ABSTRACT
Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1-/- but not Trpa1-/- mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1-/- mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons.
Subject(s)
Cadaverine , Ganglia, Spinal , Mice, Inbred C57BL , Pruritus , TRPV Cation Channels , Animals , Pruritus/metabolism , Pruritus/chemically induced , TRPV Cation Channels/metabolism , Ganglia, Spinal/metabolism , Ganglia, Spinal/drug effects , Male , Cadaverine/analogs & derivatives , Cadaverine/pharmacology , Cadaverine/metabolism , Mice , Mice, Knockout , Humans , Mast Cells/metabolism , Mast Cells/drug effects , TRPA1 Cation Channel/metabolism , Sensory Receptor Cells/metabolism , Sensory Receptor Cells/drug effects , Receptors, G-Protein-Coupled/metabolism , Capsaicin/analogs & derivativesABSTRACT
High-Ni-content layered materials are promising cathodes for next-generation lithium-ion batteries. However, investigating the atomic configurations of the delithiation-induced complex phase boundaries and their transitions remains challenging. Here, by using deep-learning-aided super-resolution electron microscopy, we resolve the intralayer transition motifs at complex phase boundaries in high-Ni cathodes. We reveal that an O3 â O1 transformation driven by delithiation leads to the formation of two types of O1-O3 interface, the continuous- and abrupt-transition interfaces. The interfacial misfit is accommodated by a continuous shear-transition zone and an abrupt structural unit, respectively. Atomic-scale simulations show that uneven in-plane Li+ distribution contributes to the formation of both types of interface, and the abrupt transition is energetically more favourable in a delithiated state where O1 is dominant, or when there is an uneven in-plane Li+ distribution in a delithiated O3 lattice. Moreover, a twin-like motif that introduces structural units analogous to the abrupt-type O1-O3 interface is also uncovered. The structural transition motifs resolved in this study provide further understanding of shear-induced phase transformations and phase boundaries in high-Ni layered cathodes.
ABSTRACT
We report the In(OTf)3-catalyzed formal (4 + 3) cycloaddition of 3-benzylideneindoline-2-thiones with 2-indolylmethanols. This reaction not only broadens the synthetic utility of 3-benzylideneindoline-2-thiones as scarce indole-based sulfur-containing four-atom building blocks, but also provides a rapid and facile access to synthesize diindole-annulated tetrahydrothiepines.
ABSTRACT
Although neuronal Toll-like receptors (TLRs) (e.g., TLR2, TLR3, and TLR7) have been implicated in itch sensation, the roles of keratinocyte TLRs in chronic itch are elusive. Herein, we evaluated the roles of keratinocyte TLR2 and TLR7 in chronic itch under dry skin and psoriasis conditions, which was induced by either acetone-ether-water treatment or 5% imiquimod cream in mice, respectively. We found that TLR2 and TLR7 signaling were significantly upregulated in dry skin and psoriatic skin in mice. Chronic itch and epidermal hyperplasia induced by dry skin or psoriasis were comparably reduced in TLR2 and TLR7 knockout mice. In the dry skin model, the enhanced messenger RNA (mRNA) expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, TNF-α, and IFN-γ were inhibited in TLR2-/- mice, while CXCL2, IL-31, and IL-6 were inhibited in TLR7-/- mice. In psoriasis model, the enhanced mRNA expression levels of pruritic CXCL1/2, IL-31, IL-33, ST2, IL-6, and TNF-α were inhibited in TLR2-/- mice, while CXCL1/2, IL-31, IL-33, ST2, IL-6, IL-17A, and TNF-α were inhibited in TLR7-/- mice. Incubation with Staphylococcus aureus (S. aureus) peptidoglycan (PGN-SA) (a TLR2 agonist), imiquimod (a TLR7 agonist), and miR142-3p (a putative TLR7 agonist) were sufficient to upregulate the expression of pruritic cytokines or chemokines in cultured keratinocyte HaCaT cells. Finally, pharmacological blockade of C-X-C Motif Chemokine Receptor 1/2 and high mobility group box protein 1 dose-dependently attenuated acute and chronic itch in mice. Together, these results indicate that keratinocyte TLR2 and TLR7 signaling pathways are distinctly involved in the pathogenesis of chronic itch.
