RESUMO
Stem cells are maintained by transcriptional programs that promote self-renewal and repress differentiation. Here, we found that the transcription factor c-Myb was essential for generating and maintaining stem cells in the CD8+ T cell memory compartment. Following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and generated fewer stem cell-like central memory cells than did Myb-sufficient T cells. c-Myb acted both as a transcriptional activator of Tcf7 (which encodes the transcription factor Tcf1) to enhance memory development and as a repressor of Zeb2 (which encodes the transcription factor Zeb2) to hinder effector differentiation. Domain-mutagenesis experiments revealed that the transactivation domain of c-Myb was necessary for restraining differentiation, whereas its negative regulatory domain was critical for cell survival. Myb overexpression enhanced CD8+ T cell memory formation, polyfunctionality and recall responses that promoted curative antitumor immunity after adoptive transfer. These findings identify c-Myb as a pivotal regulator of CD8+ T cell stemness and highlight its therapeutic potential.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Neoplasias Experimentais/imunologia , Proteínas Proto-Oncogênicas c-myb/imunologia , Células-Tronco/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Memória Imunológica/genética , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/virologia , Proteínas Proto-Oncogênicas c-myb/genética , Proteínas Proto-Oncogênicas c-myb/metabolismo , Células-Tronco/metabolismo , Células-Tronco/virologia , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/imunologia , Fator 1 de Transcrição de Linfócitos T/metabolismoRESUMO
Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Infecções/etiologia , Análise de Célula Única , Animais , Biomarcadores , Imunoprecipitação da Cromatina , Epigênese Genética , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/metabolismo , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Memória Imunológica , Infecções/metabolismo , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos , Fatores de Tempo , TranscriptomaRESUMO
T cell antigen receptor (TCR) signaling drives distinct responses depending on the differentiation state and context of CD8(+) T cells. We hypothesized that access of signal-dependent transcription factors (TFs) to enhancers is dynamically regulated to shape transcriptional responses to TCR signaling. We found that the TF BACH2 restrains terminal differentiation to enable generation of long-lived memory cells and protective immunity after viral infection. BACH2 was recruited to enhancers, where it limited expression of TCR-driven genes by attenuating the availability of activator protein-1 (AP-1) sites to Jun family signal-dependent TFs. In naive cells, this prevented TCR-driven induction of genes associated with terminal differentiation. Upon effector differentiation, reduced expression of BACH2 and its phosphorylation enabled unrestrained induction of TCR-driven effector programs.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linfócitos T CD8-Positivos/fisiologia , Fator de Transcrição AP-1/metabolismo , Vaccinia virus/imunologia , Vacínia/imunologia , Imunidade Adaptativa , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD8-Positivos/virologia , Diferenciação Celular/genética , Células Cultivadas , Elementos Facilitadores Genéticos/genética , Regulação da Expressão Gênica , Memória Imunológica/genética , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Oncogênica p65(gag-jun) , Transdução de Sinais/genética , Fator de Transcrição AP-1/genéticaRESUMO
Pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) in plants enable them to respond to pathogens by activating the production of defence metabolites that orchestrate immune responses1-4. How the production of defence metabolites is promoted by immune receptors and coordinated with broad-spectrum resistance remains elusive. Here we identify the deubiquitinase PICI1 as an immunity hub for PTI and ETI in rice (Oryza sativa). PICI1 deubiquitinates and stabilizes methionine synthetases to activate methionine-mediated immunity principally through biosynthesis of the phytohormone ethylene. PICI1 is targeted for degradation by blast fungal effectors, including AvrPi9, to dampen PTI. Nucleotide-binding domain, leucine-rich-repeat-containing receptors (NLRs) in the plant immune system, such as PigmR, protect PICI1 from effector-mediated degradation to reboot the methionine-ethylene cascade. Natural variation in the PICI1 gene contributes to divergence in basal blast resistance between the rice subspecies indica and japonica. Thus, NLRs govern an arms race with effectors, using a competitive mode that hinges on a critical defence metabolic pathway to synchronize PTI with ETI and ensure broad-spectrum resistance.
