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1.
Proc Natl Acad Sci U S A ; 121(18): e2314541121, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38657049

RESUMO

Recent evidence has demonstrated that the transsynaptic nanoscale organization of synaptic proteins plays a crucial role in regulating synaptic strength in excitatory synapses. However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated. In this study, we utilized an engineered proteolysis technique to investigate the effects of acute cleavage of neuroligin-2 (NL2) on synaptic transmission. Our results show that the rapid cleavage of NL2 led to impaired synaptic transmission by reducing both neurotransmitter release probability and quantum size. These changes were attributed to the dispersion of RIM1/2 and GABAA receptors and a weakened spatial alignment between them at the subsynaptic scale, as observed through superresolution imaging and model simulations. Importantly, we found that endogenous NL2 undergoes rapid MMP9-dependent cleavage during epileptic activities, which further exacerbates the decrease in inhibitory transmission. Overall, our study demonstrates the significant impact of nanoscale structural reorganization on inhibitory transmission and unveils ongoing modulation of mature GABAergic synapses through active cleavage of NL2 in response to hyperactivity.


Assuntos
Moléculas de Adesão Celular Neuronais , Proteínas do Tecido Nervoso , Sinapses , Transmissão Sináptica , Animais , Camundongos , Moléculas de Adesão Celular Neuronais/metabolismo , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Epilepsia/patologia , Hipocampo/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Proteólise , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia
2.
Nature ; 577(7790): 350-354, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942055

RESUMO

Transparent piezoelectrics are highly desirable for numerous hybrid ultrasound-optical devices ranging from photoacoustic imaging transducers to transparent actuators for haptic applications1-7. However, it is challenging to achieve high piezoelectricity and perfect transparency simultaneously because most high-performance piezoelectrics are ferroelectrics that contain high-density light-scattering domain walls. Here, through a combination of phase-field simulations and experiments, we demonstrate a relatively simple method of using an alternating-current electric field to engineer the domain structures of originally opaque rhombohedral Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) crystals to simultaneously generate near-perfect transparency, an ultrahigh piezoelectric coefficient d33 (greater than 2,100 picocoulombs per newton), an excellent electromechanical coupling factor k33 (about 94 per cent) and a large electro-optical coefficient γ33 (approximately 220 picometres per volt), which is far beyond the performance of the commonly used transparent ferroelectric crystal LiNbO3. We find that increasing the domain size leads to a higher d33 value for the [001]-oriented rhombohedral PMN-PT crystals, challenging the conventional wisdom that decreasing the domain size always results in higher piezoelectricity8-10. This work presents a paradigm for achieving high transparency and piezoelectricity by ferroelectric domain engineering, and we expect the transparent ferroelectric crystals reported here to provide a route to a wide range of hybrid device applications, such as medical imaging, self-energy-harvesting touch screens and invisible robotic devices.

3.
Small ; 20(27): e2309050, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38312107

RESUMO

With the growing global energy demand and environmental issues, energy saving technologies are becoming increasingly important in the building sector. Conventional windows lack energy saving and thermal insulation capabilities, while Low emissivity glass (Low-e glass) attenuates mobile communication signals while reflecting infrared. Therefore, this paper aims to design a type of windows for the "Sub 6GHz" frequency band of 5G. These windows combine the inherent transparency of traditional glass windows with the energy saving properties of Low-e glass, while also ensuring optimal communication performance within the 5G (Sub 6G) band. The metasurface glass is fabricated and subjected to simulation-guided experiments to evaluate their reliability and practicality. The metasurface glass is rigorously assessed in terms of microwave transmission performance, infrared low emissivity performance, and energy saving and thermal insulation capabilities.

