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1.
Nature ; 628(8008): 527-533, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38600389

RESUMO

Topology1-3 and interactions are foundational concepts in the modern understanding of quantum matter. Their nexus yields three important research directions: (1) the competition between distinct interactions, as in several intertwined phases, (2) the interplay between interactions and topology that drives the phenomena in twisted layered materials and topological magnets, and (3) the coalescence of several topological orders to generate distinct novel phases. The first two examples have grown into major areas of research, although the last example remains mostly unexplored, mainly because of the lack of a material platform for experimental studies. Here, using tunnelling microscopy, photoemission spectroscopy and a theoretical analysis, we unveil a 'hybrid' topological phase of matter in the simple elemental-solid arsenic. Through a unique bulk-surface-edge correspondence, we uncover that arsenic features a conjoined strong and higher-order topology that stabilizes a hybrid topological phase. Although momentum-space spectroscopy measurements show signs of topological surface states, real-space microscopy measurements unravel a unique geometry of topologically induced step-edge conduction channels revealed on various natural nanostructures on the surface. Using theoretical models, we show that the existence of gapless step-edge states in arsenic relies on the simultaneous presence of both a non-trivial strong Z2 invariant and a non-trivial higher-order topological invariant, which provide experimental evidence for hybrid topology. Our study highlights pathways for exploring the interplay of different band topologies and harnessing the associated topological conduction channels in engineered quantum or nano-devices.

2.
Nature ; 604(7907): 647-652, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35478239

RESUMO

Quantum phases can be classified by topological invariants, which take on discrete values capturing global information about the quantum state1-13. Over the past decades, these invariants have come to play a central role in describing matter, providing the foundation for understanding superfluids5, magnets6,7, the quantum Hall effect3,8, topological insulators9,10, Weyl semimetals11-13 and other phenomena. Here we report an unusual linking-number (knot theory) invariant associated with loops of electronic band crossings in a mirror-symmetric ferromagnet14-20. Using state-of-the-art spectroscopic methods, we directly observe three intertwined degeneracy loops in the material's three-torus, T3, bulk Brillouin zone. We find that each loop links each other loop twice. Through systematic spectroscopic investigation of this linked-loop quantum state, we explicitly draw its link diagram and conclude, in analogy with knot theory, that it exhibits the linking number (2, 2, 2), providing a direct determination of the invariant structure from the experimental data. We further predict and observe, on the surface of our samples, Seifert boundary states protected by the bulk linked loops, suggestive of a remarkable Seifert bulk-boundary correspondence. Our observation of a quantum loop link motivates the application of knot theory to the exploration of magnetic and superconducting quantum matter.

3.
Nat Methods ; 21(1): 92-101, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37749214

RESUMO

Natural proteins are composed of 20 proteinogenic amino acids and their post-translational modifications (PTMs). However, due to the lack of a suitable nanopore sensor that can simultaneously discriminate between all 20 amino acids and their PTMs, direct sequencing of protein with nanopores has not yet been realized. Here, we present an engineered hetero-octameric Mycobacterium smegmatis porin A (MspA) nanopore containing a sole Ni2+ modification. It enables full discrimination of all 20 proteinogenic amino acids and 4 representative modified amino acids, Nω,N'ω-dimethyl-arginine (Me-R), O-acetyl-threonine (Ac-T), N4-(ß-N-acetyl-D-glucosaminyl)-asparagine (GlcNAc-N) and O-phosphoserine (P-S). Assisted by machine learning, an accuracy of 98.6% was achieved. Amino acid supplement tablets and peptidase-digested amino acids from peptides were also analyzed using this strategy. This capacity for simultaneous discrimination of all 20 proteinogenic amino acids and their PTMs suggests the potential to achieve protein sequencing using this nanopore-based strategy.