Assuntos
Oryza , Doenças das Plantas , Metionina , Oryza/genética , Oryza/microbiologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Plantas , Transdução de Sinais/genéticaRESUMO
The flower-infecting fungus Ustilaginoidea virens causes rice false smut, which is a severe emerging disease threatening rice (Oryza sativa) production worldwide. False smut not only reduces yield, but more importantly produces toxins on grains, posing a great threat to food safety. U. virens invades spikelets via the gap between the 2 bracts (lemma and palea) enclosing the floret and specifically infects the stamen and pistil. Molecular mechanisms for the U. virens-rice interaction are largely unknown. Here, we demonstrate that rice flowers predominantly employ chitin-triggered immunity against U. virens in the lemma and palea, rather than in the stamen and pistil. We identify a crucial U. virens virulence factor, named UvGH18.1, which carries glycoside hydrolase activity. Mechanistically, UvGH18.1 functions by binding to and hydrolyzing immune elicitor chitin and interacting with the chitin receptor CHITIN ELICITOR BINDING PROTEIN (OsCEBiP) and co-receptor CHITIN ELICITOR RECEPTOR KINASE1 (OsCERK1) to impair their chitin-induced dimerization, suppressing host immunity exerted at the lemma and palea for gaining access to the stamen and pistil. Conversely, pretreatment on spikelets with chitin induces a defense response in the lemma and palea, promoting resistance against U. virens. Collectively, our data uncover a mechanism for a U. virens virulence factor and the critical location of the host-pathogen interaction in flowers and provide a potential strategy to control rice false smut disease.
Assuntos
Quitina , Flores , Hypocreales , Oryza , Doenças das Plantas , Oryza/microbiologia , Oryza/metabolismo , Oryza/genética , Doenças das Plantas/microbiologia , Quitina/metabolismo , Flores/microbiologia , Hypocreales/patogenicidade , Hypocreales/genética , Hypocreales/metabolismo , Transdução de Sinais , Interações Hospedeiro-Patógeno , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Virulência , Fatores de Virulência/metabolismo , Fatores de Virulência/genética , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genéticaRESUMO
Nucleotide-binding site leucine-rich repeat (NLR) receptors perceive pathogen effectors and trigger plant immunity. However, the mechanisms underlying NLR-triggered defense responses remain obscure. The recently discovered Pigm locus in rice encodes a cluster of NLRs, including PigmR, which confers broad-spectrum resistance to blast fungus. Here, we identify PIBP1 (PigmR-INTERACTING and BLAST RESISTANCE PROTEIN 1), an RRM (RNA-recognition motif) protein that specifically interacts with PigmR and other similar NLRs to trigger blast resistance. PigmR-promoted nuclear accumulation of PIBP1 ensures full blast resistance. We find that PIBP1 and a homolog, Os06 g02240, bind DNA and function as unconventional transcription factors at the promoters of the defense genes OsWAK14 and OsPAL1, activating their expression. Knockout of PIBP1 and Os06 g02240 greatly attenuated blast resistance. Collectively, our study discovers previously unappreciated RRM transcription factors that directly interact with NLRs to activate plant defense, establishing a direct link between transcriptional activation of immune responses with NLR-mediated pathogen perception.
