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2.
ACS Nano ; 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35549238

RESUMO

Colocalization of cascade enzymes is broadly discussed as a phenomenon that can boost the cascade reaction throughput, although a direct experimental verification is often challenging. This is mainly due to difficulties in establishing proper size regimes and in the analytical quantification of colocalization effect with adequate experimental systems and simulations. In this study, by taking advantage of reversible DNA-directed colocalization of enzymes on microspheres, we established a cascade system that can be used to directly evaluate the colocalization effect with exactly the same experimental settings except for the state of enzyme dispersion. In the regime of highly dilute microspheres of particular sizes, the colocalized cascade shows enhanced activity compared with the freely diffusing cascade, as evidenced by a shortened lag phase in the time-course production. Reaction-diffusion modeling reveals that the enhancement can be ascribed to the initial accumulation of intermediate substrate around the colocalized enzymes and is found to be carrier-size-dependent. This work demonstrates the dependence of the colocalization effect of enzyme cascades on an interplay of nano- and microscales, lending theoretical support to the rational design of highly efficient multienzyme catalysts.

3.
J Diabetes ; 2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35510608

RESUMO

BACKGROUND: To investigate the arterial stiffness (AS) risk within urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) categories and the joint effect between kidney disease parameters and metabolic goal achievement on AS risk in adult people with type 2 diabetes (T2D). METHODS: A total of 27 439 Chinese participants with T2D from 10 National Metabolic Management Centers (MMC) were categorized into four albuminuria/decreased eGFR groups. The criteria for decreased eGFR and AS were eGFR <90 ml/min/1.73 m2 and brachial-ankle pulse wave velocity value >the 75th percentile (1770.0 cm/s). Three metabolic goals were defined as glycated hemoglobin <7%, BP <130/80 mmHg, andlow-density lipoprotein cholesterol <2.6 mmol/L. RESULTS: After full adjustment, odds ratios (ORs) for AS were highest for albuminuria and decreased eGFR (2.23 [1.98-2.52]) and were higher for albuminuria and normal eGFR (1.52 [1.39-1.67]) than for those with nonalbuminuria and decreased eGFR (1.17 [1.04-1.32]). Both UACR and eGFR in the subgroup or overall population independently correlated with AS risk. The achievement of ≥2 metabolic goals counteracted the association between albuminuria and AS risk (OR: 0.93; 95% CI: 0.80-1.07; p = .311). When the metabolic goals added up to ≥2 for patients with decreased eGFR, they showed significantly lower AS risk (OR: 0.65; 95% CI: 0.56-0.74; p < .001). CONCLUSIONS: Both higher UACR and lower eGFR are determinants of AS risk, with UACR more strongly related to AS than eGFR in adults with T2D. The correlation between albuminuria/decreased eGFR and AS was modified by the achievement of multiple metabolic elements.

4.
Artigo em Inglês | MEDLINE | ID: mdl-35535851

RESUMO

Developing high-performance non-noble bifunctional catalysts is pivotal for large-scale seawater electrolysis but remains a challenge. Here we report a sandwichlike NiCo(HPO4)2@Ni3N/NF (denoted by NiCoHPi@Ni3N/NF) catalyst. Vertical Ni3N nanosheet arrays are first grown and supported on nickel foam, and then a bimetallic NiCoHPi coating is decorated on Ni3N nanosheets by one-step electrodeposition. The hierarchical sandwich like structure offers a large surface area and plenty of catalytic active sites, and the coupling of interconnected Ni3N and NiCoHPi accelerates the electron transfer. Moreover, the surficial hydrogen phosphate ions contribute to a proper OH- absorption capacity due to the Lewis acid-base reaction. As a result, the NiCoHPi@Ni3N/NF catalyst exhibits good OER and HER activity, requiring overpotentials of 365 mV (for OER) and 174 mV (for HER) to deliver 100 mA cm-2 in the alkaline simulated seawater electrolyte. When assembled the NiCoHPi@Ni3N/NF catalyst as both the anode and cathode, it only needs 1.86 V to reach 100 mA cm-2 in alkaline simulated seawater electrolyte. This work may inspire the design and exploration of self-supported hierarchical composite electrocatalysts for hydrogen production from the electrolysis of seawater.

