Identification of a novel O-conotoxin reveals an unusual and potent inhibitor of the human α9α10 nicotinic acetylcholine receptor

Conotoxins are a pool of disulfide-rich peptide neurotoxins produced by cone snails for predation and defense. They are a rich reservoir of novel ligands for ion channels, neurotransmitter receptors and transporters in the nervous system. In this study, we identified a novel conotoxin component, O-conotoxin GeXXVIIA, from the venom of Conus generalis. The native form of this component is a disulfide-linked homodimer of a 5-Cys-containing peptide. Surprisingly, our electrophysiological studies showed that, in comparison to the folded monomers, the linear peptide of this toxin had the highest inhibitory activity at the human α9α10 nicotinic acetylcholine receptor (nAChR), with an IC50 of 16.2 ± 1.4 nM. The activities of the N-terminal and C-terminal halves of the linear toxin are markedly reduced compared with the full-length toxin, suggesting that the intact sequence is required to potently inhibit the hα9α10 nAChR. α9α10 nAChRs are expressed not only in the nervous system, but also in a variety of non-neuronal cells, such as cochlear hair cells, keratinocytes, epithelial and immune cells. A potent inhibitor of human α9α10 nAChRs, such as GeXXVIIA, would facilitate unraveling the functions of this nAChR subtype. Furthermore, this unusual nAChR inhibitor may lead to the development of novel α9α10 nAChR-targeting drugs

A novel lid-covering peptide inhibitor of nicotinic acetylcholine receptors derived from αd-conotoxin GeXXA

Nicotinic acetylcholine receptors (nAChRs) play a fundamental role in nervous signal transmission, therefore various antagonists and agonists are highly desired to explore the structure and function of nAChRs. Recently, a novel dimeric αD-conotoxin GeXXA was identified to inhibit nAChRs by binding at the top surface of the receptors, and the monomeric C-terminal domain (CTD) of αD-GeXXA retains some inhibitory activity. In this study, the internal dimeric N-terminal domain (NTD) of this conopeptide was further investigated. We first developed a regio-selective protection strategy to chemically prepare the anti-parallel dimeric NTD, and found that the isolated NTD part of GeXXA possesses the nAChR-inhibitory activity, the subtype-dependence of which implies a preferred binding of NTD to the β subunits of nAChR. Deletion of the NTD N-terminal residues did not affect the activity of NTD, indicating that the N-terminus is not involved in the interaction with nAChRs. By optimizing the sequence of NTD, we obtained a fully active single-chain cyclic NTD, based on which 4 Arg residues were found to interact with nAChRs. These results demonstrate that the NTD part of αD-GeXXA is a lid-covering nAChR inhibitor, displaying a novel inhibitory mechanism distinct from other allosteric ligands of nAChRs

Tracking microRNA Processing Signals by Degradome Sequencing Data Analysis

Degradome sequencing (degradome-seq) was widely used for cleavage site mapping on the microRNA (miRNA) targets. Here, the application value of degradome-seq data in tracking the miRNA processing intermediates was reported. By adopting the parameter “signal/noise” ratio, prominent degradome signals on the miRNA precursors were extracted. For the 15 species analyzed, the processing of many miRNA precursors were supported by the degradome-seq data. We found that the supporting ratio of the “high-confidence” miRNAs annotated in miRBase was much higher than that of the “low-confidence.” For a specific species, the percentage of the miRNAs with degradome-supported processing signals was elevated by the increment of degradome sampling diversity. More interestingly, the tissue- or cell line-specific processing patterns of the miRNA precursors partially contributed to the accumulation patterns of the mature miRNAs. In this study, we also provided examples to show the value of the degradome-seq data in miRNA annotation. Based on the distribution of the processing signals, a renewed model was proposed that the stems of the miRNA precursors were diced through a “single-stranded cropping” mode, and “loop-to-base” processing was much more prevalent than previously thought. Together, our results revealed the remarkable capacity of degradome-seq in tracking miRNA processing signals

Integrated glycomic analysis of ovarian cancer side population cells

Additional file 2. The category of representative lectins for glycan profiling

Fibroblast Growth Factor 21 Deficiency Attenuates Experimental Colitis-Induced Adipose Tissue Lipolysis

Aims. Nutrient deficiencies are common in patients with inflammatory bowel disease (IBD). Adipose tissue plays a critical role in regulating energy balance. Fibroblast growth factor 21 (FGF21) is an important endocrine metabolic regulator with emerging beneficial roles in lipid homeostasis. We investigated the impact of FGF21 in experimental colitis-induced epididymal white adipose tissue (eWAT) lipolysis. Methods. Mice were given 2.5% dextran sulfate sodium (DSS) ad libitum for 7 days to induce colitis. The role of FGF21 was investigated using antibody neutralization or knockout (KO) mice. Lipolysis index and adipose lipolytic enzymes were determined. In addition, 3T3-L1 cells were pretreated with IL-6, followed by recombinant human FGF21 (rhFGF21) treatment; lipolysis was assessed. Results. DSS markedly decreased eWAT/body weight ratio and increased serum concentrations of free fatty acid (FFA) and glycerol, indicating increased adipose tissue lipolysis. eWAT intracellular lipolytic enzyme expression/activation was significantly increased. These alterations were significantly attenuated in FGF21 KO mice and by circulating FGF21 neutralization. Moreover, DSS treatment markedly increased serum IL-6 and FGF21 levels. IL-6 pretreatment was necessary for the stimulatory effect of FGF21 on adipose lipolysis in 3T3-L1 cells. Conclusions. Our results demonstrate that experimental colitis induces eWAT lipolysis via an IL-6/FGF21-mediated signaling pathway