Assuntos
Nanoporos , Aminoácidos/química , Proteínas/metabolismo , Porinas/química , Porinas/metabolismo , Peptídeos/química
4.
Nature ; 583(7817): 533-536, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32699400

RESUMO

The quantum-level interplay between geometry, topology and correlation is at the forefront of fundamental physics1-15. Kagome magnets are predicted to support intrinsic Chern quantum phases owing to their unusual lattice geometry and breaking of time-reversal symmetry14,15. However, quantum materials hosting ideal spin-orbit-coupled kagome lattices with strong out-of-plane magnetization are lacking16-21. Here, using scanning tunnelling microscopy, we identify a new topological kagome magnet, TbMn6Sn6, that is close to satisfying these criteria. We visualize its effectively defect-free, purely manganese-based ferromagnetic kagome lattice with atomic resolution. Remarkably, its electronic state shows distinct Landau quantization on application of a magnetic field, and the quantized Landau fan structure features spin-polarized Dirac dispersion with a large Chern gap. We further demonstrate the bulk-boundary correspondence between the Chern gap and the topological edge state, as well as the Berry curvature field correspondence of Chern gapped Dirac fermions. Our results point to the realization of a quantum-limit Chern phase in TbMn6Sn6, and may enable the observation of topological quantum phenomena in the RMn6Sn6 (where R is a rare earth element) family with a variety of magnetic structures. Our visualization of the magnetic bulk-boundary-Berry correspondence covering real space and momentum space demonstrates a proof-of-principle method for revealing topological magnets.

5.
Plant J ; 119(3): 1353-1368, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38829920

RESUMO

Cucumber plants are highly susceptible to the hemibiotroph oomycete Phytophthora melonis. However, the mechanism of resistance to cucumber blight remains poorly understood. Here, we demonstrated that cucumber plants with impairment in the biosynthesis of brassinosteroids (BRs) or gibberellins (GAs) were more susceptible to P. melonis. By contrast, increasing levels of endogenous BRs or exogenously application of 24-epibrassinolide enhanced the resistance of cucumber plants against P. melonis. Furthermore, we found that both knockout and overexpression of the BR biosynthesis gene CYP85A1 reduced the endogenous GA3 content compared with that of wild-type plants under the condition of inoculation with P. melonis, and the enhancement of disease resistance conferred by BR was inhibited in plants with silencing of the GA biosynthetic gene GA20ox1 or KAO. Together, these findings suggest that GA homeostasis is an essential factor mediating BRs-induced disease resistance. Moreover, BZR6, a key regulator of BR signaling, was found to physically interact with GA20ox1, thereby suppressing its transcription. Silencing of BZR6 promoted endogenous GA biosynthesis and compromised GA-mediated resistance. These findings reveal multifaceted crosstalk between BR and GA in response to pathogen infection, which can provide a new approach for genetically controlling P. melonis damage in cucumber production.


Assuntos
Brassinosteroides , Cucumis sativus , Resistência à Doença , Giberelinas , Phytophthora , Doenças das Plantas , Phytophthora/fisiologia , Brassinosteroides/metabolismo , Cucumis sativus/microbiologia , Cucumis sativus/genética , Cucumis sativus/metabolismo , Cucumis sativus/parasitologia , Resistência à Doença/genética , Doenças das Plantas/microbiologia , Doenças das Plantas/parasitologia , Doenças das Plantas/imunologia , Giberelinas/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Reguladores de Crescimento de Plantas/metabolismo , Transdução de Sinais
6.
Nat Mater ; 23(9): 1214-1221, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39009656

RESUMO

A nematic phase breaks the point-group symmetry of the crystal lattice and is known to emerge in correlated materials. Here we report the observation of an intra-unit-cell nematic order and associated Fermi surface deformation in the kagome metal ScV6Sn6. Using scanning tunnelling microscopy and scanning tunnelling spectroscopy, we reveal a stripe-like nematic order breaking the crystal rotational symmetry within the kagome lattice itself. Moreover, we identify a set of Van Hove singularities adhering to the kagome-layer electrons, which appear along one direction of the Brillouin zone and are annihilated along other high-symmetry directions, revealing rotational symmetry breaking. Via detailed spectroscopic maps, we further observe an elliptical deformation of the Fermi surface, which provides direct evidence for an electronically mediated nematic order. Our work not only bridges the gap between electronic nematicity and kagome physics but also sheds light on the potential mechanism for realizing symmetry-broken phases in correlated electron systems.

