RESUMO
Negative-stranded RNA viruses can establish long-term persistent infection in the form of large intracellular inclusions in the human host and cause chronic diseases. Here, we uncover how cellular stress disrupts the metastable host-virus equilibrium in persistent infection and induces viral replication in a culture model of mumps virus. Using a combination of cell biology, whole-cell proteomics, and cryo-electron tomography, we show that persistent viral replication factories are dynamic condensates and identify the largely disordered viral phosphoprotein as a driver of their assembly. Upon stress, increased phosphorylation of the phosphoprotein at its interaction interface with the viral polymerase coincides with the formation of a stable replication complex. By obtaining atomic models for the authentic mumps virus nucleocapsid, we elucidate a concomitant conformational change that exposes the viral genome to its replication machinery. These events constitute a stress-mediated switch within viral condensates that provide an environment to support upregulation of viral replication.
Assuntos
Vírus da Caxumba , Infecção Persistente , Humanos , Vírus da Caxumba/fisiologia , Nucleocapsídeo , Fosfoproteínas/metabolismo , Replicação ViralRESUMO
Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that G3BP condensates impede RNA entanglement and recruit additional client proteins that promote SG maturation or induce a liquid-to-solid transition that may underlie disease. We propose that condensation coupled to conformational rearrangements and heterotypic multivalent interactions may be a general principle underlying RNP granule assembly.
Assuntos
Grânulos Citoplasmáticos/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Citoplasma/metabolismo , Células HeLa , Humanos , Conformação de Ácido Nucleico , Organelas/metabolismo , Fosforilação , RNA Mensageiro/metabolismo , Estresse Fisiológico/genéticaRESUMO
Proteins such as FUS phase separate to form liquid-like condensates that can harden into less dynamic structures. However, how these properties emerge from the collective interactions of many amino acids remains largely unknown. Here, we use extensive mutagenesis to identify a sequence-encoded molecular grammar underlying the driving forces of phase separation of proteins in the FUS family and test aspects of this grammar in cells. Phase separation is primarily governed by multivalent interactions among tyrosine residues from prion-like domains and arginine residues from RNA-binding domains, which are modulated by negatively charged residues. Glycine residues enhance the fluidity, whereas glutamine and serine residues promote hardening. We develop a model to show that the measured saturation concentrations of phase separation are inversely proportional to the product of the numbers of arginine and tyrosine residues. These results suggest it is possible to predict phase-separation properties based on amino acid sequences.
Assuntos
Proteína FUS de Ligação a RNA/genética , Proteínas de Ligação a RNA/fisiologia , Sequência de Aminoácidos , Aminoácidos/química , Animais , Arginina/química , Simulação por Computador , Células HeLa , Humanos , Proteínas Intrinsicamente Desordenadas/genética , Proteínas Intrinsicamente Desordenadas/fisiologia , Transição de Fase , Proteínas Priônicas/química , Proteínas Priônicas/genética , Príons/genética , Príons/fisiologia , Domínios Proteicos , Proteína FUS de Ligação a RNA/fisiologia , Proteínas de Ligação a RNA/isolamento & purificação , Células Sf9 , Tirosina/químicaRESUMO
Glucose is required for generating heat during cold-induced nonshivering thermogenesis in adipose tissue, but the regulatory mechanism is largely unknown. CREBZF has emerged as a critical mechanism for metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). We investigated the roles of CREBZF in the control of thermogenesis and energy metabolism. Glucose induces CREBZF in human white adipose tissue (WAT) and inguinal WAT (iWAT) in mice. Lys208 acetylation modulated by transacetylase CREB-binding protein/p300 and deacetylase HDAC3 is required for glucose-induced reduction of proteasomal degradation and augmentation of protein stability of CREBZF. Glucose induces rectal temperature and thermogenesis in white adipose of control mice, which is further potentiated in adipose-specific CREBZF knockout (CREBZF FKO) mice. During cold exposure, CREBZF FKO mice display enhanced thermogenic gene expression, browning of iWAT, and adaptive thermogenesis. CREBZF associates with PGC-1α to repress thermogenic gene expression. Expression levels of CREBZF are negatively correlated with UCP1 in human adipose tissues and increased in WAT of obese ob/ob mice, which may underscore the potential role of CREBZF in the development of compromised thermogenic capability under hyperglycemic conditions. Our results reveal an important mechanism of glucose sensing and thermogenic inactivation through reversible acetylation.
