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1.
Nat Commun ; 15(1): 7024, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39147746

RESUMO

To achieve high power conversion efficiency in perovskite/silicon tandem solar cells, it is necessary to develop a promising wide-bandgap perovskite absorber and processing techniques in relevance. To date, the performance of devices based on wide-bandgap perovskite is still limited mainly by carrier recombination at their electron extraction interface. Here, we demonstrate assembling a binary two-dimensional perovskite by both alternating-cation-interlayer phase and Ruddlesden-Popper phase to passivate perovskite/C60 interface. The binary two-dimensional strategy takes effects not only at the interface but also in the bulk, which enables efficient charge transport in a wide-bandgap perovskite solar cell with a stabilized efficiency of 20.79% (1 cm2). Based on this absorber, a monolithic perovskite/silicon tandem solar cell is fabricated with a steady-state efficiency of 30.65% assessed by a third party. Moreover, the tandem devices retain 96% of their initial efficiency after 527 h of operation under full spectral continuous illumination, and 98% after 1000 h of damp-heat testing (85 °C with 85% relative humidity).

2.
Langmuir ; 2024 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-39161198

RESUMO

Oxidative desulfurization (ODS), as a novel desulfurization technique of fuel oil, possesses high desulfurization efficiency for aromatic sulfide and low cost, making it a promising approach. The key to the technology lies in the rational design of catalysts with high activity and stability. Polyoxometalates, which are environmentally friendly, cost-effective, and abundantly available, face constraints in the development of ODS applications due to their low specific surface area and difficulty in regeneration. Introducing metal oxides into carriers with large specific surface areas to obtain heterogeneous catalysts is an effective solution to this problem. Beta zeolites, with regular three-dimensional channel systems, large specific surface area, and superior thermal/hydrothermal stability, are usually used as carriers. In this work, we developed a strategy to enhance zeolite carrier utilization efficiency by introducing Ta5+ species into the rigid framework of zeolites containing confined MoO3. The Ta species in the zeolite framework and the confined MoO3 produce a synergistic effect, exhibiting extremely high catalytic activity for the aerobic oxidative desulfurization of various organic aromatic sulfur compounds under mild conditions (90 °C and atmospheric pressure) in a deep eutectic solvent, surpassing common heterogeneous catalysts for oxidative desulfurization. Moreover, it can resist the adverse effects of interferents, such as naphthalene and indole. Additionally, the confined nature of Beta zeolite endows it with exceptional stability, demonstrating distinctive recyclability.

3.
Virol Sin ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38945214

RESUMO

Hand, foot and mouth disease (HFMD), mainly caused by enterovirus 71 (EV71), has frequently occurred in the Asia-Pacific region, posing a significant threat to the health of infants and young children. Therefore, research on the infection mechanism and pathogenicity of enteroviruses is increasingly becoming important. The 3D polymerase, as the most critical RNA-dependent RNA polymerase (RdRp) for EV71 replication, is widely targeted to inhibit EV71 infection. In this study, we identified a novel host protein, AIMP2, capable of binding to 3D polymerase and inhibiting EV71 infection. Subsequent investigations revealed that AIMP2 recruits the E3 ligase SMURF2, which mediates the polyubiquitination and degradation of 3D polymerase. Furthermore, the antiviral effect of AIMP2 extended to the CVA16 and CVB1 serotypes. Our research has uncovered the dynamic regulatory function of AIMP2 during EV71 infection, revealing a novel antiviral mechanism and providing new insights for the development of antienteroviral therapeutic strategies.