Assuntos
Resistência à Doença/genética , Proteínas NLR/genética , Oryza/genética , Doenças das Plantas/genética , Proteínas de Plantas/genética , Fatores de Transcrição/genética , Sítios de Ligação , Fungos/patogenicidade , Regulação da Expressão Gênica de Plantas , Oryza/microbiologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/genética , Regiões Promotoras Genéticas , Ligação Proteica/genética , Transdução de Sinais/genéticaRESUMO
During exercise, skeletal muscle is exposed to a low oxygen condition, hypoxia. Under hypoxia, the transcription factor hypoxia-inducible factor-1α (HIF-1α) is stabilized and induces expressions of its target genes regulating glycolytic metabolism. Here, using a skeletal muscle-specific gene ablation mouse model, we show that Brg1/Brm-associated factor 155 (Baf155), a core subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, is essential for HIF-1α signaling in skeletal muscle. Muscle-specific ablation of Baf155 increases oxidative metabolism by reducing HIF-1α function, which accompanies the decreased lactate production during exercise. Furthermore, the augmented oxidation leads to high intramuscular adenosine triphosphate (ATP) level and results in the enhancement of endurance exercise capacity. Mechanistically, our chromatin immunoprecipitation (ChIP) analysis reveals that Baf155 modulates DNA-binding activity of HIF-1α to the promoters of its target genes. In addition, for this regulatory function, Baf155 requires a phospho-signal transducer and activator of transcription 3 (pSTAT3), which forms a coactivator complex with HIF-1α, to activate HIF-1α signaling. Our findings reveal the crucial role of Baf155 in energy metabolism of skeletal muscle and the interaction between Baf155 and hypoxia signaling.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia , Músculo Esquelético , Fatores de Transcrição , Animais , Camundongos , Regulação da Expressão Gênica , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Músculo Esquelético/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The role of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in renal cell carcinoma (RCC) progression, metastasis, and resistance to therapies has not been investigated thoroughly. Transcription factor E3 (TFE3) expression is related to a poorer prognosis and tumor microenvironment in patients with RCC. This study aimed to determine the relationship between TFE3 and the PI3K/Akt pathway. TFE3 down-regulation was achieved by transient transfection of siRNA and shRNA in UOK146 cells. TFE3 overexpression was induced by transient transfection with pcDNA3.1 encoding the constitutively active form of TFE3. The cells were treated with mammalian target of rapamycin (mTOR) and PI3K inhibitors. Western blot was performed to detect TFE3, programmed death-ligand 1, phospho-Akt, and Akt. Phospho-Akt expression increased significantly upon TFE3 down-regulation, and decreased significantly upon up-regulation. When RCC cells were treated with a PI3K inhibitor (LY294002), TFE3 expression increased and phospho-Akt expression decreased. Data from this study indicate that TFE3 plays a role in the PI3K/Akt pathway in RCC. The results of this study suggest that PI3K/Akt inhibitors may aid in the treatment of patients with RCC by affecting the tumor microenvironment.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Carcinoma de Células Renais , Neoplasias Renais , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Serina-Treonina Quinases TOR , Microambiente Tumoral , Humanos , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/genética , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/fisiologia , Neoplasias Renais/patologia , Neoplasias Renais/metabolismo , Neoplasias Renais/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Linhagem Celular Tumoral , Fosfatidilinositol 3-Quinases/metabolismo , Regulação Neoplásica da Expressão GênicaRESUMO
Graphdiyne (GDY) has garnered significant attention as a cutting-edge 2D material owing to its distinctive electronic, optoelectronic, and mechanical properties, including high mobility, direct bandgap, and remarkable flexibility. One of the key challenges hindering the implementation of this material in flexible applications is its large area and uniform synthesis. The facile growth of centimeter-scale bilayer hydrogen substituted graphdiyne (Bi-HsGDY) on germanium (Ge) substrate is achieved using a low-temperature chemical vapor deposition (CVD) method. This material's field effect transistors (FET) showcase a high carrier mobility of 52.6 cm2 V-1 s-1 and an exceptionally low contact resistance of 10 Ω µm. By transferring the as-grown Bi-HsGDY onto a flexible substrate, a long-distance piezoresistive strain sensor is demonstrated, which exhibits a remarkable gauge factor of 43.34 with a fast response time of ≈275 ms. As a proof of concept, communication by means of Morse code is implemented using a Bi-HsGDY strain sensor. It is believed that these results are anticipated to open new horizons in realizing Bi-HsGDY for innovative flexible device applications.
