RESUMO
Plants rely on cell-surface-localized pattern recognition receptors to detect pathogen- or host-derived danger signals and trigger an immune response1-6. Receptor-like proteins (RLPs) with a leucine-rich repeat (LRR) ectodomain constitute a subgroup of pattern recognition receptors and play a critical role in plant immunity1-3. Mechanisms underlying ligand recognition and activation of LRR-RLPs remain elusive. Here we report a crystal structure of the LRR-RLP RXEG1 from Nicotiana benthamiana that recognizes XEG1 xyloglucanase from the pathogen Phytophthora sojae. The structure reveals that specific XEG1 recognition is predominantly mediated by an amino-terminal and a carboxy-terminal loop-out region (RXEG1(ID)) of RXEG1. The two loops bind to the active-site groove of XEG1, inhibiting its enzymatic activity and suppressing Phytophthora infection of N. benthamiana. Binding of XEG1 promotes association of RXEG1(LRR) with the LRR-type co-receptor BAK1 through RXEG1(ID) and the last four conserved LRRs to trigger RXEG1-mediated immune responses. Comparison of the structures of apo-RXEG1(LRR), XEG1-RXEG1(LRR) and XEG1-BAK1-RXEG1(LRR) shows that binding of XEG1 induces conformational changes in the N-terminal region of RXEG1(ID) and enhances structural flexibility of the BAK1-associating regions of RXEG1(LRR). These changes allow fold switching of RXEG1(ID) for recruitment of BAK1(LRR). Our data reveal a conserved mechanism of ligand-induced heterodimerization of an LRR-RLP with BAK1 and suggest a dual function for the LRR-RLP in plant immunity.
Assuntos
Glicosídeo Hidrolases , Phytophthora , Imunidade Vegetal , Proteínas de Plantas , Receptores de Reconhecimento de Padrão , Motivos de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Glicosídeo Hidrolases/metabolismo , Leucina/metabolismo , Ligantes , Phytophthora/enzimologia , Phytophthora/imunologia , Phytophthora/fisiologia , Proteínas de Plantas/química , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Multimerização Proteica , Receptores de Reconhecimento de Padrão/química , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Nicotiana/química , Nicotiana/metabolismoRESUMO
Plant intracellular nucleotide-binding leucine-rich repeat receptors (NLRs) detect pathogen effectors to trigger immune responses1. Indirect recognition of a pathogen effector by the dicotyledonous Arabidopsis thaliana coiled-coil domain containing NLR (CNL) ZAR1 induces the formation of a large hetero-oligomeric protein complex, termed the ZAR1 resistosome, which functions as a calcium channel required for ZAR1-mediated immunity2-4. Whether the resistosome and channel activities are conserved among plant CNLs remains unknown. Here we report the cryo-electron microscopy structure of the wheat CNL Sr355 in complex with the effector AvrSr356 of the wheat stem rust pathogen. Direct effector binding to the leucine-rich repeats of Sr35 results in the formation of a pentameric Sr35-AvrSr35 complex, which we term the Sr35 resistosome. Wheat Sr35 and Arabidopsis ZAR1 resistosomes bear striking structural similarities, including an arginine cluster in the leucine-rich repeats domain not previously recognized as conserved, which co-occurs and forms intramolecular interactions with the 'EDVID' motif in the coiled-coil domain. Electrophysiological measurements show that the Sr35 resistosome exhibits non-selective cation channel activity. These structural insights allowed us to generate new variants of closely related wheat and barley orphan NLRs that recognize AvrSr35. Our data support the evolutionary conservation of CNL resistosomes in plants and demonstrate proof of principle for structure-based engineering of NLRs for crop improvement.
Assuntos
Canais de Cálcio , Microscopia Crioeletrônica , Proteínas NLR , Proteínas de Plantas , Receptores Imunológicos , Triticum , Arabidopsis/imunologia , Arabidopsis/metabolismo , Arginina , Canais de Cálcio/química , Canais de Cálcio/imunologia , Canais de Cálcio/metabolismo , Cátions/metabolismo , Leucina , Proteínas NLR/química , Proteínas NLR/imunologia , Proteínas NLR/metabolismo , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal , Proteínas de Plantas/química , Proteínas de Plantas/imunologia , Proteínas de Plantas/metabolismo , Receptores Imunológicos/química , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Triticum/imunologia , Triticum/metabolismo , Motivos de Aminoácidos , Sequência Conservada , EletrofisiologiaRESUMO
Nucleotide-binding domain, leucine-rich repeat receptors (NLRs) mediate innate immunity by forming inflammasomes. Activation of the NLR protein NLRP1 requires autocleavage within its function-to-find domain (FIIND)1-7. In resting cells, the dipeptidyl peptidases DPP8 and DPP9 interact with the FIIND of NLRP1 and suppress spontaneous NLRP1 activation8,9; however, the mechanisms through which this occurs remain unknown. Here we present structural and biochemical evidence that full-length rat NLRP1 (rNLRP1) and rat DPP9 (rDPP9) form a 2:1 complex that contains an autoinhibited rNLRP1 molecule and an active UPA-CARD fragment of rNLRP1. The ZU5 domain is required not only for autoinhibition of rNLRP1 but also for assembly of the 2:1 complex. Formation of the complex prevents UPA-mediated higher-order oligomerization of UPA-CARD fragments and strengthens ZU5-mediated NLRP1 autoinhibition. Structure-guided biochemical and functional assays show that both NLRP1 binding and enzymatic activity are required for DPP9 to suppress NLRP1 in human cells. Together, our data reveal the mechanism of DPP9-mediated inhibition of NLRP1 and shed light on the activation of the NLRP1 inflammasome.
