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As a sustainable approach for N2 fixation, electrocatalytic N2 reduction reaction (N2RR) to produce ammonia (NH3) is highly desirable with a precise understanding to the structure-activity relationship of electrocatalysts. Here, firstly, we obtain a novel carbon-supported oxygen-coordinated single-Fe-atom catalyst for highly efficient production of ammonia from electrocatalytic N2RR. Based on such new type of N2RR electrocatalyst, by combining operando X-ray absorption spectra (XAS) with density function theory calculation, we reveal significantly that the as-prepared active coordination structure undergoes a potential-driven two-step restructuring, firstly from FeSAO4(OH)1a to FeSAO4(OH)1a'(OH)1b with the adsorption of another -OH on FeSA at open-circuit potential (OCP) of 0.58 VRHE, and subsequently restructuring from FeSAO4(OH)1a'(OH)1b to FeSAO3(OH)1aâ³ due to the breaking of one Fe-O bond and the dissociation of one -OH at working potentials for final electrocatalytic process of N2RR, thus revealing the first potential-induced in situ formation of the real electrocatalytic active sites to boost the conversion of N2 to NH3. Moreover, the key intermediate of Fe-NNHx was detected experimentally by both operando XAS and in situ attenuated total reflection-surface-enhanced infrared absorption spectra (ATR-SEIRAS), indicating the alternating mechanism followed by N2RR on such catalyst. The results indicate the necessity of considering the potential-induced restructuring of the active sites on all kinds of electrocatalysts for such as highly efficient ammonia production from N2RR. It also paves a new way for a precise understanding to the structure-activity relationship of a catalyst and helps the design of highly efficient catalysts.
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In recent years, halide perovskites have attracted considerable attention for photocatalytic CO2 reduction. However, the presence of surface defects and the lack of specific catalytic sites for CO2 reduction lead to low photocatalytic performance. In this study, we demonstrate a facile method that post-treats CsPbBr3 with ZnBr2 for photocatalytic CO2 reduction. Our experimental and characterization results show that ZnBr2 has a dual role: the Br- ions in ZnBr2 passivate Br vacancies (VBr) on the CsPbBr3 surface, while Zn2+ cations act as catalytic sites for CO2 reduction. The ZnBr2-CsPbBr3 achieves a photocatalytic CO evolution rate of 57 µmol g-1 h-1, which is nearly three times higher than that of the pristine CsPbBr3. The enhanced performance over ZnBr2-CsPbBr3 is mainly due to the decreased VBr and lower reaction energy barrier for CO2 reduction. This work presents an effective method to simultaneously passivate surface defects and introduce catalytic sites, providing useful guidance for the regulation of perovskite photoelectric properties and the design of efficient photocatalysts.
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BACKGROUND: Prophylactic dose of rivaroxaban is often used in treatment of isolated calf muscle vein thrombosis (ICMVT); nevertheless, its effect is less reported. This study aims to evaluate short-term outcomes in patients with ICMVT who received prophylactic dose of rivaroxaban or warfarin therapy. METHODS: A retrospective analysis of 472 ICMVT patients who received 2 different treatment regimens was undertaken. Propensity score matching method was used to balance the confounding effect of baseline clinical data. Chi-squared test and logistic regression analysis were used to compare outcomes (venous thromboembolism events, bleeding events, complete clot resolution) according to the type of treatment regimens before and after propensity score matching. Univariate and multivariable analysis were used to investigate risk factors for incomplete clot resolution of ICMVT after propensity score matching. RESULTS: 242 ICMVT patients received prophylactic dose of rivaroxaban (rivaroxaban group, RG), and 230 received warfarin (warfarin group, WG). After propensity score matching, 156 patients were included in each group; Venous thromboembolism (VTE) events occurred in 14 (9.0%) patients in the RG and 10 (6.4%) in the WG (P = 0.395); no major bleeding events occurred in each group, and clinically relevant nonmajor bleeding events occurred in 5 (3.2%) patients in the RG and 10 (6.4%) in the WG (P = 0.186); complete clot resolution at 3 months occurred in 80 (51.3%) patients in the RG and 100 (64.1%) in the WG (P = 0.022). Logistic regression analysis showed that there were no significant differences between RG and WG in VTE events (odds ratio 1.439, 95% confidence interval 0.619-3.347, P = 0.397) and clinically relevant nonmajor bleeding events (odds ratio 0.483, 95% confidence interval 0.161-1.449, P = 0.194); it revealed that complete clot resolution rate at 3 months was different in the 2 groups (odds ratio 0.589, 95% confidence interval 0.375-0.928, P = 0.022). Treatment regimens (prophylactic dose of rivaroxaban), thrombosis (maximum diameter >7 mm), and risk factors for VTE (nonsurgery risk factors, mainly referring to active malignancy) were risk factors for incomplete clot resolution of ICMVT (P < 0.05). CONCLUSIONS: In this retrospective study with a short-term follow-up, ICMVT patients who received prophylactic dose of rivaroxaban had no significant differences in VTE and bleeding events compared to those who received warfarin therapy (the overall INR >2.0 for >50% of the time); but it was not conducive to complete clot resolution.
