Sulforaphane Protects the Liver against CdSe Quantum Dot-Induced Cytotoxicity.

The potential cytotoxicity of cadmium selenide (CdSe) quantum dots (QDs) presents a barrier to their use in biomedical imaging or as diagnostic and therapeutic agents. Sulforaphane (SFN) is a chemoprotective compound derived from cruciferous vegetables which can up-regulate antioxidant enzymes and induce apoptosis and autophagy. This study reports the effects of SFN on CdSe QD-induced cytotoxicity in immortalised human hepatocytes and in the livers of mice. CdSe QDs induced dose-dependent cell death in hepatocytes with an IC50 = 20.4 μM. Pre-treatment with SFN (5 μM) increased cell viability in response to CdSe QDs (20 μM) from 49.5 to 89.3%. SFN induced a pro-oxidant effect characterized by depletion of intracellular reduced glutathione during short term exposure (3-6 h), followed by up-regulation of antioxidant enzymes and glutathione levels at 24 h. SFN also caused Nrf2 translocation into the nucleus, up-regulation of antioxidant enzymes and autophagy. siRNA knockdown of Nrf2 suggests that the Nrf2 pathway plays a role in the protection against CdSe QD-induced cell death. Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death. Moreover, the role of autophagy in SFN protection against CdSe QD-induced cell death was confirmed using mouse embryonic fibroblasts lacking ATG5. CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment. In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy

High capacity silicon anodes enabled by MXene viscous aqueous ink

The ever-increasing demands for advanced lithium-ion batteries have greatly stimulated the quest for robust electrodes with a high areal capacity. Producing thick electrodes from a high-performance active material would maximize this parameter. However, above a critical thickness, solution-processed films typically encounter electrical/mechanical problems, limiting the achievable areal capacity and rate performance as a result. Herein, we show that two-dimensional titanium carbide or carbonitride nanosheets, known as MXenes, can be used as a conductive binder for silicon electrodes produced by a simple and scalable slurry-casting technique without the need of any other additives. The nanosheets form a continuous metallic network, enable fast charge transport and provide good mechanical reinforcement for the thick electrode (up to 450 µm). Consequently, very high areal capacity anodes (up to 23.3 mAh cm−2) have been demonstrated

Cellular, molecular and functional characterisation of YAC transgenic mouse models of Friedreich Ataxia

Copyright © 2014 Anjomani Virmouni et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Background - Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder, caused by a GAA repeat expansion mutation within intron 1 of the FXN gene. We have previously established and performed preliminary characterisation of several human FXN yeast artificial chromosome (YAC) transgenic FRDA mouse models containing GAA repeat expansions, Y47R (9 GAA repeats), YG8R (90 and 190 GAA repeats) and YG22R (190 GAA repeats). Methodology/Principal Findings - We now report extended cellular, molecular and functional characterisation of these FXN YAC transgenic mouse models. FXN transgene copy number analysis of the FRDA mice demonstrated that the YG22R and Y47R lines each have a single copy of the FXN transgene while the YG8R line has two copies. Single integration sites of all transgenes were confirmed by fluorescence in situ hybridisation (FISH) analysis of metaphase and interphase chromosomes. We identified significant functional deficits, together with a degree of glucose intolerance and insulin hypersensitivity, in YG8R and YG22R FRDA mice compared to Y47R and wild-type control mice. We also confirmed increased somatic GAA repeat instability in the cerebellum and brain of YG22R and YG8R mice, together with significantly reduced levels of FXN mRNA and protein in the brain and liver of YG8R and YG22R compared to Y47R. Conclusions/Significance - Together these studies provide a detailed characterisation of our GAA repeat expansion-based YAC transgenic FRDA mouse models that will help investigations of FRDA disease mechanisms and therapy.European Union, Ataxia UK and FARA

Understanding the dynamics of Toll-like Receptor 5 response to flagellin and its regulation by estradiol

© 2017 The Author(s). Toll-like receptors (TLRs) are major players of the innate immune system. Once activated, they trigger a signalling cascade that leads to NF-ΰ B translocation from the cytoplasm to the nucleus. Single cell analysis shows that NF-ΰ B signalling dynamics are a critical determinant of transcriptional regulation. Moreover, the outcome of innate immune response is also affected by the cross-talk between TLRs and estrogen signalling. Here, we characterized the dynamics of TLR5 signalling, responsible for the recognition of flagellated bacteria, and those changes induced by estradiol in its signalling at the single cell level. TLR5 activation in MCF7 cells induced a single and sustained NF-k B translocation into the nucleus that resulted in high NF-k B transcription activity. The overall magnitude of NF-k B transcription activity was not influenced by the duration of the stimulus. No significant changes are observed in the dynamics of NF-k B translocation to the nucleus when MCF7 cells are incubated with estradiol. However, estradiol significantly decreased NF-k B transcriptional activity while increasing TLR5-mediated AP-1 transcription. The effect of estradiol on transcriptional activity was dependent on the estrogen receptor activated. This fine tuning seems to occur mainly in the nucleus at the transcription level rather than affecting the translocation of the NF-k B transcription factor