RESUMO
OBJECTIVES: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a significant medical challenge, with no indisputable pathophysiological mechanism identified to date. METHODS: Based on clinical clues, we hypothesized that 5-hydroxytryptamine (5-HT) hyperactivation is implicated in the pathogenic causes of ME/CFS and the associated symptoms. We experimentally evaluated this hypothesis in a series of mouse models. RESULTS: High-dose selective serotonin reuptake inhibitor (SSRI) treatment induced intra- and extracellular serotonin spillover in the dorsal raphe nuclei of mice. This condition resulted in severe fatigue (rota-rod, fatigue rotating wheel and home-cage activity tests) and ME/CFS-associated symptoms (nest building, plantar and open field test), along with dysfunction in the hypothalamic-pituitary-adrenal (HPA) axis response to exercise challenge. These ME/CFS-like features induced by excess serotonin were additionally verified using both a 5-HT synthesis inhibitor and viral vector for Htr1a (5-HT1A receptor) gene knockdown. CONCLUSIONS: Our findings support the involvement of 5-HTergic hyperactivity in the pathophysiology of ME/CFS. This ME/CFS-mimicking animal model would be useful for understanding ME/CFS biology and its therapeutic approaches.
Assuntos
Síndrome de Fadiga Crônica , Animais , Camundongos , Serotonina , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Sistema Hipotálamo-HipofisárioRESUMO
InGaN-based long wavelength laser diodes (LDs) grown on Si are highly desirable for expanding the applications in laser display and lighting. Proper interface engineering of high In-content InGaN multi-quantum wells (MQWs) is urgently required for the epitaxial growth of InGaN-based long wavelength LD on Si, because the deteriorated interfaces and crystalline quality of InGaN MQWs can severely increase the photon scattering and further exacerbate the internal absorption loss of LDs, which prevents the lasing wavelength of InGaN-based LDs from extending. In this work, a significantly improved morphology and sharp interface of the InGaN active region are obtained by using a graded-compositional InGaN lower waveguide (LWG) capped with a 10-nm-thick Al0.1Ga0.9N layer. The V-pits density of the InGaN LWG was one order of magnitude reduction from 4.8 × 108 to 3.6 × 107â cm-2 along with the root-mean-square surface roughness decreasing from 0.3 to 0.1â nm. Therefore, a room-temperature electrically injected 480â nm InGaN-based cyan LD grown on Si under pulsed current operation was successfully achieved with a threshold current density of 18.3â kA/cm2.
RESUMO
Leaves are asymmetric, with different functions for adaxial and abaxial tissue. The bundle sheath (BS) of C3 barley (Hordeum vulgare) is dorsoventrally differentiated into three types of cells: adaxial structural, lateral S-type, and abaxial L-type BS cells. Based on plasmodesmatal connections between S-type cells and mestome sheath (parenchymatous cell layer below bundle sheath), S-type cells likely transfer assimilates toward the phloem. Here, we used single-cell RNA sequencing to investigate BS differentiation in C4 maize (Zea mays L.) plants. Abaxial BS (abBS) cells of rank-2 intermediate veins specifically expressed three SWEET sucrose uniporters (SWEET13a, b, and c) and UmamiT amino acid efflux transporters. SWEET13a, b, c mRNAs were also detected in the phloem parenchyma (PP). We show that maize has acquired a mechanism for phloem loading in which abBS cells provide the main route for apoplasmic sucrose transfer toward the phloem. This putative route predominates in veins responsible for phloem loading (rank-2 intermediate), whereas rank-1 intermediate and major veins export sucrose from the PP adjacent to the sieve element companion cell complex, as in Arabidopsis thaliana. We surmise that abBS identity is subject to dorsoventral patterning and has components of PP identity. These observations provide insights into the unique transport-specific properties of abBS cells and support a modification to the canonical phloem loading pathway in maize.
