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1.
Mol Ecol ; : e17334, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38651763

RESUMO

Visual cues are of critical importance for the attraction of animal pollinators, however, little is known about the molecular mechanisms underpinning intraspecific floral colour variation. Here, we combined comparative spectral analysis, targeted metabolite profiling, multi-tissue transcriptomics, differential gene expression, sequence analysis and functional analysis to investigate a bee-pollinated orchid species, Glossodia major with common purple- and infrequent white-flowered morphs. We found uncommon and previously unreported delphinidin-based anthocyanins responsible for the conspicuous and pollinator-perceivable colour of the purple morph and three genetic changes underpinning the loss of colour in the white morph - (1) a loss-of-function (LOF; frameshift) mutation affecting dihydroflavonol 4-reductase (DFR1) coding sequence due to a unique 4-bp insertion, (2) specific downregulation of functional DFR1 expression and (3) the unexpected discovery of chimeric Gypsy transposable element (TE)-gene (DFR) transcripts with potential consequences to the genomic stability and post-transcriptional or epigenetic regulation of DFR. This is one of few known cases where regulatory changes and LOF mutation in an anthocyanin structural gene, rather than transcription factors, are important. Furthermore, if TEs prove to be a frequent source of mutation, the interplay between environmental stress-induced TE evolution and pollinator-mediated selection for adaptive colour variation may be an overlooked mechanism maintaining floral colour polymorphism in nature.

2.
Chem Biodivers ; 21(4): e202301610, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38379194

RESUMO

BACKGROUND: SHP2 is highly expressed in a variety of cancer and has emerged as a potential target for cancer therapeutic agents. The identification of uncharged pTyr mimics is an important direction for the development of SHP2 orthosteric inhibitors. METHODS: Surface plasmon resonance analysis and cellular thermal shift assay were employed to verify the direct binding of LXQ-217 to SHP2. The inhibitory effect of LXQ-217 was characterized by linear Weaver-Burke enzyme kinetic analysis and BIOVIA Discovery Studio. The inhibition of tumor cell proliferation by LXQ-217 was characterized by cell viability assay, colony formation assays and hoechst 33258 staining. The inhibition of lung cancer proliferation in vivo was studied in nude mice after oral administration of LXQ-217. RESULTS: An electroneutral bromophenol derivative, LXQ-217, was identified as a competitive SHP2 inhibitor. LXQ-217 induced apoptosis and inhibited growth of human pulmonary epithelial cells by affecting the RAS-ERK and PI3 K-AKT signaling pathways. Long-term oral administration of LXQ-217 significantly inhibited the proliferation ability of lung cancer cells in nude mice. Moreover, mice administered LXQ-217 orally at high doses exhibited no mortality or significant changes in vital signs. CONCLUSIONS: Our findings on the uncharged orthosteric inhibitor provide a foundation for further development of a safe and effective anti-lung cancer drug.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Cinética , Neoplasias Pulmonares/tratamento farmacológico , Camundongos Nus , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Fenóis/síntese química , Fenóis/química , Fenóis/farmacologia
3.
Int J Mol Sci ; 25(6)2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38542463

RESUMO

DNA-binding with one finger (Dof) proteins comprise a large family that play central roles in stress tolerance by regulating the expression of stress-responsive genes via the DOFCORE element or by interacting with other regulatory proteins. Although the Dof TF has been identified in a variety of species, its systemic analysis in potato (Solanum tuberosum L.) is lacking and its potential role in abiotic stress responses remains unclear. A total of 36 potential Dof genes in potato were examined at the genomic and transcriptomic levels in this work. Five phylogenetic groups can be formed from these 36 Dof proteins. An analysis of cis-acting elements revealed the potential roles of Dofs in potato development, including under numerous abiotic stress conditions. The cycling Dof factors (CDFs) might be the initial step in the abiotic stress response signaling cascade. In potato, five CDFs (StCDF1/StDof19, StCDF2/StDof4, StCDF3/StDof11, StCDF4/StDof24, and StCDF5/StDof15) were identified, which are homologs of Arabidopsis CDFs. The results revealed that these genes were engaged in a variety of abiotic reactions. Moreover, an expression analysis of StDof genes in two potato cultivars ('Long10' (drought tolerant) and 'DXY' (drought susceptible)) of contrasting tolerances under drought stress was carried out. Further, a regulatory network mediated by lncRNA and its target Dofs was established. The present study provides fundamental knowledge for further investigation of the roles of Dofs in the adaptation of potato to drought stress, aiming to provide insights into a viable strategy for crop improvement and stress-resistance breeding.