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Dipeptidil Peptidases e Tripeptidil Peptidases/química , Proteínas NLR/química , Animais , Proteínas Adaptadoras de Sinalização CARD , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas do Tecido Nervoso , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , RatosRESUMO
Weyl semimetal showing open-arc surface states is a prominent example of topological quantum matter in three dimensions. With the bulk-boundary correspondence present, nontrivial surface-bulk hybridization is inevitable but less understood. Spectroscopies have been often limited to verifying the existence of surface Fermi arcs, whereas its spectral shape related to the hybridization profile in energy-momentum space is not well studied. We present an exactly solvable formalism at the surface for a wide range of prototypical Weyl semimetals. The resonant surface state and the bulk influence coexist as a surface-bulk hybrid and are treated in a unified manner. Directly accessible to angle-resolved photoemission spectroscopy, we analytically reveal universal information about the system obtained from the spectroscopy of resonant topological states. We systematically find inhomogeneous and anisotropic singular responses around the surface-bulk merging borderline crossing Weyl points, highlighting its critical role in the Weyl topology. The response in scanning tunneling spectroscopy is also discussed. The results will provide much-needed insight into the surface-bulk-coupled physical properties and guide in-depth spectroscopic investigation of the nontrivial hybrid in many topological semimetal materials.
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As obligate parasites, viruses have evolved multiple strategies to evade the host immune defense. Manipulation of the host proteasome system to degrade specific detrimental factors is a common viral countermeasure. To identify host proteins targeted for proteasomal degradation by porcine reproductive and respiratory syndrome virus (PRRSV), we conducted a quantitative proteomics screen of PRRSV-infected Marc-145 cells under the treatment with proteasome inhibitor MG132. The data revealed that the expression levels of programmed cell death 4 (PDCD4) were strongly downregulated by PRRSV and significantly rescued by MG132. Further investigation confirmed that PRRSV infection induced the translocation of PDCD4 from the nucleus to the cytoplasm, and the viral nonstructural protein 9 (Nsp9) promoted PDCD4 proteasomal degradation in the cytoplasm by activating the Akt-mTOR-S6K1 pathway. The C-terminal domain of Nsp9 was responsible for PDCD4 degradation. As for the role of PDCD4 during PRRSV infection, we demonstrated that PDCD4 knockdown favored viral replication, while its overexpression significantly attenuated replication, suggesting that PDCD4 acts as a restriction factor for PRRSV. Mechanistically, we discovered eukaryotic translation initiation factor 4A (eIF4A) was required for PRRSV. PDCD4 interacted with eIF4A through four sites (E249, D253, D414, and D418) within its two MA3 domains, disrupting eIF4A-mediated translation initiation in the 5'-untranslated region of PRRSV, thereby inhibiting PRRSV infection. Together, our study reveals the antiviral function of PDCD4 and the viral strategy to antagonize PDCD4. These results will contribute to our understanding of the immune evasion strategies employed by PRRSV and offer valuable insights for developing new antiviral targets.IMPORTANCEPorcine reproductive and respiratory syndrome virus (PRRSV) infection results in major economic losses in the global swine industry and is difficult to control effectively. Here, using a quantitative proteomics screen, we identified programmed cell death 4 (PDCD4) as a host protein targeted for proteasomal degradation by PRRSV. We demonstrated that PDCD4 restricts PRRSV replication by interacting with eukaryotic translation initiation factor 4A, which is required for translation initiation in the viral 5'-untranslated region. Additionally, four sites within two MA3 domains of PDCD4 are identified to be responsible for its antiviral function. Conversely, PRRSV nonstructural protein 9 promotes PDCD4 proteasomal degradation in the cytoplasm by activating the Akt-mTOR-S6K1 pathway, thus weakening the anti-PRRSV function. Our work unveils PDCD4 as a previously unrecognized host restriction factor for PRRSV and reveals that PRRSV develops countermeasures to overcome PDCD4. This will provide new insights into virus-host interactions and the development of new antiviral targets.
