Aberrant activation of Bruton’s tyrosine kinase (BTK) plays an important role in pathogenesis of B-cell lymphomas, suggesting that inhibition of BTK is useful in the treatment of hematological ...malignancies. The discovery of a more selective on-target covalent BTK inhibitor is of high value. Herein, we disclose the discovery and preclinical characterization of a potent, selective, and irreversible BTK inhibitor as our clinical candidate by using in vitro potency, selectivity, pharmacokinetics (PK), and in vivo pharmacodynamic for prioritizing compounds. Compound BGB-3111 (31a, Zanubrutinib) demonstrates (i) potent activity against BTK and excellent selectivity over other TEC, EGFR and Src family kinases, (ii) desirable ADME, excellent in vivo pharmacodynamic in mice and efficacy in OCI-LY10 xenograft models.
The puzzling nature of magnetic and lattice phase transitions of iron pnictides is investigated via a first-principles Wannier function analysis of representative parent compound LaOFeAs. A rare ...ferro-orbital ordering is found to give rise to the recently observed highly anisotropic magnetic coupling, and drive both phase transitions--without resorting to widely employed frustration or nesting picture. The revealed necessity of the additional orbital physics leads to a correlated electronic structure fundamentally distinct from that of the cuprates. In particular, the strong coupling to the magnons advocates active roles of light orbitons in spin dynamics and electron pairing in iron pnictides.
The varying metallic antiferromagnetic correlations observed in iron-based superconductors are unified in a model consisting of both itinerant electrons and localized spins. The decisive factor is ...found to be the sensitive competition between the superexchange antiferromagnetism and the orbital-degenerate double-exchange ferromagnetism. Our results reveal the crucial role of Hund's rule coupling for the strongly correlated nature of the system and suggest that the iron-based superconductors are closer kin to manganites than cuprates in terms of their diverse magnetism and incoherent normal-state electron transport. This unified picture would be instrumental for exploring other exotic properties and the mechanism of superconductivity in this new class of superconductors.
Aim: Roles of fibroblast growth factor 23 (FGF23) in endothelial dysfunction remain controversial, and evidence from population-based studies is lacking. The present study aimed to explore the ...effects of FGF23 on endothelial dysfunction on the basis of both clinical data of patients with coronary artery disease (CAD) and the in vitro research in human umbilical vein endothelial cells (HUVECs).Methods: A total of 321 CAD patients were enrolled after coronary angiography, brachial artery flow-mediated dilation (FMD) was assessed using ultrasound equipment. Serum FGF23, nitric oxide (NO), and endothelin-1 (ET-1) were detected via enzyme-linked immunosorbent assay. Apoptosis was determined using the annexin V-fluorescein isothiocyanate/propidium lodide apoptosis detection kit. Cell migration was evaluated by wound healing and transwell migration assays. Reactive oxide species levels were determined using fluorescent probes, and NF-κB p65 nuclear translocation was assessed via immunofluorescence.Results: Serum FGF23 was significantly increased in CAD patients combined with severe endothelial dysfunction (FMD ＜2%) compared to those with FMD ≥ 2% (P＜0.001). Furthermore, the levels of FGF23 were negatively correlated with NO, whereas positively correlated with ET-1 both in unadjusted analysis and multivariate-adjusted analysis. In HUVECs, FGF23 interfered with the bioavailability of NO via increased oxidative stress. Moreover, FGF23 directly impaired the endothelium by promoting HUVECs apoptosis and attenuating the migration of HUVECs. Additional experiments showed that FGF23 induced endothelial injury through activation of the NF-κB signaling pathway.Conclusions: Elevated FGF23 is clinically associated with endothelial dysfunction in CAD patients, and FGF23 impairs endothelial function through activation of the NF-κB signaling pathway.
Asgard archaea are widely distributed in anaerobic environments. Previous studies revealed the potential capability of Asgard archaea to utilize various organic substrates including proteins, ...carbohydrates, fatty acids, amino acids and hydrocarbons, suggesting that Asgard archaea play an important role in sediment carbon cycling. Here, we describe a previously unrecognized archaeal phylum, Hermodarchaeota, affiliated with the Asgard superphylum. The genomes of these archaea were recovered from metagenomes generated from mangrove sediments, and were found to encode alkyl/benzyl-succinate synthases and their activating enzymes that are similar to those identified in alkane-degrading sulfate-reducing bacteria. Hermodarchaeota also encode enzymes potentially involved in alkyl-coenzyme A and benzoyl-coenzyme A oxidation, the Wood-Ljungdahl pathway and nitrate reduction. These results indicate that members of this phylum have the potential to strictly anaerobically degrade alkanes and aromatic compounds, coupling the reduction of nitrate. By screening Sequence Read Archive, additional genes encoding 16S rRNA and alkyl/benzyl-succinate synthases analogous to those in Hermodarchaeota were identified in metagenomic datasets from a wide range of marine and freshwater sediments. These findings suggest that Asgard archaea capable of degrading alkanes and aromatics via formation of alkyl/benzyl-substituted succinates are ubiquitous in sediments.
The thermal aging behavior of glass fiber reinforced composites has attracted much attention because of its application in elevated temperatures environments. In this study, to improve the thermal ...aging resistance performance of composites, multilayer graphene was embedded in glass fiber reinforced composites and the damage evolution behaviors of the composites after thermal aging treatments were investigated. The mapping relationship between damage modes and acoustic emission parameters is established by principal component analysis and k‐means clustering methods, then the acoustic emission data were trained by K‐Nearest Neighbor algorithms to obtain a damage modes identification model with positive predictive values above 90%. The results showed that more matrix cracking signals are captured (or matrix cracking accumulation acoustic emission (AE) energy is abruptly raised) at the early stage of loading after 32 days of thermal aging. With the addition of multilayer graphene, the fiber/matrix debonding accumulation AE energy is significantly less than the matrix cracking accumulation AE energy, which is more obvious after thermal aging. Damage initiation and extension obtained by the acoustic emission events help to find the correlation between aging time and interior interface damage mechanism.