4.
Small ; 20(13): e2308945, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37948432

RESUMO

The family of metal-free molecular perovskites, an emerging novel class of eco-friendly semiconductor, welcomes a new member with a unique 1D hexagonal perovskite structure. Lowering dimensionality at molecular level is a facile strategy for crystal structure conversion, optoelectronic property regulation, and device performance optimization. Herein, the study reports the design, synthesis, packing structure, and photophysical properties of the 1D metal-free molecular perovskite-related single crystal, rac-3APD-NH4I3(rac-3APD= racemic-3-Aminopiperidinium), that features a quantum wire structure formed by infinite chains of face-sharing NH4I6 octahedra, enabling strong quantum confinement with strongly self-trapped excited (STE) states to give efficient warm orange emission with a photoluminescence quantum yield (PLQY) as high as ≈41.6%. The study accordingly unveils its photoexcited carrier dynamics: rac-3APD-NH4I3 relaxes to STE state with a short lifetime of 10 ps but decays to ground state by emitting photons with a relatively longer lifetime of 560 ps. Additionally, strong quantum confinement effect is conducive to charge transport along the octahedral channels that enables the co-planar single-crystal X-ray detectors to achieve a sensitivity as high as 1556 µC Gyair -1 cm-2. This work demonstrates the first case of photoluminescence mechanism and photophysical dynamics of 1D metal-free perovskite-related semiconductor, as well as the promise for high-performance X-ray detector.

5.
Opt Express ; 32(6): 9237-9244, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38571162

RESUMO

Second harmonic generation plays a vital role in frequency conversion which mutually promotes the laser technology and allows the wavebands extension of new coherent source. The monolithic crystals are supposed to be a superior choice for harmonic generation due to long interaction distance, however, the phase-mismatch brought a sharp reduction in the conversion efficiency. Although birefringent phase-matching and quasi-phase-matching techniques are commonly utilized to fill the phase gap in monolithic crystals, these techniques are limited by the natural refractive index of crystal and the domain engineering, respectively. In recent years, subwavelength structures evolve as a flexible scheme to realize phase matching by engineering the geometry features of crystals. Here, structured nanogratings are designed and fabricated on a monolithic PMN-39PT (Pb(Mg1/3Nb2/3)O3-0.39PbTiO3) substrate, a novel ferroelectric crystal with promising optical prospect, for enhancing second harmonic generation, where birefringent or quasi phase-matching is hard to achieve. The nanograting-assisted second harmonic generation enhancement is observed which is not limited by the availability of thin crystalline films. Meanwhile, a boost in the second harmonic signal synchronously promotes the cascading third harmonic generation. This method may provide an alternative solution for enhanced harmonic generation on monolithic substrates and develop potential nonlinear optical materials for frequency conversion.

6.
Environ Sci Technol ; 58(1): 63-74, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38112512

RESUMO

The detrimental effects of bisphenol (BP) exposure are a concern for vulnerable species, Indo-Pacific humpback dolphins (Sousa chinensis). To investigate the characteristics of BP profiles and their adverse impact on humpback dolphins, we assessed the concentrations of six BPs, including bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), bisphenol B (BPB), and bisphenol P (BPP) in blubber (n = 26) and kidney (n = 12) of humpback dolphins stranded in the Pearl River Estuary, China. BPS accounted for the largest proportion of the total bisphenols (∑BPs) in blubber (55%) and kidney (69%). The concentration of ∑BP in blubber was significantly higher than that in the kidney and liver. The EC50 values of five BPA alternatives were lower than those of BPA in humpback dolphin skin fibroblasts (ScSF) and human skin fibroblasts (HSF). ScSF was more sensitive to BPS, BPAF, BPB, and BPP than HSF. The enrichment pathway of BPA was found to be associated with inflammation and immune dysregulation, while BPP and BPS demonstrated a preference for genotoxicity. BPA, BPP, and BPS, which had risk quotients (RQs) > 1, were found to contribute to subhealth and chronic disease in humpback dolphins. According to the EC50-based risk assessment, BPS poses a higher health risk than BPA for humpback dolphins. This study successfully evaluated the risks of bisphenols in rare and endangered cetacean cell lines using a noninvasive method. More in vivo and in field observations are necessary to know whether the BPA alternatives are likely to be regrettable substitutions.