Assuntos
Tecido Adiposo Marrom , Glucose , Camundongos , Humanos , Animais , Glucose/metabolismo , Tecido Adiposo Marrom/metabolismo , Acetilação , Tecido Adiposo Branco/metabolismo , Metabolismo Energético , Obesidade/genética , Obesidade/metabolismo , Termogênese/genética , Camundongos Endogâmicos C57BL , Fatores de Transcrição de Zíper de Leucina Básica/metabolismoRESUMO
Nuclear pore complexes (NPCs) fuse the inner and outer membranes of the nuclear envelope. They comprise hundreds of nucleoporins (Nups) that assemble into multiple subcomplexes and form large central channels for nucleocytoplasmic exchange1,2. How this architecture facilitates messenger RNA export, NPC biogenesis and turnover remains poorly understood. Here we combine in situ structural biology and integrative modelling with correlative light and electron microscopy and molecular perturbation to structurally analyse NPCs in intact Saccharomyces cerevisiae cells within the context of nuclear envelope remodelling. We find an in situ conformation and configuration of the Nup subcomplexes that was unexpected from the results of previous in vitro analyses. The configuration of the Nup159 complex appears critical to spatially accommodate its function as an mRNA export platform, and as a mediator of NPC turnover. The omega-shaped nuclear envelope herniae that accumulate in nup116Δ cells3 conceal partially assembled NPCs lacking multiple subcomplexes, including the Nup159 complex. Under conditions of starvation, herniae of a second type are formed that cytoplasmically expose NPCs. These results point to a model of NPC turnover in which NPC-containing vesicles bud off from the nuclear envelope before degradation by the autophagy machinery. Our study emphasizes the importance of investigating the structure-function relationship of macromolecular complexes in their cellular context.
Assuntos
Microscopia Crioeletrônica , Poro Nuclear/metabolismo , Poro Nuclear/ultraestrutura , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/ultraestrutura , Autofagia , Modelos Moleculares , Poro Nuclear/química , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , TomografiaRESUMO
The dorsal and ventral human telencephalons contain different neuronal subtypes, including glutamatergic, GABAergic, and cholinergic neurons, and how these neurons are generated during early development is not well understood. Using scRNA-seq and stringent validations, we reveal here a developmental roadmap for human telencephalic neurons. Both dorsal and ventral telencephalic radial glial cells (RGs) differentiate into neurons via dividing intermediate progenitor cells (IPCs_div) and early postmitotic neuroblasts (eNBs). The transcription factor ASCL1 plays a key role in promoting fate transition from RGs to IPCs_div in both regions. RGs from the regionalized neuroectoderm show heterogeneity, with restricted glutamatergic, GABAergic, and cholinergic differentiation potencies. During neurogenesis, IPCs_div gradually exit the cell cycle and branch into sister eNBs to generate distinct neuronal subtypes. Our findings highlight a general RGs-IPCs_div-eNBs developmental scheme for human telencephalic progenitors and support that the major neuronal fates of human telencephalon are predetermined during dorsoventral regionalization with neuronal diversity being further shaped during neurogenesis and neural circuit integration.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica no Desenvolvimento , Neurogênese/genética , Neurônios/metabolismo , Telencéfalo/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Ciclo Celular/genética , Diferenciação Celular , Colina/metabolismo , Proteína Duplacortina/genética , Proteína Duplacortina/metabolismo , Feto , Ontologia Genética , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Anotação de Sequência Molecular , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neuroglia/citologia , Neuroglia/metabolismo , Neurônios/classificação , Neurônios/citologia , Fatores de Transcrição SOXC/genética , Fatores de Transcrição SOXC/metabolismo , Transdução de Sinais , Estatmina/genética , Estatmina/metabolismo , Telencéfalo/citologia , Telencéfalo/crescimento & desenvolvimento , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
In mammals, the most remarkable T cell variations with aging are the shrinking of the naïve T cell pool and the enlargement of the memory T cell pool, which are partially caused by thymic involution. However, the mechanism underlying the relationship between T-cell changes and aging remains unclear. In this study, we find that T-cell-specific Rip1 KO mice show similar age-related T cell changes and exhibit signs of accelerated aging-like phenotypes, including inflammation, multiple age-related diseases, and a shorter lifespan. Mechanistically, Rip1-deficient T cells undergo excessive apoptosis and promote chronic inflammation. Consistent with this, blocking apoptosis by co-deletion of Fadd in Rip1-deficient T cells significantly rescues lymphopenia, the imbalance between naïve and memory T cells, and aging-like phenotypes, and prolongs life span in T-cell-specific Rip1 KO mice. These results suggest that the reduction and hyperactivation of T cells can have a significant impact on organismal health and lifespan, underscoring the importance of maintaining T cell homeostasis for healthy aging and prevention or treatment of age-related diseases.