4.
J Med Chem ; 67(11): 8791-8816, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38775356

RESUMO

The spread of the influenza virus has caused devastating pandemics and huge economic losses worldwide. Antiviral drugs with diverse action modes are urgently required to overcome the challenges of viral mutation and drug resistance, and targeted protein degradation strategies constitute excellent candidates for this purpose. Herein, the first degradation of the influenza virus polymerase acidic (PA) protein using small-molecule degraders developed by hydrophobic tagging (HyT) technology to effectively combat the influenza virus was reported. The SAR results revealed that compound 19b with Boc2-(L)-Lys demonstrated excellent inhibitory activity against A/WSN/33/H1N1 (EC50 = 0.015 µM) and amantadine-resistant strain (A/PR/8/H1N1), low cytotoxicity, high selectivity, substantial degradation ability, and good drug-like properties. Mechanistic studies demonstrated that the proteasome system and autophagic lysosome pathway were the potential drivers of these HyT degraders. Thus, this study provides a powerful tool for investigating the targeted degradation of influenza virus proteins and for antiviral drug development.


Assuntos
Antivirais , Interações Hidrofóbicas e Hidrofílicas , Tioureia , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Humanos , Cães , Animais , Tioureia/farmacologia , Tioureia/análogos & derivados , Tioureia/química , Relação Estrutura-Atividade , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Células Madin Darby de Rim Canino , Proteólise/efeitos dos fármacos , Proteínas Virais/metabolismo , Proteínas Virais/química , Proteínas Virais/antagonistas & inibidores , RNA Polimerase Dependente de RNA/antagonistas & inibidores , RNA Polimerase Dependente de RNA/metabolismo , Farmacorresistência Viral/efeitos dos fármacos
5.
Nano Lett ; 24(18): 5467-5473, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38647318

RESUMO

The discovery of room-temperature ferromagnetism in van der Waals (vdW) materials opens new avenues for exploring low-dimensional magnetism and its applications in spintronics. Recently, the observation of the room-temperature topological Hall effect in the vdW ferromagnet Fe3GaTe2 suggests the possible existence of room-temperature skyrmions, yet skyrmions have not been directly observed. In this study, real-space imaging was employed to investigate the domain evolution of the labyrinth and skyrmion structure. First, Néel-type skyrmions can be created at room temperature. In addition, the influence of flake thickness and external magnetic field (during field cooling) on both labyrinth domains and the skyrmion lattice is unveiled. Due to the competition between magnetic anisotropy and dipole interactions, the specimen thickness significantly influences the density of skyrmions. These findings demonstrate that Fe3GaTe2 can host room-temperature skyrmions of various sizes, opening up avenues for further study of magnetic topological textures at room temperature.

6.
Virol Sin ; 39(2): 277-289, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38246238

RESUMO

Influenza A virus (IAV) binds sialic acid receptors on the cell surface to enter the host cells, which is the key step in initiating infection, transmission and pathogenesis. Understanding the factors that contribute to the highly efficient entry of IAV into human cells will help elucidate the mechanism of viral entry and pathogenicity, and provide new targets for intervention. In the present study, we reported a novel membrane protein, C1QTNF5, which binds to the hemagglutinin protein of IAV and promotes IAV infection in vitro and in vivo. We found that the HA1 region of IAV hemagglutinin is critical for the interaction with C1QTNF5 protein, and C1QTNF5 interacts with hemagglutinin mainly through its N-terminus (1-103 aa). In addition, we further demonstrated that overexpression of C1QTNF5 promotes IAV entry, while blocking the interaction between C1QTNF5 and IAV hemagglutinin greatly inhibits viral entry. However, C1QTNF5 does not function as a receptor to mediate IAV infection in sialic acid-deficient CHO-Lec2 cells, but promotes IAV to attach to these cells, suggesting that C1QTNF5 is an important attachment factor for IAV. This work reveals C1QTNF5 as a novel IAV attachment factor and provides a new perspective for antiviral strategies.