Assuntos
Golfinhos , Poluentes Químicos da Água , Animais , Humanos , Golfinhos/metabolismo , Poluentes Químicos da Água/toxicidade , China , Compostos Benzidrílicos/toxicidade
7.
Environ Sci Technol ; 58(21): 9102-9112, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38752859

RESUMO

Cetaceans play a pivotal role in maintaining the ecological equilibrium of ocean ecosystems. However, their populations are under global threat from environmental contaminants. Various high levels of endocrine-disrupting chemicals (EDCs) have been detected in cetaceans from the South China Sea, such as the Indo-Pacific humpback dolphins in the Pearl River Estuary (PRE), suggesting potential health risks, while the impacts of endocrine disruptors on the dolphin population remain unclear. This study aims to synthesize the population dynamics of the humpback dolphins in the PRE and their profiles of EDC contaminants from 2005 to 2019, investigating the potential role of EDCs in the population dynamics of humpback dolphins. Our comprehensive analysis indicates a sustained decline in the PRE humpback dolphin population, posing a significant risk of extinction. Variations in sex hormones induced by EDC exposure could potentially impact birth rates, further contributing to the population decline. Anthropogenic activities consistently emerge as the most significant stressor, ranking highest in importance. Conventional EDCs demonstrate more pronounced impacts on the population compared to emerging compounds. Among the conventional pollutants, DDTs take precedence, followed by zinc and chromium. The most impactful emerging EDCs are identified as alkylphenols. Notably, as the profile of EDCs changes, the significance of conventional pollutants may give way to emerging EDCs, presenting a continued challenge to the viability of the humpback dolphin population.


Assuntos
Golfinhos , Disruptores Endócrinos , Dinâmica Populacional , Animais , Disruptores Endócrinos/toxicidade , Poluentes Químicos da Água/toxicidade , Monitoramento Ambiental
8.
Environ Res ; 243: 117877, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38070855

RESUMO

In order to reduce the particulate matter pollution to human health in producing environments, series of polyethylene terephthalate/polyvinyl alcohol (PET/PVA) based nanofibrous membranes were fabricated and investigated the dust collection and antibacterial activity. Silver nanoparticles (AgNPs), berberine (Ber) and titanium oxide nanoparticles (TiO2NPs) were selected as antibacterial agents. These novel membranes were well-characterized using SEM, FTIR, TG, etc. techniques. Results of the dust filtration showed that PET/PVA/Ag membrane had the best filtration efficiency of 99.87% for sodium chloride (NaCl) and 99.89% for dioctyl sebacate (DEHS), held low pressure drop of 160.1 Pa for NaCl and 165.3 Pa for DEHS, and posed a high tensile strength of 4.91 MPa. The bacteriostasis studies exhibited that PET/PVA/TiO2 and PET/PVA/Ag membrane showed the highest bacteriological effect on Escherichia coli (98.7%) and Staphylococcus aureus (95.9%), respectively. Meanwhile, in vitro cytotoxicity test indicated no potential cytotoxicity existed in the cell culture process of these two antibacterial membranes. Moreover, the charge distribution in the nanofibers was increased by these antibacterial agents to improve the filtration performance. The dust filtration process synergistically promoted with the antibacterial process in the antibacterial membranes. It was expected that these membranes could be efficient filter medias with broad application prospects in the field of individual protection.


Assuntos
Nanopartículas Metálicas , Nanofibras , Humanos , Antibacterianos/farmacologia , Prata/farmacologia , Nanofibras/toxicidade , Nanopartículas Metálicas/toxicidade , Cloreto de Sódio/farmacologia , Escherichia coli , Poeira
9.
Environ Toxicol ; 39(5): 2502-2511, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38180308

RESUMO

The purpose of this study was to explore the effects of combined lead (Pb) and two types of microplastic (MP) (polyvinyl chloride [PVC] and polyethylene [PE]) exposure on glucose metabolism and investigate the role of the nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor-kappa B (NF-κB) signaling pathway in mediating these effects in mice. Adult C57BL/6J mice were randomly divided into four groups: control, Pb (100 mg/L), MPs (containing 10 mg/L PE and PVC), and Pb + MPs, each of which was treated with drinking water. Treatments were conducted for 6 weeks. Co-exposure to Pb + MPs exhibited increase glycosylated serum protein levels, insulin resistance, and damaged glucose tolerance compared with the control mice. Additionally, treatment with Pb + MPs caused more severe damage to hepatocytes than when exposed to them alone concomitantly, exposed to Pb + MPs exhibited improved the levels of interleukin-6, tumor necrosis factor-alpha, and malondialdehyde, but reduced superoxide dismutase, glutathione peroxidase, and catalase assay in livers. Furthermore, they increase the Kelch-like ECH-associated protein 1 (Keap1) and phosphorylated p-NF-κB protein levels but reduced the protein levels of heme oxygenase-1 and Nrf2, as well as increased Keap1 mRNA and Nrf2 mRNA. Co-exposure to Pb + MP impacts glucose metabolism via the Nrf2 /NF-κB pathway.