Assuntos
Arabidopsis , Solanum tuberosum , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Resistência à Seca , Filogenia , Melhoramento Vegetal , Arabidopsis/genética , Secas , DNA/metabolismo , Estresse Fisiológico/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
4.
Mar Drugs ; 21(2)2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36827168

RESUMO

Antarctic krill (Euphausia superba) of the Euphausiidae family comprise one of the largest biomasses in the world and play a key role in the Antarctic marine ecosystem. However, the study of E. superba-derived microbes and their secondary metabolites has been limited. Chemical investigation of the secondary metabolites of the actinomycetes Nocardiopsis sp. LX-1 (in the family of Nocardiopsaceae), isolated from E. superba, combined with molecular networking, led to the identification of 16 compounds a-p (purple nodes in the molecular network) and the isolation of one new pyrroline, nocarpyrroline A (1), along with 11 known compounds 2-12. The structure of the new compound 1 was elucidated by extensive spectroscopic investigation. Compound 2 exhibited broad-spectrum antibacterial activities against A. hydrophila, D. chrysanthemi, C. terrigena, X. citri pv. malvacearum and antifungal activity against C. albicans in a conventional broth dilution assay. The positive control was ciprofloxacin with the MIC values of <0.024 µM, 0.39 µM, 0.39 µM, 0.39 µM, and 0.20 µM, respectively. Compound 1 and compounds 7, 10, and 11 displayed antifungal activities against F. fujikuroi and D. citri, respectively, in modified agar diffusion test. Prochloraz was used as positive control and showed the inhibition zone radius of 17 mm and 15 mm against F. fujikuroi and D. citri, respectively. All the annotated compounds a-p by molecular networking were first discovered from the genus Nocardiopsis. Nocarpyrroline A (1) features an unprecedented 4,5-dihydro-pyrrole-2-carbonitrile substructure, and it is the first pyrroline isolated from the genus Nocardiopsis. This study further demonstrated the guiding significance of molecular networking in the research of microbial secondary metabolites.


Assuntos
Actinobacteria , Euphausiacea , Animais , Nocardiopsis , Euphausiacea/química , Actinomyces , Antifúngicos , Ecossistema , Pirróis , Regiões Antárticas
5.
Plant J ; 105(6): 1495-1506, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33300184

RESUMO

Vitis amurensis (Shanputao) is the most cold tolerant Vitis species and so is of great interest to grape breeders and producers in areas with low winter temperatures. Here, we report its high-quality, chromosome-level genome assembly based on a combination of sequence data from Illumina and PacBio platforms, BioNano optical mapping and high-throughput chromosome conformation Capture (Hi-C) mapping. The 604.56-Mb genome contains 32 885 protein-coding genes. Shanputao was found to share a common ancestor with PN40024 (V. vinifera) approximately 2.17-2.91 million years ago, and gene expansion observed in Shanputao might contribute to the enhancement of cold tolerance. Transcriptome analysis revealed 17 genes involved in cold signal transduction, suggesting that there was a different response mechanism to chilling temperature and freezing conditions. Furthermore, a genome-wide association study uncovered a phosphoglycerate kinase gene that may contribute to the freezing resistance of buds in the winter. The Shanputao genome sequence not only represents a valuable resource for grape breeders, but also is important for clarifying the molecular mechanisms involved in cold tolerance.


Assuntos
Genoma de Planta/genética , Vitis/genética , Resposta ao Choque Frio/genética , Congelamento , Perfilação da Expressão Gênica , Genes de Plantas/genética , Estudo de Associação Genômica Ampla , Fosfoglicerato Quinase/genética , Filogenia , Proteínas de Plantas/genética , Análise de Sequência de DNA , Vitis/metabolismo , Vitis/fisiologia
6.
Plant Physiol ; 186(3): 1660-1678, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-33752238