Assuntos
Senilidade Prematura , Linfócitos T , Animais , Camundongos , Envelhecimento/genética , Senilidade Prematura/genética , Apoptose , Inflamação , MamíferosRESUMO
Methylation of cytosine to 5-methylcytosine (5mC) is a prevalent DNA modification found in many organisms. Sequential oxidation of 5mC by ten-eleven translocation (TET) dioxygenases results in a cascade of additional epigenetic marks and promotes demethylation of DNA in mammals1,2. However, the enzymatic activity and function of TET homologues in other eukaryotes remains largely unexplored. Here we show that the green alga Chlamydomonas reinhardtii contains a 5mC-modifying enzyme (CMD1) that is a TET homologue and catalyses the conjugation of a glyceryl moiety to the methyl group of 5mC through a carbon-carbon bond, resulting in two stereoisomeric nucleobase products. The catalytic activity of CMD1 requires Fe(II) and the integrity of its binding motif His-X-Asp, which is conserved in Fe-dependent dioxygenases3. However, unlike previously described TET enzymes, which use 2-oxoglutarate as a co-substrate4, CMD1 uses L-ascorbic acid (vitamin C) as an essential co-substrate. Vitamin C donates the glyceryl moiety to 5mC with concurrent formation of glyoxylic acid and CO2. The vitamin-C-derived DNA modification is present in the genome of wild-type C. reinhardtii but at a substantially lower level in a CMD1 mutant strain. The fitness of CMD1 mutant cells during exposure to high light levels is reduced. LHCSR3, a gene that is critical for the protection of C. reinhardtii from photo-oxidative damage under high light conditions, is hypermethylated and downregulated in CMD1 mutant cells compared to wild-type cells, causing a reduced capacity for photoprotective non-photochemical quenching. Our study thus identifies a eukaryotic DNA base modification that is catalysed by a divergent TET homologue and unexpectedly derived from vitamin C, and describes its role as a potential epigenetic mark that may counteract DNA methylation in the regulation of photosynthesis.
Assuntos
5-Metilcitosina/metabolismo , Proteínas de Algas/metabolismo , Ácido Ascórbico/metabolismo , Biocatálise , Chlamydomonas reinhardtii/enzimologia , DNA/química , DNA/metabolismo , 5-Metilcitosina/química , Dióxido de Carbono/metabolismo , Metilação de DNA , Glioxilatos/metabolismo , Nucleosídeos/química , Nucleosídeos/metabolismo , FotossínteseRESUMO
Two-dimensional (2D) lead halide perovskites are excellent candidates for X-ray detection due to their high resistivity, high ion migration barrier, and large X-ray absorption coefficients. However, the high toxicity and long interlamellar distance of the 2D perovskites limit their wide application in high sensitivity X-ray detection. Herein, we demonstrate stable and toxicity-reduced 2D perovskite single crystals (SCs) realized by interlamellar-spacing engineering via a distortion self-balancing strategy. The engineered low-toxicity 2D SC detectors achieve high stability, large mobility-lifetime product, and therefore high-performance X-ray detection. Specifically, the detectors exhibit a record high sensitivity of 13488 µC Gy1- cm-2, a low detection limit of 8.23 nGy s-1, as well as a high spatial resolution of 8.56 lp mm-1 in X-ray imaging, all of which are far better than those of the high-toxicity 2D lead-based perovskite detectors. These advances provide a new technical solution for the low-cost fabrication of low-toxicity, scalable X-ray detectors.