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Selective producing ethanol from CO2 electroreduction is highly demanded, yet the competing ethylene generation route is commonly more thermodynamically preferred. Herein, we reported an efficient CO2-to-ethanol conversion (53.5 % faradaic efficiency at -0.75â V versus reversible hydrogen electrode (vs. RHE)) over an oxide-derived nanocubic catalyst featured with abundant "embossment-like" structured grain-boundaries. The catalyst also attains a 23.2 % energy efficiency to ethanol within a flow cell reactor. In situ spectroscopy and electrochemical analysis identified that these dualphase Cu(I) and Cu(0) sites stabilized by grain-boundaries are very robust over the operating potential window, which maintains a high concentration of co-adsorbed *CO and hydroxyl (*OH) species. Theoretical calculations revealed that the presence of *OHad not only promote the easier dimerization of *CO to form *OCCO (ΔG~0.20â eV) at low overpotentials but also preferentially favor the key *CHCOH intermediate hydrogenation to *CHCHOH (ethanol pathway) while suppressing its dehydration to *CCH (ethylene pathway), which is believed to determine the remarkable ethanol selectivity. Such imperative intermediates associated with the bifurcation pathway were directly distinguished by isotope labelling in situ infrared spectroscopy. Our work promotes the understanding of bifurcating mechanism of CO2ER-to-hydrocarbons more deeply, providing a feasible strategy for the design of efficient ethanol-targeted catalysts.
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BACKGROUND: Immune checkpoint blockade (ICB) therapy can be effective against clear cell renal cell carcinoma (ccRCC), but many patients show no benefit. Tumor-derived pericytes (TDPs) may promote tumor progression by influencing T cells and are an immunotherapy target; however, they may comprise functionally distinct subtypes. We aimed to identify markers of tumor-promoting TDPs and develop TDP-targeting strategies to enhance ICB therapy effectiveness against ccRCC. METHODS: We analyzed the relationship between endosialin (EN) expression and cytotoxic T-lymphocyte (CTL) infiltration in ccRCC tumor samples using flow cytometry and in a ccRCC-bearing mice inhibited for EN via knockout or antibody-mediated blockade. The function of ENhigh TDPs in CTL infiltration and tumor progression was analyzed using RNA-sequencing (RNA-seq) data from ccRCC tissue-derived TDPs and single-cell RNA-seq (scRNA-seq) data from an online database. The role of EN in TDP proliferation and migration and in CTL infiltration was examined in vitro. Finally, we examined the anti-tumor effect of combined anti-EN and anti-programmed death 1 (PD-1) antibodies in ccRCC-bearing mice. RESULTS: High EN expression was associated with low CTL infiltration in ccRCC tissues, and inhibition of EN significantly increased CTL infiltration in ccRCC-bearing mice. RNA-seq and scRNA-seq analyses indicated that high EN expression represented the TDP activation state. EN promoted TDP proliferation and migration and impeded CTL infiltration in vitro. Finally, combined treatment with anti-EN and anti-PD-1 antibodies synergistically enhanced anti-tumor efficacy. CONCLUSION: ENhigh TDPs are in an activated state and inhibit CTL infiltration into ccRCC tissues. Combined treatment with anti-EN and anti-PD-1 antibodies may improve ICB therapy effectiveness against ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Animales , Ratones , Linfocitos T CD8-positivos , Proteínas de Unión al ADN/metabolismo , Pericitos/metabolismo , Pericitos/patología , Microambiente TumoralRESUMEN
Electrochemical CO2 reduction reaction (CO2 RR) provides a promising approach for sustainable chemical fuel production of carbon neutrality. Neutral and alkaline electrolytes are predominantly employed in the current electrolysis system, but with striking drawbacks of (bi)carbonate (CO3 2- /HCO3 - ) formation and crossover due to the rapid and thermodynamically favourable reaction between hydroxide (OH- ) with CO2 , resulting in low carbon utilization efficiency and short-lived catalysis. Very recently, CO2 RR in acidic media can effectively address the (bi)carbonate issue; however, the competing hydrogen evolution reaction (HER) is more kinetically favourable