RESUMEN
Synucleinopathies are characterized by the accumulation of α-synuclein (α-Syn) aggregates in the brain. Positron emission tomography (PET) imaging of synucleinopathies requires radiopharmaceuticals that selectively bind α-Syn deposits. We report the identification of a brain permeable and rapid washout PET tracer [18F]-F0502B, which shows high binding affinity for α-Syn, but not for Aß or Tau fibrils, and preferential binding to α-Syn aggregates in the brain sections. Employing several cycles of counter screenings with in vitro fibrils, intraneuronal aggregates, and neurodegenerative disease brain sections from several mice models and human subjects, [18F]-F0502B images α-Syn deposits in the brains of mouse and non-human primate PD models. We further determined the atomic structure of the α-Syn fibril-F0502B complex by cryo-EM and revealed parallel diagonal stacking of F0502B on the fibril surface through an intense noncovalent bonding network via inter-ligand interactions. Therefore, [18F]-F0502B is a promising lead compound for imaging aggregated α-Syn in synucleinopathies.
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Enfermedades Neurodegenerativas , Sinucleinopatías , Animales , Humanos , alfa-Sinucleína/metabolismo , Sinucleinopatías/diagnóstico por imagen , Sinucleinopatías/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Tomografía de Emisión de Positrones , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.
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Enfermedad de Alzheimer , Animales , Humanos , Ratones , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Clatrina/metabolismo , Endocitosis , Ratones Transgénicos , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
As an integral lysosomal transmembrane protein, transmembrane protein 106B (TMEM106B) regulates several aspects of lysosomal function and is associated with neurodegenerative diseases. The TMEM106B gene mutations lead to lysosomal dysfunction and accelerate the pathological progression of Neurodegenerative diseases. Yet, the precise mechanism of TMEM106B in Neurodegenerative diseases remains unclear. Recently, different research teams discovered that TMEM106B is an amyloid protein and the C-terminal domain of TMEM106B forms amyloid fibrils in various Neurodegenerative diseases and normally elderly individuals. In this review, we discussed the physiological functions of TMEM106B. We also included TMEM106B gene mutations that cause neurodegenerative diseases. Finally, we summarized the identification and cryo-electronic microscopic structure of TMEM106B fibrils, and discussed the promising therapeutic strategies aimed at TMEM106B fibrils and the future directions for TMEM106B research in neurodegenerative diseases.
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Proteínas de la Membrana , Proteínas del Tejido Nervioso , Enfermedades Neurodegenerativas , Animales , Humanos , Amiloide/metabolismo , Amiloide/genética , Amiloide/química , Lisosomas/metabolismo , Lisosomas/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/química , Mutación , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/química , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/patologíaRESUMEN
Despite the extensive development of non-noble metals for the N-alkylation of amines with alcohols, the exploitation of catalysts with high selectivity, activity, and stability still faces challenges. The controllable modification of single-atom sites through asymmetric coordination with a second heteroatom offers new opportunities for enhancing the intrinsic activity of transition metal single-atom catalysts. Here, we prepared the asymmetric N/P hybrid coordination of single-atom Co1-N3P1 by absorbing the Co-P complex on ZIF-8 using a concise impregnation-pyrolysis process. The catalyst exhibits ultrahigh activity and selectivity in the N-alkylation of aniline and benzyl alcohol, achieving a turnover number (TON) value of 3480 and a turnover frequency (TOF) value of 174-h. The TON value is 1 order of magnitude higher than the reported catalysts and even 37-fold higher than that of the homogeneous catalyst CoCl2(PPh3)2. Furthermore, the catalyst maintains its high activity and selectivity even after 6 cycles of usage. Controlling experiments and isotope labeling experiments confirm that in the asymmetric Co1-N3P1 system, the N-alkylation of aniline with benzyl alcohol proceeds via a transfer hydrogenation mechanism involving the monohydride route. Theoretical calculations prove that the superior activity of asymmetric Co1-N3P1 is attributed to the higher d-band energy level of Co sites, which leads to a more stable four-membered ring transition state and a lower reaction energy barrier compared to symmetrical Co1-N4.