Subject(s)
Chemokines , Cytokines , Pruritus , Psoriasis , Toll-Like Receptor 2 , Toll-Like Receptor 7 , Animals , Mice , Cytokines/metabolism , Imiquimod/adverse effects , Interleukin-1 Receptor-Like 1 Protein , Interleukin-17 , Interleukin-33 , Interleukin-6 , Keratinocytes/metabolism , Psoriasis/drug therapy , RNA, Messenger , Toll-Like Receptor 2/genetics , Toll-Like Receptor 7/genetics , Tumor Necrosis Factor-alpha/adverse effects , Disease Models, Animal , Mice, Knockout , HaCaT Cells , HumansABSTRACT
Cation-disordered rock-salt (DRX) materials receive intensive attention as a new class of cathode candidates for high-capacity lithium-ion batteries (LIBs). Unlike traditional layered cathode materials, DRX materials have a three-dimensional (3D) percolation network for Li+ transportation. The disordered structure poses a grand challenge to a thorough understanding of the percolation network due to its multiscale complexity. In this work, we introduce the large supercell modeling for DRX material Li1.16Ti0.37Ni0.37Nb0.10O2 (LTNNO) via the reverse Monte Carlo (RMC) method combined with neutron total scattering. Through a quantitative statistical analysis of the material's local atomic environment, we experimentally verified the existence of short-range ordering (SRO) and uncovered an element-dependent behavior of transition metal (TM) site distortion. A displacement from the original octahedral site for Ti4+ cations is pervasive throughout the DRX lattice. Density functional theory (DFT) calculations revealed that site distortions quantified by the centroid offsets could alter the migration barrier for Li+ diffusion through the tetrahedral channels, which can expand the previously proposed theoretical percolating network of Li. The estimated accessible Li content is highly consistent with the observed charging capacity. The newly developed characterization method here uncovers the expandable nature of the Li percolation network in DRX materials, which may provide valuable guidelines for the design of superior DRX materials.
ABSTRACT
A Yb(OTf)3-catalyzed formal (4 + 3) cycloaddition reaction of donor-acceptor cyclopropanes with 3-benzylideneindoline-2-thiones as sulfur-containing 4π components has been successfully achieved. A series of functionalized 5,10-dihydro-2H-thiepino[2,3-b]indole derivatives were synthesized with good yields and moderate to good diastereoselectivity. The reaction described herein represented the inaugural (4 + 3) cycloaddition of 3-benzylideneindoline-2-thiones.
ABSTRACT
AlCl3-mediated nucleophilic ring-opening reactions of indoline-2-thiones with various acyl cyclopropanes, bi-cyclopropanes and spirocyclic cyclopropanes were investigated. A series of ketones functionalized with indolylthio groups were synthesized in yields ranging from moderate to good. Moreover, chemical transformations of 4-indolylthio butan-1-ones to dihydro-2H-thiepino[2,3-b]indoles and sulfone were carried out to further expand both synthetic utility and structural complexity.
ABSTRACT
The reconstruction of a blood supply system and myocardial recovery from inflamamtory reactions in the infract zone remains a challenge in cardiac regeneration after myocardial infarction. Here, we observed that the local myocardial cells and the clotted blood cells undergo cellular remodeling via cytoplasmic exocytosis and nuclear reorganization in zebrafish hearts after resection of the ventricular apex. The subsequent tissue regeneration processes were visualized by detection of the spatiotemporal expression of three tissue specific genes (α-SMA which marks for vasculature/fibrogenesis, Flk1for angiogenesis/hematopoiesis, and Pax3a for remusculogensis), and two histone modification markers (H3K9Ac and H3K9Me3 for chromatin remodeling). By analyzing the composition of the blastema tissue fractions we found that Krt5 peptide could promote F-actin assembly, BMP4-pSmad2/5/8 signaling activity, and H3K9Me3-mediated chromatin accessibility at the blastema representative genes in the cultured zebrafish embryonic fibroblasts. Further in vivo tests demonstrated that Krt5 interacted with beta actin, and promoted Gata3 expression and Flk1-GFP marked blastema angiogenesis. These results proposed a new Krt5-cytoskeleton-BMP4 mechanotransduction mechanism in the epithelial-dependent and cell phenotype conversion-based tissue regeneration.
Subject(s)
Mechanotransduction, Cellular , Zebrafish , Animals , Bone Morphogenetic Protein 4 , Cytoskeleton/metabolism , Myocytes, Cardiac/metabolism , Phenotype , Zebrafish/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
Defining the right question of interest is important to a clinical study. ICH E9 (R1) introduces the framework of an estimand and its five attributes, which provide a basis for connecting different components of a study with its clinical questions. Most of the applications of the estimand framework focus on efficacy instead of safety assessment. In this paper, we expand the estimand framework into the safety evaluation and compare/contrast the similarity and differences between safety and efficacy estimand. Furthermore, we present and discuss applications of a safety estimand to oncology trials and pooled data analyses. At last, we also discuss the potential usage of safety estimand to handle the impacts of COVID-19 pandemic on safety assessment.