in acidic electrolytes, which dramatically reduces CO2 conversion efficiency. Thus, it is a big challenge to effectively suppress HER and accelerate acidic CO2 RR. In this review, we begin by summarizing the recent progress of acidic CO2 electrolysis, discussing the key factors limiting the application of acidic electrolytes. We then systematically discuss addressing strategies for acidic CO2 electrolysis, including electrolyte microenvironment modulation, alkali cations adjusting, surface/interface functionalization, nanoconfinement structural design, and novel electrolyzer exploitation. Finally, the new challenges and perspectives of acidic CO2 electrolysis are suggested. We believe this timely review can arouse researchers' attention to CO2 crossover, inspire new insights to solve the "alkalinity problem" and enable CO2 RR as a more sustainable technology.
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BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor with a high incidence in children and adolescents. Frequent tumor metastasis and high postoperative recurrence are the most common challenges in OS. However, detailed mechanism is largely unknown. METHODS: We examined the expression of CD248 in OS tissue microarrays by immunohistochemistry (IHC) staining. We studied the biological function of CD248 in cell proliferation, invasion and migration of OS cells by CCK8 assay, transwell and wound healing assay. We also studied its function in the metastasis of OS in vivo. At last, we explored the potential mechanism how CD248 promotes OS metastasis by using RNA-seq, western blot, immunofluorescence staining and co-immunoprecipitation using CD248 knockdown OS cells. RESULTS: CD248 was highly expressed in OS tissues and its high expression was correlated with pulmonary metastasis of OS. Knockdown of CD248 in OS cells significantly inhibited cell migration, invasion and metastasis, while had no obvious effect on cell proliferation. Lung metastasis in nude mice was significantly inhibited when CD248 was knocked down. Mechanistically, we found that CD248 could promote the interaction between ITGB1 and extracellular matrix (ECM) proteins like CYR61 and FN, which activated the FAK-paxillin pathway to promote the formation of focal adhesion and metastasis of OS. CONCLUSION: Our data showed that high CD248 expression is correlated with the metastatic potential of OS. CD248 may promote migration and metastasis through enhancing the interaction between ITGB1 and certain ECM proteins. Therefore, CD248 is a potential marker for diagnosis and effective target for the treatment of metastatic OS.
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Neoplasias Óseas , Neoplasias Pulmonares , Osteosarcoma , Animales , Ratones , Antígenos CD , Antígenos de Neoplasias , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Ratones Desnudos , Osteosarcoma/genética , Osteosarcoma/patología , Paxillin/genética , Paxillin/metabolismo , Integrina beta1/metabolismoRESUMEN
Myofibroblasts, or activated fibroblasts, play a critical role in the process of renal fibrosis. Targeting myofibroblasts to inhibit their activation or induce specific cell death has been considered to be an effective strategy to attenuate renal fibrosis. However, specific biomarkers for myofibroblasts are needed to ensure the efficacy of these strategies. Here, we verified that CD248 was mainly expressed in myofibroblasts in patients with chronic kidney disease, which was inversely correlated with renal function. The same result was also confirmed in renal fibrotic mice induced by unilateral ureteral obstruction and aristolochic acid nephropathy. By using an antibody-drug conjugate (ADC) named IgG78-DM1, in which maytansinoid (DM1) was linked to a fully human antibody IgG78 through an uncleavable SMCC linker, we demonstrated that it could effectively bind with and kill CD248+ fibroblasts in vitro and alleviate renal fibrosis in mice models. Besides, we confirmed that IgG78-DM1 had qualified biosafety in vivo. Our results confirmed that CD248 can be used as a specific marker for myofibroblasts, and specific killing of CD248+ myofibroblasts by IgG78-DM1 has excellent anti-fibrotic effect in renal fibrotic mice. Our study expanded the application of ADC and provided a novel strategy for the treatment of renal fibrosis.