Assuntos
Proteínas Reguladoras de Apoptose , Fator de Iniciação 4A em Eucariotos , Vírus da Síndrome Respiratória e Reprodutiva Suína , Proteínas de Ligação a RNA , Proteínas não Estruturais Virais , Replicação Viral , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Animais , Proteínas não Estruturais Virais/metabolismo , Proteínas não Estruturais Virais/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Fator de Iniciação 4A em Eucariotos/genética , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Suínos , Linhagem Celular , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Interações Hospedeiro-Patógeno , Proteólise , Humanos , Síndrome Respiratória e Reprodutiva Suína/metabolismo , Síndrome Respiratória e Reprodutiva Suína/virologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de SinaisRESUMO
SignificanceOptically excited systems can host unprecedented phenomena and reveal key information. The spin-channel physics in the photoexcited dynamics of quantum matter remains largely unexplored. This study finds the topological surface state under contemporary time-resolved pump-probe spectroscopy an exceptionally capable platform in this regard. Spin signals exhibit interesting tornado-like spiral patterns, and the unusual topological optical activity can be indicative of spintronic applications. This exemplifies a purely nonequilibrium topological winding phenomenon, where all the hidden helicity factors in the light-matter-coupled system are robustly encoded. These results open a direction of nonequilibrium topological spin states in quantum materials.
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Recent work shed light on how plant intracellular immune receptors of the nucleotide-binding leucine-rich repeat (NLR) family are activated upon pathogen effector recognition to trigger immune responses. Activation of Toll-interleukin-1 receptor (TIR) domain-containing NLRs (TNLs) induces receptor oligomerization and close proximity of the TIR domain, which is required for TIR enzymatic activity. TIR-catalyzed small signaling molecules bind to EDS1 family heterodimers and subsequently activate downstream helper NLRs, which function as Ca2+ permeable channel to activate immune responses eventually leading to cell death. Subcellular localization requirements of TNLs and signaling partners are not well understood, although they are required to understand fully the mechanisms underlying NLR early signaling. TNLs show diverse subcellular localization while EDS1 shows nucleocytosolic localization. Here, we studied the impact of TIR and EDS1 mislocalization on the signaling activation of different TNLs. In Nicotiana benthamiana, our results suggest that close proximity of TIR domains isolated from flax L6 and Arabidopsis RPS4 and SNC1 TNLs drives signaling activation from different cell compartments. Nevertheless, both Golgi-membrane anchored L6 and nucleocytosolic RPS4 have the same requirements for EDS1 subcellular localization in Arabidopsis thaliana. By using mislocalized variants of EDS1, we found that autoimmune L6 and RPS4 TIR domain can induce seedling cell death when EDS1 is present in the cytosol. However, when EDS1 is restricted to the nucleus, both induce a stunting phenotype but no cell death. Our data point out the importance of thoroughly investigating the dynamics of TNLs and signaling partners subcellular localization to understand TNL signaling fully.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/metabolismo , Proteínas de Ligação a DNA/genética , Arabidopsis/metabolismo , Receptores Imunológicos/metabolismo , Morte Celular/genética , Imunidade Vegetal/genética , Doenças das PlantasRESUMO
BACKGROUND: Ischemic heart disease is one of the leading causes of mortality worldwide, and thus calls for development of more effective therapeutic strategies. This study aimed to identify potential therapeutic targets for coronary heart disease (CHD) and myocardial infarction (MI) by investigating the causal relationship between plasma proteins and these conditions. METHODS: A two-sample Mendelian randomization (MR) study was performed to evaluate more than 1600 plasma proteins for their causal associations with CHD and MI. The MR findings were further confirmed through Bayesian colocalization, Summary-data-based Mendelian Randomization (SMR), and Transcriptome-Wide Association Studies (TWAS) analyses. Further analyses, including enrichment analysis, single-cell analysis, MR analysis of cardiovascular risk factors, phenome-wide Mendelian Randomization (Phe-MR), and protein-protein interaction (PPI) network construction were conducted to verify the roles of selected causal proteins. RESULTS: Thirteen proteins were causally associated with CHD, seven of which were also causal for MI. Among them, FES and PCSK9 were causal proteins for both diseases as determined by several analytical methods. PCSK9 was a risk factor of CHD (OR = 1.25, 95% CI: 1.13-1.38, P = 7.47E-06) and MI (OR = 1.36, 95% CI: 1.21-1.54, P = 2.30E-07), whereas FES was protective against CHD (OR = 0.68, 95% CI: 0.59-0.79, P = 6.40E-07) and MI (OR = 0.65, 95% CI: 0.54-0.77, P = 5.38E-07). Further validation through enrichment and single-cell analysis confirmed the causal effects of these proteins. Moreover, MR analysis of cardiovascular risk factors, Phe-MR, and PPI network provided insights into the potential drug development based on the proteins. CONCLUSIONS: This study investigated the causal pathways associated with CHD and MI, highlighting the protective and risk roles of FES and PCSK9, respectively. FES. Specifically, the results showed that these proteins are promising therapeutic targets for future drug development.