5.
J Phys Chem Lett ; 13(14): 3202-3208, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35377652

RESUMO

Short-range protein electron transfer (ET) is crucially important in light-induced biological processes such as in photoenzymes and photoreceptors and often occurs on time scales similar to those of environment fluctuations, leading to a coupled dynamic process. Herein, we use semiquinone Anabaena flavodoxin to characterize the ultrafast photoinduced redox cycle of the wild type and seven mutants by ultrafast spectroscopy. We have found that the forward and backward ET dynamics show stretched behaviors in a few picoseconds (1-5 ps), indicating a coupling with the local protein fluctuations. By comparison with the results from semiquinone D. vulgaris flavodoxin, we find that the electronic coupling is crucial to the ET rates. With our new nonergodic model, we obtain smaller values of the outer reorganization energy (λoγ) of environment fluctuations and the reaction free energy force (ΔGγ), a signature of nonequilibrium ET dynamics.


Assuntos
Transporte de Elétrons , Elétrons , Flavodoxina , Anabaena/metabolismo , Transporte de Elétrons/fisiologia , Flavodoxina/química , Flavodoxina/metabolismo , Oxirredução , Proteínas/metabolismo , Termodinâmica
6.
Org Biomol Chem ; 20(17): 3550-3557, 2022 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-35411904

RESUMO

A divergent radical borylation of vinyl azides with N-heterocyclic carbene (NHC) boranes in the presence of tBuSH is described. The protocol enables the divergent synthesis of α-boryl ketones and borylated triazoles with excellent functional group tolerance and a broad substrate scope. Remarkably, this work shows that vinyl azides can serve as unprecedented five-atom synthons for the construction of 1,2,3-triazoles without N2 extrusion.


Assuntos
Boranos , Azidas , Cetonas , Metano/análogos & derivados , Triazóis
7.
Mol Plant Pathol ; 2022 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-35430769

RESUMO

The initial stage of rice blast fungus, Magnaporthe oryzae, infection, before 36 h postinoculation, is a critical timespan for deploying pathogen effectors to overcome the host's defences and ultimately cause the disease. However, how this process is regulated at the transcription level remains largely unknown. This study functionally characterized two M. oryzae Early Infection-induced Transcription Factor genes (MOEITF1 and MOEITF2) and analysed their roles in this process. Target gene deletion and mutant phenotype analysis showed that the mutants Δmoeitf1 and Δmoeitf2 were only defective for infection growth but not for vegetative growth, asexual/sexual sporulation, conidial germination, and appressoria formation. Gene expression analysis of 30 putative effectors revealed that most effector genes were down-regulated in mutants, implying a potential regulation by the transcription factors. Artificial overexpression of two severely down-regulated effectors, T1REP and T2REP, in the mutants partially restored the pathogenicity of Δmoeitf1 and Δmoeitf2, respectively, indicating that these are directly regulated. Yeast one-hybrid assay and electrophoretic mobility shift assay indicated that Moeitf1 specifically bound the T1REP promoter and Moeitf2 specifically bound the T2REP promoter. Both T1REP and T2REP were predicted to be secreted during infection, and the mutants of T2REP were severely reduced in pathogenicity. Our results indicate crucial roles for the fungal-specific Moeitf1 and Moeitf2 transcription factors in regulating an essential step in M. oryzae early establishment after penetrating rice epidermal cells, highlighting these as possible targets for disease control.