Assuntos
NF-kappa B , Plásticos , Camundongos , Animais , NF-kappa B/metabolismo , Plásticos/metabolismo , Plásticos/farmacologia , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Microplásticos , Chumbo , Camundongos Endogâmicos C57BL , Estresse Oxidativo , RNA Mensageiro/metabolismo , Glucose/farmacologia
10.
Small ; 19(43): e2302623, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37357165

RESUMO

Bismuth chalcohalides (BiSeI and BiSI), a class of superior light absorbers, have recently garnered great attention owing to their promise in constructing next-generation optoelectronic devices. However, to date, the photodetection application of bismuth chalcohalides is still limited due to the challenge in controllable preparation. Herein, the synthesis of large-scale quasi-1D BiSeI nanowires via chemical vapor deposition growth is reported. By precisely tuning the growth temperature and the Se supply, it can effectively control the growth thermodynamics and kinetics of BiSeI crystal, and thus achieve high purity quasi-1D BiSeI nanowires with high crystal quality, uniform diameter, and tunable domain length. Theory and optical characterizations of the quasi-1D BiSeI nanowires reveal an indirect bandgap of 1.57 eV with prominent optical linear dichroism. As a result, the quasi-1D BiSeI nanowire-based photodetector demonstrates a broadband photoresponse (400-800 nm) with high responsivity of 5880 mA W-1 , fast response speed of 0.11 ms and superior air stability. More importantly, the photodetector displays strong polarization sensitivity (anisotropic ratio = 1.77) under the 532 nm light irradiation. This work will provide important guides to the synthesis of other quais-1D metal chalcohalides and shed light on their potential in constructing novel multifunctional optoelectronic devices.

11.
J Transl Med ; 21(1): 335, 2023 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-37211606

RESUMO

BACKGROUND: Interleukin-17A (IL-17A), a proinflammatory cytokine primarily secreted by Th17 cells, γδT cells and natural killer T (NKT) cells, performs essential roles in the microenvironment of certain inflammation-related tumours by regulating cancer growth and tumour elimination proved in previous literature. In this study, the mechanism of IL-17A that induces mitochondrial dysfunction promoted pyroptosis has been explored in colorectal cancer cells. METHOD: The records of 78 patients diagnosed with CRC were reviewed via the public database to evaluate clinicopathological parameters and prognosis associations of IL-17A expression. The colorectal cancer cells were treated with IL-17A, and the morphological characteristics of those cells were indicated by scanning electron microscope and transmission electron microscope. After IL-17A treatment, mitochondrial dysfunction was tested by mitochondrial membrane potential (MMP) and reactive oxygen species (ROS). The expression of pyroptosis associated proteins including cleaved caspase-4, cleaved gasdermin-D (GSDMD), IL-1ß, receptor activator of nuclear NOD-like receptor family pyrin domain containing 3 (NLRP3), apoptosis-associated speck like protein containing a card (ASC), and factor-kappa B was measured through western blotting. RESULTS: Positive IL-17A protein expression was observed in CRC compared to the non-tumour tissue. IL-17A expression indicates a better differentiation, earlier stage, and better overall survival in CRC. IL-17A treatment could induce mitochondrial dysfunction and stimulate intracellular reactive oxygen species (ROS) production. Furthermore, IL-17A could promote pyroptosis of colorectal cancer cells and significantly increase the secretion of inflammatory factors. Nevertheless, the pyroptosis induced by IL-17A could be inhibited through the pre-treatment with Mito-TEMPO (a mitochondria-targeted superoxide dismutase mimetic with superoxide and alkyl radical scavenging properties) or Z-LEVD-FMK (caspase-4 inhibitor, fluoromethylketone). Additionally, after being treated with IL-17A, an increasing number of CD8 + T cells showed in mouse-derived allograft colon cancer models. CONCLUSION: IL-17A, as a cytokine mainly secreted by γδT cells in the colorectal tumour immune microenvironment, can regulate the tumour microenvironment in multiple ways. IL-17A could induce mitochondrial dysfunction and pyroptosis through the ROS/NLRP3/caspase-4/GSDMD pathway, and promote intracellular ROS accumulation. In addition, IL-17A can promote the secretion of inflammatory factors such as IL-1ß、IL-18 and immune antigens, and recruit CD8 + T cells to infiltrate tumours.


