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Alzheimer's disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition1,2. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice3-7. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-ß and Tau deposition and impair cognition in mice displaying features of Alzheimer's disease. Blocking FSH action in these mice abrogates the Alzheimer's disease-like phenotype by inhibiting the neuronal C/EBPß-δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer's disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer's disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent.
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Doença de Alzheimer , Hormônio Foliculoestimulante , Idoso , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Densidade Óssea , Cognição , Feminino , Hormônio Foliculoestimulante/metabolismo , Humanos , Camundongos , TermogêneseRESUMO
Photorespiration is an energetically costly metabolic pathway in plants that responds to environmental stresses. The molecular basis of the regulation of the photorespiratory cycle under stress conditions remains unclear. Here, we discovered that FERONIA (FER) regulates photorespiratory flow under salt stress in Arabidopsis (Arabidopsis thaliana). FER mutation results in hypersensitivity to salt stress, but disruption of ferredoxin-dependent glutamate synthase 1 (GLU1), an enzyme that participates in the photorespiratory pathway by producing glutamate, greatly suppresses fer-4 hypersensitivity to salt stress primarily due to reduced glycine yield. In contrast, disrupting mitochondrial serine hydroxymethyltransferase1 (SHM1), which is supposed to increase glycine levels by hampering the conversion of glycine to serine in the photorespiratory cycle, aggravates fer-4 hypersensitivity to salt stress. Biochemical data show that FER interacts with and phosphorylates SHM1, and this phosphorylation modulates SHM1 stability. Additionally, the production of proline and its intermediate â³1-pyrroline-5-carboxylate (P5C), which are both synthesized from glutamate, also contributes to fer-4 hypersensitivity to salt stress. In conclusion, this study elucidates the functional mechanism of FER in regulating salt tolerance by modulating photorespiratory flux, which greatly broadens our understanding of how plants adapt to high salinity.
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Humans are able to adapt to the fast-changing world by estimating statistical regularities of the environment. Although fear can profoundly impact adaptive behaviors, the computational and neural mechanisms underlying this phenomenon remain elusive. Here, we conducted a behavioral experiment (n = 21) and a functional magnetic resonance imaging experiment (n = 37) with a novel cue-biased adaptation learning task, during which we simultaneously manipulated emotional valence (fearful/neutral expressions of the cue) and environmental volatility (frequent/infrequent reversals of reward probabilities). Across 2 experiments, computational modeling consistently revealed a higher learning rate for the environment with frequent versus infrequent reversals following neutral cues. In contrast, this flexible adjustment was absent in the environment with fearful cues, suggesting a suppressive role of fear in adaptation to environmental volatility. This suppressive effect was underpinned by activity of the ventral striatum, hippocampus, and dorsal anterior cingulate cortex (dACC) as well as increased functional connectivity between the dACC and temporal-parietal junction (TPJ) for fear with environmental volatility. Dynamic causal modeling identified that the driving effect was located in the TPJ and was associated with dACC activation, suggesting that the suppression of fear on adaptive behaviors occurs at the early stage of bottom-up processing. These findings provide a neuro-computational account of how fear interferes with adaptation to volatility during dynamic environments.
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Mapeamento Encefálico , Medo , Humanos , Mapeamento Encefálico/métodos , Medo/fisiologia , Aprendizagem , Emoções , Sinais (Psicologia) , Imageamento por Ressonância MagnéticaRESUMO
Identification of a conserved G-quadruplex in E165R of ASFVAfrican swine fever virus (ASFV) is a double-stranded DNA arbovirus with high transmissibility and mortality rates. It has caused immense economic losses to the global pig industry. Currently, no effective vaccines or medications are to combat ASFV infection. G-quadruplex (G4) structures have attracted increasing interest because of their regulatory role in vital biological processes. In this study, we identified a conserved G-rich sequence within the E165R gene of ASFV. Subsequently, using various methods, we verified that this sequence could fold into a parallel G4. In addition, the G4-stabilizers pyridostatin and 5,10,15,20-tetrakis-(N-methyl-4-pyridyl) porphin (TMPyP4) can bind and stabilize this G4 structure, thereby inhibiting E165R gene expression, and the inhibitory effect is associated with G4 formation. Moreover, the G4 ligand pyridostatin substantially impeded ASFV proliferation in Vero cells by reducing gene copy number and viral protein expression. These compelling findings suggest that G4 structures may represent a promising and novel antiviral target against ASFV.