8.
Nat Commun ; 13(1): 2182, 2022 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-35449138

RESUMO

Quorum sensing (QS) is a ubiquitous cell-cell communication mechanism that can be employed to autonomously and dynamically control metabolic fluxes. However, since the functions of genetic components in the circuits are not fully understood, the developed QS circuits are still less sophisticated for regulating multiple sets of genes or operons in metabolic engineering applications. Here, we discover the regulatory roles of a CRP-binding site and the lux box to -10 region within luxR-luxI intergenic sequence in controlling the lux-type QS promoters. By varying the numbers of the CRP-binding site and redesigning the lux box to -10 site sequence, we create a library of QS variants that possess both high dynamic ranges and low leakiness. These circuits are successfully applied to achieve diverse metabolic control in salicylic acid and 4-hydroxycoumarin biosynthetic pathways in Escherichia coli. This work expands the toolbox for dynamic control of multiple metabolic fluxes under complex metabolic background and presents paradigms to engineer metabolic pathways for high-level synthesis of target products.


Assuntos
Regulação Bacteriana da Expressão Gênica , Percepção de Quorum , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Escherichia coli/metabolismo , Engenharia Metabólica , Óperon/genética , Percepção de Quorum/genética
9.
ISA Trans ; 2022 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-35369992

RESUMO

In this study, an event-triggered fixed-time multiple stratospheric airship formation trajectory tracking controller is designed, and it is composed of two parts: the airship leader trajectory tracking controller (ALTTC) and the airship follower formation tracking controller (AFFTC). First, based on the framework of backstepping, the fixed-time ALTTC is designed to allow the trajectory tracking error to converge to zero within a fixed time. Subsequently, the event-triggered fixed-time AFFTC is designed to reduce the formation tracking error to zero within a fixed time. Two event-triggering conditions are designed to reduce the transmission times of control inputs and calculation times of control outputs. The fixed-time stability and the trajectory-tracking and formation-tracking performance of event-triggered closed-loop systems are theoretically shown to be ensured, and Zeno behavior is excluded in the proposed asynchronous event-triggering mechanism. Finally, simulations indicate the effectiveness of the proposed controller.

10.
Sensors (Basel) ; 22(7)2022 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-35408348

RESUMO

This article first investigates the dynamic coverage control problem for the multiple stratospheric airships (MSAs) system considering its practical application scenarios. A dynamic coverage control framework is put forward, in which the MSA system can be guided and controlled to fully cover the observation target region. Once a specific target is detected, the coverage target can be switched. First, the location information of the monitored target is predicted by an autoregressive model against processing delay. Second, the coverage control scheme consists of two layers: a novel potential field-based virtual control law to generate the desired velocity and angular velocity and an adaptive tracking controller to track them. In the virtual control law, a dynamic artificial potential field is introduced to adapt to the dynamic scenarios. In the tracking controller, which is combined with the adaptive control technique and the saturation compensator theory, the external disturbances and input saturation are addressed. Third, the event-triggered mechanism is designed to reduce the control frequency to prolong the actuator life. The simulation results are given to substantiate the capability of the proposed dynamic coverage control framework.

11.
Nano Lett ; 22(8): 3503-3511, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35315671

RESUMO

Metal ion substitution and anion exchange are two effective strategies for regulating the electronic and geometric structure of spinel. However, the optimal location of foreign metallic cations and the exact role of these metals and anions remain elusive. Herein, CoFe2O4-based hollow nanospheres with outstanding oxygen evolution reaction activity are prepared by Cr3+ substitution and S2- exchange. X-ray absorption spectra and theoretical calculations reveal that Cr3+ can be precisely doped into octahedral (Oh) Fe sites and simultaneously induce Co vacancy, which can activate adjacent tetrahedral (Td) Fe3+. Furthermore, S2- exchange results in structure distortion of Td-Fe due to compressive strain effect. The change in the local geometry of Td-Fe causes the *OOH intermediate to deviate from the y-axis plane, thus enhancing the adsorption of the *OOH. The Co vacancy and S2- exchange can adjust the geometric and electronic structure of Td-Fe, thus activating the inert Td-Fe and improving the electrochemical performance.