Assuntos
Neoplasias Colorretais , Proteína 3 que Contém Domínio de Pirina da Família NLR , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Interleucina-17/metabolismo , Mitocôndrias/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias Colorretais/metabolismo , Inflamassomos/metabolismo , Microambiente Tumoral
12.
Neuropathol Appl Neurobiol ; 49(4): e12924, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37461203

RESUMO

AIMS: Synaptic strength depends strongly on the subsynaptic organisation of presynaptic transmitter release and postsynaptic receptor densities, and their alterations are expected to underlie pathologies. Although synaptic dysfunctions are common pathogenic traits of Alzheimer's disease (AD), it remains unknown whether synaptic protein nano-organisation is altered in AD. Here, we systematically characterised the alterations in the subsynaptic organisation in cellular and mouse models of AD. METHODS: We used immunostaining and super-resolution stochastic optical reconstruction microscopy imaging to quantitatively examine the synaptic protein nano-organisation in both Aß1-42-treated neuronal cultures and cortical sections from a mouse model of AD, APP23 mice. RESULTS: We found that Aß1-42-treatment of cultured hippocampal neurons decreased the synaptic retention of postsynaptic scaffolds and receptors and disrupted their nanoscale alignment to presynaptic transmitter release sites. In cortical sections, we found that while GluA1 receptors in wild-type mice were organised in subsynaptic nanoclusters with high local densities, receptors in APP23 mice distributed more homogeneously within synapses. This reorganisation, together with the reduced overall receptor density, led to reduced glutamatergic synaptic transmission. Meanwhile, the transsynaptic alignment between presynaptic release-guiding RIM1/2 and postsynaptic scaffolding protein PSD-95 was reduced in APP23 mice. Importantly, these reorganisations were progressive with age and were more pronounced in synapses in close vicinity of Aß plaques with dense cores. CONCLUSIONS: Our study revealed a spatiotemporal-specific reorganisation of synaptic nanostructures in AD and identifies dense-core amyloid plaques as the major local inductor in APP23 mice.


Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/patologia , Sinapses/patologia , Neurônios/patologia , Transmissão Sináptica/fisiologia , Peptídeos beta-Amiloides/metabolismo , Modelos Animais de Doenças , Camundongos Transgênicos
13.
Opt Express ; 31(3): 3731-3742, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36785359

RESUMO

Present study reports a novel visible-light transparent, microwave broadband absorbing metamaterial. The designed structure is implemented using three different sizes of indium tin oxide (ITO) conductive film patch arrays, which is capable of achieving a reflection coefficient ≤ -10 dB from 2.2 to 18 GHz in simulations. Moreover, a fractional bandwidth of about 156.4% and the absorber thickness of only 0.088 times the cutoff wavelength (the lowest absorption frequency) was achieved. Changing the angle of incidence ensures a good absorption effect with large angle stability, and the absorber has good transmission in the visible range. In accordance with the simulation, a sample with a size of 299 × 299 mm was fabricated, and its wave absorption performance was assessed. The experimental results and the various incidence angles in the simulation of the TE and TM modes correspond well, allowing for the realization of large angle broadband absorption at frequencies ranging from 2.2 to 18 GHz. Thus, it has been found that the structure has good optical transparency and broadband radar absorption capability, both of which will have a wide range of applications in the fields of multi-spectrum stealth and electromagnetic compatibility.

