT11) within the 5H-cat-3 domain and the deletion of cka results in a significant decrease in H3T11 phosphorylation. Furthermore, the loss of kinase activity of CKII results in a significant reduction of H3pT11, H3K9me3 (histone H3 lysine 9 trimethylation) and DNA methylation levels, suggesting that CKII regulates heterochromatin formation by promoting H3T11 phosphorylation. Together, our results establish that histone H3 phosphorylation by CKII is a critical event required for heterochromatin formation.
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The fabrication of solid-state proton-conducting electrolytes possessing both high performance and long-life reusability is significant but challenging. An "all-in-one" composite, H3PO4@PyTFB-1-SO3H, including imidazole, sulfonic acid, and phosphoric acid, which are essential for proton conduction, was successfully prepared by chemical post-modification and physical loading in the rationally pre-synthesized imidazole-based nanoporous covalent organic framework (COF), PyTFB-1. The resultant H3PO4@PyTFB-1-SO3H exhibits superhigh proton conductivity with its value even highly up to 1.15 × 10-1 S cm-1 at 353 K and 98% relative humidity (RH), making it one of the highest COF-based composites reported so far under the same conditions. Experimental studies and theoretical calculations further confirmed that the imidazole and sulfonic acid groups have strong interactions with the H3PO4 molecules and the synergistic effect of these three groups dramatically improves the proton conductivity properties of H3PO4@PyTFB-1-SO3H. This work demonstrated that by aggregating multiple proton carriers into one composite, effective proton-conducting electrolyte can be feasibly achieved.
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Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.
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Cavity optomechanical (COM) entanglement, playing an essential role in building quantum networks and enhancing quantum sensors, is usually weak and easily destroyed by noises. As feasible and effective ways to overcome this obstacle, optical or mechanical parametric modulations have been used to improve the quality of quantum squeezing or entanglement in various COM systems. However, the possibility of combining these powerful means to enhance COM entanglement has yet to be explored. Here, we fill this gap by studying a COM system containing an intra-cavity optical parametric amplifier (OPA), driven optically and mechanically. By tuning the relative strength and the frequency mismatch of optical and mechanical driving fields, we find that constructive interference can emerge and significantly improve the strength of COM entanglement and its robustness to thermal noises. This work sheds what we believe to be a new light on preparing and protecting quantum states with multi-field driven COM systems for diverse applications.
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Hypertensive renal disease (HRD) contributes to the progression of kidney dysfunction and ultimately leads to end-stage renal disease. Understanding the mechanisms underlying HRD is critical for the development of therapeutic strategies. Deubiquitinating enzymes (DUBs) have been recently highlighted in renal pathophysiology. In this study, we investigated the role of a DUB, OTU Domain-Containing Protein 1 (OTUD1), in HRD models. HRD was induced in wild-type or Otud1 knockout mice by chronic infusion of angiotensin II (Ang II, 1 µg/kg per min) through a micro-osmotic pump for 4 weeks. We found that OTUD1 expression levels were significantly elevated in the kidney tissues of Ang II-treated mice. Otud1 knockout significantly ameliorated Ang II-induced HRD, whereas OTUD1 overexpression exacerbated Ang II-induced kidney damage and fibrosis. Similar results were observed in TCMK-1 cells but not in SV40 MES-13 cells following Ang II (1 µM) treatment. In Ang II-challenged TCMK-1 cells, we demonstrated that OTUD1 bound to CDK9 and induced CDK9 deubiquitination: OTUD1 catalyzed K63 deubiquitination on CDK9 with its Cys320 playing a critical role, promoting CDK9 phosphorylation and activation to induce inflammatory responses and fibrosis in kidney epithelial cells. Administration of a CDK9 inhibitor NVP-2 significantly ameliorated Ang II-induced HRD in mice. This study demonstrates that OTUD1 mediates HRD by targeting CDK9 in kidney epithelial cells, suggesting OTUD1 is a potential target in treating this disease.