Assuntos
Vírus da Influenza A , Infecções por Orthomyxoviridae , Ligação Viral , Internalização do Vírus , Animais , Humanos , Camundongos , Células A549 , Células CHO , Cricetulus , Células HEK293 , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Vírus da Influenza A/patogenicidade , Influenza Humana/genética , Influenza Humana/metabolismo , Infecções por Orthomyxoviridae/metabolismo , Ligação Proteica , Receptores Virais/metabolismo , Receptores Virais/genética , Colágeno/genética , Colágeno/metabolismo
7.
Sci Adv ; 10(1): eadi5894, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38170776

RESUMO

Randomly distributed topological defects created during the spontaneous symmetry breaking are the fingerprints to trace the evolution of symmetry, range of interaction, and order parameters in condensed matter systems. However, the effective mean to manipulate topological defects into ordered form is elusive due to the topological protection. Here, we establish a strategy to effectively align the topological domain networks in hexagonal manganites through a mechanical approach. It is found that the nanoindentation strain gives rise to a threefold Magnus-type force distribution, leading to a sixfold symmetric domain pattern by driving the vortex and antivortex in opposite directions. On the basis of this rationale, sizeable mono-chirality topological stripe is readily achieved by expanding the nanoindentation to scratch, directly transferring the randomly distributed topological defects into an ordered form. This discovery provides a mechanical strategy to manipulate topological protected domains not only on ferroelectrics but also on ferromagnets/antiferromagnets and ferroelastics.

8.
Nat Commun ; 14(1): 3941, 2023 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-37402744

RESUMO

Solomon rings, upholding the symbol of wisdom with profound historical roots, were widely used as decorations in ancient architecture and clothing. However, it was only recently discovered that such topological structures can be formed by self-organization in biological/chemical molecules, liquid crystals, etc. Here, we report the observation of polar Solomon rings in a ferroelectric nanocrystal, which consist of two intertwined vortices and are mathematically equivalent to a [Formula: see text] link in topology. By combining piezoresponse force microscopy observations and phase-field simulations, we demonstrate the reversible switching between polar Solomon rings and vertex textures by an electric field. The two types of topological polar textures exhibit distinct absorption of terahertz infrared waves, which can be exploited in infrared displays with a nanoscale resolution. Our study establishes, both experimentally and computationally, the existence and electrical manipulation of polar Solomon rings, a new form of topological polar structures that may provide a simple way for fast, robust, and high-resolution optoelectronic devices.

9.
Adv Mater ; 35(36): e2302320, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37358059

RESUMO

Deterministic control of ferroelectric domain is critical in the ferroelectric functional electronics. Ferroelectric polarization can be manipulated mechanically with a nano-tip through flexoelectricity. However, it usually occurs in a very localized area in ultrathin films, with possible permanent surface damage caused by a large tip-force. Here it is demonstrated that the deliberate engineering of transverse flexoelectricity offers a powerful tool for improving the mechanical domain switching. Sizable-area domain switching under an ultralow tip-force can be realized in suspended van der Waals ferroelectrics with the surface intact, due to the enhanced transverse flexoelectric field. The film thickness range for domain switching in suspended ferroelectrics is significantly improved by an order of magnitude to hundreds of nanometers, being far beyond the limited range of the substrate-supported ones. The experimental results and phase-field simulations further reveal the crucial role of the transverse flexoelectricity in the domain manipulation. This large-scale mechanical manipulation of ferroelectric domain provides opportunities for the flexoelectricity-based domain controls in emerging low-dimensional ferroelectrics and related devices.

10.
Cell Rep ; 42(7): 112700, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-37379216

RESUMO

How pathogens manipulate host UPRER to mediate immune evasion is largely unknown. Here, we identify the host zinc finger protein ZPR1 as an interacting partner of the enteropathogenic E. coli (EPEC) effector NleE using proximity-enabled protein crosslinking. We show that ZPR1 assembles via liquid-liquid phase separation (LLPS) in vitro and regulates CHOP-mediated UPRER at the transcriptional level. Interestingly, in vitro studies show that the ZPR1 binding ability with K63-ubiquitin chains, which promotes LLPS of ZPR1, is disrupted by NleE. Further analyses indicate that EPEC restricts host UPRER pathways at the transcription level in a NleE-ZPR1 cascade-dependent manner. Together, our study reveals the mechanism by which EPEC interferes with CHOP-UPRER via regulating ZPR1 to help pathogens escape host defense.