Assuntos
Metais , Oxigênio , Catálise , Cátions/química , Metais/química , Oxigênio/química
12.
EBioMedicine ; 78: 103969, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35349825

RESUMO

BACKGROUND: Some circulating proteins are linked to central adiposity. Gremlin 2 (GREM2) functions as a secreted factor involved in osteogenesis and adipogenesis. Here, we investigated the association of blood GREM2 levels and central adiposity, and the biological roles of GREM2 in the browning program of visceral preadipocytes. METHODS: Three independent cohorts were applied to detect circulating GREM2 levels. Recombinant Grem2 protein, Grem2 overexpression and knockout mouse models, and preadipocyte-specific Bmpr2 knockout mice were used to assess the roles of Grem2 in the browning program. FINDINGS: We detected the presence of GREM2 protein in human serum using an ELISA approach. We revealed elevated GREM2 levels in severely obese subjects and validated this finding in a large-scale community population involving 10,327 subjects. Notably, serum GREM2 was positively associated with visceral fat volume, as quantified by 3D reconstruction methods. In mice, Grem2 was highly expressed in visceral fat and liver tissues, while surgical removal of visceral fat lowered circulating Grem2 levels. Visceral fat secreted more Grem2 in obese mice. Grem2-overexpressed mice exhibited a reduced browning ability of visceral fat, whereas Grem2 ablation enhanced the browning capacity and reduced visceral fat content. Mechanistically, Grem2 attenuated the browning program of visceral preadipocytes partially by antagonizing BMP4/7-SMAD1/5/8 signaling pathway. Further, genetic deletion of Bmpr2 in Pdgfrα+ preadipocytes abolished the antagonistic effect of Grem2. INTERPRETATION: These findings indicate that GREM2 might function as a circulating protein factor associated with human visceral adiposity, and Grem2 inhibits the browning capacity of visceral preadipocytes partially by BMP4/7-BMPR2 signaling pathway. FUNDING: The complete list of funders can be found in the Acknowledgement section.


Assuntos
Citocinas , Obesidade Abdominal , Adipogenia/genética , Tecido Adiposo Marrom , Animais , Citocinas/genética , Humanos , Gordura Intra-Abdominal/metabolismo , Camundongos , Camundongos Obesos , Obesidade Abdominal/genética
13.
Pharm Stat ; 2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35332674

RESUMO

An immunotherapy trial often uses the phase I/II design to identify the optimal biological dose, which monitors the efficacy and toxicity outcomes simultaneously in a single trial. The progression-free survival rate is often used as the efficacy outcome in phase I/II immunotherapy trials. As a result, patients developing disease progression in phase I/II immunotherapy trials are generally seriously ill and are often treated off the trial for ethical consideration. Consequently, the happening of disease progression will terminate the toxicity event but not vice versa, so the issue of the semi-competing risks arises. Moreover, this issue can become more intractable with the late-onset outcomes, which happens when a relatively long follow-up time is required to ascertain progression-free survival. This paper proposes a novel Bayesian adaptive phase I/II design accounting for semi-competing risks outcomes for immunotherapy trials, referred to as the dose-finding design accounting for semi-competing risks outcomes for immunotherapy trials (SCI) design. To tackle the issue of the semi-competing risks in the presence of late-onset outcomes, we re-construct the likelihood function based on each patient's actual follow-up time and develop a data augmentation method to efficiently draw posterior samples from a series of Beta-binomial distributions. We propose a concise curve-free dose-finding algorithm to adaptively identify the optimal biological dose using accumulated data without making any parametric dose-response assumptions. Numerical studies show that the proposed SCI design yields good operating characteristics in dose selection, patient allocation, and trial duration.