Assuntos
Proteínas Sanguíneas , Doença das Coronárias , Análise da Randomização Mendeliana , Infarto do Miocárdio , Proteômica , Humanos , Infarto do Miocárdio/sangue , Infarto do Miocárdio/genética , Proteômica/métodos , Doença das Coronárias/sangue , Doença das Coronárias/genética , Proteínas Sanguíneas/metabolismo , Mapas de Interação de Proteínas/genética , Teorema de Bayes , Terapia de Alvo Molecular , Fatores de Risco , Estudo de Associação Genômica Ampla , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/sangue , Pró-Proteína Convertase 9/metabolismoRESUMO
Hantaan virus (HTNV) infection can cause hemorrhagic fever with renal syndrome (HFRS) in humans, and currently, there are no long-standing protective vaccines or specific antivirals available. Guanylate-binding protein 1 (GBP1) is an interferon-stimulated gene that defends against various pathogen infections. However, the function of GBP1 in HTNV infection remains unknown. Here, we describe how GBP1 prevents HTNV infection by obstructing virus entry. We found that HTNV infection induced GBP1 expression and that overexpression of GBP1 inhibited HTNV infection, while knockout of GBP1 had the opposite effect. Interestingly, GBP1 did not affect interferon (IFN) signaling during HTNV infection. Instead, GBP1 prevented HTNV from entering cells through clathrin-mediated endocytosis (CME). We also discovered that GBP1 specifically interacted with actin but not dynamin 2 (DNM2) and made it difficult for DNM2 to be recruited by actin, which may account for the suppression of CME during HTNV infection. These findings establish an antiviral role for GBP1 in inhibiting HTNV infection and help us better understand how GBP1 regulates HTNV entry and could potentially aid in developing treatments for this virus.
Assuntos
Endocitose , Proteínas de Ligação ao GTP , Vírus Hantaan , Internalização do Vírus , Humanos , Actinas/metabolismo , Linhagem Celular , Dinamina II/metabolismo , Dinamina II/genética , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Vírus Hantaan/fisiologia , Células HEK293 , Febre Hemorrágica com Síndrome Renal/virologia , Interações Hospedeiro-PatógenoRESUMO
PURPOSE: To evaluate the performance of multi-pool Chemical exchange saturation transfer (CEST) MRI in prediction of glioma grade, isocitrate dehydrogenase (IDH) mutation, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss and Ki-67 labeling index (LI), based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5). METHODS: 95 patients with adult-type diffuse gliomas were analyzed. The amide, direct water saturation (DS), nuclear Overhauser enhancement (NOE), semi-solid magnetization transfer (MT) and amine signals were derived using Lorentzian fitting, and asymmetry-based amide proton transfer-weighted (APTwasym) signal was calculated. The mean value of tumor region was measured and intergroup differences were estimated using student-t test. The receiver operating curve (ROC) and area under the curve (AUC) analysis were used to evaluate the diagnostic performance of signals and their combinations. Spearman correlation analysis was performed to evaluate tumor proliferation. RESULTS: The amide and DS signals were significantly higher in high-grade gliomas compared to low-grade gliomas, as well as in IDH-wildtype gliomas compared to IDH-mutant gliomas (all p < 0.001). The DS, MT and amine signals showed significantly differences between ATRX loss and retention in grade 2/3 IDH-mutant gliomas (all p < 0.05). The combination of signals showed the highest AUC in prediction of grade (0.857), IDH mutation (0.814) and ATRX loss (0.769). Additionally, the amide and DS signals were positively correlated with Ki-67 LI (both p < 0.001). CONCLUSION: Multi-pool CEST MRI demonstrated good potential to predict glioma grade, IDH mutation, ATRX loss and Ki-67 LI.