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Mutations in NOTCH3 underlie cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common inherited cerebral small vessel disease. Two cleavages of NOTCH3 protein, at Asp80 and Asp121, were previously described in CADASIL pathological samples. Using monoclonal antibodies developed against a NOTCH3 neoepitope, we identified a third cleavage at Asp964 between an Asp-Pro sequence. We characterized the structural requirements for proteolysis at Asp964 and the vascular distribution of the cleavage event. A proteome-wide analysis was performed to find proteins that interact with the cleavage product. Finally, we investigated the biochemical determinants of this third cleavage event. Cleavage at Asp964 was critically dependent on the proline adjacent to the aspartate residue. In addition, the cleavage product was highly enriched in CADASIL brain tissue and localized to the media of degenerating arteries, where it deposited with the two additional NOTCH3 cleavage products. Recombinant NOTCH3 terminating at Asp964 was used to probe protein microarrays. We identified multiple molecules that bound to the cleaved NOTCH3 more than to uncleaved protein, suggesting that cleavage may alter the local protein interactome within disease-affected blood vessels. The cleavage of purified NOTCH3 protein at Asp964 in vitro was activated by reducing agents and NOTCH3 protein; cleavage was inhibited by specific dicarboxylic acids, as seen with cleavage at Asp80 and Asp121. Overall, we propose homologous redox-driven Asp-Pro cleavages and alterations in protein interactions as potential mechanisms in inherited small vessel disease; similarities in protein cleavage characteristics may indicate common biochemical modulators of pathological NOTCH3 processing.
Assuntos
CADASIL , Receptor Notch3 , Humanos , Encéfalo/metabolismo , CADASIL/genética , CADASIL/patologia , Doenças de Pequenos Vasos Cerebrais/genética , Doenças de Pequenos Vasos Cerebrais/patologia , Mutação , Receptor Notch3/genética , Receptor Notch3/metabolismo , Ligação Proteica , Análise Serial de Proteínas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease that results from mutations in NOTCH3. How mutations in NOTCH3 ultimately result in disease is not clear, although there is a predilection for mutations to alter the number of cysteines of the gene product, supporting a model in which alterations of conserved disulfide bonds of NOTCH3 drives the disease process. We have found that recombinant proteins with CADASIL NOTCH3 EGF domains 1 to 3 fused to the C terminus of Fc are distinguished from wildtype proteins by slowed mobility in nonreducing gels. We use this gel mobility shift assay to define the effects of mutations in the first three EGF-like domains of NOTCH3 in 167 unique recombinant protein constructs. This assay permits a readout on NOTCH3 protein mobility that indicates that (1) any loss of cysteine mutation in the first three EGF motifs results in structural abnormalities; (2) for loss of cysteine mutants, the mutant amino acid residue plays a minimal role; (3) the majority of changes that result in a new cysteine are poorly tolerated; (4) at residue 75, only cysteine, proline, and glycine induce structural shifts; (5) specific second mutations in conserved cysteines suppress the impact of loss of cysteine CADASIL mutations. These studies support the importance of NOTCH3 cysteines and disulfide bonds in maintaining normal protein structure. Double mutant analysis suggests that suppression of protein abnormalities can be achieved through modification of cysteine reactivity, a potential therapeutic strategy.
Assuntos
CADASIL , Receptor Notch3 , Humanos , CADASIL/genética , Cisteína/genética , Cisteína/metabolismo , Dissulfetos , Fator de Crescimento Epidérmico/genética , Mutação , Receptor Notch3/genéticaRESUMO
Recent studies on co-transformation of the growth regulator, TaGRF4-GIF1 chimera (Growth Regulating Factor 4-GRF Interacting Factor 1), in cultivated wheat varieties (Triticum aestivum), showed improved regeneration efficiency, marking a significant breakthrough. Here, a simple and reproducible protocol using the GRF4-GIF1 chimera was established and tested in the medicinal orchid Dendrobium catenatum, a monocot orchid species. TaGRF4-GIF1 from T. aestivum and DcGRF4-GIF1 from D. catenatum were reconstructed, with the chimeras significantly enhancing the regeneration efficiency of D. catenatum through in planta transformation. Further, mutating the microRNA396 (miR396) target sites in TaGRF4 and DcGRF4 improved regeneration efficiency. The target mimicry version of miR396 (MIM396) not only boosted shoot regeneration but also enhanced plant growth. Our methods revealed a powerful tool for the enhanced regeneration and genetic transformation of D. catenatum.