RESUMO

Cultivated grapevine (Vitis) is a highly valued horticultural crop, and cold stress affects its growth and productivity. Wild Amur grape (Vitis amurensis) PAT1 (Phytochrome A signal transduction 1, VaPAT1) is induced by low temperature, and ectopic expression of VaPAT1 enhances cold tolerance in Arabidopsis (Arabidopsis thaliana). However, little is known about the molecular mechanism of VaPAT1 during the cold stress response in grapevine. Here, we confirmed the overexpression of VaPAT1 in transformed grape calli enhanced cold tolerance. Yeast two-hybrid and bimolecular fluorescence complementation assays highlighted an interaction between VaPAT1 with INDETERMINATE-DOMAIN 3 (VaIDD3). A role of VaIDD3 in cold tolerance was also indicated. Transcriptome analysis revealed VaPAT1 and VaIDD3 overexpression and cold treatment coordinately modulate the expression of stress-related genes including lipoxygenase 3 (LOX3), a gene encoding a key jasmonate biosynthesis enzyme. Co-expression network analysis indicated LOX3 might be a downstream target of VaPAT1. Both electrophoretic mobility shift and dual luciferase reporter assays showed the VaPAT1-IDD3 complex binds to the IDD-box (AGACAAA) in the VaLOX3 promoter to activate its expression. Overexpression of both VaPAT1 and VaIDD3 increased the transcription of VaLOX3 and JA levels in transgenic grape calli. Conversely, VaPAT1-SRDX (dominant repression) and CRISPR/Cas9-mediated mutagenesis of PAT1-ED causing the loss of the C-terminus in grape calli dramatically prohibited the accumulation of VaLOX3 and JA levels during cold treatment. Together, these findings point to a pivotal role of VaPAT1 in the cold stress response in grape by regulating JA biosynthesis.


Assuntos
Resposta ao Choque Frio/genética , Resposta ao Choque Frio/fisiologia , Ciclopentanos/metabolismo , Oxilipinas/metabolismo , Fatores de Transcrição , Vitis/genética , Vitis/metabolismo , Produtos Agrícolas/genética , Produtos Agrícolas/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Variação Genética , Genótipo , Plantas Geneticamente Modificadas , Especificidade da Espécie
7.
Mar Drugs ; 20(5)2022 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-35621985

RESUMO

With the increasingly serious antimicrobial resistance, discovering novel antibiotics has grown impendency. The Antarctic abundant microbial resources, especially fungi, can produce unique bioactive compounds for adapting to the hostile environment. In this study, three Antarctic fungi, Chrysosporium sp. HSXSD-11-1, Cladosporium sp. HSXSD-12 and Acrostalagmus luteoalbus CH-6, were found to have the potential to produce antimicrobial compounds. Furthermore, the crude extracts of CH-6 displayed the strongest antimicrobial activities with 72.3-84.8% growth inhibition against C. albicans and Aeromonas salmonicida. The secondary metabolites of CH-6 were researched by bioactivity tracking combined with molecular networking and led to the isolation of two new α-pyrones, acrostalapyrones A (1) and B (2), along with one known analog (3), and three known indole diketopiperazines (4-6). The absolute configurations of 1 and 2 were identified through modified Mosher's method. Compounds 4 and 6 showed strong antimicrobial activities. Remarkably, the antibacterial activity of 6 against A. salmonicida displayed two times higher than that of the positive drug Ciprofloxacin. This is the first report to discover α-pyrones from the genus Acrostalagmus, and the significant antimicrobial activities of 4 and 6 against C. albicans and A. salmonicida. This study further demonstrates the great potential of Antarctic fungi in the development of new compounds and antibiotics.


Assuntos
Ascomicetos , Pironas , Regiões Antárticas , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Ascomicetos/metabolismo
8.
Plant Cell Physiol ; 62(10): 1615-1629, 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34279666

RESUMO

Cold tolerance is regulated by a variety of transcription factors (TFs) and their target genes. Except for the well-characterized C-repeat binding factors (CBFs)-dependent transcriptional cascade, the mechanisms of cold tolerance mediated by other transcriptional regulatory networks are still largely unknown. Here, we used the assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA-seq to identify cold responsive TFs in Vitis amurensis, a grape species with high cold hardiness. Nine TFs, including CBF4, RAV1 and ERF104, were identified after cold treatment. Weighted gene co-expression network analysis (WGCNA) and gene ontology (GO) analysis revealed that these TFs may regulate cold response through different pathways. As a prime candidate TF, overexpression of VaRAV1 in grape cells improved its cold tolerance. The transgenic cells exhibited low electrolyte leakage and malondialdehyde content and high peroxidase activity. Moreover, the TF gene TCP8 and a gene involving in homogalacturonan biosynthesis were found to be regulated by VaRAV1, suggesting that the contribution of VaRAV1 to cold tolerance may be achieved by enhancing the stability of cell membrane and regulating the expression of target genes involved in plant cell wall composition. Our work provides novel insights into plant response to cold stress and demonstrates the utility of ATAC-seq and RNA-seq for the rapid identification of TFs in response to cold stress in grapevine. VaRAV1 may play an important role in adaption to cold stress.