Assuntos
Neoplasias Encefálicas , Glioma , Isocitrato Desidrogenase , Imageamento por Ressonância Magnética , Mutação , Gradação de Tumores , Humanos , Glioma/genética , Glioma/diagnóstico por imagem , Glioma/metabolismo , Glioma/patologia , Glioma/classificação , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Imageamento por Ressonância Magnética/métodos , Isocitrato Desidrogenase/genética , Idoso , Adulto Jovem , Proliferação de Células , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismo , Antígeno Ki-67/metabolismoRESUMO
Although brown adipose tissue (BAT) has historically been viewed as a major site for energy dissipation through thermogenesis, its endocrine function has been increasingly recognized. However, the circulating factors in BAT that play a key role in controlling systemic energy homeostasis remain largely unexplored. Here, we performed a peptidomic analysis to profile the extracellular peptides released from human brown adipocytes upon exposure to thermogenic stimuli. Specifically, we identified a secreted peptide that modulates adipocyte thermogenesis in a cell-autonomous manner, and we named it BATSP1. BATSP1 promoted BAT thermogenesis and induced browning of white adipose tissue in vivo, leading to increased energy expenditure under cold stress. BATSP1 treatment in mice prevented high-fat diet-induced obesity and improved glucose tolerance and insulin resistance. Mechanistically, BATSP1 facilitated the nucleocytoplasmic shuttling of forkhead transcription factor 1 (FOXO1) and released its transcriptional inhibition of uncoupling protein 1 (UCP1). Overall, we provide a comprehensive analysis of the human brown adipocyte extracellular peptidome following acute forskolin (FSK) stimulation and identify BATSP1 as a novel regulator of thermogenesis that may offer a potential approach for obesity treatment.
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Tecido Adiposo Marrom , Obesidade , Camundongos , Humanos , Animais , Obesidade/metabolismo , Tecido Adiposo Marrom/metabolismo , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/metabolismo , Peptídeos/farmacologia , Peptídeos/metabolismo , Termogênese/fisiologia , Camundongos Endogâmicos C57BLRESUMO
PURPOSE: Circadian disruption has been a common issue due to modern lifestyles. Ventricular remodeling (VR) is a pivotal progressive pathologic change after acute myocardial infarction (AMI) and circadian disruption may have a negative influence on VR according to the latest research. Whether or not Guanxin V (GXV) has a positive effect on VR after AMI with circadian disruption drew our interest. METHODS: Rats were randomly divided into a sham group, an AMI group, an AMI with circadian disruption group, and an AMI with circadian disruption treated with the GXV group according to a random number table. RNA sequencing (RNA-Seq) was utilized to confirm the different expressed genes regulated by circadian disruption. Cardiac function, inflammation factors, pathological evaluation, and mitochondrial dynamics after the intervention were conducted to reveal the mechanism by which GXV regulated VR after AMI with circadian disruption. RESULTS: RNA-Seq demonstrated that NF-κB was up-regulated by circadian disruption in rats with AMI. Functional and pathological evaluation indicated that compared with the AMI group, circadian disruption was associcataed with deteriorated cardiac function, expanded infarcted size, and exacerbated fibrosis and cardiomyocyte apoptosis. Further investigation demonstrated that mitochondrial dynamics imbalance was induced by circadian disruption. GXV intervention reversed the inflammatory status including down-regulation of NF-κB. Reserved cardiac function, limited infarct size, and ameliorated fibrosis and apoptosis were also observed in the GXV treated group. GXV maintained mitochondrial fission/fusion imbalance through suppressed expression of mitochondrial fission-associated proteins. CONCLUSION: The study findings suggest that identified mitochondrial dysfunctions may underlie the link between circadian disruption and VR. GXV may exert cardioprotection after AMI with circadian disruption through regulating mitochondrial dynamics.
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Dinâmica Mitocondrial , Infarto do Miocárdio , Remodelação Ventricular , Animais , Infarto do Miocárdio/patologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologia , Ratos , Dinâmica Mitocondrial/efeitos dos fármacos , Masculino , Ratos Sprague-Dawley , Medicamentos de Ervas Chinesas/farmacologia , Transtornos Cronobiológicos/tratamento farmacológico , Transtornos Cronobiológicos/fisiopatologia , Transtornos Cronobiológicos/genética , Modelos Animais de DoençasRESUMO
Blood pH is tightly maintained between 7.35 and 7.45, and acidosis (pH <7.3) indicates poor prognosis in sepsis, wherein lactic acid from anoxic tissues overwhelms the buffering capacity of blood. Poor sepsis prognosis is also associated with low zinc levels and the release of High mobility group box 1 (HMGB1) from activated and/or necrotic cells. HMGB1 added to whole blood at physiological pH did not bind leukocyte receptors, but lowering pH with lactic acid to mimic sepsis conditions allowed binding, implying the presence of natural inhibitor(s) preventing binding at normal pH. Testing micromolar concentrations of divalent cations showed that zinc supported the robust binding of sialylated glycoproteins with HMGB1. Further characterizing HMGB1 as a sialic acid-binding lectin, we found that optimal binding takes place at normal blood pH and is markedly reduced when pH is adjusted with lactic acid to levels found in sepsis. Glycan array studies confirmed the binding of HMGB1 to sialylated glycan sequences typically found on plasma glycoproteins, with binding again being dependent on zinc and normal blood pH. Thus, HMGB1-mediated hyperactivation of innate immunity in sepsis requires acidosis, and micromolar zinc concentrations are protective. We suggest that the potent inflammatory effects of HMGB1 are kept in check via sequestration by plasma sialoglycoproteins at physiological pH and triggered when pH and zinc levels fall in late stages of sepsis. Current clinical trials independently studying zinc supplementation, HMGB1 inhibition, or pH normalization may be more successful if these approaches are combined and perhaps supplemented by infusions of heavily sialylated molecules.