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Vírus da Febre Suína Africana , Antivirais , Quadruplex G , Vírus da Febre Suína Africana/genética , Vírus da Febre Suína Africana/metabolismo , Animais , Chlorocebus aethiops , Células Vero , Antivirais/farmacologia , Antivirais/química , Suínos , Febre Suína Africana/virologia , Febre Suína Africana/metabolismo , Porfirinas/química , Porfirinas/farmacologia , Ácidos Picolínicos/química , Ácidos Picolínicos/farmacologia , Ácidos Picolínicos/metabolismo , Replicação Viral/efeitos dos fármacos , Proteínas Virais/genética , Proteínas Virais/metabolismo , Proteínas Virais/química , AminoquinolinasRESUMO
The N6-methyladenosine (m6 A) RNA modification serves crucial functions in RNA metabolism; however, the molecular mechanisms underlying the regulation of m6 A are not well understood. Here, we establish arginine methylation of METTL14, a component of the m6 A methyltransferase complex, as a novel pathway that controls m6 A deposition in mammalian cells. Specifically, protein arginine methyltransferase 1 (PRMT1) interacts with, and methylates the intrinsically disordered C terminus of METTL14, which promotes its interaction with RNA substrates, enhances its RNA methylation activity, and is crucial for its interaction with RNA polymerase II (RNAPII). Mouse embryonic stem cells (mESCs) expressing arginine methylation-deficient METTL14 exhibit significantly reduced global m6 A levels. Transcriptome-wide m6 A analysis identified 1,701 METTL14 arginine methylation-dependent m6 A sites located in 1,290 genes involved in various cellular processes, including stem cell maintenance and DNA repair. These arginine methylation-dependent m6 A sites are associated with enhanced translation of genes essential for the repair of DNA interstrand crosslinks; thus, METTL14 arginine methylation-deficient mESCs are hypersensitive to DNA crosslinking agents. Collectively, these findings reveal important aspects of m6 A regulation and new functions of arginine methylation in RNA metabolism.
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Adenosina/análogos & derivados , Arginina/química , Metiltransferases/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Processamento de Proteína Pós-Traducional , Proteína-Arginina N-Metiltransferases/metabolismo , RNA Polimerase II/metabolismo , Adenosina/química , Animais , Citoplasma , Metiltransferases/química , Metiltransferases/genética , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Proteína-Arginina N-Metiltransferases/genética , RNA Polimerase II/genética , TranscriptomaRESUMO
The recently reported machine learning- or deep learning-based scoring functions (SFs) have shown exciting performance in predicting protein-ligand binding affinities with fruitful application prospects. However, the differentiation between highly similar ligand conformations, including the native binding pose (the global energy minimum state), remains challenging that could greatly enhance the docking. In this work, we propose a fully differentiable, end-to-end framework for ligand pose optimization based on a hybrid SF called DeepRMSD+Vina combined with a multi-layer perceptron (DeepRMSD) and the traditional AutoDock Vina SF. The DeepRMSD+Vina, which combines (1) the root mean square deviation (RMSD) of the docking pose with respect to the native pose and (2) the AutoDock Vina score, is fully differentiable; thus is capable of optimizing the ligand binding pose to the energy-lowest conformation. Evaluated by the CASF-2016 docking power dataset, the DeepRMSD+Vina reaches a success rate of 94.4%, which outperforms most reported SFs to date. We evaluated the ligand conformation optimization framework in practical molecular docking scenarios (redocking and cross-docking tasks), revealing the high potentialities of this framework in drug design and discovery. Structural analysis shows that this framework has the ability to identify key physical interactions in protein-ligand binding, such as hydrogen-bonding. Our work provides a paradigm for optimizing ligand conformations based on deep learning algorithms. The DeepRMSD+Vina model and the optimization framework are available at GitHub repository https://github.com/zchwang/DeepRMSD-Vina_Optimization.