7.
Arterioscler Thromb Vasc Biol ; 44(1): 218-237, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37970714

RESUMO

BACKGROUND: The formation of large necrotic cores results in vulnerable atherosclerotic plaques, which can lead to severe cardiovascular diseases. However, the specific regulatory mechanisms underlying the development of necrotic cores remain unclear. METHODS: To evaluate how the modes of lesional cell death are reprogrammed during the development of atherosclerosis, the expression levels of key proteins that are involved in the necroptotic, apoptotic, and pyroptotic pathways were compared between different stages of plaques in humans and mice. Luciferase assays and loss-of-function studies were performed to identify the microRNA-mediated regulatory mechanism that protects foamy macrophages from necroptotic cell death. The role of this mechanism in atherosclerosis was determined by using a knockout mouse model with perivascular drug administration and tail vein injection of microRNA inhibitors in Apoe-/- mice. RESULTS: Here, we demonstrate that the necroptotic, rather than the apoptotic or pyroptotic, pathway is more activated in advanced unstable plaques compared with stable plaques in both humans and mice, which closely correlates with necrotic core formation. The upregulated expression of Ripk3 (receptor-interacting protein kinase 3) promotes the C/EBPß (CCAAT/enhancer binding protein beta)-dependent transcription of the microRNA miR-223-3p, which conversely inhibits Ripk3 expression and forms a negative feedback loop to regulate the necroptosis of foamy macrophages. The knockout of the Mir223 gene in bone marrow cells accelerates atherosclerosis in Apoe-/- mice, but this effect can be rescued by Ripk3 deficiency or treatment with the necroptosis inhibitors necrostatin-1 and GSK-872. Like the Mir223 knockout, treating Apoe-/- mice with miR-223-3p inhibitors increases atherosclerosis. CONCLUSIONS: Our study suggests that miR-223-3p expression in macrophages protects against atherosclerotic plaque rupture by limiting the formation of necrotic cores, thus providing a potential microRNA therapeutic candidate for atherosclerosis.


Assuntos
Aterosclerose , MicroRNAs , Placa Aterosclerótica , Humanos , Animais , Camundongos , Retroalimentação , Aterosclerose/genética , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , Placa Aterosclerótica/metabolismo , Macrófagos/metabolismo , Necrose/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Camundongos Knockout , Apolipoproteínas E , Camundongos Endogâmicos C57BL , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo
8.
Nano Lett ; 24(1): 305-311, 2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38149630

RESUMO

Thyroid hormones (THs) are a variety of iodine-containing hormones that demonstrate critical physiological impacts on cellular activities. The assessment of thyroid function and the diagnosis of thyroid disorders require accurate measurement of TH levels. However, largely due to their structural similarities, the simultaneous discrimination of different THs is challenging. Nanopores, single-molecule sensors with a high resolution, are suitable for this task. In this paper, a hetero-octameric Mycobacterium smegmatis porin A (MspA) nanopore containing a single nickel ion immobilized to the pore constriction has enabled simultaneous identification of five representative THs including l-thyroxine (T4), 3,3',5-triiodo-l-thyronine (T3), 3,3',5'-triiodo-l-thyronine (rT3), 3,5-diiodo-l-thyronine (3,5-T2) and 3,3'-diiodo-l-thyronine (3,3'-T2). To automate event classification and avoid human bias, a machine learning algorithm was also developed, reporting an accuracy of 99.0%. This sensing strategy is also applied in the analysis of TH in a real human serum environment, suggesting its potential use in a clinical diagnosis.