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Acidose/sangue , Proteína HMGB1/sangue , Sepse/sangue , Sialoglicoproteínas/sangue , Zinco/sangue , Acidose/imunologia , Acidose/metabolismo , Acidose/patologia , Proteínas de Transporte , Proteína HMGB1/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Imunidade Inata , Lipopolissacarídeos/farmacologia , Polissacarídeos/química , Sepse/imunologia , Sepse/patologia , Ácidos Siálicos/química , Sialoglicoproteínas/química , Zinco/metabolismoRESUMO
Objective: To observe the impact of a clinical nursing teaching model based on institutional collaboration on the teaching quality of nursing programs in colleges and universities and the effectiveness of undergraduate practical nurses in practice. Methods: One hundred and twenty-three undergraduate student nurses graduating from June 2020 to July 2021 were selected for the study, 59 of whom received the traditional teaching model (control group) and 64 of whom received the institutional cooperative teaching model (research group). Upon completion of their internship, a clinical nursing skills assessment was conducted for the two groups, and the clinical internship performance was evaluated using the self-assessment scale of clinical practice behavior performance of nursing undergraduates. A teaching evaluation questionnaire was used to survey the intern nurses' evaluation of the teaching model and their satisfaction with the teaching model was surveyed in the middle and after the completion of the internship, respectively. Upon completion of the internship, the intern nurses filled out a self-satisfaction evaluation form. Results: The research group had a lower failure rate than the control group and a higher excellent rate than the control group (P < .05). There were no differences in the scores of the professional and self-development domains between the two groups (P > .05), while for all other clinical placement performances, the scores were higher in the research group than in the control group (P < .05). In addition, the research group had higher subject presentation, post-lesson acquisition, total score, and teaching satisfaction than the control group (P < .05). In terms of self-satisfaction, the number of satisfied intern nurses was also higher than the control group (P < .05). Conclusion: The reform of clinical nursing teaching mode based on institutional cooperation can effectively improve the quality of nursing teaching in universities and the effectiveness of undergraduate practical nursing.
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Trypsin is one of the most diverse and widely studied protease hydrolases. However, the diversity and characteristics of the Trypsin superfamily of genes have not been well understood, and their role in insecticide resistance is yet to be investigated. In this study, a total of 342 Trypsin genes were identified and classified into seven families based on homology, characteristic domains and phylogenetics in Anopheles sinensis, and the LY-Domain and CLECT-Domain families are specific to the species. Four Trypsin genes, (Astry2b, Astry43a, Astry90, Astry113c) were identified to be associated with pyrethroid resistance based on transcriptome analyses of three field resistant populations and qRT-PCR validation, and the knock-down of these genes significantly decrease the pyrethroid resistance of Anopheles sinensis based on RNAi. The activity of Astry43a can be reduced by five selected insecticides (indoxacarb, DDT, temephos, imidacloprid and deltamethrin); and however, the Astry43a could not directly metabolize these five insecticides, like the trypsin NYD-Tr did in earlier reports. This study provides the overall information frame of Trypsin genes, and proposes the role of Trypsin genes to insecticide resistance. Further researches are necessary to investigate the metabolism function of these trypsins to insecticides.
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Anopheles , Resistência a Inseticidas , Inseticidas , Piretrinas , Tripsina , Animais , Anopheles/genética , Anopheles/efeitos dos fármacos , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Tripsina/genética , Tripsina/metabolismo , Piretrinas/farmacologia , Filogenia , Mosquitos Vetores/genética , Mosquitos Vetores/efeitos dos fármacos , Malária/transmissão , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismoRESUMO
In recent years, heavy metal pollution has become a global environmental problem and poses a great threat to the health of people and ecosystems. Therefore, strategies for the effective remediation of Cd from contaminated soil are urgently needed. In this study, ryegrass was utilized as a remediation plant, and its remediation potential was enhanced through the application of Citric Acid (CA) in conjunction with Bacillus megaterium (B. megaterium). The P3 treatment (CA + Bacillus megaterium) exhibited a significantly higher efficiency in promoting cadmium extraction by ryegrass, resulting in a 1.79-fold increase in shoot cadmium accumulation compared to the control group (CK) with no Bacillus megaterium or CA. Moreover, the P3 treatment led to an increased abundance of Actinobacteriota, Acidobacteriota, and Patescibacteria in the rhizosphere. The concentration of amino derivatives (such as betaine, sulfolithocholylglycine, N-alpha-acetyl-lysine, glycocholic acid, arginyl-threonine) showed significant upregulation following the P3 treatment. In summary, this study proposes a viable approach for phytoremediation of soil contaminated with cadmium by harnessing the mobilizing abilities of soil bacteria.