Assuntos
Cromatina/metabolismo , Temperatura Baixa , Expressão Gênica , Proteínas de Plantas/genética , Fatores de Transcrição/genética , Vitis/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Fatores de Transcrição/metabolismo , Vitis/metabolismo
9.
Planta ; 253(2): 55, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33523295

RESUMO

MAIN CONCLUSION: Dof genes enhance cold tolerance in grapevine and VaDof17d is tightly associated with the cold-responsive pathway and with the raffinose family oligosaccharides. DNA-binding with one finger (Dof) proteins comprise a large family that plays important roles in the regulation of abiotic stresses. No in-depth analysis of Dof genes has been performed in the grapevine. In this study, we analyzed a total of 25 putative Dof genes in grapevine at genomic and transcriptomic levels, compiled expression profiles of 11 selected VaDof genes under cold stress and studied the potential function of the VaDof17d gene in grapevine calli. The 25 Dof proteins can be classified into four phylogenetic groups. RNA-seq and qRT-PCR results demonstrated that a total of 11 VaDof genes responded to cold stress. Comparative mRNA sequencing of 35S::VaDof17d grape calli showed that VaDof17d was tightly associated with the cold-responsive pathway and with the raffinose family oligosaccharides (RFOs), as observed by the up-regulation of galactinol synthase (GolS) and raffinose synthase genes. We found that the Dof17d-ED (CRISPR/Cas9-mediated mutagenesis of Dof17d-ED) mutant had low cold tolerance with a decreased RFOs level during cold stress. These results formed the fundamental knowledge for further analysis of the biological roles of Dof genes in the grapevine's adaption to cold stresses.


Assuntos
Resposta ao Choque Frio , Proteínas de Plantas , Resposta ao Choque Frio/genética , Regulação da Expressão Gênica de Plantas , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transcriptoma/genética
10.
Opt Express ; 29(14): 21921-21935, 2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34265968

RESUMO

Monitoring cloud droplet effective radius (re) is of great significance for studying aerosol-cloud interactions (ACI). Passive satellite retrieval, e.g., MODIS (Moderate Resolution Imaging Spectroradiometer), requires sunlight. This requirement prompted developing re retrieval using active sensors, e.g., CALIOP (Cloud-Aerosol Lidar with Orthogonal Polarization). Given the highest sensitivity of vertically homogeneous clouds to aerosols that feed to cloud base, here CALIOP profile measurements were used for the first time to quantify cloud vertical homogeneity and estimate cloud re during both day and night. Comparison using simultaneous Aqua-MODIS measurements demonstrates that CALIOP retrieval has the highest accuracy for vertically homogeneous clouds, with R2 (MAE, RMSE) of 0.72 (1.75 µm, 2.25 µm), while the accuracy is lowest for non-homogeneous clouds, with R2 (MAE, RMSE) of 0.60 (2.90 µm, 3.70 µm). The improved re retrieval in vertically homogeneous clouds provides a basis for possible breakthrough insights in ACI by CALIOP since re in such clouds reflects most directly aerosol effects on cloud properties. Global day-night maps of cloud vertical homogeneity and respective re are presented.

11.
J Opt Soc Am A Opt Image Sci Vis ; 38(4): 579-586, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33798188

RESUMO

Registration of 3D lidar point clouds with optical images is critical in the combination of multisource data. Geometric misalignment originally exists in the pose data between lidar point clouds and optical images. To improve the accuracy of the initial pose and the applicability of the integration of 3D points and image data, we develop a simple but efficient registration method. We first extract point features from lidar point clouds and images: point features are extracted from single-frame lidar and point features are extracted from images using a classical Canny operator. The cost map is subsequently built based on Canny image edge detection. The optimization direction is guided by the cost map, where low cost represents the desired direction, and loss function is also considered to improve the robustness of the proposed method. Experiments show positive results.