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Genome-wide association studies (GWASs) have identified genetic susceptibility loci associated with juvenile dermatomyositis (JDM). Single nucleotide polymorphisms related to phosphorylation (phosSNPs) are critical nonsynonymous mutations exerting substantial influence on gene expression regulation. The aim of this study was to identify JDM susceptibility genes in the GWAS loci by the use of phosSNPs. We explored quantitative trait loci (QTLs) among the phosSNPs associated with JDM using data from eQTL (bulk tissues and single-cell) and pQTL studies. For gene expression and protein levels significantly influenced by JDM-associated phosSNPs, we assessed their associations with JDM through MR analyses. Additionally, we conducted differential expression gene analyses, incorporating single-cell transcriptomic profiling of 6 JDM cases and 11 juvenile controls (99,396 cells). We identified 31 phosSNPs situated in the 6p21 locus that were associated with JDM. Half of these phosSNPs showed effects on gene expression in various cells and circulating protein levels. In MR analyses, we established associations between the expression levels of pivotal JDM-associated genes, including MICB, C4A, HLA-DRB1, HLA-DRB5, and PSMB9, in skin, muscle, or blood cells and circulating levels of C4A, with JDM. Utilizing single-cell eQTL data, we identified a total of 276 association signals across 14 distinct immune cell types for 28 phosSNPs. Further insights were gained through single-cell differential expression analysis, revealing differential expression of PSMB9, HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1, and HLA-DRB1 in immune cells. The present study pinpointed phosSNPs within susceptibility genes for JDM and unraveled the intricate relationships among these SNPs, gene expression levels, and JDM.
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Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction, which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin (ADR) to mimic human FSGS. In vivo, global AEP knockout mice manifested increased injury-susceptibility of podocytes in ADR-induced nephropathy (ADRN). Podocyte-specific AEP knockout mice exhibited much more severe glomerular lesions and podocyte injury after ADR injection. In contrast, podocyte-specific augmentation of AEP in mice protected against ADRN. In vitro, knockdown and overexpression of AEP in human podocytes revealed the cytoprotection of AEP as a cytoskeleton regulator. Furthermore, transgelin, an actin-binding protein regulating actin dynamics, was cleaved by AEP, and, as a result, removed its actin-binding regulatory domain. The truncated transgelin regulated podocyte actin dynamics and repressed podocyte hypermotility, compared to the native full-length transgelin. Together, our data reveal a link between lysosomal protease AEP and podocyte cytoskeletal homeostasis, which suggests a potential therapeutic role for AEP in proteinuria disease.
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Cisteína Endopeptidasas , Glomeruloesclerosis Focal y Segmentaria , Enfermedades Renales , Podocitos , Animales , Humanos , Ratones , Actinas/genética , Actinas/metabolismo , Doxorrubicina/efectos adversos , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/genética , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Enfermedades Renales/metabolismo , Ratones Noqueados , Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Podocitos/metabolismo , Proteinuria/metabolismo , Proteinuria/patología , Cisteína Endopeptidasas/genéticaRESUMEN
Neural tube defects (NTDs), which are caused by impaired embryonic neural tube closure, are one of the most serious and common birth defects. Peptidyl-prolyl cis/trans isomerase 1 (Pin1) is a prolyl isomerase that uniquely regulates cell signaling by manipulating protein conformation following phosphorylation, although its involvement in neuronal development remains unknown. In this study, we explored the involvement of Pin1 in NTDs and its potential mechanisms both in vitro and in vivo. The levels of Pin1 expression were reduced in NTD models induced by all-trans retinoic acid (Atra). Pin1 plays a significant role in regulating the apoptosis, proliferation, differentiation, and migration of neurons. Moreover, Pin1 knockdown significantly was found to exacerbate oxidative stress (OS) and endoplasmic reticulum stress (ERs) in neuronal cells. Further studies showed that the Notch1-Nrf2 signaling pathway may participate in Pin1 regulation of NTDs, as evidenced by the inhibition and overexpression of the Notch1-Nrf2 pathway. In addition, immunofluorescence (IF), co-immunoprecipitation (Co-IP), and GST pull-down experiments also showed that Pin1 interacts directly with Notch1 and Nrf2. Thus, our study suggested that the knocking down of Pin1 promotes NTD progression by inhibiting the activation of the Notch1-Nrf2 signaling pathway, and it is possible that this effect is achieved by disrupting the interaction of Pin1 with Notch1 and Nrf2, affecting their proteostasis. Our research identified that the regulation of Pin1 by retinoic acid (RA) and its involvement in the development of NTDs through the Notch1-Nrf2 axis could enhance our comprehension of the mechanism behind RA-induced brain abnormalities.
