The TET (ten-eleven translocation) family of α-ketoglutarate (α-KG)-dependent dioxygenases catalyzes the sequential oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), ...5-formylcytosine and 5-carboxylcytosine, leading to eventual DNA demethylation. The TET2 gene is a bona fide tumor suppressor frequently mutated in leukemia, and TET enzyme activity is inhibited in IDH1/2-mutated tumors by the oncometabolite 2-hydroxyglutarate, an antagonist of α-KG, linking 5mC oxidation to cancer development. We report here that the levels of 5hmC are dramatically reduced in human breast, liver, lung, pancreatic and prostate cancers when compared with the matched surrounding normal tissues. Associated with the 5hmC decrease is the substantial reduction of the expression of all three TET genes, revealing a possible mechanism for the reduced 5hmC in cancer cells. The decrease of 5hmC was also observed during tumor development in different genetically engineered mouse models. Together, our results identify 5hmC as a biomarker whose decrease is broadly and tightly associated with tumor development.
Carbon nanotube (CNT) thin-film transistor (TFT) is a promising candidate for flexible and wearable electronics. However, it usually suffers from low semiconducting tube purity, low device yield, and ...the mismatch between p- and n-type TFTs. Here, we report low-voltage and high-performance digital and analog CNT TFT circuits based on high-yield (19.9%) and ultrahigh purity (99.997%) polymer-sorted semiconducting CNTs. Using high-uniformity deposition and pseudo-CMOS design, we demonstrated CNT TFTs with good uniformity and high performance at low operation voltage of 3 V. We tested forty-four 2-µm channel 5-stage ring oscillators on the same flexible substrate (1,056 TFTs). All worked as expected with gate delays of 42.7 ± 13.1 ns. With these high-performance TFTs, we demonstrated 8-stage shift registers running at 50 kHz and the first tunable-gain amplifier with 1,000 gain at 20 kHz. These results show great potentials of using solution-processed CNT TFTs for large-scale flexible electronics.
The emergence of the H7N9 influenza virus in humans in Eastern China has raised concerns that a new influenza pandemic could occur. Here, we used a ferret model to evaluate the infectivity and ...transmissibility of A/Shanghai/2/2013 (SH2), a human H7N9 virus isolate. This virus replicated in the upper and lower respiratory tracts of the ferrets and was shed at high titers for 6 to 7 days, with ferrets showing relatively mild clinical signs. SH2 was efficiently transmitted between ferrets via direct contact, but less efficiently by airborne exposure. Pigs were productively infected by SH2 and shed virus for 6 days but were unable to transmit the virus to naïve pigs or ferrets. Under appropriate conditions, human-to-human transmission of the H7N9 virus may be possible.
Previous studies have established the link between aberrant microRNA (miRNA) expression and hypoxia in various neoplasms. However, how these hypoxia-related miRNAs modulate tumor progression is still ...unclear. Therefore, the patterns of miRNA in colorectal carcinoma cell lines in response to hypoxia or not were first screened and the hypoxia-induced repression of the miR-15-16 cluster was confirmed. Then, this repression was found to be associated with high tumor stage and poor prognosis in colorectal carcinoma and is shown to promote tumor angiogenesis and metastasis by the loss of restriction of its target gene, fibroblast growth factor-2 (FGF2). Moreover, the general and alterative promoters of the miR-15-16 host (deleted in lymphocytic leukemia 2, DLEU2) were mapped, and three c-Myc/Max binding sites in response to the hypoxia-induced repression of miR-15-16 were further identified. Finally, an enhanced stability of c-Myc/Max heterodimer promoted by increased hypoxia-inducible factor-2α (HIF-2α) was validated, and we also verified that the enhancement contributed to the hypoxia-induced repression of miR-15-16. In brief, the c-Myc-mediated transcriptional repression of miR-15-16 in hypoxia is induced by increased HIF-2α and promoted tumor angiogenesis and hematogenous metastasis by the further loss of post-transcriptional inhibition of FGF2. Our study provides a better understanding of the coping mechanisms in response to tumor hypoxia and may be helpful in developing an effective prognostic marker or treatment target against solid tumors.