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Hipertensão Renal , Rim , Nefrite , Proteases Específicas de Ubiquitina , Animais , Camundongos , Angiotensina II/metabolismo , Células Epiteliais/metabolismo , Fibrose , Hipertensão Renal/enzimologia , Hipertensão Renal/patologia , Rim/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrite/enzimologia , Nefrite/patologia , Proteases Específicas de Ubiquitina/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND: Diabetic nephropathy (DN) and atherosclerosis (AS) are prevalent and severe complications associated with diabetes, exhibiting lesions in the basement membrane, an essential component found within the glomerulus, tubules, and arteries. These lesions contribute significantly to the progression of both diseases, however, the precise underlying mechanisms, as well as any potential shared pathogenic processes between them, remain elusive. METHODS: Our study analyzed transcriptomic profiles from DN and AS patients, sourced from the Gene Expression Omnibus database. A combination of integrated bioinformatics approaches and machine learning models were deployed to identify crucial genes connected to basement membrane lesions in both conditions. The role of integrin subunit alpha M (ITGAM) was further explored using immune infiltration analysis and genetic correlation studies. Single-cell sequencing analysis was employed to delineate the expression of ITGAM across different cell types within DN and AS tissues. RESULTS: Our analyses identified ITGAM as a key gene involved in basement membrane alterations and revealed its primary expression within macrophages in both DN and AS. ITGAM was significantly correlated with tissue immune infiltration within these diseases. Furthermore, the expression of genes encoding core components of the basement membrane was influenced by the expression level of ITGAM. CONCLUSION: Our findings suggest that macrophages may contribute to basement membrane lesions in DN and AS through the action of ITGAM. Moreover, therapeutic strategies that target ITGAM may offer potential avenues to mitigate basement membrane lesions in these two diabetes-related complications.
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Aterosclerose , Diabetes Mellitus , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/patologia , Membrana Basal/metabolismo , Glomérulos Renais/patologia , Aterosclerose/complicações , Macrófagos/metabolismo , Diabetes Mellitus/metabolismo , Antígeno CD11b/metabolismoRESUMO
Ambient fine particulate matter (PM2.5) is a threat to public health. The P2 X 7purinergic receptor (P2X7R) is a modulator that responds to inflammation. Yet the role of P2X7R in the mediation of PM2.5-induced pulmonary cytotoxicity is rarely investigated. In this study, the expression of P2X7R and its effect on cell viability, oxidative damage, apoptosis, mitochondrial dysfunction and underlying mechanism following PM2.5 treatment in rat alveolar macrophages (NR8383) were analyzed. The outcome indicated that PM2.5 exposure significantly increased the expression of P2X7R, while P2X7R antagonist oATP markedly alleviate the production of reactive oxygen species (ROS), Nitrite Oxidation (NO), mitochondrial membrane potential, apoptosis rate, and release of inflammatory cytokines. In contrast, P2X7 agonist BzATP showed opposite effect in PM2.5-treated NR8383 cells. Therefore, these results demonstrated that P2X7R participated in PM2.5-induced pulmonary toxicity, while the blockade of P2X7R is a promising therapeutic approach of treating PM2.5-induced lung diseases.
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Material Particulado , Receptores Purinérgicos P2X7 , Ratos , Animais , Receptores Purinérgicos P2X7/metabolismo , Material Particulado/toxicidade , Pulmão , Espécies Reativas de Oxigênio/metabolismo , Estresse OxidativoRESUMO
INTRODUCTION: Laparoendoscopic single-site inguinal lymphadenectomy (LESS-IL), a minimally invasive technique, has been reported in patients with vulvar or vaginal cancer regarding its safety and feasibility. However, the long-term outcomes, especially oncologic outcomes, are still lacking. We aimed to evaluate the long-term outcomes of LESS-IL to confirm its safety further. PATIENTS AND METHODS: Data were prospectively collected from patients with vulvar or vaginal cancer who underwent LESS-IL at our institution between July 2018 and June 2021. The patients were followed up for at least 12 months. All procedures were performed according to treatment standards. Short- and long-term complications and oncologic outcomes were analysed. RESULTS: A total of 16 patients undergoing 28 LESS-IL procedures were identified, amongst whom 4 underwent unilateral LESS-IL. The median numbers of excised groin lymph nodes were 9.0 (6.5-11.8) and 10.5 (8.3-12.0) in each left and right groin, respectively. Short-term complications occurred in 4 (25%) patients, including 18.7% lymphocele and 6.3% wound infection. Long-term complications regarding lower-limb lymphoedema appeared in 6 (37.5%) patients. Most short- and long-term complications were Clavien-Dindo 1 or 2, accounting for 90% of all post-operative issues. After a median follow-up of 27 (21.3-35.8) months, only 1 (6.3%) patient had isolated inguinal recurrence at 13 months postoperatively. No local or distant recurrence occurred. CONCLUSION: Our results suggest that LESS-IL is associated with little incidence of complications and promising oncologic outcomes, further demonstrating the safety and feasibility of the LESS-IL technique in patients requiring IL.