Assuntos
Dendrobium , MicroRNAs , Brotos de Planta , Regeneração , Dendrobium/genética , Dendrobium/crescimento & desenvolvimento , MicroRNAs/genética , MicroRNAs/metabolismo , Brotos de Planta/genética , Brotos de Planta/crescimento & desenvolvimento , Regeneração/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Geneticamente Modificadas/genéticaRESUMO
BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.
Assuntos
Carcinoma Hepatocelular , Quimiocina CCL2 , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas , Proteínas Serina-Treonina Quinases , Microambiente Tumoral , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/radioterapia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/radioterapia , Humanos , Animais , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Quimiocina CCL2/metabolismo , Linhagem Celular Tumoral , Tolerância a Radiação , Prognóstico , Fator de Transcrição STAT3/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , MicroRNAs/genéticaRESUMO
Methamphetamine use disorder (MAUD) can substantially jeopardize public security due to its high-risk social psychology and behaviour. Given that the dopamine reward system is intimately correlated with MAUD, we investigated the association of single nucleotide polymorphisms (SNPs), as well as methylation status of dopamine receptor type 4 (DRD4), catechol-O-methyltransferase (COMT) genes, and paranoid and motor-impulsive symptoms in MAUD patients. A total of 189 MAUD patients participated in our study. Peripheral blood samples were used to detect 3 SNPs and 35 CpG units of methylation in the DRD4 gene promoter region and 5 SNPs and 39 CpG units in the COMT gene. MAUD patients with the DRD4 rs1800955 C allele have a lower percentage of paranoid symptoms than those with the rs1800955 TT allele. Individuals with paranoid symptoms exhibited a reduced methylation degree at a particular DRD4 CpG2.3 unit. The interaction of the DRD4 rs1800955 C allele and the reduced DRD4CpG2.3 methylation degree were associated with a lower occurrence of paranoid symptoms. Meanwhile, those with the COMT rs4818 CC allele had lower motor-impulsivity scores in MAUD patients but greater COMT methylation levels in the promoter region and methylation degree at the COMT CpG 51.52 unit. Therefore, based only on the COMT rs4818 CC polymorphism, there was a negative correlation between COMT methylation and motor-impulsive scores. Our preliminary results provide a clue that the combination of SNP genotype and methylation status of the DRD4 and COMT genes serve as biological indicators for the prevalence of relatively high-risk psychotic symptoms in MAUD patients.
Assuntos
Metanfetamina , Polimorfismo de Nucleotídeo Único , Humanos , Catecol O-Metiltransferase/genética , Dopamina , Metanfetamina/efeitos adversos , Genótipo , MetilaçãoRESUMO
1D nanostructures exhibit a large surface area and a short network distance, facilitating electron and ion transport. In this study, a 1D van der Waals material, tin iodide phosphide (SnIP), is synthesized and used as an electrocatalyst for the conversion of CO2 to formate. The electrochemical treatment of SnIP reconstructs it into a web-like structure, dissolves the I and P components, and increases the number of oxygen vacancies. The resulting oxygen vacancies promote the activity of the CO2 reduction reaction (CO2RR), increasing the local pH of the electrode surface and maintaining the oxidative metal site of the catalyst despite the electrochemically reducing environment. This strategy, which stabilizes the oxidation state of the catalyst, also helps to improve the durability of CO2RR. In practice, 1D structured SnIP catalyst exhibits outstanding performance with >92% formate faradaic efficiency (FEformate) at 300 mA cm-2, a maximum partial current density for formate of 343 mA cm-2, and excellent long-term stability (>100 h at 100 mA cm-2 with >86% FEformate). This study introduced a method to easily generate oxygen vacancies on the catalyst surface by utilizing 1D materials and a strategy to improve the durability of CO2RR by stabilizing the oxidation state of the catalyst.