Assuntos
Escherichia coli Enteropatogênica , Infecções por Escherichia coli , Proteínas de Escherichia coli , Humanos , Células HeLa , Fatores de Virulência/metabolismo , Escherichia coli Enteropatogênica/metabolismo , Proteínas de Escherichia coli/metabolismo
11.
J Appl Genet ; 64(3): 393-408, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37219731

RESUMO

MAP65 is a microtubule-binding protein family in plants and plays crucial roles in regulating cell growth and development, intercellular communication, and plant responses to various environmental stresses. However, MAP65s in Cucurbitaceae are still less understood. In this study, a total of 40 MAP65s were identified from six Cucurbitaceae species (Cucumis sativus L., Citrullus lanatus, Cucumis melo L., Cucurbita moschata, Lagenaria siceraria, and Benincasa hispida) and classified into five groups by phylogenetic analysis according to gene structures and conserved domains. A conserved domain (MAP65_ASE1) was found in all MAP65 proteins. In cucumber, we isolated six CsaMAP65s with different expression patterns in tissues including root, stem, leaf, female flower, male flower, and fruit. Subcellular localizations of CsaMAP65s verified that all CsaMAP65s were localized in microtubule and microfilament. Analyses of the promoter regions of CsaMAP65s have screened different cis-acting regulatory elements involved in growth and development and responses to hormone and stresses. In addition, CsaMAP65-5 in leaves was significantly upregulated by salt stress, and this promotion effect was higher in cucumber cultivars with salt tolerant than that without salt tolerant. CsaMAP65-1 in leaves was significantly upregulated by cold stress, and this promotion was higher in cold-tolerant cultivar than intolerant cultivar. With the genome-wide characterization and phylogenetic analysis of Cucurbitaceae MAP65s, and the expression profile of CsaMAP65s in cucumber, this study laid a foundation for further study on MAP65 functions in developmental processes and responses to abiotic stress in Cucurbitaceae species.


Assuntos
Cucumis sativus , Cucurbitaceae , Cucumis sativus/genética , Cucumis sativus/metabolismo , Cucurbitaceae/genética , Cucurbitaceae/metabolismo , Genoma de Planta , Proteínas Associadas aos Microtúbulos/genética , Filogenia , Proteínas de Plantas/genética , Regulação da Expressão Gênica de Plantas
12.
Angew Chem Int Ed Engl ; 62(24): e202303176, 2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-37060295

RESUMO

Possessed with advantageous optoelectronic properties, perovskites have boosted the rapid development of solution-processed solar cells. The performance of perovskite solar cells (PSCs) is significantly weakened by the carrier loss at grain boundary grooves (GBGs); however, it receives limited attention and there lacks effective approach to solve this issue. Herein, for the first time, we constructed the tungstate/perovskite heterointerface via a "two step" in situ reaction approach that provides effective defect passivation and ensures efficient carrier dynamics at the GBGs. The exposed perovskite at grain boundaries is converted to wide-band-gap PbWO4 via an in-situ reaction between Pb2+ and tungstate ions, which passivate defects due to the strong ionic bonding. Moreover, recombination loss is further suppressed via the heterointerface energetics modification based on an additional transformation from PbWO4 to CaWO4 . PSCs based on this groove modification strategy showed good universality in both normal and inverted structure, with an improved efficiency of 23.25 % in the n-i-p device and 23.33 % in the p-i-n device. Stable power output of the modified device could maintain 91.7 % after around 1100 h, and the device efficiency could retain 92.5 % after aging in air for around 2110 h, and 93.1 % after aging at 85 °C in N2 for 972 h.