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BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions. MAIN BODY: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes. CONCLUSIONS: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target.
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Neuromielite Óptica , Animais , Humanos , Camundongos , Tirosina Quinase da Agamaglobulinemia/metabolismo , Aquaporina 4 , Linfócitos B/metabolismo , Microglia/metabolismo , Neuromielite Óptica/patologia , Receptores de Antígenos de Linfócitos B/metabolismoRESUMO
Converting CO2 into value-added chemicals to solve the issues caused by carbon emission is promising but challenging. Herein, by embedding metal ions (Co2+ , Ni2+ , Cu2+ , and Zn2+ ) into an imidazole-linked robust photosensitive covalent organic framework (PyPor-COF), effective photocatalysts for CO2 conversion are rationally designed and constructed. Characterizations display that all of the metallized PyPor-COFs (M-PyPor-COFs) display remarkably high enhancement in their photochemical properties. Photocatalysis reactions reveal that the Co-metallized PyPor-COF (Co-PyPor-COF) achieves a CO production rate as high as up to 9645 µmol g-1 h-1 with a selectivity of 96.7% under light irradiation, which is more than 45 times higher than that of the metal-free PyPor-COF, while Ni-metallized PyPor-COF (Ni-PyPor-COF) can further tandem catalyze the generated CO to CH4 with a production rate of 463.2 µmol g-1 h-1 . Experimental analyses and theory calculations reveal that their remarkable performance enhancement on CO2 photoreduction should be attributed to the incorporated metal sites in the COF skeleton, which promotes the adsorption and activation of CO2 and the desorption of generated CO and even reduces the reaction energy barrier for the formation of different intermediates. This work demonstrates that by metallizing photoactive COFs, effective photocatalysts for CO2 conversion can be achieved.
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Parkinson's disease (PD) is a progressive neurodegenerative disorder with a complex etiology. Neuroinflammation and oxidative stress are important factors driving the progression of PD. It has been reported that 1,3,4-oxadiazole and flavone derivatives have numerous biological functions, especially in the aspect of anti-inflammatory and antioxidant. Based on the strategy of pharmacodynamic combination, we introduced 1,3,4-oxadiazole moiety into the flavonoid backbone, designed and synthesized a series of novel flavonoid 1,3,4-oxadiazole derivatives. Further, we evaluated their toxicity, anti-inflammatory and antioxidant activities using BV2 microglia. Following a comprehensive analysis, compound F12 showed the best pharmacological activity. In vivo, we induced the classical PD animal model by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into C57/BL6J mice. Our results showed that compound F12 ameliorated MPTP-induced dysfunction in mice. Further, compound F12 reduced oxidative stress by promoting the nucleation of nuclear factor erythroid 2-related factor 2 (Nrf2) and decreased the inflammatory response by inhibiting the nuclear translocation of nuclear factor-κB (NF-κB) in vivo and in vitro. Meanwhile, compound F12 inhibited the mitochondrial apoptotic pathway to rescue microglia inflammation-mediated loss of dopaminergic neurons. In conclusion, compound F12 reduced oxidative stress and inflammation and could be as a potential agent for PD treatment.