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Aprendizado Profundo , Ligantes , Simulação de Acoplamento Molecular , Proteínas/química , Desenho de Fármacos , Ligação ProteicaRESUMO
Early onset familial Alzheimer's disease (FAD) with APP, PS1/2 (presenilins) mutation accounts for only a small portion of AD cases, and most are late-onset sporadic. However, majority of AD mouse models are developed to mimic the genetic cause of human AD by overexpressing mutated forms of human APP, PS1/2, and/or Tau protein, though there is no Tau mutation in AD, and no single mouse model recapitulates all aspects of AD pathology. Here, we report Thy1-ApoE4/C/EBPß double transgenic mouse model that demonstrates key AD pathologies in an age-dependent manner in absence of any human APP or PS1/2 mutation. Using the clinical diagnosis criteria, we show that this mouse model exhibits tempo-spatial features in AD patient brains, including progressive cognitive decline associated with brain atrophy, which is accompanied with extensive neuronal degeneration. Remarkably, the mice display gradual Aß aggregation and neurofibrillary tangles formation in the brain validated by Aß PET and Tau PET. Moreover, the mice reveal widespread neuroinflammation as shown in AD brains. Hence, Thy1-ApoE4/C/EBPß mouse model acts as a sporadic AD mouse model, reconstituting the major AD pathologies.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Encéfalo , Modelos Animais de Doenças , Camundongos Transgênicos , Proteínas tau , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Camundongos , Humanos , Encéfalo/metabolismo , Encéfalo/patologia , Peptídeos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Masculino , Feminino , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Mutação/genéticaRESUMO
The impact of others' choices on decision-making is influenced by individual preferences. However, the specific roles of individual preferences in social decision-making remain unclear. In this study, we examine the contributions of risk and loss preferences as well as social influence in decision-making under uncertainty using a gambling task. Our findings indicate that while both individual preferences and social influence affect decision-making in social contexts, loss aversion plays a dominant role, especially in individuals with high loss aversion. This phenomenon is accompanied by increased functional connectivity between the anterior insular cortex and the temporoparietal junction. These results highlight the critical involvement of loss aversion and the anterior insular cortex-temporoparietal junction neural pathway in social decision-making under uncertainty. Our findings provide a computational account of how individual preferences and social information collectively shape our social decision-making behaviors.
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Tomada de Decisões , Jogo de Azar , Imageamento por Ressonância Magnética , Conformidade Social , Humanos , Masculino , Feminino , Tomada de Decisões/fisiologia , Adulto Jovem , Adulto , Jogo de Azar/psicologia , Córtex Insular/fisiologia , Córtex Insular/diagnóstico por imagem , Incerteza , Mapeamento Encefálico , Vias Neurais/fisiologia , Encéfalo/fisiologiaRESUMO
Delta-secretase, a lysosomal asparagine endopeptidase (AEP), simultaneously cleaves both APP and tau, controlling the onset of pathogenesis of Alzheimer's disease (AD). However, how this protease is post-translationally regulated remains unclear. Here we report that serine-arginine protein kinase 2 (SRPK2) phosphorylates delta-secretase and enhances its enzymatic activity. SRPK2 phosphorylates serine 226 on delta-secretase and accelerates its autocatalytic cleavage, leading to its cytoplasmic translocation and escalated enzymatic activities. Delta-secretase is highly phosphorylated in human AD brains, tightly correlated with SRPK2 activity. Overexpression of a phosphorylation mimetic (S226D) in young 3xTg mice strongly promotes APP and tau fragmentation and facilitates amyloid plaque deposits and neurofibrillary tangle (NFT) formation, resulting in cognitive impairment. Conversely, viral injection of the non-phosphorylatable mutant (S226A) into 5XFAD mice decreases APP and tau proteolytic cleavage, attenuates AD pathologies, and reverses cognitive defects. Our findings support that delta-secretase phosphorylation by SRPK2 plays a critical role in aggravating AD pathogenesis.