Subject(s)
COVID-19 , Neoplasms , Humans , Research Design , Pandemics , Data Interpretation, StatisticalABSTRACT
Over the past decades, the primary interest in vaccine efficacy or immunogenicity evaluation mostly focuses on the biological effect of immunization in complying with the vaccination schedule in a targeted population. The safety questions, which are essential for vaccines as they are generally given to large healthy populations, need to be clearly defined to reflect the risk assessment of interest. ICH E9 (R1) provides a structured framework to clarify the clinical questions and formulate the treatment effect as an estimand. This paper applies the estimand framework to vaccine clinical trials on common clinical questions regarding efficacy, immunogenicity, and safety.
Subject(s)
Vaccines , Humans , Data Interpretation, Statistical , Vaccines/therapeutic use , Vaccination , Research DesignABSTRACT
The selective C-H/C-C bond scission in CO2-assisted alkane activation represents an opportunity for simultaneously upgrading greenhouse gas CO2 and light alkanes for the synthesis of value-added syngas (CO and H2), olefins, aromatics, and oxygenates. Here, Pd bimetallic (PdMx)-derived catalysts were investigated for ethane-CO2 reactions by combining kinetic analysis, in situ characterization, and density functional theory calculations. Two types of catalyst structures were identified under the reaction conditions, with the PdCox alloy surface favoring ethoxy formation, a critical precursor for further C-C bond scission, and the reaction-induced InOx/Pd interface promoting C-H bond scission. Our results revealed a general strategy to capture the reaction-induced surface configurations and in turn control the selectivity in C-C/C-H bond scission over PdMx-derived catalysts, featuring the interplay of two general descriptors: formation energy of PdMx surfaces and their binding energy to oxygen. Our study provides insight into the rational design of selective catalysts for light alkane-CO2 reactions.
ABSTRACT
Conversion of CO2 to useful fuels and chemicals has gained great attention in the past decades; yet the challenge persists due to the inert nature of CO2 and the wide range of products formed. Pd-based catalysts are extensively studied to facilitate CO2 hydrogenation to methanol via a reverse water gas shift (rWGS) pathway or formate pathway where formic acid may serve as an intermediate species. Here, we report the selective production of formic acid on the stable Pd(111) surface phase under CO2 hydrogenation conditions, which is fully covered by chemisorbed hydrogen, using combined Density Functional Theory (DFT) and Kinetic Monte Carlo (KMC) simulations. The results show that with the full coverage of hydrogen, instead of producing methanol as reported for Pd(111), the CO2 activation is highly selective to formic acid via a multi-step process involving the carboxyl intermediate. The high formic acid selectivity is associated with surface hydrogen species on Pd(111), which not only acts as a hydrogen reservoir to facilitate the hydrogenation steps, but also enables the formation of confined vacancy sites to facilitate the production and removal of formic acid. Our study highlights the importance of reactive environments, which can transform the surface structures and thus tune the activity/selectivity of catalysts.
ABSTRACT
This study researched the function of long non-coding RNA LINC00365 in lung adenocarcinoma (LAD) progression. LINC00365, miR-429, and KCTD12 expression in the LAD clinical tissues and cells were detcetd by qRT-PCR and Western blot. LINC00365, miR-429, and KCTD12 effects on H1975 cells malignant phenotype were detected by cell counting kit-8 assay, clone formation experiment, Transwell experiment, and glycolysis. Dual luciferase reporter gene assay and RNA pull-down assay were implemented. LINC00365 effect on H1975 cells in vivo growth was detected. LINC00365 was low expressed in the LAD patients and cells, associating with poor outcome. LINC00365 up-regulation attenuated H1975 cells proliferation, migration, invasion, glycolysis and in vivo growth. LINC00365 inhibited KCTD12 expression by sponging miR-429. miR-429 up-regulation and KCTD12 down-regulation partial reversed LINC00365 inhibition on H1975 cells malignant phenotype. Thus, LINC00365 inhibited LAD progression and glycolysis via targeting miR-429/KCTD12 axis. LINC00365 might be a potential candidate for LAD target treatment clinically.