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Peptidilprolil Isomerasa de Interacción con NIMA , Defectos del Tubo Neural , Tretinoina , Animales , Femenino , Humanos , Ratones , Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Tubo Neural/metabolismo , Tubo Neural/efectos de los fármacos , Defectos del Tubo Neural/metabolismo , Defectos del Tubo Neural/genética , Defectos del Tubo Neural/inducido químicamente , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Peptidilprolil Isomerasa de Interacción con NIMA/metabolismo , Peptidilprolil Isomerasa de Interacción con NIMA/genética , Estrés Oxidativo/efectos de los fármacos , Receptor Notch1/metabolismo , Receptor Notch1/genética , Transducción de Señal/efectos de los fármacos , Tretinoina/metabolismo , Tretinoina/farmacologíaRESUMEN
BACKGROUND: This study aims to quantify the impacts of chilling at the grain filling stage on rice yield and grain quality. A factorial experiment with four levels of temperature and duration of chilling treatments at the early and late grain filling stages was conducted in 2017, 2018 and 2019. RESULTS: Per 10 °C·day increase in the accumulated cooling degree day at the early and late grain filling stages, the rice emergence-maturity duration was delayed by 0.8% (0.6%) and rice yield decreased by 2.2% (1.7%). Chilling at the early grain filling stage decreased the rice heading rate, while chilling at the late grain filling stage increased rice amylose but decreased protein content. For chilling treatment at the early grain filling stage, rice yield and grain quality were mainly correlated with seed-setting rate, whereas for chilling treatment at the late grain filling stage the rice yield and grain quality were mainly correlated with 1000-grain weight. CONCLUSION: This study improved the understanding of how chilling at the grain filling stages affects rice phenology, yield and grain quality, providing a theoretical basis for maintaining rice yield while ensuring grain quality. The results could be used to guide the rice-growing community in combating chilling at grain filling stages. © 2024 Society of Chemical Industry.
RESUMEN
Parkinson's disease (PD) is an age-related chronic neurological disorder, mainly characterized by the pathological feature of α-synuclein (α-syn) aggregation, with the exact disease pathogenesis unclear. During the onset and progression of PD, synaptic dysfunction, including dysregulation of axonal transport, impaired exocytosis, and endocytosis are identified as crucial events of PD pathogenesis. It has been reported that over-expression of α-syn impairs clathrin-mediated endocytosis (CME) in the synapses. However, the underlying mechanisms still needs to be explored. In this study, we investigated the molecular events underlying the synaptic dysfunction caused by over-expression of wild-type human α-syn and its mutant form, involving series of proteins participating in CME. We found that excessive human α-syn causes impaired fission and uncoating of clathrin-coated vesicles during synaptic vesicle recycling, leading to reduced clustering of synaptic vesicles near the active zone and increased size of plasma membrane and number of endocytic intermediates. Furthermore, over-expressed human α-syn induced changes of CME-associated proteins, among which synaptojanin1 (SYNJ1) showed significant reduction in various brain regions. Over-expression of SYNJ1 in primary hippocampal neurons from α-syn transgenic mice recovered the synaptic vesicle density, clustering and endocytosis. Using fluorescence-conjugated transferrin, we demonstrated that SYNJ1 re-boosted the CME activity by restoring the phosphatidylinositol-4,5-bisphosphate homeostasis. Our data suggested that over-expression of α-syn disrupts synaptic function through interfering with vesicle recycling, which could be alleviated by re-availing of SYNJ1. Our study unrevealed a molecular mechanism of the synaptic dysfunction in PD pathogenesis and provided a potential therapeutic target for treating PD.