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Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Encéfalo/enzimologia , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Secretases da Proteína Precursora do Amiloide/genética , Animais , Comportamento Animal , Encéfalo/patologia , Encéfalo/fisiopatologia , Cognição , Modelos Animais de Doenças , Predisposição Genética para Doença , Células HEK293 , Células HeLa , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Fenótipo , Fosforilação , Placa Amiloide , Proteínas Serina-Treonina Quinases/genética , Transporte Proteico , Interferência de RNA , Serina , Especificidade por Substrato , Fatores de Tempo , Transfecção , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
The architectural protein histone-like protein from Escherichia coli strain U93 (HU) is the most abundant bacterial DNA binding protein and highly conserved among bacteria and Apicomplexan parasites. It not only binds to double-stranded DNA (dsDNA) to maintain DNA stability but also, interacts with RNAs to regulate transcription and translation. Importantly, HU is essential to cell viability for many bacteria; hence, it is an important antibiotic target. Here, we report that Gp46 from bacteriophage SPO1 of Bacillus subtilis is an HU inhibitor whose expression prevents nucleoid segregation and causes filamentous morphology and growth defects in bacteria. We determined the solution structure of Gp46 and revealed a striking negatively charged surface. An NMR-derived structural model for the Gp46-HU complex shows that Gp46 occupies the DNA binding motif of the HU and therefore, occludes DNA binding, revealing a distinct strategy for HU inhibition. We identified the key residues responsible for the interaction that are conserved among HUs of bacteria and Apicomplexans, including clinically significant Mycobacterium tuberculosis, Acinetobacter baumannii, and Plasmodium falciparum, and confirm that Gp46 can also interact with these HUs. Our findings provide detailed insight into a mode of HU inhibition that provides a useful foundation for the development of antibacteria and antimalaria drugs.
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Proteínas de Bactérias/antagonistas & inibidores , Bacteriófagos/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Glicoproteínas/metabolismo , Proteínas Virais/metabolismo , Proteínas de Bactérias/metabolismo , DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Ligação ProteicaRESUMO
Single-crystal semiconductor-based photocatalysts exposing unique crystallographic facets show promising applications in energy and environmental technologies; however, crystal facet engineering through solid-state synthesis for photocatalytic overall water splitting is still challenging. Herein, we develop a novel crystal facet engineering strategy through solid-state recrystallization to synthesize uniform SrTiO3 single crystals exposing tailored {111} facets. The presynthesized low-crystalline SrTiO3 precursors enable the formation of well-defined single crystals through kinetically improved crystal structure transformation during solid-state recrystallization process. By employing subtle Al3+ ions as surface morphology modulators, the crystal surface orientation can be precisely tuned to a controlled percentage of {111} facets. The photocatalytic overall water splitting activity increases with the exposure percentage of {111} facets. Owing to the outstanding crystallinity and favorable anisotropic surface structure, the SrTiO3 single crystals with 36.6% of {111} facets lead to a 3-fold enhancement of photocatalytic hydrogen evolution rates up to 1.55 mmol·h-1 in a stoichiometric ratio of 2:1 than thermodynamically stable SrTiO3 enclosed with isotropic {100} facets.
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BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.
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Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Humanos , Multiômica , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/terapia , Imunoterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Análise por Conglomerados , PrognósticoRESUMO
Due to their significant capacity and reliable reversibility, transition metal sulphides (TMSs) have received attention as potential anode materials for sodium-ion batteries (SIBs). Nonetheless, a prevalent challenge with TMSs lies in their significant volume expansion and sluggish kinetics, impeding their capacity for rapid and enduring Na+ storage. Herein, a Cu1.96S@NC nanodisc material enriched with copper vacancies is synthesised via a hydrothermal and annealing procedure. Density functional theory (DFT) calculations reveal that the incorporation of copper vacancies significantly boosts electrical conductivity by reducing the energy barrier for ion diffusion, thereby promoting efficient electron/ion transport. Moreover, the presence of copper vacancies creates ample active sites for the integration of sodium ions, streamlines charge transfer, boosts electronic conductivity, and, ultimately, significantly enhances the overall performance of SIBs. This novel anode material, Cu1.96S@NC, demonstrates a reversible capacity of 339 mAh g-1 after 2000 cycles at a rate of 5 A g-1. In addition, it maintains a noteworthy reversible capacity of 314 mAh g-1 with an exceptional capacity retention of 96% even after 2000 cycles at 20 A g-1. The results demonstrate that creating cationic vacancies is a highly effective strategy for engineering anode materials with high capacity and rapid reactivity.