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Antígenos CD/metabolismo , Antígenos de Neoplasias/metabolismo , Sistemas de Liberación de Medicamentos , Inmunoconjugados/farmacología , Maitansina/farmacología , Miofibroblastos/metabolismo , Insuficiencia Renal Crónica , Animales , Fibrosis , Masculino , Ratones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/metabolismoRESUMEN
Specific medications to combat cerebellar ataxias, a group of debilitating movement disorders characterized by difficulty with walking, balance and coordination, are still lacking. Notably, cerebellar microglial activation appears to be a common feature in different types of ataxic patients and rodent models. However, direct evidence that cerebellar microglial activation in vivo is sufficient to induce ataxia is still lacking. Here, by employing chemogenetic approaches to manipulate cerebellar microglia selectively and directly, we found that specific chemogenetic activation of microglia in the cerebellar vermis directly leads to ataxia symptoms in wild-type mice and aggravated ataxic motor deficits in 3-acetylpyridine (3-AP) mice, a classic mouse model of cerebellar ataxia. Mechanistically, cerebellar microglial proinflammatory activation induced by either chemogenetic M3D(Gq) stimulation or 3-AP modeling hyperexcites Purkinje cells (PCs), which consequently triggers ataxia. Blockade of microglia-derived TNF-α, one of the most important proinflammatory cytokines, attenuates the hyperactivity of PCs driven by microglia. Moreover, chemogenetic inhibition of cerebellar microglial activation or suppression of cerebellar microglial activation by PLX3397 and minocycline reduces the production of proinflammatory cytokines, including TNF-α, to effectively restore the overactivation of PCs and alleviate motor deficits in 3-AP mice. These results suggest that cerebellar microglial activation may aggravate the neuroinflammatory response and subsequently induce dysfunction of PCs, which in turn triggers ataxic motor deficits. Our findings thus reveal a causal relationship between proinflammatory activation of cerebellar microglia and ataxic motor symptoms, which may offer novel evidence for therapeutic intervention for cerebellar ataxias by targeting microglia and microglia-derived inflammatory mediators.
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Ataxia Cerebelosa , Ratones , Animales , Ataxia Cerebelosa/inducido químicamente , Células de Purkinje/fisiología , Microglía , Factor de Necrosis Tumoral alfa/farmacología , Cerebelo , CitocinasRESUMEN
BACKGROUND: Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. METHODS: CD248 expression was examined in patients with liver cirrhosis and in mice with CCl4-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl4-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. RESULTS: CD248 expression was upregulated in patients with liver cirrhosis and in CCl4-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)+ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248+ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. CONCLUSIONS: Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors.
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Inmunoconjugados , Miofibroblastos , Animales , Antígenos CD/metabolismo , Antígenos de Neoplasias/efectos adversos , Antígenos de Neoplasias/metabolismo , Fibrosis , Células Estrelladas Hepáticas/metabolismo , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/metabolismo , Hígado/metabolismo , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Ratones , Miofibroblastos/metabolismoRESUMEN
Metal halide perovskites, primarily used as optoelectronic devices, have not been applied for electrochemical conversion due to their insufficient stability in moisture. Herein, two bismuth-based perovskites are introduced as novel electrocatalysts to convert CO2 into HCOOH in aqueous acidic media (pHâ 2.5), exhibiting a high Faradaic efficiency for HCOOH of >80 % in a wide potential range from -0.75 to -1.25â V. Their structural evolution against water was dynamically monitored by inâ situ spectra. Theoretical calculations further reveal that the formation of intermediate OCHO* on bismuth sites of Cs3 Bi2 Br9 (111) play a pivotal role toward HCOOH production, which has a lower energy barrier than that on Cs2 AgBiBr6 (001) surfaces. Significantly, CO2 reacts with protons instead of water which can enhance CO2 reduction rate and suppress hydrogen evolution by avoiding carbonate formation in acidic electrolytes. This work paves the way for the extensive investigation of halide perovskites in aqueous systems.