14.
Front Bioeng Biotechnol ; 10: 844540, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35356774

RESUMO

Osteosarcomas commonly develop in the metaphysis of the long diaphysis, resulting in pronounced malignancy and high rates of early pulmonary metastasis. At present, osteosarcoma patients exhibit relatively poor survival rates owing these metastases and to the emergence of tumor chemoresistance. As such, there is an urgent need to identify other approaches to treating affected patients. Herein, we synthesized Fe3O4@PDA nanocomposites that exhibited excellent biocompatibility and low toxicity in human and animal model systems. The resultant nanoparticles were able to improve T2 magnetic resonance imaging and to enhance the signal-to-noise ratio associated with osteosarcoma tumors in animal models. Moreover, we were able to successfully leverage these Fe3O4@PDA particles as a photothermal agent capable of significantly inhibiting the growth of tumors and preventing their metastasis to the lung compartment. Together, these results highlight a novel therapeutic platform that has the potential to guide both the more effective diagnosis and treatment of osteosarcoma patients in clinical applications.

15.
Front Cardiovasc Med ; 9: 799253, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35310991

RESUMO

Background: Left ventricular ejection fraction (LVEF) is a vital variable to describe left ventricle systolic function and contractility of left ventricle. However, the association between LVEF and the prognostic effect in patients with moderate or severe mitral regurgitation (MR) is still controversial. Methods: This study comprised 30,775 coronary artery disease (CAD) patients who underwent coronary arteriography (CAG) in the Cardiorenal ImprovemeNt (CIN) registry from January 2007 to December 2018. Patients were divided into none or mild MR group and moderate or severe MR group, and 3 levels of LVEF ≥50, 40-50%, and <40% were further distinguished according to hospital baseline. Univariate and multivariate Cox proportional analyses were used to investigate the association between LVEF levels and long-term all-cause mortality in patients with different MR severities. Results: Of 30,775 CAD patients (62.9 ± 10.6 years, females 23.8%), 26,474 (86.0%) patients had none or mild MR. Compared with none or mild MR patients, patients with moderate or severe MR were older and had worse cardio-renal function. In multivariable Cox proportional analysis, LVEF <40% was independently associated with higher mortality compared with LVEF ≥ 50% in all kinds of MR severity {none or mild MR [adjusted hazard ratio (HR): 1.79; 95% CI: 1.56-2.05, p < 0.001], moderate or severe MR [adjusted HR: 1.57; 95% CI: 1.29-1.91, p < 0.001]}. Conclusions: LVEF is a reliable prognostic index in CAD patients, even in those with moderate or severe MR. LVEF monitoring would still be clinically useful in CAD patients with moderate or severe MR. Clinical trials are needed to prospectively evaluate the optimal threshold for LVEF in patients with moderate or severe MR.

16.
Atten Percept Psychophys ; 84(3): 861-877, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35304697

RESUMO

Recently a theory (Zhaoping, Vision Research, 136, 32-49, 2017) proposed that top-down feedback from higher to lower visual cortical areas, to aid visual recognition, is stronger in the central than in the peripheral visual fields. Since top-down feedback helps feature binding, a critical visual recognition process, this theory predicts that insufficient feedback in the periphery should make feature misbinding more likely. To test this prediction, this study assessed binding between color and motion features, or between luminance and motion features, at different visual field eccentricities. We first used color-motion stimuli containing equiluminant red and green dots moving in opposite directions, for example, red dots moved leftward while green dots moved rightward. Such stimuli were shown in both a central reference strip and a peripheral test strip; participants reported whether it was the first or second interval in a trial in which the dots of each color moved in the opposite directions between the two strips. The center of the test strip was at 4° or 15° away from the gaze fixation. Participants' performance was much worse when the test strip was more peripheral, suggesting that feature misbinding occurred more frequently there. This held even when the size and density of the dots were adjusted by eccentricity-dependent cortical magnification factors, and even when red/green dots were replaced by yellow/blue dots or black/white dots to suit the retinal input sampling peripherally. Our findings support that top-down feedback is more directed to central vision, which can resolve ambiguities in feature binding at more central visual locations.