12.
Angew Chem Int Ed Engl ; 60(25): 13871-13876, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-33851763

RESUMO

Palladium-catalyzed direct C-H activation of indole benzenoid moiety has been achieved in the past decade. However, palladium-catalyzed remote C-H activation of indoles is rare. Herein, we report a challenging palladium-catalyzed remote C4-H phosphonylation of indoles by a radical approach. The method provides access to a series of C4-phosphonylated indoles, including tryptophan and tryptophan-containing dipeptides, which are typically inaccessible by direct C4-H activation due to its heavy reliance on C3 directing groups. Notably, unexpected C6-phosphonylated indoles were obtained through blocking of the C4 position. The preliminary mechanistic studies indicated that the reactions may proceed via a C7-palladacycle/remote-activation process. Based on the strategy, examples of remote C4-H difluoromethylation with BrCF2 COOEt are also presented, suggesting that the strategy may offer a general blueprint for other cross-couplings.

13.
J Neurosci ; 39(3): 557-575, 2019 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-30446533

RESUMO

Epileptic networks are characterized by two outputs: brief interictal spikes and rarer, more prolonged seizures. Although either output state is readily modeled in silico and induced experimentally, the transition mechanisms are unknown, in part because no models exhibit both output states spontaneously. In silico small-world neural networks were built using single-compartment neurons whose physiological parameters were derived from dual whole-cell recordings of pyramidal cells in organotypic hippocampal slice cultures that were generating spontaneous seizure-like activity. In silico, neurons were connected by abundant local synapses and rare long-distance synapses. Activity-dependent synaptic depression and gradual recovery delimited synchronous activity. Full synaptic recovery engendered interictal population spikes that spread via long-distance synapses. When synaptic recovery was incomplete, postsynaptic neurons required coincident activation of multiple presynaptic terminals to reach firing threshold. Only local connections were sufficiently dense to spread activity under these conditions. This coalesced network activity into traveling waves whose velocity varied with synaptic recovery. Seizures were comprised of sustained traveling waves that were similar to those recorded during experimental and human neocortical seizures. Sustained traveling waves occurred only when wave velocity, network dimensions, and the rate of synaptic recovery enabled wave reentry into previously depressed areas at precisely ictogenic levels of synaptic recovery. Wide-field, cellular-resolution GCamP7b calcium imaging demonstrated similar initial patterns of activation in the hippocampus, although the anatomical distribution of traveling waves of synaptic activation was altered by the pattern of synaptic connectivity in the organotypic hippocampal cultures.SIGNIFICANCE STATEMENT When computerized distributed neural network models are required to generate both features of epileptic networks (i.e., spontaneous interictal population spikes and seizures), the network structure is substantially constrained. These constraints provide important new hypotheses regarding the nature of epileptic networks and mechanisms of seizure onset.


Assuntos
Epilepsia/fisiopatologia , Convulsões/fisiopatologia , Algoritmos , Animais , Simulação por Computador , Progressão da Doença , Eletroencefalografia/métodos , Potenciais Pós-Sinápticos Excitadores , Feminino , Hipocampo/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Neocórtex/fisiopatologia , Rede Nervosa/fisiopatologia , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas , Células Piramidais , Sinapses
14.
Plant Cell Physiol ; 61(4): 775-786, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31967299

RESUMO

Late embryogenesis abundant (LEA) proteins comprise a large family that plays important roles in the regulation of abiotic stress, however, no in-depth analysis of LEA genes has been performed in grapevine to date. In this study, we analyzed a total of 52 putative LEA genes in grapevine at the genomic and transcriptomic level, compiled expression profiles of four selected (V. amurensis) VamLEA genes under cold and osmotic stresses, and studied the potential function of the V. amurensis DEHYDRIN3 (VamDHN3) gene in grapevine callus. The 52 LEA proteins were classified into seven phylogenetic groups. RNA-seq and quantitative real-time PCR results demonstrated that a total of 16 and 23 VamLEA genes were upregulated under cold and osmotic stresses, respectively. In addition, overexpression of VamDHN3 enhanced the stability of the cell membrane in grapevine callus, suggesting that VamDHN3 is involved in osmotic regulation. These results provide fundamental knowledge for the further analysis of the biological roles of grapevine LEA genes in adaption to abiotic stress.