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Fármacos Neuroprotetores , Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , NF-kappa B/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Antioxidantes/farmacologia , Flavonoides/farmacologia , Flavonoides/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais , Inflamação/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Modelos Animais de Doenças , Camundongos Endogâmicos C57BLRESUMO
Diabetes-related vascular complications include diabetic cardiovascular diseases (CVD), diabetic nephropathy (DN) and diabetic retinopathy, etc. DN can promote the process of end-stage renal disease. On the other hand, atherosclerosis accelerates kidney damage. It is really an urge to explore the mechanisms of diabetes-exacerbated atherosclerosis as well as new agents for treatment of diabetes-exacerbated atherosclerosis and the complications. In this study we investigated the therapeutic effects of fisetin, a natural flavonoid from fruits and vegetables, on kidney injury caused by streptozotocin (STZ)-induced diabetic atherosclerosis in low density lipoprotein receptor deficient (LDLR-/-) mice. Diabetes was induced in LDLR-/- mice by injecting STZ, and the mice were fed high-fat diet (HFD) containing fisetin for 12 weeks. We found that fisetin treatment effectively attenuated diabetes-exacerbated atherosclerosis. Furthermore, we showed that fisetin treatment significantly ameliorated atherosclerosis-enhanced diabetic kidney injury, evidenced by regulating uric acid, urea and creatinine levels in urine and serum, and ameliorating morphological damages and fibrosis in the kidney. In addition, we found that the improvement of glomerular function by fisetin was mediated by reducing the production of reactive oxygen species (ROS), advanced glycosylation end products (AGEs) and inflammatory cytokines. Furthermore, fisetin treatment reduced accumulation of extracellular matrix (ECM) in the kidney by inhibiting the expression of vascular endothelial growth factor A (VEGFA), fibronectin and collagens, while enhancing matrix metalloproteinases 2 (MMP2) and MMP9, which was mainly mediated by inactivating transforming growth factor ß (TGFß)/SMAD family member 2/3 (Smad2/3) pathways. In both in vivo and in vitro experiments, we demonstrated that the therapeutic effects of fisetin on kidney fibrosis resulted from inhibiting CD36 expression. In conclusion, our results suggest that fisetin is a promising natural agent for the treatment of renal injury caused by diabetes and atherosclerosis. We reveal that fisetin is an inhibitor of CD36 for reducing the progression of kidney fibrosis, and fisetin-regulated CD36 may be a therapeutic target for the treatment of renal fibrosis.
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Diabetes Mellitus Experimental , Nefropatias Diabéticas , Animais , Camundongos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Fibrose/tratamento farmacológico , Rim/patologia , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/metabolismo , Antígenos CD36/efeitos dos fármacosRESUMO
Bufei Jianpi granule (BJG) is clinically effective for treating chronic obstructive pulmonary disease (COPD). At present, there is no report regarding the drug metabolism of BJG in vivo. This work developed an ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry method with high accuracy and sensitivity to determine drug metabolism of this compound in vivo. After continuous administration of BJG, the concentrations of 10 components in rat plasma, namely betaine, peimine, peiminine, astragaloside A, sinensetin, nobiletin, naringin, calycosin, formononetin, and magnolol, were determined at different time points. Meanwhile, the pharmacokinetic parameters and metabolic rules of these 10 components were evaluated: Cmax , 8.624-574.645 ng/mL; Tmax , 0.250-8.667 h; AUC0-t , 17.640-8947.393 ng h/mL; T1/2 , 3.405-66.014 h; mean residence time (MRT), 6.893-11.223 h. All these components possessed anti-inflammatory, antioxidant, and other biological activities to varying degrees, contributing to improving lung function, mitigating pneumonia and pulmonary fibrosis, and preventing and treating chronic obstructive pulmonary disease. Exploring the pharmacokinetic parameters and the laws of chemical components in BJG forms the scientific basis for applying the compound clinically and identifying quality markers for the control of the compound.
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Medicamentos de Ervas Chinesas , Doença Pulmonar Obstrutiva Crônica , Ratos , Animais , Ratos Sprague-Dawley , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Espectrometria de Massas , TecnologiaRESUMO
The use of imaging technologies has been critical in deciphering biological phenomena, structures, and mechanisms across a wide range of spatial scales. The spatial resolution of traditional imaging modalities cannot meet the needs of high-precision research and diagnosis in biomedical fields. Plasmon resonance is the light-matter interaction that allows localizing far-field radiation in the near field with an intense electromagnetic field, enhancing the nanometric ablation, elastic/inelastic scattering of the adsorbate, and photoluminescence of the fluorophore nearby. Further, plasmon resonance scattering of nanoparticles can sensitively indicate the local environmental changes. This is accomplished by combining the spatially resolved capability with molecular spectrometry techniques such as Raman, infrared, fluorescence, etc., leading to a series of excellent imaging techniques to interrogate diverse biological processes from the tissue to subcellular level. In this tutorial review, we first provide the fundamental aspects of plasmonics. Then we give a systematic discussion of the working principle of these plasmon-based imaging techniques with an emphasis on the achievable spatial resolutions: surface-enhanced Raman spectroscopy (micrometre to nanometre), tip-enhanced ablation and ionization mass spectrometry (submicrometre), scattering-type scanning near-field optical microscopy (nanometre), tip-enhanced Raman spectroscopy (nanometre), tip-enhanced fluorescence spectroscopy (nanometre), and plasmon/molecular ruler microscopy (nanometre to angstrom). We also review the recent developments of the bioimaging applications of these techniques and expect that the plasmon-based techniques will not only pave a new way to decipher mysteries in life sciences but also hold great potential to be extended from fundamental research studies to real-life biomedical applications.