13.
Nat Commun ; 14(1): 840, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36792610

RESUMO

Multiferroic materials have great potential in non-volatile devices for low-power and ultra-high density information storage, owing to their unique characteristic of coexisting ferroelectric and ferromagnetic orders. The effective manipulation of their intrinsic anisotropy makes it promising to control multiple degrees of the storage "medium". Here, we have discovered intriguing in-plane electrical and magnetic anisotropies in van der Waals (vdW) multiferroic CuCrP2S6. The uniaxial anisotropies of current rectifications, magnetic properties and magnon modes are demonstrated and manipulated by electric direction/polarity, temperature variation and magnetic field. More important, we have discovered the spin-flop transition corresponding to specific resonance modes, and determined the anisotropy parameters by consistent model fittings and theoretical calculations. Our work provides in-depth investigation and quantitative analysis of electrical and magnetic anisotropies with the same easy axis in vdW multiferroics, which will stimulate potential device applications of artificial bionic synapses, multi-terminal spintronic chips and magnetoelectric devices.

14.
Sensors (Basel) ; 23(2)2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36679369

RESUMO

In this paper, a control method of a novel tilt-rotor UAV with a blended wing body layout is studied. The novel UAV is capable of vertical take-off and landing and has strong stealth capabilities that can be applied to carrier-borne reconnaissance aircraft. However, the high aspect ratio of blended wing body UAVs leads to a wingtip or oar-tip touchdown problem when adopting the conventional position-attitude control (CPAC) scheme with a large crosswind disturbance. Moreover, when the UAV is subject to interference during reconnaissance, aerial photography, and landing missions, the conventional scheme cannot provide both attitude stability and track accuracy. First, a direct thrust vectoring control (DTVC) scheme is proposed. The control authority of the rotor tilt mechanism was added to enable the decoupling of the attitude and trajectory and to improve the response rate and response bandwidth of the flight trajectory. Second, considering the problems of strong couplings and parameter uncertainties and the nonlinear features and mismatched perturbations that are inevitable in the tilt-rotor, we designed a robust UAV controller based on the backstepping sliding mode control method and determined the stability of the control system through the Lyapunov function. Finally, in the case of crosswire interference during vertical takeoff and landing and the aerial photography missions of the UAV, the numerical simulation of the CPAC scheme and the DTVC scheme was carried out, respectively, and the Monte Carlo random test method was introduced to conduct the statistical test of the landing accuracy. The simulation results show that the DTVC scheme improves the landing accuracy and speed compared to the CAPC scheme and decouples the position control loop from the attitude control loop, finally enabling the UAV to complete the flight control in the VTOL phase.


Assuntos
Aeronaves , Processos Grupais , Animais , Simulação por Computador , Método de Monte Carlo , Fotografação
15.
J Biomed Mater Res B Appl Biomater ; 111(3): 551-559, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36200602

RESUMO

We previously showed decellularized fish swim bladder can be used as vascular patch and tube graft in rats, mesenchymal stem cells (MSCs) have showed the capability to inhibit neointimal hyperplasia in different animal models. We hypothesized that decellularized fish swim bladder patch loaded with MSCs (bioinspired patch) can inhibit neointimal hyperplasia in a rat aortic patch angioplasty model. Rat MSCs were grown in vitro and flow cytometry was used to confirm their quality. 3.6 × 105 MSCs were mixed into 100 µl of sodium alginate (SA)/hyaluronic acid (HA) hydrogel, two layers of fish swim bladders (5 mm × 5 mm) were sutured together, bioinspired patch was created by injection of hydrogel with MSCs into the space between two layers of fish swim bladder patches. Decellularized rat thoracic aorta patch was used as control. Patches were harvested at days 1 and 14 after implantation. Samples were examined by histology, immunohistochemistry, and immunofluorescence. The decellularized rat thoracic aorta patch and the fish swim bladder patch had a similar healing process after implantation. The bioinspired patch had a similar structure like native aorta. Bioinspired patch showed a decreased neointimal thickness (p = .0053), fewer macrophages infiltration (p = .0090), and lower proliferation rate (p = .0291) compared to the double layers fish swim bladder patch group. Decellularized fish swim bladder patch loaded with MSCs can inhibit neointimal hyperplasia effectively. Although this is a preliminary animal study, it may have a potential application in large animals or clinical research.