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The FeOOH/Zn(OH)2/CoS (FZC) nanocomposites are synthesized and show the outstanding electrochemical properties in both supercapacitor and catalytic hydrogen production. The specific area capacitance reaches 17.04 F cm-2, which is more than ten times higher than that of FeOOH/Zn(OH)2 (FZ) substrate: 1.58 F cm-2). FZC nanocomposites also exhibit the excellent cycling stability with an initial capacity retention rate of 93.6% after 10 000 long-term cycles. The electrolytic cell (FZC//FZC) assembled with FZC as both anode and cathode in the UOR (urea oxidation reaction)|| HER (hydrogen evolution reaction) coupled system requires a cell voltage of only 1.453 V to drive a current density of 10 mA cm-2. Especially, the electrochemical performances of FZC nanocomposites are enhanced in magnetic field, and the mechanism is proposed based on Stern double layer model at electrode-electrolyte interface (EEI). More electrolyte ions reach the surface of FZC electrode material under Kelvin force, moreover, the warburg impedance of FZC nanocomposites decrease under magnetic field action, which results in the enhanced behaviors for both the energy storage and urea oxidation reaction .
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Accurate and rapid autofocus technology plays a crucial role in various fields, including automatic optical inspection technology, bio-chips scanning, and semiconductor manufacturing. The current photoelectric autofocus methods have limitations because of detecting the focal plane solely at the center of the microscope field of view. In the application of Stereo-seq the risk of autofocus errors will be increased, which have reduced the robustness of the system, like when the surface of the tested samples are wrinkling and inconsistent thickness, or the detection spot is at the edge of the sample. To enhance the robustness of the autofocus system and mitigate the constraints of the photoelectric autofocus methods, the laser-based arrayed spots photoelectric autofocus method has been proposed. To achieve the uniform light splitting, a 2D-Dammann grating is incorporated into the optical path of the autofocus system, resulting in the formation of an n × n arrayed spots on the surface of the sample. Through experimental verification, it has been demonstrated that this method can achieve the autofocus range of ±100µm and the autofocus accuracy of ±1/4 DOF when applied to a microscope equipped with a 10× objective lens, thereby satisfying the requirements for microscopic focusing. The arrayed light autofocus method devised in this study presents what we believe is a novel research concept for active autofocus detection and holds significant application value.
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Laser wireless power transmission (LWPT) systems have significant applications in the field of wireless energy transmission, including spacecraft sensor networks, satellite-to-satellite communication, and remote power supply. However, continuous laser exposure increases the temperature of the photovoltaic (PV) cells in the LWPT system, thus decreasing the electrical output performance. This work, which we believe is a new approach, is on the basis of a notch film designed by a combined merit function proposed to maintain the electrical output performance while under 1064-nm continuous laser irradiation. Moreover, the thermal stability of PV cells under laser irradiation was investigated, which revealed the recoverability of the open-circuit voltage (Voc) of the cells at different temperatures, and the thermal damage to cells was a gradual process. This process began with the vaporization of the encapsulation adhesive, followed by a decline in, but still recoverable and functional, electrical performance, and finally, the cell was completely damaged. The thermal stability of the PV cells coated with the notch film increased ten-fold compared to those without it. Furthermore, the correlation between the minimum Voc and maximum temperature of the cells with notch films of different performances was established. These investigations serve as references for further optimization of LWPT.