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BACKGROUND: Inflammatory response has been recognized as a pivotal pathophysiological process during cerebral ischemia. ChemR23 signaling is involved in the pathophysiology of various inflammatory diseases. Nevertheless, the role of ChemR23 signaling in ischemic stroke remains largely unknown. METHODS: Permanent ischemic stroke mouse model was accomplished by middle cerebral artery occlusion (MCAO). Resolvin E1 (RvE1) or chemerin-9 (C-9), the agonists of ChemR23, were administered by intracerebroventricular (i.c.v) injection before MCAO induction. Then, analysis of neurobehavioral deficits and brain sampling were done at Day 1 after MCAO. The brain samples were further analyzed by histological staining, immunofluorescence, RNA sequencing, ELISA, transmission electron microscope, and western blots. Furthermore, oxygen-glucose deprivation (OGD) was employed in SH-SY5Y to mimic MCAO in vitro, and ChemR23 signaling pathway was further studied by overexpression of ChemR23 or administration of related agonists or antagonists. Analysis of cell death and related pathway markers were performed. RESULTS: ChemR23 expression was upregulated following MCAO. Under in vitro and in vivo ischemic conditions, ChemR23 deficiency or inhibition contributed to excessive NLRP3-mediated maturation and release of IL-1ß and IL-18, as well as enhanced cleavage of GSDMD-N and neuronal pyroptosis. These influences ultimately aggravated brain injury and neuronal damage. On the other hand, ChemR23 activation by RvE1 or C-9 mitigated the above pathophysiological abnormalities in vivo and in vitro, and overexpression of ChemR23 in SH-SY5Y cells also rescued OGD-induced neuronal pyroptosis. Blockade of NLRP3 mimics the protective effects of ChemR23 activation in vitro. CONCLUSION: Our data indicated that ChemR23 modulates NLRP3 inflammasome-mediated neuronal pyroptosis in ischemic stroke. Activation of ChemR23 may serve as a promising potential target for neuroprotection in cerebral ischemia.
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Isquemia Encefálica , AVC Isquêmico , Neuroblastoma , Receptores de Quimiocinas , Traumatismo por Reperfusão , Animais , Humanos , Camundongos , Isquemia Encefálica/complicações , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Quimiocinas , Infarto da Artéria Cerebral Média/complicações , Inflamassomos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , AVC Isquêmico/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Piroptose , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Receptores de Quimiocinas/metabolismoRESUMO
The binocular structured light 3D measurement system is widely used in situ industrial inspection and shape measurement, where the system structure is generally unstable due to mechanical loosening or environmental disturbance. Timely corrections to the changing structural parameters thus is an essential task for online high-accuracy measurement, which is difficult for traditional unidirectional fringe projection methods to self-correct the structural change. To this end, we propose an online self-correction method based on the investigation that orthogonal fringe projection can intrinsically relax the constraint on the epipolar geometry relationship and provide bidirectional phases for accurate corresponding point searching. Since orthogonal fringe projection may sacrifice the measurement efficiency, we further design a searching strategy by locally unwrapping one directional phase to reduce the number of projection patterns. Experimental results demonstrate that the proposed method is effective for online self-correction of unstable system structure to achieve high-accuracy 3D measurement under complex measurement environments.
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Fringe projection profilometry (FPP) faces significant challenges regarding calibration difficulty and stitching error accumulation when operating across scenes ranging from tens to hundreds of meters. This Letter presents a calibration-free 3D measurement method by integrating a binocular vision of a FPP scanner with a wide field-of-view (FoV) vision that constructs global benchmarks to unify local 3D scanning and global 3D stitching, which is adaptable to arbitrarily large-scale scenes. A posterior global optimization model is then established to determine the reconstruction parameters and stitching poses simultaneously at each scanning node with adaptively distributed benchmarks. Consequently, the integrated vision measurement system not only eliminates the large-scale pre-calibration and stitching error accumulation but also overcomes system structural instability during moving measurement. With the proposed method, we achieved 3D measurements with an accuracy of 0.25 mm and a density of 0.5 mm for over 50-m-long scenes.