Chronic unpredictable mild stress (CUMS) can not only lead to depression-like behavior but also change the composition of the gut microbiome. Regulating the gut microbiome can have an antidepressant ...effect, but the mechanism by which it improves depressive symptoms is not clear. Short-chain fatty acids (SCFAs) are small molecular compounds produced by the fermentation of non-digestible carbohydrates. SFCAs are ubiquitous in intestinal endocrine and immune cells, making them important mediators of gut microbiome-regulated body functions. The balance between the pro- and anti-inflammatory microglia plays an important role in the occurrence and treatment of depression caused by chronic stress. Non-absorbable antibiotic rifaximin can regulate the structure of the gut microbiome. We hypothesized that rifaximin protects against stress-induced inflammation and depression-like behaviors by regulating the abundance of fecal microbial metabolites and the microglial functions.
We administered 150 mg/kg rifaximin intragastrically to rats exposed to CUMS for 4 weeks and investigated the composition of the fecal microbiome, the content of short-chain fatty acids in the serum and brain, the functional profiles of microglia and hippocampal neurogenesis.
Our results show that rifaximin ameliorated depressive-like behavior induced by CUMS, as reflected by sucrose preference, the open field test and the Morris water maze. Rifaximin increased the relative abundance of Ruminococcaceae and Lachnospiraceae, which were significantly positively correlated with the high level of butyrate in the brain. Rifaximin increased the content of anti-inflammatory factors released by microglia, and prevented the neurogenic abnormalities caused by CUMS.
These results suggest that rifaximin can regulate the inflammatory function of microglia and play a protective role in pubertal neurodevelopment during CUMS by regulating the gut microbiome and short-chain fatty acids.
The issue of whether local magnetic moments can be formed by introducing adatoms into graphene is of intense research interest because it opens the window to fundamental studies of magnetism in ...graphene, as well as of its potential spintronics applications. To investigate this question, we measure, by exploiting the well-established weak localization physics, the phase coherence length L(Φ) in dilute fluorinated graphene. L(Φ) reveals an unusual saturation below ~10 K, which cannot be explained by nonmagnetic origins. The corresponding phase-breaking rate increases with decreasing carrier density and increases with increasing fluorine density. These results provide strong evidence for spin-flip scattering and point to the existence of an adatom-induced local magnetic moment in fluorinated graphene. Our results will stimulate further investigations of magnetism and spintronics applications in adatom-engineered graphene.
Genetic polymorphisms of CYP2C9 significantly influence the pharmacokinetics and pharmacodynamics of some drugs, which might result in adverse drug effects and therapeutic failure. Several studies ...have been performed on CYP2C9 genetic polymorphisms in Han Chinese populations. However, these studies only focused on two commonly investigated alleles, *2 and *3, in relatively small sample sizes. To scale up the gene-scanning region and determine relatively precise data on the genetic distribution pattern in Chinese populations, unrelated healthy Han Chinese volunteers from Zhejiang Province (n=1127) and Hebei (n=1000) Province were recruited as subjects for the direct sequencing of all exons of CYP2C9. As a result, 14 previously reported alleles were detected in this work, and 8 of these alleles (*14, *16, *19, *23, *27, *29, *33 and *34) were described for the first time in Chinese populations. In addition, 37 novel mutations were also detected, of which 22 variants were non-synonymous, and 21 new alleles, *36-*56, were designated by the Human CYP Allele Nomenclature Committee. In vitro functional analysis of these 22 novel CYP2C9 variants revealed that 17 mutations had a significant influence on the protein's catalytic activity. Our study provides the most accurate data on CYP2C9 polymorphisms in Han Chinese populations and detects the largest number of novel allelic variants existing to date. These new alleles will greatly enrich the current knowledge of naturally occurring CYP2C9 variants in Chinese populations.