Subject(s)
Adenocarcinoma of Lung , Adenocarcinoma , Lung Neoplasms , MicroRNAs , RNA, Long Noncoding , Adenocarcinoma/pathology , Adenocarcinoma of Lung/genetics , Adenocarcinoma of Lung/pathology , Cell Line, Tumor , Cell Movement/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic , Glycolysis/genetics , Humans , Lung Neoplasms/pathology , MicroRNAs/genetics , MicroRNAs/metabolism , Proteins/genetics , Proteins/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolismABSTRACT
The efficient conversion of carbon dioxide, a major air pollutant, into ethanol or higher alcohols is a big challenge in heterogeneous catalysis, generating great interest in both basic scientific research and commercial applications. Here, we report the facilitated methanol synthesis and the enabled ethanol synthesis from carbon dioxide hydrogenation on a catalyst generated by codepositing Cs and Cu on a ZnO(0001Ì ) substrate. A combination of catalytic testing, X-ray photoelectron spectroscopy (XPS) measurements, and calculations based on density functional theory (DFT) and kinetic Monte Carlo (KMC) simulation was used. The results of XPS showed a clear change in the reaction mechanism when going from Cs/Cu(111) to a Cs/Cu/ZnO(0001Ì ) catalyst. The Cs-promoting effect on C-C coupling is a result of a synergy among Cs, Cu, and ZnO components that leads to the presence of CHx and CHyO species on the surface. According to the DFT-based KMC simulations, the deposition of Cs introduces multifunctional sites with a unique structure at the Cu-Cs-ZnO interface, particularly being able to promote the interaction with CO2 and thus the methanol synthesis predominantly via the formate pathway. More importantly, it tunes the CHO binding strongly enough to facilitate the HCOOH decomposition to CHO via the formate pathway, but weakly enough to allow further hydrogenation to methanol. The fine-tuning of CHO binding also enables a close alignment of a CHO pair to facilitate the C-C coupling and eventually ethanol synthesis. Our study opens new possibilities to allow the highly active and selective conversion of carbon dioxide to higher alcohols on widely used and low-cost Cu-based catalysts.
ABSTRACT
BACKGROUND: DNA methylation alteration is frequently observed in Lung adenocarcinoma (LUAD) and may play important roles in carcinogenesis, diagnosis, and prognosis. Thus, this study aimed to construct a reliable methylation-based nomogram, guiding prognostic classification screening and personalized medicine for LUAD patients. METHOD: The DNA methylation data, gene expression data and corresponding clinical information of lung adenocarcinoma samples were extracted from The Cancer Genome Atlas (TCGA) database. Differentially methylated sites (DMSs) and differentially expressed genes (DEGs) were obtained and then calculated correlation by pearson correlation coefficient. Functional enrichment analysis and Protein-protein interaction network were used to explore the biological roles of aberrant methylation genes. A prognostic risk score model was constructed using univariate Cox and LASSO analysis and was assessed in an independent cohort. A methylation-based nomogram that included the risk score and the clinical risk factors was developed, which was evaluated by concordance index and calibration curves. RESULT: We identified a total of 1362 DMSs corresponding to 471 DEGs with significant negative correlation, including 752 hypermethylation sites and 610 hypomethylation sites. Univariate cox regression analysis showed that 59 DMSs were significantly associated with overall survival. Using LASSO method, we constructed a three-DMSs signature that was independent predictive of prognosis in the training cohort. Patients in high-risk group had a significant shorter overall survival than patients in low-risk group classified by three-DMSs signature (log-rank p = 1.9E-04). Multivariate cox regression analysis proved that the three-DMSs signature was an independent prognostic factor for LUAD in TCGA-LUAD cohort (HR = 2.29, 95%CI: 1.47-3.57, P = 2.36E-04) and GSE56044 cohort (HR = 2.16, 95%CI: 1.19-3.91, P = 0.011). Furthermore, a nomogram, combining the risk score with clinical risk factors, was developed with C-indexes of 0.71 and 0.70 in TCGA-LUAD and GSE56044 respectively. CONCLUSIONS: The present study established a robust three-DMSs signature for the prediction of overall survival and further developed a nomogram that could be a clinically available guide for personalized treatment of LUAD patients.
Subject(s)
Adenocarcinoma of Lung/mortality , DNA Methylation/genetics , Lung Neoplasms/mortality , Nomograms , Female , Humans , Male , Prognosis , Survival AnalysisABSTRACT
Bimetallic alloys have attracted considerable attention due to the tunable catalytic activity and selectivity that can be different from those of pure metals. Here, we study the superior catalytic behaviors of the Pt3Ni nanowire (NW) over each individual, Pt and Ni NWs during the reverse Water Gas Shift (rWGS) reaction, using density functional theory. The results show that the promoted rWGS activity by Pt3Ni strongly depends on the ensemble effect (a particular arrangement of active sites introduced by alloying), while the contributions from ligand and strain effects, which are of great importance in electrocatalysis, are rather subtle. As a result, a unique Ni-Pt hybrid ensemble is observed at the 110/111 edge of the Pt3Ni NW, where the synergy between Ni and Pt sites is active enough to stabilize carbon dioxide on the surface readily for the rWGS reaction but moderate enough to allow for the facile removal of carbon monoxide and hydrogenation of hydroxyl species. Our study highlights the importance of the ensemble effect in heterogeneous catalysis of metal alloys, enabling selective binding-tuning and promotion of catalytic activity.