Our aim was to gain a comprehensive understanding of the mechanisms involved in phytoremediation. These findings contribute to the existing knowledge by providing insights into the mechanism of phytoremediation in Cd-contaminated soil. They are expected to serve as a theoretical foundation for further elucidation of the phytoremediation mechanisms employed in Cd-contaminated soil.
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INTRODUCTION: To investigate the role of a novel type of protein kinase C delta (PKCδ) in the neuroinflammation of Alzheimer's disease (AD). METHODS: We analyzed PKCδ and inflammatory cytokines levels in cerebrospinal fluid (CSF) of AD and normal controls, as well as their correlations. The cellular expression pattern of PKCδ and the effects of PKCδ modulation on microglia-mediated neuroinflammation were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR), western blot, RNA sequencing (RNA-seq), and immunofluorescence staining. RESULTS: PKCδ levels were increased dramatically in the CSF of AD patients and positively correlated with cytokines. PKCδ is expressed mainly in microglia in the brain. Amyloid beta (Aß) stimulation increased PKCδ expression and secretion, which led to upregulation of the nuclear factor kappa B (NF-κB) pathway and overproduction of proinflammatory cytokines. Downregulation or inhibition of PKCδ attenuated Aß-induced microglial responses and improved cognitive function in an AD mouse model. DISCUSSION: Our study identifies PKCδ as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD. HIGHLIGHTS: Protein kinase C delta (PKCδ) levels increase in cerebrospinal fluid (CSF) of patients with Alzheimer's disease (AD), and positively correlate with elevated inflammatory cytokines in human subjects. PKCδ is expressed mainly in microglia in vivo, whereas amyloid beta (Aß) stimulation increases PKCδ expression and secretion, causing upregulation of the nuclear factor kappa B (NF-κB) pathway and production of inflammatory cytokines. Downregulation or inhibition of PKCδ attenuates Aß-enhanced NF-κB signaling and cytokine production in microglia and improves cognitive function in AD mice. PKCδ serves as a potential biomarker and therapeutic target for microglia-mediated neuroinflammation in AD.
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Doença de Alzheimer , Biomarcadores , Citocinas , Microglia , Doenças Neuroinflamatórias , Proteína Quinase C-delta , Proteína Quinase C-delta/metabolismo , Microglia/metabolismo , Animais , Camundongos , Humanos , Biomarcadores/líquido cefalorraquidiano , Doenças Neuroinflamatórias/tratamento farmacológico , Masculino , Citocinas/metabolismo , Citocinas/líquido cefalorraquidiano , Modelos Animais de Doenças , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Feminino , Idoso , Camundongos Transgênicos , NF-kappa B/metabolismoRESUMO
BACKGROUND: To investigate the association between gestational weight gain (GWG) and preterm birth (PTB) according to pre-pregnancy body mass index (pp-BMI) and glycated haemoglobin (HbA1c) within the normal range. METHODS: We conducted a population-based retrospective cohort study between July 2017 and January 2020 at Women's Hospital, Zhejiang University School of Medicine. Women were classified into three groups (inadequate GWG, appropriate GWG, and excessive GWG). In addition, women were divided into different subgroups according to pp-BMI and HbA1c. We estimated the odds ratios (OR) with 95% confidence intervals (CI) to assess the associations between GWG and the risk of PTB. Meanwhile, we adjusted for possible confounding factors, including maternal age, infant sex, family history of diabetes, education, pregnancy mode, delivery mode, parity, and gravidity. RESULTS: The study involved 23,699 pregnant women, of which 1124 (4.70%) were PTB. Women who had inadequate GWG were found to have a significantly higher risk of PTB compared to women with appropriate GWG. In contrast, women with excessive GWG had a reduced risk of PTB. Similarly, GWG and PTB had similar risk associations in the HbA1c and pp-BMI subgroups. Among women with pp-BMI <18.5 kg/m2, women with inadequate GWG had a significantly increased risk of PTB compared with women in the control group (HbA1c 4.6-5.0%, appropriate GWG), and the risk increased with increasing HbA1c levels. Similar results were observed in women with normal pp-BMI. CONCLUSIONS: There was a significant association between GWG and the risk of PTB, but the risk varied by pp-BMI and HbA1c levels. Reasonable weight gain during pregnancy is essential to prevent PTB. Furthermore, while HbA1c is within the normal range, the higher levels should be noticed.