14.
Opt Express ; 31(15): 25104-25116, 2023 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-37475323

RESUMO

Deep-learning (DL) methods have gained significant attention in ghost imaging (GI) as promising approaches to attain high-quality reconstructions with limited sampling rates. However, existing DL-based GI methods primarily emphasize pixel-level loss and one-to-one mapping from bucket signals or low-quality GI images to high-quality images, tending to overlook the diversity in image reconstruction. Interpreting image reconstruction from the perspective of conditional probability, we propose the utilization of the denoising diffusion probabilistic model (DDPM) framework to address this challenge. Our designed method, known as DDPMGI, can not only achieve better quality but also generate reconstruction results with high diversity. At a sampling rate of 10%, our method achieves an average PSNR of 21.19 dB and an SSIM of 0.64, surpassing the performance of other comparison methods. The results of physical experiments further validate the effectiveness of our approach in real-world scenarios. Furthermore, we explore the potential application of our method in color GI reconstruction, where the average PSNR and SSIM reach 20.055 dB and 0.723, respectively. These results highlight the significant advancements and potential of our method in achieving high-quality image reconstructions in GI, including color image reconstruction.

15.
Chemistry ; 29(65): e202301883, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37653541

RESUMO

Enantiomerically pure acyclic O,O-acetal compounds (up to 97 % ee) have been accessed through chemo-, regio- and enantioselective palladium-catalyzed addition of oximes to alkoxyallenes. DFT calculations support that a protonative hydropalladation pathway is favourable, in which the hydrogen bonding interaction between the amide group of the diphosphine ligand and the alkoxyallene is critical for the highly stereoselective formation of the dioxygenated stereogenic center.

16.
FASEB J ; 36(5): e22329, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35476303

RESUMO

USP2 contributes to the quality control of multiple oncogenic proteins including cyclin D1, Mdm2, Aurora-A, etc., and it is a potential target for anti-cancer drug development. However, currently only a few inhibitors with moderate inhibition activities against USP2 have been discovered. USP2-targeted active compounds with either new scaffolds or enhanced activities are in need. Here in this study, Ub-AMC hydrolysis assay-based screening against ~4000 commercially available drugs and drug candidates was performed to identify USP2-targeted inhibitors. COH29, which was originally developed as an anti-cancer agent by blocking the function of human ribonucleotide reductase (RNR, IC50  = 16 µM), was found to exhibit an inhibition activity against USP2 with the IC50 value at 2.02 ± 0.16 µM. The following conducted biophysical and biochemical experiments demonstrated that COH29 could specifically interact with USP2 and inhibit its enzymatic activity in a noncompetitive inhibition mode (Ki  = 1.73 ± 0.14 µM). Since COH29 shows similar inhibitory potencies against RNR (RRM2) and USP2, USP2 inhibition-dependent cellular consequences of COH29 are expected. The results of cellular assays confirmed that the application of COH29 could downregulate the level of cyclin D1 by enhancing its degradation via ubiquitin-proteasome system (UPS), and the modulation effect of COH29 on cyclin D1 is independent of RRM2. Since cyclin D1 acts as an oncogenic driver in human cancer, our findings suggest that USP2 might be a promising therapeutic target for cyclin D1-addicted cancers, and COH29 could serve as a starting compound for high selectivity inhibitor development against USP2.


Assuntos
Benzamidas , Ciclina D1 , Neoplasias , Ribonucleotídeo Redutases , Tiazóis , Ubiquitina Tiolesterase , Benzamidas/farmacologia , Ciclina D1/genética , Ciclina D1/metabolismo , Regulação para Baixo , Inibidores Enzimáticos/farmacologia , Holoenzimas , Humanos , Neoplasias/metabolismo , Ribonucleotídeo Redutases/antagonistas & inibidores , Ribonucleotídeo Redutases/metabolismo , Tiazóis/farmacologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo , Proteases Específicas de Ubiquitina
17.
Brain ; 145(12): 4232-4245, 2022 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-35139179