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Enfermedad de Parkinson , alfa-Sinucleína , Animales , Humanos , Ratones , alfa-Sinucleína/metabolismo , Clatrina/metabolismo , Endocitosis/fisiología , Ratones Transgénicos , Enfermedad de Parkinson/metabolismo , Sinapsis/metabolismoRESUMEN
MAIN CONCLUSION: PPO was purified from Cistanche deserticola, and its enzymatic characteristics were clarified. It was found that microwave treatment was an efficient way to inactivate PPO. Polyphenol oxidase (PPO) from Cistanche deserticola was obtained and purified through an acetone precipitation and anion exchange column, the enzymatic characteristics and inactivation kinetics of PPO were studied. The specific activity of PPO was 73135.15 ± 6625.7 U/mg after purification, the purification multiple was 48.91 ± 4.43 times, and the recovery was 30.96 ± 0.27%. The molecular weight of the PPO component is about 66 kDa by SDS-PAGE analysis. The optimum substrate of PPO was catechol (Vmax = 0.048 U/mL, Km = 21.70 mM) and the optimum temperature and pH were 30 °C and 7, respectively. When the temperature is above 50 °C, pH < 3 or pH > 10, the enzyme activity can be significantly inhibited. The first-order kinetic fitting shows that microwave inactivation has lesser k values, larger D values and shorter t1/2. It was found that microwave treatment is considered as an efficient and feasible way to inactive PPO by comparing the Z values and Ea values of the two thermal treatments.
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Cistanche , Cistanche/metabolismo , Catecol Oxidasa/química , Catecol Oxidasa/metabolismo , Cinética , Temperatura , Peso Molecular , Concentración de Iones de HidrógenoRESUMEN
AIMS: Accumulation and propagation of pathological α-synuclein (α-Syn) are the major contributing factors to the pathogenesis of Parkinson's disease (PD). Therapy to halt the spreading of α-Syn pathology needs to be established. METHODS: After phage display and affinity maturation, human-derived anti-α-Syn autoantibodies were selected and applied to biochemical, cellular and animal models of PD. RESULTS: The novel naturally occurring anti-α-Syn autoantibodies (α-Syn-nAbs), P21 and P22, selectively bind α-Syn preformed fibrils (PFFs), recognise Lewy bodies (LBs) and Lewy neurites (LNs) in human PD brains, block α-Syn fibrillization and inhibit the seeding of α-Syn PFFs. Moreover, systematic administration of P21 and P22 attenuates α-Syn pathology, degeneration of the nigrostriatal pathway and motor deficits in mice injected with α-Syn PFFs. CONCLUSIONS: P21 and P22 attenuate α-synuclein pathology and are promising candidates for PD treatment.
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Enfermedad de Parkinson , Sinucleinopatías , Ratones , Humanos , Animales , Enfermedad de Parkinson/patología , alfa-Sinucleína/metabolismo , Autoanticuerpos/metabolismo , Encéfalo/patología , Modelos Animales de EnfermedadRESUMEN
BACKGROUND: The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27-OHC plays a role in α-Syn aggregation and propagation remains elusive. OBJECTIVE: The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation. METHODS: Purified recombinant α-Syn, neuronal cultures, and α-Syn fibril-injected mouse model of PD were treated with 27-OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27-OHC on α-Syn pathology in vivo. RESULTS: 27-OHC accelerates the aggregation of α-Syn and enhances the seeding activity of α-Syn fibrils. Furthermore, the 27-OHC-modified α-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified α-Syn fibrils induces enhanced spread of α-Syn pathology and dopaminergic neurodegeneration compared with pure α-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of α-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic α-Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27-OHC plays an important role in the pathogenesis of PD. CONCLUSIONS: 27-OHC promotes the aggregation and spread of α-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a disease-modifying therapy to halt the progression of α-Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Humanos , Ratones , Animales , Enfermedad de Parkinson/genética , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo , Hidroxicolesteroles/farmacología , ColesterolRESUMEN
Borate esters have been applied widely as coupling partners in organic synthesis. However, the direct utilization of borate acceptors in O-glycosylation with glycal donors remains underexplored. Herein, we describe a novel O-glycosylation resulting in the formation of 2,3-unsaturated O-glycosides and 2-deoxy O-glycosides mediated by palladium and copper catalysis, respectively. This O-glycosylation method tolerated a broad scope of trialkyl/triaryl borates and various glycals with exclusive stereoselectivities in high yields. All the desired aliphatic/aromatic O-glycosides and 2-deoxy O-glycosides were generated successfully, without the hemiacetal byproducts and OâC rearrangement because of the nature of borate esters. The utility of this strategy was demonstrated by functionalizing the 2,3-unsaturated glycoside products to form saturated ß-O-glycosides, 2,3-deoxy O-glycosides, and 2,3-epoxy O-glycosides.
