Eag1 K +

Ether-à-go-go1 (Eag1, Kv10.1, KCNH1) K+ channel is a member of the voltage-gated K+ channel family mainly distributed in the central nervous system and cancer cells. Like other types of voltage-gated K+ channels, the EAG1 channels are regulated by a variety of endogenous signals including reactive oxygen species, rendering the EAG1 to be in the redox-regulated ion channel family. The role of EAG1 channels in tumor development and its therapeutic significance have been well established. Meanwhile, the importance of hEAG1 channels in the nervous system is now increasingly appreciated. The present review will focus on the recent progress on the channel regulation by endogenous signals and the potential functions of EAG1 channels in normal neuronal signaling as well as neurological diseases

Clonal evolution in liver cancer at single-cell and single-variant resolution.

Genetic heterogeneity of tumor is closely related to its clonal evolution, phenotypic diversity and treatment resistance, and such heterogeneity has only been characterized at single-cell sub-chromosomal scale in liver cancer. Here we reconstructed the single-variant resolution clonal evolution in human liver cancer based on single-cell mutational profiles. The results indicated that key genetic events occurred early during tumorigenesis, and an early metastasis followed by independent evolution was observed in primary liver tumor and intrahepatic metastatic portal vein tumor thrombus. By parallel single-cell RNA-Seq, the transcriptomic phenotype of HCC was found to be related with genetic heterogeneity. For the first time we reconstructed the single-cell and single-variant clonal evolution in human liver cancer, and dissection of both genetic and phenotypic heterogeneity will facilitate better understanding of their relationship

Hepatitis C virus genotypes and subtypes circulating in Mainland China

The hepatitis C virus (HCV) exhibits global genotypic diversity. HCV genotyping plays an important role in epidemiological studies and clinical management. Herein, we report the results of HCV genotype and subtype detection in a large number of clinical samples, as performed by an independent laboratory in China. In total, four HCV genotypes and 18 subtypes were identified among 32 030 patients from 29 provinces and municipalities in China. Five dominant subtypes were detected from 98.84% of the samples: 1b (n=16 713, 52.18%), 2a (n=9188, 28.69%), 3b (n=2261, 7.06%), 6a (n=2052, 6.41%) and 3a (n=1479, 4.62%). Twelve rare subtypes were detected, of which four (that is, 6b, 6j, 6q and 6r) are reported for the first time in the Chinese population. Genotypes 4, 5 and 7 were not detected. Mixed infections of the dominant subtypes were found in a small portion of samples (n=65, 0.203%), in the following combinations: 1b–2a, 1b–3b, 1b–6a, 3a–3b, 1b–3a and 2a–6a. No mixed infections with rare subtypes were found. Males, compared with females, showed higher HCV subtype diversity, a lower percentage of HCV1b and 2a and a higher percentage of rare subtypes and mixed infections. Our analyses revealed the comprehensive distribution patterns of HCV genotypes in the general population of mainland China. HCV genotypic patterns were differentially distributed on the basis of geography, sex and age.Emerging Microbes & Infections (2017) 6, e95; doi:10.1038/emi.2017.77; published online 1 November 201

Provenance and Implication of Carboniferous–Permian Detrital Zircons from the Upper Paleozoic, Southern Ordos Basin, China: Evidence from U-Pb Geochronology and Hf Isotopes

Carboniferous–Permian detrital zircons are recognized in the Upper Paleozoic of the whole Ordos Basin. Previous studies revealed that these Carboniferous–Permian zircons occurred in the Northern Ordos Basin mainly originated from the Yinshan Block. What has not been well documented until now is where this period’s zircons in the Southern Ordos Basin came from, and very little discussion about their provenance. To identify the provenance of the detrital zircons dating from ~350 to 260 Ma, five sandstone samples from the Shan 1 Member of Shanxi Formation and eight sandstone samples from the He 8 Member of Shihezi Formation were analyzed for detrital zircon U-Pb age dating and in situ Lu-Hf isotopic compositions. The results indicate that the two age clusters of 520–378 Ma and ~350–260 Ma in the Southern Ordos Basin most likely derived from the North Qinling Orogenic Belt–North Qilian Orogenic Belt and the North Qinling Orogenic Belt, respectively. Furthermore, we propose that the zircons aging ~320–260 Ma are representative of the important tectonothermal events occurred in the North Qinling Orogenic Belt during the Late Paleozoic

Bilirubin oxidation end products directly alter K+ channels important in the regulation of vascular tone

The exact etiology of delayed cerebral vasospasm following cerebral hemorrhage is not clear, but a family of compounds termed ‘bilirubin oxidation end products (BOXes)' derived from heme has been implicated. As proper regulation of vascular smooth muscle tone involves large-conductance Ca2+- and voltage-dependent Slo1 K+ (BK, maxiK, KCa1.1) channels, we examined whether BOXes altered functional properties of the channel. Electrophysiological measurements of Slo1 channels heterologously expressed in a human cell line and of native mouse BK channels in isolated cerebral myocytes showed that BOXes markedly diminished open probability. Biophysically, BOXes specifically stabilized the conformations of the channel with its ion conduction gate closed. The results of chemical amino-acid modifications and molecular mutagenesis together suggest that two specific lysine residues in the structural element linking the transmembrane ion-permeation domain to the carboxyl cytosolic domain of the Slo1 channel are critical in determining the sensitivity of the channel to BOXes. Inhibition of Slo1 BK channels by BOXes may contribute to the development of delayed cerebral vasospasm following brain hemorrhage

A New Product of Bilirubin Degradation by H2O2 and Its Formation in Activated Neutrophils and in an Inflammatory Mouse Model

Bilirubin (BR) is a tetrapyrrolic compound stemming from heme catabolism with diverse physiological functions. It can be oxidized by H2O2 to form several degradation products, some of which have been detected in vivo and may contribute to the pathogenesis of certain diseases. However, the oxidative degradation of BR is complex and the conditions that BR degradation occurs pathophysiologically remain obscure. Neutrophils are known to generate large amounts of reactive oxygen species, including H2O2, upon activation and they are mobilized to inflammatory sites; therefore, we hypothesized that activated neutrophils could cause BR degradation, which could occur at inflammatory sites. In the present study, we investigated BR degradation by H2O2 and identified hematinic acid (BHP1) and a new product BHP2, whose structure was characterized as 2,5-diformyl-4-methyl-1H-pyrrole-3-propanoic acid. An LC-MS/MS method for the quantitation of the two compounds was then established. Using the LC-MS/MS method, we observed the concentration-dependent formation of BHP1 and BHP2 in mouse neutrophils incubated with 10 and 30 μM of BR with the yields being 16 ± 3.2 and 31 ± 5.9 pmol/106 cells for BHP1, and 25 ± 4.4 and 71 ± 26 pmol/106 cells for BHP2, respectively. After adding phorbol 12-myristate 13-acetate, a neutrophil agonist, to 30 μM of BR-treated cells, the BHP1 yield increased to 43 ± 6.6 pmol/106 cells, whereas the BHP2 one decreased to 47 ± 9.2 pmol/106 cells. The two products were also detected in hemorrhagic skins of mice with dermal inflammation and hemorrhage at levels of 4.5 ± 1.9 and 0.18 ± 0.10 nmol/g tissue, respectively, which were significantly higher than those in the non-hemorrhagic skins. BHP2 was neurotoxic starting at 0.10 μM but BHP1 was not, as assessed using Caenorhabditis elegans as the animal model. Neutrophil-mediated BR degradation may be a universally pathophysiological process in inflammation and can be particularly important under pathological conditions concerning hemorrhage