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BACKGROUND: Application of drug-coated balloons (DCBs) is popular for the treatment of percutaneous coronary intervention (PCI). A new DCB has been designed as ultrasound-controlled paclitaxel releasing. This study was conducted to determine whether a DCB-only strategy has a similar safety profile and equal angiographic and clinical outcomes to DES implantation in primary ST-elevation myocardial infarction (STEMI) patients, as well as determine the efficiency and safety of this new DCB.MethodsâandâResults:Overall, 184 pretreated STEMI patients were randomized into DCB and DES groups with a 1:1 allocation. The main study end-point was late lumen loss (LLL) during the 9 months after PCI. Late lumen loss was reported to be 0.24±0.39 mm in the DCB group and 0.31±0.38 mm in the DES group (P=0.215). Diameter stenosis was 28.27±15.35% in the DCB group and 25.73±15.41% in the DES group (P=0.312). Major adverse cardiovascular events (MACEs) were reported in 3 patients (3.4%) in the DCB group and 4 patients (4.7%) in the DES group (P=0.718). TLR and TVR in the DCB group was 2.3%, 3.4% and 2.4%, 3.5% in the DES group (P=1.000), respectively. No cardiac death and stent thrombosis (ST) was found in the DCB group at 12 months clinical follow up. CONCLUSIONS: The DCB-only strategy showed good angiographic and clinical outcomes in the 9- and 12-month follow-up periods, respectively. The VasoguardTM DCB is safe and feasible to treat STEMI patients.
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Angioplastia Coronaria con Balón , Stents Liberadores de Fármacos , Intervención Coronaria Percutánea , Infarto del Miocardio con Elevación del ST , Angioplastia Coronaria con Balón/métodos , Humanos , Paclitaxel/efectos adversos , Intervención Coronaria Percutánea/efectos adversos , Estudios Prospectivos , Infarto del Miocardio con Elevación del ST/diagnóstico por imagen , Infarto del Miocardio con Elevación del ST/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: Increasing evidence has indicated that circular RNAs (circRNAs) play a role in various diseases. However, the influence of circRNAs in nephritis remains unknown. METHODS: Microarray analysis and RT-qPCR were used to detect the expression of circRNA. Type I IFN were administrated to RMC and HEK293 cells to establish a nephritis cell model. CCK-8, MTT assay, and flow cytometry were used to assess cell proliferation, viability, and apoptosis of cells. Bioinformatics analysis and dual luciferase reporter assay detect the interaction of circ_0007059, miRNA-1278, and SHP-1. Glomerulonephritis was performed in a mouse model by administration of IFNα-expressing adenovirus. IHC staining showed the pathogenic changes. RESULTS: In the present study, the expression of circ_0007059 in type I interferon (IFN)-treated renal mesangial cells (RMCs), lupus nephritis (LN) specimens, and HEK293 cells was downregulated compared with that in normal healthy samples and untreated cells. Circ_0007059 overexpression resulted in increased cell proliferation, cell viability, apoptosis, and inflammation-associated factors (CXCL10, IFIT1, ISG15, and MX1) in RMCs and HEK293 cells. In addition, circ_0007059 overexpression significantly restored cell proliferation and viability and inhibited IFN-induced apoptosis. Further, the increased expression resulted in reduced inflammation and the downregulation of CXCL10, IFIT1, ISG15, and MX1 in RMCs and HEK293 cells. Circ_0007059 serves as a sponge for miR-1278 so that the latter can target the 3'-untranslated region of SHP-1. Overexpressed circ_0007059 inhibited miR-1278 expression and elevated SHP-1 expression, subsequently reducing STAT3 phosphorylation. Meanwhile, miR-1278 was upregulated and SHP-1 was downregulated in LN samples and IFN-treated cells. The restoration of miR-1278 counteracted the effect of circ_0007059 on viability, apoptosis, and inflammation as well as on SHP-1/STAT3 signaling in RMCs and HEK293 cells. We also investigated the role of SHP-1 overexpression in IFN-treated RMCs and HEK293 cells; SHP-1 overexpression resulted in a similar phenotype as that observed with circ_0007059 expression. CONCLUSIONS: The study indicates that circ_0007059 protects RMCs against apoptosis and inflammation during nephritis by attenuating miR-1278/SHP-1/STAT3 signaling.