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Boratos , Glicósidos , Estereoisomerismo , Glicosilación , Ésteres , CatálisisRESUMEN
In the field of recycling CO2, the photocatalytic CO2 reduction reaction (CO2RR) is a typical example, and researchers have designed a variety of photocatalysts to improve the conversion rate of CO2 over the years. In this paper, two metal-oxygen clusters are designed and formulated as [Co3Zn(OH)6(SO4)]·4H2O (1) and [Ni3Zn(OH)6(SO4)]·4H2O (2). As for compound 1, the main structure is composed of {CoO6} octahedra connected by edge-sharing to form a two-dimensional layer, on which {ZnO4} and {SO4} tetrahedra are supported. More interestingly, compound 1 has outstanding photocatalytic activity, which is mainly attributed to the open-framework structure and the cobalt ions as active sites. Upon catalysis for eight hours, its maximum CO generation rate is 9982.13 µmol g-1 h-1, with a selectivity of 81.8%. Additionally, compound 1 takes on weak antiferromagnetic coupling due to Co(II) ions.
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The aggregation and prion-like propagation of α-synuclein are involved in the pathogenesis of Parkinson's disease. However, the underlying mechanisms regulating the assembly and spreading of α-synuclein fibrils remain poorly understood. Tau co-deposits with α-synuclein in the brains of Parkinson's disease patients, suggesting a pathological interplay between them. Here we show that tau interacts with α-synuclein and accelerates its aggregation. Compared with pure α-synuclein fibrils, the tau-modified α-synuclein fibrils show enhanced seeding activity, inducing mitochondrial dysfunction, synaptic impairment and neurotoxicity in vitro. Injection of the tau-modified α-synuclein fibrils into the striatum of mice induces more severe α-synuclein pathology, motor dysfunction and cognitive impairment when compared with the mice injected with pure α-synuclein fibrils. Knockout of tau attenuates the propagation of α-synuclein pathology and Parkinson's disease-like symptoms both in mice injected with α-syn fibrils and α-syn A53T transgenic mice. In conclusion, tau facilitates α-synuclein aggregation and propagation in Parkinson's disease.
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Enfermedad de Parkinson , Priones , Sinucleinopatías , Animales , Ratones , alfa-Sinucleína , Enfermedad de Parkinson/patología , Ratones Noqueados , Ratones TransgénicosRESUMEN
BACKGROUND: Against the background of global warming, heat stress has become more frequent, which adversely affects the growth and development of spring maize plants in Northeast China. To adapt the regional maize production to climate change, it is imperative to understand the spatio-temporal characteristics of heat stress. In the present study, we analyzed three of the indices for heat stress, including the number of heat stress days, heating degree days (HDD, the total heat degree-days during critical stages), and the percentage of stations with heat stress. RESULTS: From 1981 to 2019, the number of heat stress days varied greatly among the study years, ranging from 0 to 14 and 27 days, respectively. The average HDD was 7.8 and 5.0 °C day from 1981 to 2000, respectively, and the main hot-spots of heat stress occurred in the southwest regions. Moreover, compared with 1981-2000, the region of HDD during anthesis higher than 10 °C day in 2041-2060 under the SSP1-2.6 and SSP5-8.5 climate scenarios increased by 9.1-50.1% and 0.1-28.6%. The average HDD during the critical stages from 2041 to 2060 increased under the SSP5-8.5 climate scenario, being 1.5 times higher than that during 1981-2000. HDD during maize anthesis and the grain-filling period showed an overall increasing trend with years. About 19% and 58% of the study locations showed heat stress during the past 39 years, respectively. CONCLUSION: Heat stress during anthesis and the grain-filling period for spring maize in Northeast China is projected to increase toward the mid-21st century. © 2023 Society of Chemical Industry.