Assuntos
Células-Tronco Mesenquimais , Bexiga Urinária , Ratos , Animais , Hiperplasia/prevenção & controle , Hiperplasia/patologia , Neointima/prevenção & controle , Neointima/patologia , Células-Tronco Mesenquimais/patologia , Hidrogéis
16.
Sensors (Basel) ; 22(24)2022 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-36560106

RESUMO

The optimal trajectory planning for a novel tilt-rotor unmanned aerial vehicle (UAV) in different take-off schemes was studied. A novel tilt-rotor UAV that possesses characteristics of both tilt-rotors and a blended wing body is introduced. The aerodynamic modeling of the rotor based on blade element momentum theory (BEMT) is established. An analytical method for determining the taking-off envelope of tilt angle versus airspeed is presented. A novel takeoff-tilting scheme, namely tilting take-off (TTO), is developed, and its optimal trajectory is designed based on the direct collocation method. Parameters such as the rotor thrust, tilt angle of rotor and angle of attack are chosen as control variables, and the forward velocity, vertical velocity and altitude are selected as state variables. The time and the energy consumption are considered in the performance optimization indexes. The optimal trajectories of the TTO scheme and other conventional schemes including vertical take-off (VTO) and short take-off (STO) are compared and analyzed. Simulation results indicate that the TTO scheme consumes 47 percent less time and 75 percent less energy than the VTO scheme. Moreover, with minor differences in time and energy consumption compared to the STO scheme, but without the need for sliding distance, TTO is the optimal take-off scheme to satisfy the flight constraints of a novel tilt-rotor UAV.

17.
Nanoscale ; 14(42): 15869-15874, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36260020

RESUMO

The stacking heterostructure of graphene on bulk h-BN produces a moiré pattern with topographic corrugation. The corrugation of the moiré pattern expectantly induces a considerable curvature and a flexoelectric response, which calls for a detailed study. In this work, we used lateral force microscopy, a scanning technique to locally observe the moiré pattern and topographic corrugation. The curvature and flexoelectric potentials are derived from the measured topographic corrugation, revealing a huge curvature of ∼107 m-1 and a flexoelectric potential of ∼10 mV in the hexagonal domain wall region (∼3-4 nm) of the moiré pattern. In addition, the domain walls of the moiré pattern also generate a clear electromechanical and frictional response, arising from the corrugation-induced flexoelectric response. In summary, the results of this work provide insights into the understanding of the flexoelectricity in the graphene/bulk h-BN and its associated electromechanical coupling behavior in the moiré pattern of a van der Waals stacking heterostructure.

18.
Nat Commun ; 13(1): 6241, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271005

RESUMO

At the interface of van der Waals heterostructures, the crystal symmetry and the electronic structure can be reconstructed, giving rise to physical properties superior to or absent in parent materials. Here by studying a Bernal bilayer graphene moiré superlattice encapsulated by 30°-twisted boron nitride flakes, we report an unprecedented ferroelectric polarization with the areal charge density up to 1013 cm-2, which is far beyond the capacity of a moiré band. The translated polarization ~5 pC m-1 is among the highest interfacial ferroelectrics engineered by artificially stacking van der Waals crystals. The gate-specific ferroelectricity and co-occurring anomalous screening are further visualized via Landau levels, and remain robust for Fermi surfaces outside moiré bands, confirming their independence on correlated electrons. We also find that the gate-specific resistance hysteresis loops could be turned off by the other gate, providing an additional control knob. Furthermore, the ferroelectric switching can be applied to intrinsic properties such as topological valley current. Overall, the gate-specific ferroelectricity with strongly enhanced charge polarization may encourage more explorations to optimize and enrich this novel class of ferroelectricity, and promote device applications for ferroelectric switching of various quantum phenomena.