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Regulación de la Expresión Génica , MicroARNs/genética , Nefritis/etiología , Nefritis/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , ARN Circular , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Adulto , Animales , Biomarcadores , Línea Celular , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Nefritis Lúpica , Masculino , Ratones , Persona de Mediana Edad , Nefritis/patología , Adulto JovenRESUMEN
An understanding of flower and panicle development is crucial for improving yield and quality in majority of grass crops. In this study, we used mapping-based cloning to identify MULTI-FLORET SPIKELET2 (MFS2), which encodes a MYB transcription factor and regulates flower and spikelet development in rice (Oryza sativa). In the mfs2 mutant, specification of palea identity was severely disturbed and showed degradation or transformation into a lemma-like organ, and the number of all floral organs was increased to varying degrees. Due to the increase in the number of floral organs and development of extra transformed palea/marginal region of the palea-like organs, some mfs2 spikelets had a tendency to produce two florets. These defects implied that the mfs2 mutation caused abnormal specification of palea identity and partial loss of spikelet determination. We confirm that MFS2 is a transcriptional repressor that shows strong repression activity by means of two typical ethylene-responsive element binding factor-associated amphiphilic motifs, one of which locates at the C terminus and is capable of interaction with three rice TOPLESS and TOPLESS-related proteins. The results indicate that MFS2 acts as a repressor that regulates floral organ identities and spikelet meristem determinacy in rice by forming a repression complex with rice TOPLESS and TOPLESS-related proteins.
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Flores/crecimiento & desarrollo , Meristema/citología , Meristema/crecimiento & desarrollo , Oryza/citología , Oryza/crecimiento & desarrollo , Oryza/genética , Oryza/metabolismo , Productos Agrícolas/citología , Productos Agrícolas/genética , Productos Agrícolas/crecimiento & desarrollo , Productos Agrícolas/metabolismo , Flores/citología , Flores/genética , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Variación Genética , Genotipo , Meristema/genética , Meristema/metabolismo , Mutación , Fenotipo , Factores de Transcripción/fisiologíaRESUMEN
OBJECTIVES: Corynebacterium glutamicum (C. glutamicum) has been harnessed for multi-million-ton scale production of glutamate and lysine. To further increase its amino acid production for fermentation industry, there is an acute need to develop next-generation genome manipulation tool for its metabolic engineering. All reported methods for genome editing triggered with CRISPR-Cas are based on the homologous recombination. While, it requires the generation of DNA repair template, which is a bottle-neck for its extensive application. RESULTS: In this study, we developed a method for gene knockout in C. glutamicum via CRISPR-Cpf1-coupled non-homologous end-joining (CC-NHEJ). Specifically, CRISPR-Cpf1 introduced double-strand breaks in the genome of C. glutamicum, which was further repaired by ectopically expressed two NHEJ key proteins (Mycobacterium tuberculosis Ku and ligase D). We provide the proof of concept, for CC-NHEJ, by the successful knockout of the crtYf/e gene in C. glutamicum with the efficiency of 22.00 ± 5.56%, or something like that. CONCLUSION: The present study reported a novel genome manipulation method for C. glutamicum.
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Sistemas CRISPR-Cas/genética , Corynebacterium glutamicum/genética , Reparación del ADN por Unión de Extremidades/genética , Ingeniería Metabólica , Corynebacterium glutamicum/metabolismo , Edición Génica , Técnicas de Inactivación de Genes , Genoma Bacteriano/genética , Ácido Glutámico/biosíntesis , Autoantígeno Ku/genética , Lisina/biosíntesis , Mycobacterium tuberculosis/genéticaRESUMEN
Oxygen-containing groups on carbon materials can induce high catalytic activity for some reactions. Herein, on the basis of a series of metal-free single-layer graphene nanodisks (GNDs) with different surface contents of oxygen-containing groups for highly efficient electrocatalytic reduction reaction of CO2 (CO2RR) to produce formate (HCOO-), we find that the CO2RR catalytic performance is only positively correlated with the surface content of carboxyl groups. While significantly, the density functional theory calculations demonstrate that the observed high CO2RR catalytic activity originates not from the solo carboxyl or other oxygen-containing groups, but from the synergistic effect between carboxyl groups and adjacent other types of groups (namely, hydroxyl, epoxide, and carbonyl) on GNDs. Inspired by such new knowledge, we further find that if the GND catalyst can "alternate work with rest", its electrocatalytic activity for CO2RR can be regenerated cyclically via a simple electro-oxidation method to regenerate the surface carboxyl groups, achieving a remarkable long-term durability for CO2RR. Such work deepens our understanding of the role of oxygen-containing groups in catalysis and provides a new strategy for the design and synthesis of high-performance metal-free carbon-based catalysts.