Assuntos
Nanoporos , Humanos , Níquel , Hormônios Tireóideos/análise , Hormônios Tireóideos/química , Tiroxina , Tironinas
9.
Lab Invest ; 104(8): 102090, 2024 08.
Artigo em Inglês | MEDLINE | ID: mdl-38830579

RESUMO

Gastric cancer (GC) is one of the most common clinical malignant tumors worldwide, with high morbidity and mortality. Presently, the overall response rate to immunotherapy is low, and current methods for predicting the prognosis of GC are not optimal. Therefore, novel biomarkers with accuracy, efficiency, stability, performance ratio, and wide clinical application are needed. Based on public data sets, the chemotherapy cohort and immunotherapy cohort from Sun Yat-sen University Cancer Center, a series of bioinformatics analyses, such as differential expression analysis, survival analysis, drug sensitivity prediction, enrichment analysis, tumor immune dysfunction and exclusion analysis, single-sample gene set enrichment analysis, stemness index calculation, and immune cell infiltration analysis, were performed for screening and preliminary exploration. Immunohistochemical staining and in vitro experiments were performed for further verification. Overexpression of COX7A1 promoted the resistance of GC cells to Oxaliplatin. COX7A1 may induce immune escape by regulating the number of fibroblasts and their cellular communication with immune cells. In summary, measuring the expression levels of COX7A1 in the clinic may be useful in predicting the prognosis of GC patients, the degree of chemotherapy resistance, and the efficacy of immunotherapy.


Assuntos
Antineoplásicos , Resistencia a Medicamentos Antineoplásicos , Imunoterapia , Oxaliplatina , Neoplasias Gástricas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Imunoterapia/métodos , Oxaliplatina/uso terapêutico , Oxaliplatina/farmacologia , Prognóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/terapia
10.
BMC Plant Biol ; 24(1): 335, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664614

RESUMO

BACKGROUND: The vivid red, purple, and blue hues that are observed in a variety of plant fruits, flowers, and leaves are produced by anthocyanins, which are naturally occurring pigments produced by a series of biochemical processes occurring inside the plant cells. The purple-stalked Chinese kale, a popular vegetable that contains anthocyanins, has many health benefits but needs to be investigated further to identify the genes involved in the anthocyanin biosynthesis and translocation in this vegetable. RESULTS: In this study, the purple- and green-stalked Chinese kale were examined using integrative transcriptome and metabolome analyses. The content of anthocyanins such as cyanidin-3-O-(6″-O-feruloyl) sophoroside-5-O-glucoside, cyanidin-3,5-O-diglucoside (cyanin), and cyanidin-3-O-(6″-O-p-hydroxybenzoyl) sophoroside-5-O-glucoside were considerably higher in purple-stalked Chinese kale than in its green-stalked relative. RNA-seq analysis indicated that 23 important anthocyanin biosynthesis genes, including 3 PAL, 2 C4H, 3 4CL, 3 CHS, 1 CHI, 1 F3H, 2 FLS, 2 F3'H, 1 DFR, 3 ANS, and 2 UFGT, along with the transcription factor BoMYB114, were significantly differentially expressed between the purple- and green-stalked varieties. Results of analyzing the expression levels of 11 genes involved in anthocyanin production using qRT-PCR further supported our findings. Association analysis between genes and metabolites revealed a strong correlation between BoGSTF12 and anthocyanin. We overexpressed BoGSTF12 in Arabidopsis thaliana tt19, an anthocyanin transport mutant, and this rescued the anthocyanin-loss phenotype in the stem and rosette leaves, indicating BoGSTF12 encodes an anthocyanin transporter that affects the accumulation of anthocyanins. CONCLUSION: This work represents a key step forward in our understanding of the molecular processes underlying anthocyanin production in Chinese kale. Our comprehensive metabolomic and transcriptome analyses provide important insights into the regulatory system that controls anthocyanin production and transport, while providing a foundation for further research to elucidate the physiological importance of the metabolites found in this nutritionally significant vegetable.