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Nanopartículas , Ressonância de Plasmônio de Superfície , Ressonância de Plasmônio de Superfície/métodos , Análise Espectral Raman/métodos , Microscopia/métodos , Nanopartículas/químicaRESUMO
Many studies have shown that returning fresh straw to the field can promote mercury accumulation in crops; therefore, it is necessary to find an appropriate way to use agricultural organic materials in mercury-contaminated farmlands. In this study, pot experiments were conducted to study the effects of composted agricultural organic materials on mercury bioaccumulation in the paddy field ecosystem by adding fresh rice straw (RS), composted rice straw (CRS), cow dung (CD) and composted cow dung (CCD) to the soils. Compared with RS and CD, the CRS and CCD amendments reduced dissolved organic matter (DOM) contents in soil, but increased the aromaticity and small molecule proportion of DOM, and also increased the tartaric acid contents in soil, as well as the methylation and release of mercury in soil. However, the increased available mercury and methylmercury in the soils in the CRS and CCD treatments were not effectively absorbed by rice plants. Overall, compared with fresh organic materials, composted organic materials amendments could reduce mercury accumulation in rice to a certain extent.
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Mercúrio , Compostos de Metilmercúrio , Oryza , Poluentes do Solo , Mercúrio/análise , Solo , Metilação , Ecossistema , Poluentes do Solo/análiseRESUMO
The secondary active transporter NBCe1 couples the transmembrane movement of Na+ and carbonate species with an apparent stoichiometry of 1Na+ :2HCO3- (the 'influx' mode) or 1Na+ :3HCO3- (the 'efflux' mode). Here, we employed molecular biology, electrophysiology and structural biology approaches to investigate the molecular mechanism for the transport coupling of Na+ and HCO3- in NBCe1. In Xenopus oocytes, decreasing extracellular [HCO3- ] from 66 to 4 mm progressively decreases the Na+ affinity of NBCe1. However, decreasing [Na+ ] from 96 to 35 mm has little effect on the HCO3- affinity. The residues responsible for the coordination of Na+ and HCO3- in the substrate pocket of NBCe1 were respectively determined by mutational and molecular simulation studies. Mutation to the residues for HCO3- coordination decreased the affinities of NBCe1 for both Na+ and HCO3- . However, mutation to the residues for Na+ coordination decreased the affinity for Na+ but had little effect on the affinity for HCO3- . Molecular simulation showed that NBCe1 has the capacity to coordinate only two ions of HCO3- or CO32- . We propose that (1) NBCe1 has an ordered substrate-binding kinetics with the binding of HCO3- preceding that of Na+ ; (2) NBCe1 operating in the influx mode moves 1Na+ + 2HCO3- , whereas NBCe1 in the efflux mode moves 1Na+ + 1HCO3- + 1CO32- . The substrate-binding kinetics of NBCe1 is distinct from the known kinetics models of many other Na+ -coupled transporters with Na+ binding preceding the driven solute. KEY POINTS: Under physiological conditions, the secondary active transporter NBCe1 can operate in the 'influx' mode with an apparent stoichiometry of 1Na+ :2HCO3- or in the 'efflux' mode with an apparent stoichiometry of 1Na+ :3HCO3- . NBCe1 has an ordered substrate-binding kinetics with HCO3- preceding the binding of Na+ . The kinetics of NBCe1 is distinct from the known kinetics of many other Na+ -driven cotransporters for which the binding of Na+ usually precedes the driven substrate. The residues responsible for the coordination of Na+ and those for carbonate species in the substrate-binding pocket of NBCe1 were determined by mutation and molecular simulation studies. The substrate-binding pocket of NBCe1 contains just two coordination sites for HCO3- or CO32- . It is proposed that NBCe1 in the influx mode moves 1Na+ + 2HCO3- across the plasma membrane, whereas NBCe1 in the efflux mode moves 1Na+ +1HCO3- +1CO32- .