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Grano Comestible , Zea mays , Cambio Climático , China , Respuesta al Choque TérmicoRESUMEN
Parkinson's disease (PD) is the most common motor-associated neurodegenerative disease. Although the pathogenesis of PD is still wrapped in the mist, accumulating evidence indicates that mitochondrial dysfunction contributes to the onset and progression of PD. We previously reported that the lysosomal protease asparagine endopeptidase (AEP) cleaves α-synuclein in the brains of PD patients. The major product, α-synuclein 1-103, significantly promotes PD-like histological changes and motor dysfunction. However, the underlying molecular mechanisms remain unknown. Here we show that α-synuclein 1-103 fragment interacts with mitochondria and induces morphological and functional abnormalities of mitochondria. Furthermore, we investigated the protective effects of 7,8-dihydroxyflavone (7,8-DHF) on mitochondrial dysfunction induced by α-synuclein 1-103 fragment. We found that 7,8-DHF ameliorated α-synuclein 1-103-induced mitochondrial impairment and motor dysfunction. These results indicate that 7,8-DHF represents a novel oral bioactive therapeutic agent for treating PD.
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Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Animales , Flavonas , Humanos , Ratones , Ratones Transgénicos , Mitocondrias/patología , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/patología , alfa-SinucleínaRESUMEN
Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with abnormal dopamine metabolism by MAO-B (monoamine oxidase-B) and intracellular α-Synuclein (α-Syn) aggregates, called the Lewy body. However, the molecular relationship between α-Syn and MAO-B remains unclear. Here, we show that α-Syn directly binds to MAO-B and stimulates its enzymatic activity, which triggers AEP (asparagine endopeptidase; legumain) activation and subsequent α-Syn cleavage at N103, leading to dopaminergic neurodegeneration. Interestingly, the dopamine metabolite, DOPAL, strongly activates AEP, and the N103 fragment of α-Syn binds and activates MAO-B. Accordingly, overexpression of AEP in SNCA transgenic mice elicits α-Syn N103 cleavage and accelerates PD pathogenesis, and inhibition of MAO-B by Rasagiline diminishes α-Syn-mediated PD pathology and motor dysfunction. Moreover, virally mediated expression of α-Syn N103 induces PD pathogenesis in wild-type, but not MAO-B-null mice. Our findings thus support that AEP-mediated cleavage of α-Syn at N103 is required for the association and activation of MAO-B, mediating PD pathogenesis.
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Cisteína Endopeptidasas/metabolismo , Monoaminooxidasa/metabolismo , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Animales , Cisteína Endopeptidasas/genética , Modelos Animales de Enfermedad , Dopamina/genética , Dopamina/metabolismo , Indanos/farmacología , Ratones , Ratones Transgénicos , Monoaminooxidasa/genética , Inhibidores de la Monoaminooxidasa/farmacología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , alfa-Sinucleína/genéticaRESUMEN
BACKGROUND: The deposition of α-synuclein (α-Syn) in the brain is the pathological hallmark of Parkinson's disease (PD). Epidemiological data indicate that exposure to fine particulate matter (≤2.5 µm in aerodynamic diameter [PM2.5]) is associated with an increased risk for PD. OBJECTIVE: The aim of this study is to investigate whether PM2.5 has a direct effect on α-Syn pathology and how it drives the risk for PD. METHODS: PM2.5 was added into α-Syn monomers and different cell models to test whether PM2.5 can promote the fibrillization and aggregation of α-Syn. α-Syn A53T transgenic mice and α-Syn knockout mice were used to investigate the effects of PM2.5 on PD-like pathology. RESULTS: PM2.5 triggers the fibrillization of α-Syn and promotes the formation of α-Syn fibrils with enhanced seeding activity and neurotoxicity. PM2.5 also induces mitochondrial dysfunction and oxidative stress. Intrastriatal injection or intranasal administration of PM2.5 exacerbates α-Syn pathology and dopaminergic neuronal degeneration in α-Syn A53T transgenic mice. The detrimental effect of PM2.5 was attenuated in α-Syn knockout mice. CONCLUSIONS: Our results identify that PM2.5 exposure could promote the α-Syn pathology, providing mechanistic insights into how PM2.5 increases the risk for PD. © 2022 International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Sinucleinopatías , Animales , Ratones , Ratones Noqueados , Ratones Transgénicos , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/patología , Material Particulado/toxicidad , alfa-Sinucleína/genéticaRESUMEN
BACKGROUND: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. OBJECTIVES: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross-sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. METHODS: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face-to-face interviews biennially. RESULTS: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD-MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early-onset PD (EOPD, age at onset ≤50 years) and late-onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa-induced dyskinesias in women. CONCLUSIONS: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society.