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OBJECTIVE: To compare and rank the effectiveness of four primary categories of exercise modalities (aerobic, resistance, mind-body, and combined exercise [CE]) in improving the Quality of life (QoL) of women with breast cancer in a network meta-analysis (NMA). METHODS: Articles published in English and indexed in the PubMed (MEDLINE), EBSCO, Web of Science, SPORTDiscus, The Cochrane Library, Google Scholar, PsycINFO, EMBASE, and CINAHL Plus databases were identified from inception to 12 October 2023. Studies that met the eligibility criteria were assessed for risk of bias. A frequentist NMA was conducted to appraise the efficacy of different exercise types. RESULTS: This study included 56 studies with 3904 participants. Aerobic, mind-body, and combined exercises effectively improved QoL compared to controls. The surface under the cumulative ranking curve (SUCRA) indicated that CE best improved patients' QoL (SUCRA = 96.7%). Analysis of the secondary outcomes suggests that exercise reduced patients' depression (standardized mean difference [SMD] = -0.38, 95% confidence interval [CI] = -0.70 to -0.06, p < 0.001; I2 = 79%) and anxiety (SMD = -0.50, 95% CI = -0.69 to -0.31, p < 0.001; I2 = 27.4%) but did not affect self-esteem. CONCLUSION: All exercise types but resistance were effective in improving the QoL of women with breast cancer, CE (the combination of aerobic and resistance exercise) had the highest likelihood of being optimal for improving QoL.
Assuntos
Ansiedade , Neoplasias da Mama , Terapia por Exercício , Metanálise em Rede , Qualidade de Vida , Humanos , Qualidade de Vida/psicologia , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Feminino , Terapia por Exercício/métodos , Ansiedade/psicologia , Depressão/psicologia , Exercício Físico/psicologiaRESUMO
OBJECTIVES: Heart failure with preserved ejection fraction (HFpEF) is a syndrome with significant clinical heterogeneity. Myocardial fibrosis has been considered a common pathological process in the development and progress of HFpEF. This study aimed to consolidate data on the prognostic effect of myocardial fibrosis, evaluated by cardiovascular magnetic resonance (CMR) imaging in patients with HFpEF. METHODS: Three medical databases were searched for potentially related articles up to February 28, 2023. Cohort studies reporting associations between myocardial fibrosis and risk of all-cause mortality or composite major adverse cardiac outcomes (MACE) were included. Cardiac fibrosis was evaluated by CMR metrics, including late gadolinium enhancement (LGE) or myocardial extracellular volume (ECV). The hazard ratios (HRs) and 95% confidence intervals (CI) of the outcomes for higher myocardial fibrosis were calculated. RESULTS: Twelve studies with 2787 patients with HFpEF were included for analysis. After a median follow-up duration of 31.2 months, a higher level of cardiac fibrosis was associated with a significant increase in the risk of MACE (HR = 1.34, 95% CI = 1.14-1.57) and all-cause mortality (HR = 1.74, 95% CI = 1.27-2.39), respectively. Furthermore, the increased risk of outcomes was both observed when cardiac fibrosis was defined according to LGE or ECV, respectively. CONCLUSIONS: Higher burden of myocardial fibrosis evaluated by CMR can predict a poor prognosis in patients with HFpEF. Evaluation of LGE or ECV based on CMR could be recommended in these patients for risk stratification and guiding further treatment. CLINICAL RELEVANCE STATEMENT: Inclusion of cardiovascular magnetic resonance examination in the diagnostic and risk-evaluation algorithms in patients with heart failure with preserved ejection fraction should be considered in clinical practice and future studies. KEY POINTS: ⢠Myocardial fibrosis is a common pathological process in heart failure with preserved ejection fraction. ⢠A higher myocardial fibrosis burden on cardiac magnetic resonance predicts a poor prognosis in patients with heart failure with preserved ejection fraction. ⢠Evaluation of myocardial fibrosis may be useful in patients with heart failure with preserved ejection fraction for risk stratification and treatment guidance.