The water-rich nature of the dentin bonding microenvironment, coupled with the stresses on the bonding interface, contributes to the hydrolytic degradation of the hybrid layer, resulting in a decline ...in bonding durability and, ultimately, restoration failure. Currently, the 3-step etch-and-rinse technique remains the gold standard for dentin bonding, and the bonding mechanism mainly involves a physical interaction with little chemical bonding. In this study, we have developed a siloxane-modified polyurethane monomer (SPU) with acrylate and siloxane modifications that chemically binds to both collagen and hydroxyapatite in dentin. Formulated as a bisphenol A-glycidyl methacrylate alternative, the SPU monomer-based adhesive was designed to improve dentin bonding quality and durability. Attenuated total reflection Fourier transform infrared spectroscopy, thermogravimetric analysis, X-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscope, and hydroxyproline release assays were performed on SPU-treated collagen, hydroxyapatite, and acid-etched dentin slices to dentin. The physicochemical properties of the configured SPU adhesives were profiled for polymerization behavior, water contact angle, and tensile strain and strength. The bonding effectiveness was assessed through micro-tensile strength, nano-leakage tests conducted on the bonded samples before and after thermal cycle aging. Finally, we further conducted in vivo and in vitro experiments to assess the biocompatibility of adhesives. The results showed that the siloxane groups of SPU monomer could covalently bind to dentin collagen and hydroxyapatite. The incorporation of SPU in the adhesive led to a significant increase in adhesive polymerization (P < 0.05) and tensile strain at break up to 134.11%. Furthermore, the SPU adhesive significantly improved dentin bond strength (P < 0.05), reduced interfacial nano-leakage (P < 0.05), and displayed good biocompatibility. In conclusion, the application of SPU, which achieves dual chemical bonding with dentin, can improve the quality of the hybrid layer, buffer the interfacial stresses, enhance the interfacial resistance to hydrolysis, and provide a feasible strategy to extend the service life of adhesive restorations.
Recently, intense interest has focused on the antioxidant properties of natural products. In particular, Chinese herbal medicines (CHM) have become hot topics for life science researchers since many ...are reported to possess cardioprotective compounds, many of which remain to be identified. Indeed, the exact mechanisms by which CHM work remain unknown. Although many of these herbal remedies are undoubtedly efficacious, few have been scientifically investigated for their active chemical constituents and biological activities. We have previously reported higher activities of antioxidant defence enzymes such as superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferases in the liver of rats treated with the herb Salvia miltiorrhiza in a model of acute myocardial infarction. Using well established in vitro antioxidant assays employing 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) and diphenyl-l-picrylhydrazyl (DPPH) we have shown that in addition to elevating endogenous antioxidant enzyme activity, Salvia miltiorrhiza and other CHM traditionally used for cardiovascular disorders (such as Rhizoma ligustici, Herba leonuri, Radix achyranthis bidentatae, and Camellia sinensis) contain potent antioxidant moieties in addition to their phenolic constituents. Furthermore, these novel non-phenolic components are effective inhibitors of oxidative reactions mediated by the inflammatory oxidants, peroxynitrite,hypochlorous acid and hydroxyl radical as well as iron-dependent lipid peroxidation. In this review, we discuss the various antioxidant properties of CHM in the context of their biochemical mechanisms.
The increase in the resistivity with decreasing temperature followed by a drop by more than one order of magnitude is observed on the metallic side near the zero-magnetic-field metal-insulator ...transition in a strongly interacting two-dimensional electron system in ultra-clean SiGe/Si/SiGe quantum wells. We find that the temperature Formula: see text, at which the resistivity exhibits a maximum, is close to the renormalized Fermi temperature. However, rather than increasing along with the Fermi temperature, the value Formula: see text decreases appreciably for spinless electrons in spin-polarizing (parallel) magnetic fields. The observed behaviour of Formula: see text cannot be described by existing theories. The results indicate the spin-related origin of the effect.
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