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PURPOSE: This study focused on the mechanisms of pyroptosis and oxidative damage exacerbation by NOD-like receptor thermal protein domain associated protein 3 (NLRP3) during the infection of canine corneal epithelial cells (CCECs) with Staphylococcus pseudintermedius. METHODS: The CCECs treated with dimethyl fumarate (DMF), recombinant high mobility group protein 1 (HMGB1), or N-acetylcysteine (NAC). The gasdermin (GSDM) family and HMGB1 mRNA expression levels were detected using quantitative reverse transcription polymerase chain reaction. Lactate dehydrogenase activity, bacterial counts, the pyroptosis rate, reactive oxygen species (ROS) content, and antioxidant enzyme activity were used to reflect pyroptosis and oxidation level. RESULTS: Regulation of NLRP3 significantly affected the pyroptosis rate and GSDMD-N expression levels during S. pseudintermedius infection. Inhibition of GSDMD-N protein activation by DMF reversed the exacerbation of pyroptosis induced by NLRP3 overexpression and reduced the levels of cleaved interleukin-1ß (IL-1ß), cleaved cysteinyl aspartate-specific protease-1, and NLRP3. In addition, NLRP3 was found to target the HMGB1 promoter and regulate its protein expression, to increase ROS accumulation and GSDMD-N expression levels, and activate the NLRP3-HMGB1-ROS-GSDMD signaling axis to aggravate pyroptosis during infection. CONCLUSIONS: NLRP3 aggravates pyroptosis and oxidative damage associated with the activation of NLRP3-GSDMD and NLRP3-HMGB1-ROS-GSDMD signaling pathways during the infection of CCECs with S. pseudintermedius.
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Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.
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Depressão , Hipocampo , Estresse Psicológico , Animais , Hipocampo/metabolismo , Camundongos , Depressão/metabolismo , Masculino , Estresse Psicológico/metabolismo , Receptor trkB/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Comportamento Animal/fisiologia , Transdução de Sinais/fisiologia , Doença de Alzheimer/metabolismo , Glicoproteínas de Membrana/metabolismoRESUMO
Bioorthogonal reactions present a promising strategy for minimizing off-target toxicity in cancer chemotherapy, yet a dependable nanoplatform is urgently required. Here, we have fabricated an acid-responsive polymer micelle for the specific delivery and activation of the prodrug within tumor cells through Ru catalyst-mediated bioorthogonal reactions. The decomposition of micelles, triggered by the cleavage of the hydrazone bond in the acidic lysosomal environment, facilitated the concurrent release of Alloc-DOX and the Ru catalyst within the cells. Subsequently, the uncaging process of Alloc-DOX was demonstrated to be induced by the high levels of glutathione within tumor cells. Notably, the limited glutathione inside normal cells prevented the conversion of Alloc-DOX into active DOX, thereby minimizing the toxicity toward normal cells. In tumor-bearing mice, this nanoplatform exhibited enhanced efficacy in tumor suppression while minimizing off-target toxicity. Our study provides an innovative approach for in situ drug activation that combines safety and effectiveness in cancer chemotherapy.
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Doxorrubicina , Micelas , Polímeros , Pró-Fármacos , Rutênio , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Animais , Humanos , Camundongos , Doxorrubicina/farmacologia , Doxorrubicina/química , Rutênio/química , Polímeros/química , Catálise , Sistemas de Liberação de Medicamentos/métodos , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Camundongos NusRESUMO
Pigeon paramyxovirus type 1 (PPMV-1) poses significant economic challenges to the pigeon industry in China. However, information about the prevalence, genetic diversity, and epidemiology of PPMV-1 in China is still lacking. In this study, we isolated six strains of PPMV-1 from Hubei and Zhejiang provinces in 2022. All six isolates were found to belong to subgenotype VI.2.1.1.2.2. Five of them were identified as mesogenic and one as lentogenic. Multiple mutations were observed in the F and HN proteins of these isolates. Comprehensive analysis of global PPMV-1 strains highlighted the dominance of genotype VI, showing that VI.2.1.1.2.2 has been the dominant subgenotype since 2011. We also identified 36 host-specific amino acid substitutions that are unique to PPMV-1 in comparison to chicken-origin NDVs. The data reported here contribute to our understanding of the epidemiology, genetic diversity, and prevalence of PPMV-1 and serve as a valuable reference for the prevention and control of PPMV-1.