First documentation of seismic stratigraphy and depositional signatures of Zhongsha atoll (Macclesfield Bank), South China Sea

Carbonate platforms form informative archives for paleoclimates and their internal structures can also hold crucial information about the tectonic history and carbonate evolution of the ocean basins. The Zhongsha atoll (Macclesfield Bank) forms the largest atoll system in the South China Sea with a surface area of 23500 km2. However, the internal structure and evolution of this atoll system is completely unknown. 2D multichannel seismic reflection data were acquired in 2017 over the Zhongsha atoll in the South China Sea to unravel the stratigraphy, geomorphology, depositional processes, and seismic facies of one of the world's largest atoll for the first time. This Neogene carbonate platform comprises more than 1 km thick carbonate sequence and overlies a metamorphic basement. The southeastern part of the atoll comprises a fault-controlled graben system, which was formed during the Cenozoic rifting stage of the South China Sea. Most of the faults trend NE-SW and E-W and terminate at or slightly above the top of Middle Miocene strata. Atolls and abundant organic reefs initiated on the positive relief and closely mimicked the underlying topography during the Early Miocene. Shallow-water carbonates continued growing through Middle Miocene to present times. Regional uplift led to subaerial exposure, termination of platform growth and karstification during the Miocene. We also reveal a number of fluid-flow features such as vertical sub-bottom venting features (chimneys and pipes), chaotic reflection zones, which provide the first evidence of active fluid venting in the area of Zhongsha atoll. The Neogene sedimentation history of Zhongsha atoll further provide an important paleoenvironmental context for future scientific drilling to better constrain the evolution of Asia Monsoon

Multicenter validation of the value of BASFI and BASDAI in Chinese ankylosing spondylitis and undifferentiated spondyloarthropathy patients

The objectives of this study were to evaluate the reliability of Bath ankylosing spondylitis functional index (BASFI) and Bath ankylosing spondylitis disease activity index (BASDAI) in Chinese ankylosing spondylitis (AS) and undifferentiated spondyloarthropathy (USpA) patients. 664 AS patients by the revised New York criteria for AS and 252 USpA patients by the European Spondyloarthropathy Study Group criteria were enrolled. BASDAI and BASFI questionnaires were translated into Chinese. Participants were required to fill in BASFI and BASDAI questionnaires again after 24 h. Moreover, BASDAI and BASFI were compared in AS patients receiving Enbrel or infliximab before and after treatment. For AS group, BASDAI ICC: 0.9502 (95% CI: 0.9330–0.9502, α = 0.9702), BASFI ICC: 0.9587 (95% CI: 0.9521–0.9645, α = 0.9789). For USpA group, BASDAI ICC: 0.9530 (95% CI: 0.9402–0.9632, α = 0.9760), BASFI ICC: 0.9900 (95% CI: 0.9871–0.9922, α = 0.9950). In the AS group, disease duration, occipital wall distance, modified Schober test, chest expansion, ESR, and CRP showed significant correlation with BASDAI and BASFI (all P < 0.01). In the USpA group, onset age, ESR, and CRP were significantly correlated with BASDAI (all P < 0.05), while modified Schober test, ESR, and CRP were significantly associated with BASFI (all P < 0.05). The change in BASDAI and BASFI via Enbrel or infliximab treatment showed a significant positive correlation (P < 0.01). The two instruments have good reliability and reference value regarding the evaluation of patient’s condition and anti-TNF-α treatment response

Activation of Sirt1 by Resveratrol Inhibits TNF-α Induced Inflammation in Fibroblasts

Inflammation is one of main mechanisms of autoimmune disorders and a common feature of most diseases. Appropriate suppression of inflammation is a key resolution to treat the diseases. Sirtuin1 (Sirt1) has been shown to play a role in regulation of inflammation. Resveratrol, a potent Sirt1 activator, has anti-inflammation property. However, the detailed mechanism is not fully understood. In this study, we investigated the anti-inflammation role of Sirt1 in NIH/3T3 fibroblast cell line. Upregulation of matrix metalloproteinases 9 (MMP-9), interleukin-1beta (IL-1β), IL-6 and inducible nitric oxide synthase (iNOS) were induced by tumor necrosis factor alpha (TNF-α) in 3T3 cells and resveratrol suppressed overexpression of these pro-inflammatory molecules in a dose-dependent manner. Knockdown of Sirt1 by RNA interference caused 3T3 cells susceptible to TNF-α stimulation and diminished anti-inflammatory effect of resveratrol. We also explored potential anti-inflammatory mechanisms of resveratrol. Resveratrol reduced NF-κB subunit RelA/p65 acetylation, which is notably Sirt1 dependent. Resveratrol also attenuated phosphorylation of mammalian target of rapamycin (mTOR) and S6 ribosomal protein (S6RP) while ameliorating inflammation. Our data demonstrate that resveratrol inhibits TNF-α-induced inflammation via Sirt1. It suggests that Sirt1 is an efficient target for regulation of inflammation. This study provides insight on treatment of inflammation-related diseases