RESUMO

RAC1 is a highly conserved Rho GTPase critical for many cellular and developmental processes. De novo missense RAC1 variants cause a highly variable neurodevelopmental disorder. Some of these variants have previously been shown to have a dominant negative effect. Most previously reported patients with this disorder have either severe microcephaly or severe macrocephaly. Here, we describe eight patients with pathogenic missense RAC1 variants affecting residues between Q61 and R68 within the switch II region of RAC1. These patients display variable combinations of developmental delay, intellectual disability, brain anomalies such as polymicrogyria and cardiovascular defects with normocephaly or relatively milder micro- or macrocephaly. Pulldown assays, NIH3T3 fibroblast spreading assays and staining for activated PAK1/2/3 and WAVE2 suggest that these variants increase RAC1 activity and over-activate downstream signalling targets. Axons of neurons isolated from Drosophila embryos expressing the most common of the activating variants are significantly shorter, with an increased density of filopodial protrusions. In vivo, these embryos exhibit frequent defects in axonal organization. Class IV dendritic arborization neurons expressing this variant exhibit a significant reduction in the total area of the dendritic arbour, increased branching and failure of self-avoidance. RNAi knock down of the WAVE regulatory complex component Cyfip significantly rescues these morphological defects. These results establish that activating substitutions affecting residues Q61-R68 within the switch II region of RAC1 cause a developmental syndrome. Our findings reveal that these variants cause altered downstream signalling, resulting in abnormal neuronal morphology and reveal the WAVE regulatory complex/Arp2/3 pathway as a possible therapeutic target for activating RAC1 variants. These insights also have the potential to inform the mechanism and therapy for other disorders caused by variants in genes encoding other Rho GTPases, their regulators and downstream effectors.


Assuntos
Megalencefalia , Transtornos do Neurodesenvolvimento , Proteínas rac1 de Ligação ao GTP , Animais , Camundongos , Megalencefalia/genética , Transtornos do Neurodesenvolvimento/genética , Neurônios , Células NIH 3T3 , Transdução de Sinais/genética
18.
Environ Res ; 226: 115699, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36933635

RESUMO

Pneumoconiosis in mines occupied more than 90% of the total number of occupational diseases, poses tremendous pressure and challenges on the development of personal protection materials with high dust filtration efficiency and long-lasting comfortable wearing. In this study, a kind of polyethylene terephthalate (PET) based filter media with the bead-on-string structure and hydrophobic/oleophobic property was designed and fabricated by electrospinning technology. Nanoscale silicon dioxide (SiO2NPs) and fluorinated polyurethane (PU) used in this work were benefited for the microstructure, surface energy and hydrophobic/oleophobic property, respectively. The morphology and composition of the membranes were conducted by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and fourier transform infrared spectroscopy (FTIR). Furthermore, the filtration performance, pressure drop, moisture permeability and breathing comfortable performance were measured for the study of personal protection of dust. The results showed that at the air flow of 85 L min-1, PET/SiO2/FPU double-layer nanofibrous membrane showed high filtration efficiency and low pressure drop with the filtration efficiency of 99.96%, pressure drop of 142.5 Pa and quality factor of 0.055 Pa-1, respectively. A long term of 24 h water vapor test had proved that this membrane held an outstanding moisture permeability ability of 5296.325 g (m2 24 h)-1. Compared with the commercial 3701CN filter media, the advantages of the regular breathing frequency and strong heart rate control ability indicated that this PET/SiO2/FPU double-layer membrane had the better wearing comfortable performance with broad application prospects in the personal protection of dust in mines.


Assuntos
Poeira , Nanofibras , Dióxido de Silício , Filtração/métodos , Interações Hidrofóbicas e Hidrofílicas
19.
Nano Lett ; 22(14): 5973-5981, 2022 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-35819349

RESUMO

Next-generation wearable electronics requires mechanical robustness. In addition to the previously reported eco-friendliness, low cost, and light weight of molecular perovskites, flexibility is also a desired merit for their practical use. Here we design a flexible X-ray detector based on a novel molecular perovskite, DABCO-CsBr3 (DABCO = N-N'-diazabicyclo[2.2.2]octonium), which is the missing link between metal-free molecular perovskites A(NH4)X3 (A = divalent organic ammoniums) and conventional metal halide based ABX3 (B = divalent metal cations) perovskites. DABCO-CsBr3 inherits its band nature from A(NH4)X3, while it exhibits a stronger stopping power. DABCO-CsBr3 shows potential for high-performance ionizing radiation detectors due to low dark current, low ion migration, and an efficient mobility-lifetime (µτ) product. Finally, a molecular-perovskite-based flexible X-ray detector is demonstrated on the basis of the DABCO-CsBr3/poly(vinylidene fluoride) composite, with a sensitivity of 106.7 µC Gyair-1 cm-2. This work enriches the molecular perovskite family and highlights the promise of molecular perovskites for the next-generation eco-friendly and wearable optoelectronic devices.