Assuntos
Resposta ao Choque Frio , Perfilação da Expressão Gênica , Família Multigênica , Pressão Osmótica , Proteínas de Plantas/genética , Estresse Fisiológico/genética , Vitis/genética , Adaptação Fisiológica/genética , Cromossomos de Plantas/genética , Clonagem Molecular , Desenvolvimento Embrionário/genética , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Filogenia , Proteínas de Plantas/metabolismo , RNA de Plantas/genética , RNA de Plantas/isolamento & purificação , Análise de Sequência de RNA , Vitis/metabolismo
15.
Acta Neuropathol ; 139(3): 503-526, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31853635

RESUMO

Neurodegenerative diseases are an enormous public health problem, affecting tens of millions of people worldwide. Nearly all of these diseases are characterized by oligomerization and fibrillization of neuronal proteins, and there is great interest in therapeutic targeting of these aggregates. Here, we show that soluble aggregates of α-synuclein and tau bind to plate-immobilized PrP in vitro and on mouse cortical neurons, and that this binding requires at least one of the same N-terminal sites at which soluble Aß aggregates bind. Moreover, soluble aggregates of tau, α-synuclein and Aß cause both functional (impairment of LTP) and structural (neuritic dystrophy) compromise and these deficits are absent when PrP is ablated, knocked-down, or when neurons are pre-treated with anti-PrP blocking antibodies. Using an all-human experimental paradigm involving: (1) isogenic iPSC-derived neurons expressing or lacking PRNP, and (2) aqueous extracts from brains of individuals who died with Alzheimer's disease, dementia with Lewy bodies, and Pick's disease, we demonstrate that Aß, α-synuclein and tau are toxic to neurons in a manner that requires PrPC. These results indicate that PrP is likely to play an important role in a variety of late-life neurodegenerative diseases and that therapeutic targeting of PrP, rather than individual disease proteins, may have more benefit for conditions which involve the aggregation of more than one protein.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Príons/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Ligação Proteica
16.
Opt Lett ; 45(15): 4172-4175, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32735251

RESUMO

We investigated and prepared a chirped long-period grating for high sensitivity bending measurement. The novel fiber structure is composed of the multimode fiber (MMF) with fixed length and gradually longer single-mode fiber using the continuous splicing method. The powerful ability of refractive index modulation in the MMF renders the miniaturization of the sensor. The total length of the sensor is 3.45 mm. Chirped period arrangement is adopted to improve the bending sensitivity. Through numerical calculation, the chirp coefficient is determined, and the clear resonance peaks are obtained using the wavelength scanning. The experimental results of several samples show that the maximum bending sensitivity is 53.68nm/m-1 at 0-1.803m-1. With the advantages of small size and high sensitivity, the sensor is especially suitable for bending sensing with a micro-structure.

17.
J Org Chem ; 85(5): 3954-3962, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-31994398

RESUMO

A strategy for the synthesis of cis-hydrocarbazole with a C3 quaternary carbon center has been developed through nickel/Lewis acid dual-catalyzed arylcyanation. A wide array of cis-hydrocarbazoles was accessed with high diastereoselectivities and atom economies in a good yield. The rich chemistry of the installed nitrile group was demonstrated in the preparation of tryptamine- and tryptophol-derived cis-hydrocarbazoles.

18.
Brain ; 142(5): 1441-1457, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31032851

RESUMO

The primary structure of canonical amyloid-ß-protein was elucidated more than 30 years ago, yet the forms of amyloid-ß that play a role in Alzheimer's disease pathogenesis remain poorly defined. Studies of Alzheimer's disease brain extracts suggest that amyloid-ß, which migrates on sodium dodecyl sulphate polyacrylamide gel electrophoresis with a molecular weight of ∼7 kDa (7kDa-Aß), is particularly toxic; however, the nature of this species has been controversial. Using sophisticated mass spectrometry and sensitive assays of disease-relevant toxicity we show that brain-derived bioactive 7kDa-Aß contains a heterogeneous mixture of covalently cross-linked dimers in the absence of any other detectable proteins. The identification of amyloid-ß dimers may open a new phase of Alzheimer's research and allow a better understanding of Alzheimer's disease, and how to monitor and treat this devastating disorder. Future studies investigating the bioactivity of individual dimers cross-linked at known sites will be critical to this effort.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Multimerização Proteica/fisiologia , Idoso , Idoso de 80 Anos ou mais , Peptídeos beta-Amiloides/análise , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos
19.
Arch Toxicol ; 94(8): 2873-2884, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32435917