Assuntos
Antocianinas , Brassica , Perfilação da Expressão Gênica , Metaboloma , Proteínas de Plantas , Antocianinas/metabolismo , Antocianinas/biossíntese , Brassica/genética , Brassica/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Transcriptoma , Regulação da Expressão Gênica de Plantas , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética
11.
Small ; 20(42): e2402534, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-38850182

RESUMO

In this study, the copper-nickel (Cu-Ni) bimetallic electrocatalysts for electrochemical CO2 reduction reaction(CO2RR) are fabricated by taking the finely designed poly(ionic liquids) (PIL) containing abundant Salen and imidazolium chelating sites as the surficial layer, wherein Cu-Ni, PIL-Cu and PIL-Ni interaction can be readily regulated by different synthetic scheme. As a proof of concept, Cu@Salen-PIL@Ni(NO3)2 and Cu@Salen-PIL(Ni) hybrids differ significantly in the types and distribution of Ni species and Cu species at the surface, thereby delivering distinct Cu-Ni cooperation fashion for the CO2RR. Remarkably, Cu@Salen-PIL@Ni(NO3)2 provides a C2+ faradaic efficiency (FEC2+) of 80.9% with partial current density (jC 2+) of 262.9 mA cm-2 at -0.80 V (versus reversible hydrogen electrode, RHE) in 1 m KOH in a flow cell, while Cu@Salen-PIL(Ni) delivers the optimal FEC2+ of 63.8% at jC2+ of 146.7 mA cm-2 at -0.78 V. Mechanistic studies indicates that the presence of Cu-Ni interfaces in Cu@Salen-PIL@Ni(NO3)2 accounts for the preserve of high-valence Cu(I) species under CO2RR conditions. It results in a high activity of both CO2-to-CO conversion and C-C coupling while inhibition of the competitive HER.

12.
Glob Chang Biol ; 30(1): e17155, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38273528

RESUMO

There is growing evidence that land-use management practices such as livestock grazing can strongly impact the local diversity, functioning, and stability of grassland communities. However, whether these impacts depend on environmental condition and propagate to larger spatial scales remains unclear. Using an 8-year grassland exclosure experiment conducted at nine sites in the Tibetan Plateau covering a large precipitation gradient, we found that herbivore exclusion increased the temporal stability of alpine grassland biomass production at both the local and larger (site) spatial scales. Higher local community stability was attributed to greater stability of dominant species, whereas higher stability at the larger scale was linked to higher spatial asynchrony of productivity among local communities. Additionally, sites with higher mean annual precipitation had lower dominant species stability and lower grassland stability at both the spatial scales considered. Our study provides novel evidence that livestock grazing can impair grassland stability across spatial scales and climatic gradients.


Assuntos
Pradaria , Herbivoria , Animais , Biomassa , Gado , Ecossistema
13.
FASEB J ; 37(4): e22873, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36929360

RESUMO

Trabecular meshwork (TM) cell dysfunction is the leading cause of elevated intraocular pressure (IOP) and glaucoma. The long non-coding RNA (lncRNA) small nucleolar RNA host gene 11 (SNHG11) is associated with cell proliferation and apoptosis, but its biological functions and role in glaucoma pathogenesis remain unclear. In the present study, we investigated the role of SNHG11 in TM cells using immortalized human TM and glaucomatous human TM (GTM3 ) cells and an acute ocular hypertension mouse model. SNHG11 expression was depleted using siRNA targeting SNHG11. Transwell assays, quantitative real-time PCR analysis (qRT-PCR), western blotting, and CCK-8 assay were used to evaluate cell migration, apoptosis, autophagy, and proliferation. Wnt/ß-catenin pathway activity was inferred from qRT-PCR, western blotting, immunofluorescence, and luciferase reporter and TOPFlash reporter assays. The expression of Rho kinases (ROCKs) was detected using qRT-PCR and western blotting. SNHG11 was downregulated in GTM3 cells and mice with acute ocular hypertension. In TM cells, SNHG11 knockdown inhibited cell proliferation and migration, activated autophagy, and apoptosis, repressing the Wnt/ß-catenin signaling pathway, and activated Rho/ROCK. Wnt/ß-catenin signaling pathway activity increased in TM cells treated with ROCK inhibitor. SNHG11 regulated Wnt/ß-catenin signaling through Rho/ROCK by increasing GSK-3ß expression and ß-catenin phosphorylation at Ser33/37/Thr41 while decreasing ß-catenin phosphorylation at Ser675. We demonstrate that the lncRNA SNHG11 regulates Wnt/ß-catenin signaling through Rho/ROCK via ß-catenin phosphorylation at Ser675 or GSK-3ß-mediated phosphorylation at Ser33/37/Thr41, affecting cell proliferation, migration, apoptosis, and autophagy. Through its effects on Wnt/ß-catenin signaling, SNHG11 is implicated in glaucoma pathogenesis and is a potential therapeutic target.