ABSTRACT
BACKGROUND Aberrant DNA methylation is an important biological regulatory mechanism in malignant tumors. However, it remains underutilized for establishing prognostic models for triple-negative breast cancer (TNBC). MATERIAL AND METHODS Methylation data and expression data downloaded from The Cancer Genome Atlas (TCGA) were used to identify differentially methylated sites (DMSs). The prognosis-related DMSs were selected by univariate Cox regression analysis. Functional enrichment was analyzed using DAVID. A protein-protein interaction (PPI) network was constructed using STRING. Finally, a methylation-based prognostic signature was constructed using LASSO method and further validated in 2 validation cohorts. RESULTS Firstly, we identified 743 DMSs corresponding to 332 genes, including 357 hypermethylated sites and 386 hypomethylated sites. Furthermore, we selected 103 prognosis-related DMSs by univariate Cox regression. Using a LASSO algorithm, we established a 5-DMSs prognostic signature in TCGA-TNBC cohort, which could classify TNBC patients with significant survival difference (log-rank p=4.97E-03). Patients in the high-risk group had shorter overall survival than patients in the low-risk group. The excellent performance was validated in GSE78754 (HR=2.42, 95%CI: 1.27-4.59, log-rank P=0.0055). Moreover, for disease-free survival, the prognostic performance was verified in GSE141441 (HR=2.09, 95%CI: 1.28-3.44, log-rank P=0.0027). Multivariate Cox regression analysis indicated that the 5-DMSs signature could serve as an independent risk factor. CONCLUSIONS We constructed a 5-DMSs signature with excellent performance for the prediction of disease-free survival and overall survival, providing a guide for clinicians in directing personalized therapeutic regimen selection of TNBC patients.
Subject(s)
DNA Methylation/genetics , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Cohort Studies , Disease-Free Survival , Gene Expression Regulation, Neoplastic/genetics , Humans , Middle Aged , Prognosis , Protein Interaction Maps/geneticsABSTRACT
A chemical approach to the deposition of thin films on solid surfaces is highly desirable but prone to affect the final properties of the film. To better understand the origin of these complications, the initial stages of the atomic layer deposition of titania films on silica mesoporous materials were characterized. Adsorption-desorption measurements indicated that the films grow in a layer-by-layer fashion, as desired, but initially exhibit surprisingly low densities, about one-quarter of that of bulk titanium oxide. Electron microscopy, X-ray diffraction, UV/visible, and X-ray absorption spectroscopy data pointed to the amorphous nature of the first monolayers, and EXAFS and 29Si CP/MAS NMR results to an initial growth via the formation of individual tetrahedral Ti-oxide units on isolated Si-OH surface groups with unusually long Ti-O bonds. Density functional theory calculations were used to propose a mechanism where the film growth starts at the nucleation centers to form an open 2D structure.
ABSTRACT
Metastasis is a key component of cancer progression and is strongly associated with poor prognosis. Perineural invasion is thought to be related to pain, tumor recurrence, and other conditions. However, the exact molecular mechanism is unclear. This study was conducted to identify the key components and signaling pathways involved in the perineural invasion of pancreatic cancer and alterations in the phenotype after the interaction between the dorsal root ganglion (DRG) and pancreatic cancer cells. The results indicated that the p38 mitogen-activated protein kinase signaling pathway was activated after coculture of the DRG and pancreatic cancer cells and lead to the promotion of cell growth and chemoresistance.
ABSTRACT
Li- and Mn-rich (LMR) layered cathode materials have demonstrated impressive capacity and specific energy density thanks to their intertwined redox centers including transition metal cations and oxygen anions. Although tremendous efforts have been devoted to the investigation of the electrochemically driven redox evolution in LMR cathode at ambient temperature, their behavior under a mildly elevated temperature (up to â¼100 °C), with or without electrochemical driving force, remains largely unexplored. Here we show a systematic study of the thermally driven surface-to-bulk redox coupling effect in charged Li1.2Ni0.15Co0.1Mn0.55O2. We for the first time observed a charge transfer between the bulk oxygen anions and the surface transition metal cations under â¼100 °C, which is attributed to the thermally driven redistribution of Li ions. This finding highlights the nonequilibrium state and dynamic nature of the LMR material at deeply delithiated state upon a mild temperature perturbation.