Assuntos
Floema/metabolismo , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Zea mays/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Floema/genética , Folhas de Planta/genética , Proteínas de Plantas/genética , Zea mays/genéticaRESUMO
In the INO80 chromatin remodeling complex, all of the accessory subunits are assembled on the following three domains of INO80: N-terminal domain (NTD), HSA domain, and ATPase domain. Although the ATPase and HSA domains and their interacting accessory subunits are known to be responsible for chromatin remodeling, it is largely unknown how the accessory subunits that interact with the INO80 NTD regulate chromatin status. Here, we identify both conserved and nonconserved accessory subunits that interact with the three domains in the INO80 complex in Arabidopsis thaliana. While the accessory subunits that interact with all the three INO80 domains can mediate transcriptional repression, the INO80 NTD and the accessory subunits interact with it can contribute to transcriptional activation even when the ATPase domain is absent, suggesting that INO80 has an ATPase-independent role. A subclass of the COMPASS histone H3K4 methyltransferase complexes interact with the INO80 NTD in the INO80 complex and function together with the other accessory subunits that interact with the INO80 NTD, thereby facilitating H3K4 trimethylation and transcriptional activation. This study suggests that the opposite effects of the INO80 complex on transcription are required for the balance between vegetative growth and flowering under diverse environmental conditions.
Assuntos
Adenosina Trifosfatases/genética , Proteínas de Arabidopsis/genética , Arabidopsis/genética , Proteínas de Ligação a DNA/genética , Histonas/metabolismo , Adenosina Trifosfatases/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Ligação a DNA/metabolismo , MetilaçãoRESUMO
The leaf vasculature plays a key role in solute translocation. Veins consist of at least seven distinct cell types, with specific roles in transport, metabolism, and signaling. Little is known about leaf vascular cells, in particular the phloem parenchyma (PP). PP effluxes sucrose into the apoplasm as a basis for phloem loading, yet PP has been characterized only microscopically. Here, we enriched vascular cells from Arabidopsis leaves to generate a single-cell transcriptome atlas of leaf vasculature. We identified at least 19 cell clusters, encompassing epidermis, guard cells, hydathodes, mesophyll, and all vascular cell types, and used metabolic pathway analysis to define their roles. Clusters comprising PP cells were enriched for transporters, including SWEET11 and SWEET12 sucrose and UmamiT amino acid efflux carriers. We provide evidence that PP development occurs independently from ALTERED PHLOEM DEVELOPMENT, a transcription factor required for phloem differentiation. PP cells have a unique pattern of amino acid metabolism activity distinct from companion cells (CCs), explaining differential distribution/metabolism of amino acids in veins. The kinship relation of the vascular clusters is strikingly similar to the vein morphology, except for a clear separation of CC from the other vascular cells including PP. In summary, our single-cell RNA-sequencing analysis provides a wide range of information into the leaf vasculature and the role and relationship of the leaf cell types.