19.
EClinicalMedicine ; 53: 101639, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36105873

RESUMO

Background: Acute ischaemic stroke (AIS) is a highly heterogeneous disorder and warrants further investigation to stratify patients with different outcomes and treatment responses. Using a large-scale stroke registry cohort, we applied data-driven approach to identify novel phenotypes based on multiple biomarkers. Methods: In a nationwide, prospective, 201-hospital registry study taking place in China between August 01, 2015 and March 31, 2018, the patients with AIS who were over 18 years of age and admitted to the hospital within 7 days from symptom onset were included. 92 biomarkers were included in the analysis. In the derivation cohort (n=9539), an unsupervised Gaussian mixture model was applied to categorize patients into distinct phenotypes. A classifier was developed using the most important biomarkers and was applied to categorize patients into their corresponding phenotypes in an validation cohort (n=2496). The differences in biological features, clinical outcomes, and treatment response were compared across the phenotypes. Findings: We identified four phenotypes with distinct characteristics in 9288 patients with non-cardioembolic ischaemic stroke. Phenotype 1 was associated with abnormal glucose and lipid metabolism. Phenotype 2 was characterized by inflammation and abnormal renal function. Phenotype 3 had the least laboratory abnormalities and small infarct lesions. Phenotype 4 was characterized by disturbance in homocysteine metabolism. Findings were replicated in the validation cohort. In comparison with phenotype 3, the risk of stroke recurrence (adjusted hazard ratio [aHR] 2.02, 95% confidence intervals [CI] 1.04-3.94), and mortality (aHR 18.14, 95%CI 6.62-49.71) at 3-month post-stroke were highest in phenotype 2, followed by phenotype 4 and phenotype 1, after adjustment for age, gender, smoking, drinking, history of stroke, hypertension, diabetes mellitus, dyslipidemia, and coronary heart disease. The Monte Carlo simulation showed that the patients with phenotype 2 could benefit from high-intensity statin therapy. Interpretation: A data-driven approach could aid in the identification of patients at a higher risk of adverse clinical outcomes following non-cardioembolic ischaemic stroke. These phenotypes, based on different pathophysiology, can suggest individualized treatment plans. Funding: Beijing Natural Science Foundation (grant number Z200016), Beijing Municipal Committee of Science and Technology (grant number Z201100005620010), National Natural Science Foundation of China (grant number 82101360, 92046016, 82171270), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (grant number 2019-I2M-5-029).

20.
Commun Biol ; 5(1): 887, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36042378

RESUMO

Whether membrane-anchored PD-L1 homodimerizes in living cells is controversial. The biological significance of the homodimer waits to be expeditiously explored. However, characterization of the membrane-anchored full-length PD-L1 homodimer is challenging, and unconventional approaches are needed. By using genetically incorporated crosslinkers, we showed that full length PD-L1 forms homodimers and tetramers in living cells. Importantly, the homodimerized intracellular domains of PD-L1 play critical roles in its complex glycosylation. Further analysis identified three key arginine residues in the intracellular domain of PD-L1 as the regulating unit. In the PD-L1/PD-L1-3RE homodimer, mutations result in a decrease in the membrane abundance and an increase in the Golgi of wild-type PD-L1. Notably, PD-1 binding to abnormally glycosylated PD-L1 on cancer cells was attenuated, and subsequent T-cell induced toxicity increased. Collectively, our study demonstrated that PD-L1 indeed forms homodimers in cells, and the homodimers play important roles in PD-L1 complex glycosylation and T-cell mediated toxicity.


Assuntos
Antígeno B7-H1 , Linfócitos T , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Glicosilação , Linfócitos T/metabolismo
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