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Simportadores de Sódio-Bicarbonato , Simportadores , Bicarbonatos/metabolismo , Íons/metabolismo , Cinética , Sódio/metabolismo , Simportadores de Sódio-Bicarbonato/metabolismo , Simportadores/metabolismoRESUMO
Surface-enhanced Raman spectroscopy (SERS) has been widely applied in many fields as a sensitive vibrational fingerprint technique. However, SERS faces challenges in quantitative analysis due to the heterogeneity of hot spots. An internal standard (IS) strategy has been employed for correcting the variation of hot spots. However, the method suffers from limitations due to the competitive adsorption between the IS and the target analyte. In this work, we combined the IS strategy with the 3D hybrid nanostructures to develop a bifunctional SERS substrate. The substrate had two functional units. The bottom self-assembly layer consisted of Au@IS@SiO2 nanoparticles, which provided a stable reference signal and functioned as the calibration unit. The top one consisted of appropriate-sized Au octahedrons for the detection of target analytes, which was the detection unit. Within the 3D hybrid nanostructure, the calibration unit improved the SERS performance of the detection unit, which was demonstrated by the 6-fold increase of SERS intensity when compared with the 2D substrate. Meanwhile, the reproducibility of the detection was greatly improved by correcting the hot spot changes through the calibration unit. Two biomedical molecules of cotinine and creatinine in ultrapure water and artificial urine, respectively, were sensitively determined by the 3D hybrid substrate. We expect that the developed bifunctional 3D substrate will open up new ways to advance the applications of SERS.
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Ouro , Nanopartículas Metálicas , Calibragem , Ouro/química , Nanopartículas Metálicas/química , Reprodutibilidade dos Testes , Dióxido de Silício , Análise Espectral Raman/métodosRESUMO
Genomic fusions of anaplastic lymphoma kinase (ALK) are a well-established therapeutic target in non-small-cell lung cancer (NSCLC). Although various ALK fusion variants have been identified in NSCLC, their responses to ALK tyrosine-kinase inhibitors (TKIs) are heterogeneous. We report the case of a 71-year-old female patient diagnosed with lung adenocarcinoma with liver metastases. A novel CTNND1 (exon 14)-ALK (exon 20) fusion was identified from the biopsy sample by next-generation sequencing (NGS) and validated by immunohistochemistry (IHC) staining. Alectinib was administered, and the patient soon achieved partial response (PR). The progression-free survival (PFS) exceeded 15 months as of January 25, 2022. Our findings expand the spectrum of ALK rearrangements and provide a potential treatment option for lung adenocarcinoma patients with CTNND1-ALK fusions.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Quinase do Linfoma Anaplásico/genética , Carbazóis , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/uso terapêutico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Quantum memories at telecom wavelengths are crucial for the construction of large-scale quantum networks based on existing fiber networks. On-demand storage of telecom photonic qubits is an essential request for such networking applications but yet to be demonstrated. Here we demonstrate the storage and on-demand retrieval of telecom photonic qubits using a laser-written waveguide fabricated in an ^{167}Er^{3+}:Y_{2}SiO_{5} crystal. Both ends of the waveguide memory are directly connected with fiber arrays with a fiber-to-fiber efficiency of 51%. Storage fidelity of 98.3(1)% can be obtained for time-bin qubits encoded with single-photon-level coherent pulses, which is far beyond the maximal fidelity that can be achieved with a classical measure and prepared strategy. This device features high reliability and easy scalability, and it can be directly integrated into fiber networks, which could play an essential role in fiber-based quantum networks.
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Photonic polarization qubits are widely used in quantum computation and quantum communication due to the robustness in transmission and the easy qubit manipulation. An integrated quantum memory for polarization qubits is a useful building block for large-scale integrated quantum networks. However, on-demand storing polarization qubits in an integrated quantum memory is a long-standing challenge due to the anisotropic absorption of solids and the polarization-dependent features of microstructures. Here we demonstrate a reliable on-demand quantum memory for polarization qubits, using a depressed-cladding waveguide fabricated in a ^{151}Eu^{3+}:Y_{2}SiO_{5} crystal. The site-2 ^{151}Eu^{3+} ions in Y_{2}SiO_{5} crystal provides a near-uniform absorption for arbitrary polarization states and a new pump sequence is developed to prepare a wideband and enhanced absorption profile. A fidelity of 99.4±0.6% is obtained for the qubit storage process with an input of 0.32 photons per pulse, together with a storage bandwidth of 10 MHz. This reliable integrated quantum memory for polarization qubits reveals the potential for use in the construction of integrated quantum networks.