RESUMO

Dieldrin has been shown to induce liver tumors selectively in mice. Although the exact mechanism is not fully understood, previous studies from our laboratory and others have shown that dieldrin induced liver tumors in mice through a non-genotoxic mechanism acting on tumor promotion stage. Two studies were performed to examine the role of nuclear receptor activation as a possible mode of action (MOA) for dieldrin-induced mouse liver tumors. In the initial study, male C57BL/6 mice (6- to 8-week old) were treated with dieldrin in diet (10 ppm) for 7, 14, and 28 days. Phenobarbital (PB), beta-naphthoflavone (BNF) and Di (2-ethylhexyl) phthalate (DEHP) were included as positive controls in this study for evaluating the involvement of CAR (constitutive androstane receptor), AhR (aryl hydrocarbon receptor) or PPARα (peroxisome proliferator activated receptor alpha) in the MOA of dieldrin hepatocarcinogenesis. A significant increase in hepatocyte DNA synthesis (BrdU incorporation) was seen in treated mice compared with the untreated controls. Analysis of the expression of the nuclear receptor responsive genes revealed that dieldrin induced a significant increase in the expression of genes specific to CAR activation (Cyp2b10, up to 400- to 2700-fold) and PXR activation (Cyp3a11, up to 5- to 11-fold) over untreated controls. The AhR target genes Cyp1a1 and Cyp1a2 were also slightly induced (2.0- to 3.7-fold and 1.7- to 2.8-fold, respectively). PPARα activation was not seen in the liver following dieldrin treatment. In addition, consistent with previous studies in our lab, treatment with dieldrin produced significant elevation in the hepatic oxidative stress. In a subsequent study using CAR, PXR, and CAR/PXR knockout mice, we confirmed that the dieldrin-induced liver effects in mouse were only mediated by the activation of CAR receptor. Based on these findings, we propose that dieldrin induced liver tumors in mice through a nuclear receptor CAR-mediated mode of action. The previously observed oxidative stress/damage may be an associated or modifying factor in the process of dieldrin-induced liver tumor formation subsequent to the CAR activation.


Assuntos
Transformação Celular Neoplásica/induzido quimicamente , Dieldrin/toxicidade , Inseticidas/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/agonistas , Animais , Hidrocarboneto de Aril Hidroxilases/biossíntese , Hidrocarboneto de Aril Hidroxilases/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Receptor Constitutivo de Androstano , Família 2 do Citocromo P450/biossíntese , Família 2 do Citocromo P450/genética , Replicação do DNA/efeitos dos fármacos , Indução Enzimática , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Receptor de Pregnano X/genética , Receptor de Pregnano X/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais , Esteroide Hidroxilases/biossíntese , Esteroide Hidroxilases/genética
20.
Sensors (Basel) ; 20(23)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33271903

RESUMO

The ionospheric error can significantly affect the synthetic aperture radar (SAR) signals, particularly in the case of L band and lower frequency SAR systems. The ionospheric distortions are mixed with terrain and ground deformation signals, lowering the precision of the interferometric measurements. Moreover, it is often difficult to detect the small-scale ionospheric structure due to its rapid changes and may have more influence on ionospheric phase compensation for InSAR measurements. In this paper, we present a Faraday rotation (FR) inversion method and corresponding procedure to compensate the ionospheric error for SAR interferograms and to detect the variations of small-scale ionospheric disturbances. This method retrieves the absolute total electron content (TEC) based on the FR estimation and corrects the ionospheric error for synthetic aperture radar interferometry (InSAR) measurements by transforming the differential TEC into the ionospheric phase. In two selected study cases, located in high latitude and equatorial regions where ionospheric disturbances occur frequently, we test the method using the Phased Array L-band Synthetic Aperture Radar (PALSAR) full-polarimetric SAR images. Our results show that the proposed procedure can effectively compensate the ionospheric phase. In order to validate the results, we present the results of ionospheric phase compensation based on the split-spectrum method as a comparison to the proposed method. To analyze the ability of our proposed method in detecting small-scale ionospheric disturbances, TEC derived from FR estimation are also compared with those derived from the global ionosphere maps (GIM). Our research provides a robust choice for the correction of ionospheric error in SAR interferograms. It also provides a powerful tool to measure small-scale ionospheric structure.

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