Assuntos
Compostos de Cálcio , Óxidos , Titânio , Raios X
20.
Zhongguo Zhong Yao Za Zhi ; 48(5): 1289-1299, 2023 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-37005813

RESUMO

This study compared the ameliorating effects of L-borneol, natural borneol, and synthetic borneol on the injury of different brain regions in the rat model of acute phase of cerebral ischemia/reperfusion(I/R) for the first time, which provides a reference for guiding the rational application of borneol in the early treatment of ischemic stroke and has important academic and application values. Healthy specific pathogen-free(SPF)-grade SD male rats were randomly assigned into 13 groups: a sham-operation group, a model group, a Tween model group, a positive drug(nimodipine) group, and high-, medium-, and low-dose(0.2, 0.1, and 0.05 g·kg~(-1), respectively) groups of L-borneol, natural borneol, and synthetic borneol according to body weight. After 3 days of pre-administration, the rat model of I/R was established by suture-occluded method and confirmed by laser speckle imaging. The corresponding agents in different groups were then administered for 1 day. The body temperature was monitored regularly before pre-administration, days 1, 2, and 3 of pre-administration, 2 h after model awakening, and 1 d after model establishment. Neurological function was evaluated based on Zea-Longa score and modified neurological severity score(mNSS) 2 h and next day after awakening. The rats were anesthetized 30 min after the last administration, and blood was collected from the abdominal aorta. Enzyme-linked immunoassay assay(ELISA) was employed to determine the serum levels of tumor necrosis factor-alpha(TNF-α), interleukin-6(IL-6), IL-4, and transforming growth factor-beta1(TGF-ß1). The brain tissues were stained with triphenyltetrazolium chloride(TTC) for the calculation of cerebral infarction rate, and hematoxylin-eosin(HE) staining was used for observing and semi-quantitatively evaluating the pathological damage in different brain regions. Immunohistochemistry was employed to detect the expression of ionized calcium binding adapter molecule 1(IBA1) in microglia. q-PCR was carried out to determine the mRNA levels of iNOS and arginase 1(Arg1), markers of polarization phenotype M1 and M2 in microglia. Compared with the sham-operation group, the model group and the Tween model group showed significantly elevated body temperature, Zea-Longa score, mNSS, and cerebral infarction rate, severely damaged cortex, hippocampus, and striatum, increased serum levels of IL-6 and TNF-α, and decreased serum levels of IL-4 and TGF-ß1. The three borneol products had a tendency to reduce the body temperature of rats 1 day after modeling. Synthetic borneol at the doses of 0.2 and 0.05 g·kg~(-1), as well as L-borneol of 0.1 g·kg~(-1), significantly reduced Zea-Longa score and mNSS. The three borneol products at the dose of 0.2 g·kg~(-1) significantly reduced the cerebral infarction rate. L-borneol at the doses of 0.2 and 0.1 g·kg~(-1) and natural borneol at the dose of 0.1 g·kg~(-1) significantly reduced the pathological damage of the cortex. L-borneol and natural borneol at the dose of 0.1 g·kg~(-1) attenuated the pathological damage of hippocampus, and 0.2 g·kg~(-1) L-borneol attenuated the damage of striatum. The 0.2 g·kg~(-1) L-borneol and the three doses of natural borneol and synthetic borneol significantly reduced the serum level of TNF-α, and the 0.1 g·kg~(-1) synthetic borneol reduced the level of IL-6. L-borneol and synthetic borneol at the dose of 0.2 g·kg~(-1) significantly inhibited the activation of cortical microglia, and 0.2 g·kg~(-1) L-borneol up-regulated the expression of Arg1 and down-regulated the expression level of iNOS. In conclusion, the three borneol products may alleviate inflammation to ameliorate the pathological damage of brain regions of rats in the acute phase of I/R by inhibiting the activation of microglia and promoting the polarization of microglia from M1 type to M2 type. The protective effect on brain followed a trend of L-borneol > synthetic borneol > natural borneol. We suggest L-borneol the first choice for the treatment of I/R in the acute phase.


Assuntos
Isquemia Encefálica , Traumatismo por Reperfusão , Ratos , Masculino , Animais , Fator de Crescimento Transformador beta1/metabolismo , Ratos Sprague-Dawley , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Interleucina-4/metabolismo , Polissorbatos , Encéfalo , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo , Infarto Cerebral , Reperfusão
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