Assuntos
Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Transcriptoma/genética , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Floema/metabolismo , Folhas de Planta/genética , Proteínas de Plantas/genéticaRESUMO
BACKGROUND: A major challenge in prevention and early treatment of acute kidney injury (AKI) is the lack of high-performance predictors in critically ill patients. Therefore, we innovatively constructed U-AKIpredTM for predicting AKI in critically ill patients within 12 h of panel measurement. METHODS: The prospective cohort study included 680 patients in the training set and 249 patients in the validation set. After performing inclusion and exclusion criteria, 417 patients were enrolled in the training set and 164 patients were enrolled in the validation set finally. AKI was diagnosed by Kidney Disease Improving Global Outcomes (KDIGO) criteria. RESULTS: Twelve urinary kidney injury biomarkers (mALB, IgG, TRF, α1MG, NAG, NGAL, KIM-1, L-FABP, TIMP2, IGFBP7, CAF22 and IL-18) exhibited good predictive performance for AKI within 12 h in critically ill patients. U-AKIpredTM, combined with three crucial biomarkers (α1MG, L-FABP and IGFBP7) by multivariate logistic regression analysis, exhibited better predictive performance for AKI in critically ill patients within 12 h than the other twelve kidney injury biomarkers. The area under the curve (AUC) of the U-AKIpredTM, as a predictor of AKI within 12 h, was 0.802 (95% CI: 0.771-0.833, P < 0.001) in the training set and 0.844 (95% CI: 0.792-0.896, P < 0.001) in validation cohort. A nomogram based on the results of the training and validation sets of U-AKIpredTM was developed which showed optimal predictive performance for AKI. The fitting effect and prediction accuracy of U-AKIpredTM was evaluated by multiple statistical indicators. To provide a more flexible predictive tool, the dynamic nomogram (https://www.xsmartanalysis.com/model/U-AKIpredTM) was constructed using a web-calculator. Decision curve analysis (DCA) and a clinical impact curve were used to reveal that U-AKIpredTM with the three crucial biomarkers had a higher net benefit than these twelve kidney injury biomarkers respectively. The net reclassification index (NRI) and integrated discrimination index (IDI) were used to improve the significant risk reclassification of AKI compared with the 12 kidney injury biomarkers. The predictive efficiency of U-AKIpredTM was better than the NephroCheck® when testing for AKI and severe AKI. CONCLUSION: U-AKIpredTM is an excellent predictive model of AKI in critically ill patients within 12 h and would assist clinicians in identifying those at high risk of AKI.
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An ambient-light-promoted stereospecific olefinic C(sp2)-S bond construction of thioacids and 1,1-diarylethenes has been demonstrated, affording various (Z)-vinyl thioesters in 51-85% yields under solvent- and catalyst-free conditions. Mechanistic studies indicated that the formation of thioacid-olefin complexes is responsible for generating a carbonyl thiyl radical and dioxygen in the air participates in the reaction and functions as a traceless reagent. Moreover, synthetic applications have been demonstrated by the gram scale synthesis and aggregation-induced emission property of representative compound 3i.
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This study aims to explore the anti-inflammatory mechanisms of sargachromenol in both RAW 264.7 cells and lipopolysaccharide (LPS)-treated mice, as previous reports have suggested that sargachromenol possesses anti-aging, anti-inflammatory, antioxidant, and neuroprotective properties. Although the precise mechanism behind its anti-inflammatory activity remains unclear, pretreatment with sargachromenol effectively reduced the production of nitric oxide, prostaglandin E2, and interleukin (IL)-1ß in LPS-stimulated RAW 264.7 cells by inhibiting cyclooxygenase-2. Moreover, sargachromenol inhibited the activation of nuclear factor-κB (NF-κB) by preventing the degradation of the inhibitor of κB-α (IκB-α) and inhibiting protein kinase B (Akt) phosphorylation in LPS-stimulated cells. We also found that sargachromenol induced the production of heme oxygenase-1 (HO-1) by activating the nuclear transcription factor erythroid-2-related factor 2 (Nrf2). In LPS-treated mice, oral administration of sargachromenol effectively reduced the levels of IL-1ß, IL-6, and tumor necrosis factor-α (TNF-α) in the serum, suggesting its ability to suppress the production of inflammatory mediators by inhibiting the Akt/NF-κB pathway and upregulating the Nrf2/HO-1 pathway.