Preterm birth (PTB) rates have recently increased in China, drawing increased attention from physicians and society. Even though various risk factors for PTB have been well known, risk factors for PTB still need to be explored. This study aimed to investigate the association between gestational weight gain (GWG) and preterm birth (PTB) according to pre-pregnancy body mass index (pp-BMI) and glycated haemoglobin (HbA1c) within the normal range. Our research revealed that the underweight (pp-BMI <18.5 kg/m2) and normal weight (pp-BMI 18.524.9 kg/m2) groups' risk of preterm birth increased with rising HbA1c levels when GWG was inadequate. Despite HbA1c within the normal range, higher levels of HbA1c should be considered. As a result, among women with inadequate GWG, high levels of HbA1c confer a higher risk of PTB, which could alert clinicians to carry out early intervention to prevent PTB.
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Índice de Massa Corporal , Ganho de Peso na Gestação , Hemoglobinas Glicadas , Nascimento Prematuro , Humanos , Feminino , Gravidez , Hemoglobinas Glicadas/análise , Adulto , Estudos Retrospectivos , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/sangue , Nascimento Prematuro/etiologia , Fatores de Risco , China/epidemiologiaRESUMO
BACKGROUND: This meta-analysis seeks to assess the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. METHODS: Databases from PubMed, Embase, and the Cochrane Library were all thoroughly searched for pertinent research. Outcomes include complete response (CR), partial response (PR), stable disease (SD), disease progression (PD), overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and adverse events (AEs) were retrieved for further analysis. RESULTS: Ten trials with 721 patients were included in this meta-analysis. The pooled results for patients with cervical cancer receiving pembrolizumab were as follows: CR (0.06, 95%CI: 0.02-0.10), PR (0.15, 95%CI: 0.08-0.22), SD (0.16, 95%CI: 0.13-0.20), PD (0.50, 95%CI: 0.25-0.75), ORR (0.26, 95%CI: 0.11-0.41) and DCR (0.42, 95%CI: 0.13-0.71), respectively. Regarding survival analysis, the pooled mPFS and mOS were 3.81 and 10.15 months. Subgroup analysis showed that pembrolizumab in combination was more beneficial in CR (0.16 vs. 0.03, p = 0.012), PR (0.24 vs. 0.08, p = 0.032), SD (0.11 vs. 0.19, p = 0.043), ORR (0.42 vs. 0.11, p = 0.014), and mPFS (5.54 months vs. 2.27 months, p < 0.001) than as single agent. The three most common AEs were diarrhoea (0.25), anaemia (0.25), and nausea (0.21), and the incidence of grade 3-5 AEs was significantly lower, rarely surpassing 0.10. CONCLUSIONS: For patients with advanced or recurrent cervical cancer, this systematic review and meta-analysis demonstrated that pembrolizumab had a favourable efficacy and tolerability. Future research will primarily focus on optimising customised regiments that optimally integrate pembrolizumab into new therapies and combination strategies. Designed to maximise patient benefit and efficiently control adverse effects while maintaining a high standard of living.
This study demonstrated the efficacy and safety of pembrolizumab in individuals with advanced or recurrent cervical cancer. The study found that an upfront combination of chemotherapy and pembrolizumab immunotherapy appears to be a compelling strategy for these patients. More large-scale and multicentre randomised controlled trials will be required in the future to validate the precise benefits of pembrolizumab in new therapies and combination strategies for the treatment of cervical cancer.
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Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos , Recidiva Local de Neoplasia , Neoplasias do Colo do Útero , Humanos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/mortalidade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Resultado do Tratamento , Intervalo Livre de Progressão , Pessoa de Meia-IdadeRESUMO
The discipline development is the pillar for the development of traditional Chinese medicine( TCM). The academic progress in TCM is the commanding height of the discipline development of TCM. To lead and promote the development and academic progress of TCM, the China Association of Chinese Medicine has summarized the Top Ten Academic Achievements in Traditional Chinese Medicine during 2020-2022, the Major Scientific Problems, Engineering Technical Problems, and Industrial Technical Problems in Traditional Chinese Medicine during 2019-2023, and the Remarkable Research Achievements of Traditional Chinese Medicine during 2012-2022. Based on the above research reports and the research achievements awarded the national science and technology prizes in TCM in the last 20 years and according to the current situation and layout of TCM discipline development, this paper reviews the major research achievements of TCM in the last two decades and the latest research progress in TCM during 2020-2023. The major scientific, engineering technical, and industrial technical problems in TCM are analyzed and the emerging trends of TCM are prospected in accordance with the development laws and characteristics of TCM. This review provides new ideas and reference for the high-quality development of TCM in the new era.