Assuntos
Percepção de Movimento , Córtex Visual , Percepção de Cores , Retroalimentação , Humanos , Visão Ocular , Campos Visuais
18.
Cell Res ; 32(4): 375-382, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35210606

RESUMO

Monoclonal antibodies represent important weapons in our arsenal to against the COVID-19 pandemic. However, this potential is severely limited by the time-consuming process of developing effective antibodies and the relative high cost of manufacturing. Herein, we present a rapid and cost-effective lipid nanoparticle (LNP) encapsulated-mRNA platform for in vivo delivery of SARS-CoV-2 neutralization antibodies. Two mRNAs encoding the light and heavy chains of a potent SARS-CoV-2 neutralizing antibody HB27, which is currently being evaluated in clinical trials, were encapsulated into clinical grade LNP formulations (named as mRNA-HB27-LNP). In vivo characterization demonstrated that intravenous administration of mRNA-HB27-LNP in mice resulted in a longer circulating half-life compared with the original HB27 antibody in protein format. More importantly, a single prophylactic administration of mRNA-HB27-LNP provided protection against SARS-CoV-2 challenge in mice at 1, 7 and even 63 days post administration. In a close contact transmission model, prophylactic administration of mRNA-HB27-LNP prevented SARS-CoV-2 infection between hamsters in a dose-dependent manner. Overall, our results demonstrate a superior long-term protection against SARS-CoV-2 conferred by a single administration of this unique mRNA antibody, highlighting the potential of this universal platform for antibody-based disease prevention and therapy against COVID-19 as well as a variety of other infectious diseases.


Assuntos
COVID-19 , SARS-CoV-2 , Animais , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , COVID-19/prevenção & controle , Cricetinae , Humanos , Lipossomos , Camundongos , Nanopartículas , Pandemias/prevenção & controle , RNA Mensageiro/genética , Glicoproteína da Espícula de Coronavírus
19.
Methods Mol Biol ; 2459: 85-92, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35212957

RESUMO

Potassium ion (K+) efflux is often considered as an upstream signaling event of NLRP3 activation. The main evidence to demonstrate the importance of K+ efflux is that high concentration of extracellular K+ inhibits NLRP3 inflammasome assembly. However, the conditions used to prevent K+ flowing also breaks down a basic parameter of eukaryotic biology, leading to sustained membrane potential depolarization and affecting normal signal transduction in cells. Therefore, direct measurement of intracellular ion concentration can more truly reflect the role of K+ flow during the activation of NLRP3. In this chapter, we will provide the rationale and a method to evaluate intracellular K+ concentration by ICP-OES (Inductively Coupled Plasma Optical Emission Spectroscopy), which helps us understand how disturbances in intracellular K+ level orchestrates NLRP3 inflammasome activation.


Assuntos
Proteína 3 que Contém Domínio de Pirina da Família NLR , Potássio , Inflamassomos , Íons , Transdução de Sinais
20.
Molecules ; 27(4)2022 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-35209131

RESUMO

With the emergence of fifth-generation (5G) cellular networks, millimeter-wave (mmW) and terahertz (THz) frequencies have attracted ever-growing interest for advanced wireless applications. The traditional printed circuit board materials have become uncompetitive at such high frequencies due to their high dielectric loss and large water absorption rates. As a promising high-frequency alternative, liquid crystal polymers (LCPs) have been widely investigated for use in circuit devices, chip integration, and module packaging over the last decade due to their low loss tangent up to 1.8 THz and good hermeticity. The previous review articles have summarized the chemical properties of LCP films, flexible LCP antennas, and LCP-based antenna-in-package and system-in-package technologies for 5G applications, although these articles did not discuss synthetic LCP technologies. In addition to wireless applications, the attractive mechanical, chemical, and thermal properties of LCP films enable interesting applications in micro-electro-mechanical systems (MEMS), biomedical electronics, and microfluidics, which have not been summarized to date. Here, a comprehensive review of flexible LCP technologies covering electric circuits, antennas, integration and packaging technologies, front-end modules, MEMS, biomedical devices, and microfluidics from microwave to THz frequencies is presented for the first time, which gives a broad introduction for those outside or just entering the field and provides perspective and breadth for those who are well established in the field.

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