Assuntos
Lipopolissacarídeos , NF-kappa B , Animais , Camundongos , NF-kappa B/metabolismo , Células RAW 264.7 , Lipopolissacarídeos/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Anti-Inflamatórios/farmacologia , Heme Oxigenase-1/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Ciclo-Oxigenase 2/metabolismoRESUMO
BACKGROUND: To develop and validate a nomogram model based on Gd-EOB-DTPA enhanced MRI for differentiation between hepatocellular carcinoma (HCC) and focal nodular hyperplasia (FNH) showing iso- or hyperintensity in the hepatobiliary phase (HBP). METHODS: A total of 75 patients with 49 HCCs and 26 FNHs randomly divided into a training cohort (n = 52: 34 HCC; 18 FNH) and an internal validation cohort (n = 23: 15 HCC; 8 FNH). A total of 37 patients (n = 37: 25 HCC; 12 FNH) acted as an external test cohort. The clinical and imaging characteristics between HCC and FNH groups in the training cohort were compared. The statistically significant parameters were included into the FAE software, and a multivariate logistic regression classifier was used to identify independent predictors and establish a nomogram model. Receiver operating characteristic (ROC) curves were used to evaluate the prediction ability of the model, while the calibration and decision curves were used for model validation. Subanalysis was used to compare qualitative and quantitative characteristics of patients with chronic hepatitis and cirrhosis between the HCC and FNH groups. RESULTS: In the training cohort, gender, age, enhancement rate in the arterial phase (AP), focal defects in uptake were significant predictors for HCC showing iso- or hyperintensity in the HBP. In the training cohort, area under the curve (AUC), sensitivity and specificity of the nomogram model were 0.989(95%CI: 0.967-1.000), 97.1% and 94.4%. In the internal validation cohort, the above three indicators were 0.917(95%CI: 0.782-1.000), 93.3% and 87.5%. In the external test cohort, the above three indicators were 0.960(95%CI: 0.905-1.000), 84.0% and 100.0%. The results of subanalysis showed that age was the independent predictor in the patients with chronic hepatitis and cirrhosis between HCC and FNH groups. CONCLUSIONS: Gd-EOB-DTPA enhanced MRI nomogram model may be useful for discriminating HCC and FNH showing iso- or hyperintensity in the HBP before surgery.
Assuntos
Carcinoma Hepatocelular , Meios de Contraste , Hiperplasia Nodular Focal do Fígado , Gadolínio DTPA , Neoplasias Hepáticas , Imageamento por Ressonância Magnética , Nomogramas , Humanos , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Feminino , Masculino , Hiperplasia Nodular Focal do Fígado/diagnóstico por imagem , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Diagnóstico Diferencial , Adulto , Idoso , Estudos Retrospectivos , Curva ROCRESUMO
OBJECTIVES: This study evaluated the effectiveness, psychological effects, and sleep quality using intramuscular diazepam infusion compared with placebo in patients with herpes zoster (HZ)-related pain. METHODS: The patients were randomized to either the diazepam or control group. The diazepam group received an intramuscular injection of diazepam for 3 consecutive days, while the control group received an intramuscular injection of 0.9% normal saline. The primary outcome was pain relief on posttreatment day 4, as measured using the Visual Analog Scale (VAS). Moreover, anxiety and depression were evaluated using the Generalized Anxiety Disorder-7 (GAD7) and Patient Health Questionnaire-9 (PHQ9), respectively. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: In total, 78 patients were enrolled in the trial. The mean differences in VAS scores between the two groups were 0.62 (P = 0.049) on posttreatment day 3 and 0.66 (P = 0.037) on posttreatment day 4. The effective rates of pain management in the diazepam group ranged from 10.26 to 66.67%, which were higher than those in the control group on posttreatment days 3 and 4 (P < 0.05). The mean difference in PSQI scores between the diazepam and control groups was 1.36 (P = 0.034) on posttreatment day 7. No differences were found in the incidence of analgesia-adverse 1reactions between the diazepam and placebo groups. CONCLUSIONS: The intramuscular injection of diazepam for 3 consecutive days provides effective pain management and improves the quality of life. Our study suggests that diazepam is more effective than the placebo in patients with HZ-related pain. TRIAL REGISTRATION: The study was prospectively registered at https://www.isrctn.com/trialist(Registration date: 24/01/2018; Trial ID: ISRCTN12682696).