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As yet, there was no effective pharmacological therapy approved for non-alcoholic fatty liver disease (NAFLD). Here, we aimed to evaluate the therapeutic potential of puerarin against NAFLD and explored the underlying mechanisms. C57BL/6J mice were fed with a high-fat high-sucrose (HFHS) diet with or without puerarin coadministration intragastrically. The levels of hepatocellular injury, steatosis, fibrosis, and mitochondrial and metabolism alteration were detected. First, puerarin ameliorated histopathologic abnormalities due to HFHS. We observed a marked increase in hepatic lipid content, inflammation, and fibrosis level, which were attenuated by puerarin. Possible mechanisms were related to puerarin-mediated activation of PI3K/AKT pathway and further improvement in fatty acid metabolism. Puerarin restored the NAD+ content and beneficially affected the hepatic mitochondrial function, which attenuated HFHS-induced steatosis and metabolic disturbances. Finally, hepatic PARP-1 was activated due to excessive fat intake. Puerarin attenuated the PARP-1 expression in HFHS-fed mice, and PJ34, the PARP inhibitor, could mimic these protections of puerarin. However, pharmacological inhibition of PI3K disabled the protection of puerarin or PJ34 toward NAD+ refilling and mitochondrial homeostasis. In conclusion, our findings indicated that puerarin could be a promising and practical therapeutic strategy in NAFLD through modulating PARP-1/PI3K/AKT signaling pathway and further facilitating mitochondrial function.
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Dieta Alta en Grasa/efectos adversos , Isoflavonas/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sacarosa/efectos adversos , Vasodilatadores/uso terapéutico , Animales , Humanos , Isoflavonas/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Vasodilatadores/farmacologíaRESUMEN
Herein, a type of Fe, N-codoped carbon electrocatalyst (FeNx /C, Fe-N-BCNT#BP) containing bamboo carbon nanotubes and displaying bifunctional high catalytic efficiency for both oxygen reduction reaction (ORR) and carbon dioxide reduction reaction (CO2RR) is reported. It shows high electrocatalytic activity and stability for both the ORR process with onset potential of 1.03 VRHE in alkaline and the CO2RR to CO with high faradic efficiency up to 90% and selectivity of about 100% at low overpotential of 0.49 V. For CO2RR to CO, it is revealed that Fe3 C is active but the activity of FeNx centers is lower than that of C-N-based centers, contrary with that observed for ORR. Due to its low cost and high electrocatalytic performance for these two reduction reactions, the obtained catalyst is very promising for extensive application in future. The revealed huge activity difference of the same types of active sites for different reactions can efficiently guide the synthesis of advanced materials with multifunction.
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A series of novel ruthenium(II) complexes supported by a symmetrical NNN ligand were prepared and fully characterized. These complexes exhibited good performance in transfer hydrogenation to form new C-C bonds using alcohols as the alkylating agents, generating water as the only byproduct. A broad range of substrates, including (hetero)aryl- or alkyl-ketones and alcohols, were well tolerated under the optimized conditions. Notably, α-substituted methylene ketones were also investigated, which afforded α-branched steric hindrance products. A potential application of α-alkylation of methylene acetone to synthesize donepezil was demonstrated, which provided the desired product in 83% yield. Finally, this catalytic system could be applied to a one-pot double alkylation procedure with sequential addition of two different alcohols. The current protocol is featured with several characteristics, including a broad substrate scope, low catalyst (0.50 mol %) loadings, and environmental benignity.