Assuntos
Glaucoma , Hipertensão Ocular , RNA Longo não Codificante , Humanos , Animais , Camundongos , Via de Sinalização Wnt/fisiologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Malha Trabecular/metabolismo , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Proliferação de Células/genética , Glaucoma/genética , Glaucoma/metabolismo , Hipertensão Ocular/metabolismo , Linhagem Celular Tumoral
14.
Virol J ; 21(1): 151, 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38965616

RESUMO

BACKGROUND: The canine influenza virus (CIV) outbreak has garnered considerable attention as it poses a significant threat to dog health. During the H3N2 CIV evolution in beagles, the virus formed a new clade after 2019 and gradually became more adaptable to other mammals. Therefore, successfully elucidating the biological characteristics and constructing a canine influenza infection model is required for CIV characterization. METHODS: We performed genetic analyses to examine the biological characteristics and infection dynamics of CIV. RESULTS: The genotype of our H3N2 CIV strain (from 2019 in Shanghai) belonged to the 5.1 clade, which is now prevalent in China. Using MDCK cells, we investigated viral cytopathic effects. Virus size and morphology were observed using transmission electron microscopy. Beagles were also infected with 104, 105, and 106 50% egg-infectious doses (EID50). When compared with the other groups, the 106 EID50 group showed the most obvious clinical symptoms, the highest virus titers, and typical lung pathological changes. Our results suggested that the other two treatments caused mild clinical manifestations and pathological changes. Subsequently, CIV distribution in the 106 EID50 group was detected by hematoxylin and eosin (H&E) and immunofluorescence (IF) staining, which indicated that CIV primarily infected the lungs. CONCLUSIONS: The framework established in this study will guide further CIV prevention strategies.


Assuntos
Doenças do Cão , Genótipo , Vírus da Influenza A Subtipo H3N2 , Infecções por Orthomyxoviridae , Animais , Cães , Vírus da Influenza A Subtipo H3N2/genética , Infecções por Orthomyxoviridae/virologia , Infecções por Orthomyxoviridae/patologia , Doenças do Cão/virologia , Células Madin Darby de Rim Canino , China/epidemiologia , Pulmão/virologia , Pulmão/patologia , Filogenia , Carga Viral , Modelos Animais de Doenças
15.
Diabetes Obes Metab ; 2024 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-39364690

RESUMO

AIMS: Participants with cardiovascular diseases (CVD) often exhibit liver function abnormalities, hepatic fibrosis and cirrhosis. The extent of liver fibrosis is closely related to the prognosis of CVD. However, the association between the liver fibrosis-8 (FIB-8) index, a marker of liver fibrosis, and all-cause mortality in CVD participants remains unclear. This study aims to investigate the relationship between the FIB-8 index and all-cause mortality among individuals with CVD. MATERIALS AND METHODS: A total of 1727 CVD American participants were enrolled from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2018. Initially, we constructed weighted COX regression models and performed sensitivity analyses to examine the correlation between the FIB-8 index and all-cause mortality in CVD participants. Subsequently, we employed restricted cubic spline (RCS) to visualize their linear relationship. Finally, the stratified analyses and interaction tests of covariates were performed and presented in the forest plot. RESULTS: A total of 1727 participants were included in our study, with a mean age of 61.68 ± 0.47 years, with men accounting for 59.19%. After adjustment for relevant covariables, weighted COX regression models indicated that the hazard ratio (HR) and 95% confidence interval (95% CI) for the association between the FIB-8 index and all-cause mortality in CVD participants was 1.21 (1.12, 1.30). Sensitivity analysis was then conducted, revealing that the results remained stable. In fully adjusted model, individuals in quartiles 3 and 4 demonstrated significant statistical differences compared to the lowest FIB-8 index quartile, with HR (95% CI) values of 1.88 (1.23, 2.87) and 2.17 (1.33, 3.53), respectively. Subsequently, RCS showed a linear relationship between the FIB-8 index and all-cause mortality among CVD participants. Finally, the interaction test revealed that no other covariables had significant interactions with the FIB-8 index in this study. CONCLUSIONS: A positive and linear correlation was observed between the FIB-8 index and all-cause mortality among CVD adult participants in NHANES from 1999 to 2018. Our findings indicated that the FIB-8 index could serve as an excellent indicator for assessing all-cause mortality within the CVD population. The lower the FIB-8 index, the lower the all-cause mortality among CVD participants.