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•This review describes the recent progress in Chemical structures and bioactivities of limonoids.•This review summarizes the origin of Citrus limonoids from different species.•The ...possibility of Citrus limonoids as drug lead was discussed.•The recent progress in the metabolic study of Citrus limonoids was discussed.
Citrus limonoids are tetranortriterpenoids compounds mainly found in oranges, lemons, grapefruits, and other fruits of Citrus. They are proved to be the leading cause of bitterness in Citrus fruits and are mainly consumed for therapeutic purposes and as food. Numerous studies have focused on Citrus limonoids and intend to develop new chemotherapeutic or complementary medicine in recent years. Citrus limonoids showed various bioactivities such as anti-tumor, antioxidative, anti-inflammatory, anti-neurological diseases, immunomodulatory, anti-insect, anti-bacteria, antiviral activities, etc. This review summarized limonoids from Citrus to date, along with their chemical structures and biological activities with a particular focus on their anti-tumor potential.
ABSTRACT
GPCR kinase 2–interacting protein‐1 (GIT1) is a scaffold protein that plays an important role in cell adaptation, proliferation, migration, and differentiation; however, the role of GIT1 in ...the regulation of neuronal death after spinal cord injury remains obscure. Here, we demonstrate that GIT1 deficiency remarkably increased neuronal apoptosis and enhanced JNK/p38 signaling, which resulted in stronger motor deficits by ischemia‐reperfusion in vivo, consistent with the finding of oxygen‐glucose deprivation/reoxygenation–induced neuronal injury in vitro. After treatment with JNK and p38 inhibitors, abnormally necroptotic cell death caused by GIT1 knockdown could be partially rescued, with the recovery of neuronal viability, which was still poorer than that in control neurons. Meanwhile, overactivation of JNK/p38 after GIT1 depletion was concomitant with excessive activity of apoptosis signal‐regulating kinase‐1 (ASK1) that could be abolished by ASK1 silencing in HEK293T cells. Finally, GIT1 could disrupt the oligomerization of ASK1 via interaction between the synaptic localization domain that contains the coiled‐coil (CC)‐2 domain of GIT1 and the C‐terminal CC domain of ASK1. It suppressed the autophosphorylation of ASK1 and led to decreasing activity of the ASK1/JNK/p38 pathway. These data reveal a protective role for GIT1 in neuronal damage by modulating ASK1/JNK/p38 signaling.—Chen, J., Wang, Q., Zhou, W., Zhou, Z., Tang, P.‐Y., Xu, T., Liu, W., Li, L.‐W., Cheng, L., Zhou, Z.‐M., Fan, J., Yin, G.‐Y. GPCR kinase 2‐interacting protein‐1 protects against ischemia‐reperfusion injury of the spinal cord by modulating ASK1/JNK/p38 signaling. FASEB J. 32, 6833–6847 (2018). www.fasebj.org
Cyclic nucleotide-gated ion channels (CNGCs) are calcium-permeable channels that participate in a variety of biological functions, such as signaling pathways, plant development, and environmental ...stress and stimulus responses. Nevertheless, there have been few studies on CNGC gene family in cotton. In this study, a total of 114 CNGC genes were identified from the genomes of 4 cotton species. These genes clustered into 5 main groups: I, II, III, IVa, and IVb. Gene structure and protein motif analysis showed that CNGCs on the same branch were highly conserved. In addition, collinearity analysis showed that the CNGC gene family had expanded mainly by whole-genome duplication (WGD). Promoter analysis of the GhCNGCs showed that there were a large number of cis-acting elements related to abscisic acid (ABA). Combination of transcriptome data and the results of quantitative RT-PCR (qRT-PCR) analysis revealed that some GhCNGC genes were induced in response to salt and drought stress and to exogenous ABA. Virus-induced gene silencing (VIGS) experiments showed that the silencing of the GhCNGC32 and GhCNGC35 genes decreased the salt tolerance of cotton plants (TRV:00). Specifically, physiological indexes showed that the malondialdehyde (MDA) content in gene-silenced plants (TRV:GhCNGC32 and TRV:GhCNGC35) increased significantly under salt stress but that the peroxidase (POD) activity decreased. After salt stress, the expression level of ABA-related genes increased significantly, indicating that salt stress can trigger the ABA signal regulatory mechanism. we comprehensively analyzed CNGC genes in four cotton species, and found that GhCNGC32 and GhCNGC35 genes play an important role in cotton salt tolerance. These results laid a foundation for the subsequent study of the involvement of cotton CNGC genes in salt tolerance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Escherichia fergusonii is a rare opportunistic pathogen in humans and animals, especially with biofilm.
In one case, E. fergusonii with biofilm was detected in the bile, and silver staining was used ...to prove it had biofilm. The clinical characteristics and drug susceptibility of eight cases of E. fergusonii retrieved from the literature were also summarized.
This is a case of E. fergusonii with biofilm, which has not been reported in China. The 8 cases retrieved from the literature did not specify whether they had biofilm, but we analyzed their clinical characteristics and drug susceptibility. All patients were treated with antimicrobial drugs. 8 cases showed sensitivity to piperacillin/tazobactam and imipenem in 6 cases (75%), but poor sensitivity to levofloxacin and ciprofloxacin.
The silver staining method proved biofilm in this case, which is the first case of E. fergusonii with biofilm in China.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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