16.
Bioorg Chem ; 144: 107175, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38335757

RESUMO

Eight undescribed (1-8) and 46 known compounds (9-54) were isolated from the deep-sea-derived Aspergillus sp. MCCC 3A00392. Compounds 1-3 were three novel oxoindolo diterpenoids, 4-6 were three bisabolane sesquiterpenoids, while 7 and 8 were two monocyclic cyclopropanes. Their structures were established by exhaustive analyses of the HRESIMS, NMR, and theoretical calculations of the NMR data and ECD spectra. Compounds 10, 33, 38, and 39 were able to inhibit tumor necrosis factor (TNF)-induced necroptosis in murine L929 cell lines. Functional experiments verified that compounds 10 and 39 inhibited necroptosis by downregulating the phosphorylation of RIPK3 and MLKL. Moreover, compound 39 also reduced the phosphorylation of RIPK1. Compounds 10, 33, and 34 displayed potent inhibitory activities against RSL-3 induced ferroptosis with the EC50 value of 3.0 µM, 0.4 µM, and 0.1 µM, respectively. Compound 10 inhibited ferroptosis by the downregulation of HMOX1, while compounds 33 and 34 inhibited ferroptosis through regulation of NRF2/SLC7A11/GCLM axis. However, these compounds only showed weak effect in either the necroptosis or ferroptosis relative mouse disease models. Further studies of pharmacokinetics and pharmacodynamics might improve their in vivo bioactivities.


Assuntos
Ferroptose , Sesquiterpenos , Camundongos , Animais , Necroptose , Aspergillus/química , Sesquiterpenos/química , Sesquiterpenos Monocíclicos
17.
Mol Ther ; 31(6): 1756-1774, 2023 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-36461633

RESUMO

Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/metabolismo , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética
18.
J Thromb Thrombolysis ; 57(2): 194-203, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38180590

RESUMO

This meta-analysis compared the efficacy and safety of different antithrombotic regimens after left atrial appendage closure (LAAC). PubMed, Embase, Medline, Cochrane Library databases were systematically searched from their inception to March 2023. Patients were divided into short-term oral anticoagulation (OAC) group and antiplatelet therapy (APT) group. The incidence of events were performed using RevMan 5.4. The events including device-related thrombus (DRT), ischemic stroke/systemic embolization (SE), major bleeding, any bleeding, any major adverse event and all-cause mortality. Subgroup analysis were based on OAC alone or OAC plus single antiplatelet therapy (SAPT) in OAC group. Oral anticoagulants include warfarin and direct oral anticoagulant (DOAC). Fourteen studies with 35,166 patients were included. We found that the incidence of DRT (OR = 0.49, 95% CI 0.36-0.66, P<0.0001) and all-cause mortality (OR = 0.71, 95% CI 0.57-0.89, P = 0.002) were significantly lower in OAC group than APT group. However, there was no statistical differences in the incidence rates of ischemic stroke/SE (OR = 0.77, 95% CI 0.49-1.20, P = 0.25), major bleeding (OR = 0.84, 95% CI 0.55-1.27, P = 0.84), any bleeding (OR = 0.83, 95% CI 0.56-1.22, P = 0.34) and any major adverse event (OR = 0.56, 95% CI 0.30-1.03, P = 0.06) in the two groups. Subgroup analysis found that the incidence of DRT, all-cause mortality and any major adverse event in OAC monotherapy were lower than that in APT group (P<0.05), but not statistically different from other outcome. The incidence of DRT, all-cause mortality, any major adverse event and any bleeding in DOAC were significantly better than APT group (P<0.05). While warfarin only has better incidence of DRT than APT (P<0.05), there was no statistical difference between the two groups in other outcome (P>0.05). The incidence of DRT was significantly lower than APT group (P<0.05), major bleeding were higher, and the rest of the outcome did not show any statistically significant differences(P>0.05) when OAC plus SAPT. Based on the existing data, short-term OAC may be favored over APT for patients who undergo LAAC. DOAC monotherapy may be favored over warfarin monotherapy or OAC plus APT, when selecting anticoagulant therapies.


Assuntos
Anticoagulantes , Apêndice Atrial , Fibrilação Atrial , Inibidores da Agregação Plaquetária , Humanos , Apêndice Atrial/cirurgia , Inibidores da Agregação Plaquetária/uso terapêutico , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/administração & dosagem , Anticoagulantes/uso terapêutico , Anticoagulantes/efeitos adversos , Anticoagulantes/administração & dosagem , Fibrilação Atrial/tratamento farmacológico , Hemorragia/induzido quimicamente , Trombose/etiologia , Trombose/prevenção & controle , Trombose/epidemiologia , Resultado do Tratamento , Oclusão do Apêndice Atrial Esquerdo
19.
Chem Biodivers ; 21(6): e202400507, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38606561

RESUMO

Three new C10 and C12 aliphatic δ-lactones (1-3), three new fatty acid methyl esters (4-6), and eight known compounds (7-14) were isolated from the marine Aureobasidium sp. LUO5. Their structures were established by detailed analyses of the NMR, HRESIMS, optical rotation, and ECD data. All isolates were tested for their inhibitory effects on nitric oxide production in LPS-induced BV-2 cells. Notably, compound 4 displayed the strongest inhibitory effect with the IC50 value of 120.3 nM.


Assuntos
Aureobasidium , Óxido Nítrico , Animais , Camundongos , Aureobasidium/química , Aureobasidium/metabolismo , Linhagem Celular , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Conformação Molecular , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Óxido Nítrico/metabolismo , Lactonas
20.
BMC Med Educ ; 24(1): 1100, 2024 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-39375768

RESUMO

BACKGROUND: Based on the perspective of social network theory, this study explored the network indicator system that facilitated optimal knowledge sharing effect in Medication Therapy Management Services (MTMS) training teams. The aim was to provide a reference for optimizing MTMS training and improving training quality. METHODS: Utilizing social network analysis combined with a questionnaire survey, a knowledge sharing matrix for MTMS training teams was constructed. Knowledge sharing behavior was assessed from three perspectives: individual networks, whole networks, and cohesive subgroups. RESULTS: Individual network analysis showed that the knowledge sharing effect within the training team reached its peak when the out-degree centrality was ≥ 3.5, in-degree centrality was ≥ 2.5, eigenvector centrality was ≥ 0.065, and closeness centrality was ≥ 7.86. Whole network analysis indicated that the optimal knowledge sharing effect occurred when the network density of the training team was higher than 0.0343 and the training size was less than 117 participants. Cohesion subgroups analysis demonstrated that knowledge sharing was more effective when members with similar working years participated in training together. CONCLUSIONS: The knowledge sharing indicator system developed for MTMS training teams, based on social network analysis, can assist in optimizing the MTMS training model and improving training effectiveness.


Assuntos
Conduta do Tratamento Medicamentoso , Análise de Rede Social , Humanos , Inquéritos e Questionários , Disseminação de Informação , Masculino , Feminino , Adulto
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