WTH3 is a direct target of the p53 protein

Previous results showed that overexpression of the WTH3 gene in multidrug resistance (MDR) cells reduced MDR1 gene expression and converted their resistance to sensitivity to various anticancer drugs. The WTH3 gene promoter was found to be differentially regulated in paired MDR vs non-MDR MCF7 cells owing to epigenetic modifications and transcription factor modulations. To understand further the mechanisms that govern WTH3's differential expression, we uncovered a p53-binding site in its promoter, which indicated that WTH3 could be regulated by the p53 gene. This hypothesis was then tested by different strategies. The resulting data revealed that (1) the WTH3 promoter was upregulated by the p53 transgene in diverse host cells; (2) there was a correlation between WTH3 expression levels and p53 gene status in a cell line panel; (3) a WTH3 promoter region was directly targeted by the p53 protein in vitro and in vivo. In addition, overexpression of the WTH3 gene promoted the apoptotic phenotype in host cells. On the basis of these findings, we believe that the negative role played by the WTH3 gene in MDR development is through its proapoptotic potential that is regulated by multiple mechanisms at the transcription level, and one of these mechanisms is linked to the p53 gene

Association between amebic liver abscess and Human Immunodeficiency Virus infection in Taiwanese subjects

<p>Abstract</p> <p>Purpose</p> <p>Invasive amebiasis is an emerging parasitic disorder in Taiwan, especially in patients diagnosed with human immunodeficiency virus (HIV) infection. Thirty-three Taiwanese subjects with amebic liver abscess (ALA) were examined and a possible correlation between ALA and HIV infection was investigated.</p> <p>Results</p> <p>Among ALA patients, the proportion of HIV-positive individuals increased during the study period. ALA was the first major clinical presentation in 54% of HIV patients with ALA. Overall, 58% (14/24) of HIV-infected patients had a CD4+ count > 200 cells/μL and 82.1% (23/28) had no concurrent opportunistic infection or other evidence of HIV infection. There was no marked difference in clinical characteristics between HIV-positive and HIV-negative ALA patients except the level of leukocytosis.</p> <p>Conclusion</p> <p>While the clinical characteristics described herein cannot be used to determine whether ALA patients have HIV infection, routine HIV testing is recommended in patients with ALA, even in the absence of HIV symptoms.</p

Methylation of WTH3, a possible drug resistant gene, inhibits p53 regulated expression

<p>Abstract</p> <p>Background</p> <p>Previous results showed that over-expression of the <it>WTH3 </it>gene in MDR cells reduced <it>MDR1 </it>gene expression and converted their resistance to sensitivity to various anticancer drugs. In addition, the <it>WTH3 </it>gene promoter was hypermethylated in the MCF7/AdrR cell line and primary drug resistant breast cancer epithelial cells. <it>WTH3 </it>was also found to be directly targeted and up regulated by the <it>p53 </it>gene. Furthermore, over expression of the <it>WTH3 </it>gene promoted the apoptotic phenotype in various host cells.</p> <p>Methods</p> <p>To further confirm <it>WTH3</it>'s drug resistant related characteristics, we recently employed the small hairpin RNA (shRNA) strategy to knockdown its expression in HEK293 cells. In addition, since the <it>WTH3 </it>promoter's p53-binding site was located in a CpG island that was targeted by methylation, we were interested in testing the possible effect this epigenetic modification had on the <it>p53 </it>transcription factor relative to <it>WTH3 </it>expression. To do so, the <it>in vitro </it>methylation method was utilized to examine the <it>p53 </it>transgene's influence on either the methylated or non-methylated <it>WTH3 </it>promoter.</p> <p>Results</p> <p>The results generated from the gene knockdown strategy showed that reduction of <it>WTH3 </it>expression increased <it>MDR1 </it>expression and elevated resistance to Doxorubicin as compared to the original control cells. Data produced from the methylation studies demonstrated that DNA methylation adversely affected the positive impact of <it>p53 </it>on <it>WTH3 </it>promoter activity.</p> <p>Conclusion</p> <p>Taken together, our studies provided further evidence that <it>WTH3 </it>played an important role in MDR development and revealed one of its transcription regulatory mechanisms, DNA methylation, which antagonized <it>p53</it>'s positive impact on <it>WTH3 </it>expression.</p

Visualizing size-dependent deformation mechanism transition in Sn

Displacive deformation via dislocation slip and deformation twinning usually plays a dominant role in the plasticity of crystalline solids at room temperature. Here we report in situ quantitative transmission electron microscope deformation tests of single crystal Sn samples. We found that when the sample size was reduced from 450 nm down to 130 nm, diffusional deformation replaces displacive plasticity as the dominant deformation mechanism at room temperature. At the same time, the strength-size relationship changed from “smaller is stronger” to “smaller is much weaker”. The effective surface diffusivity calculated based on our experimental data matches well with that reported in literature for boundary diffusion. The observed change in the deformation mode arises from the sample size-dependent competition between the Hall-Petch-like strengthening of displacive processes and Coble diffusion softening processes. Our findings have important implications for the stability and reliability of nanoscale devices such as metallic nanogaps.National Science Foundation (U.S.) (CMMI-0728069)National Science Foundation (U.S.) (DMR-1008104)National Science Foundation (U.S.) (DMR-1120901)United States. Air Force Office of Scientific Research (FA9550-08-1-0325

Acupuncture in the treatment of rheumatoid arthritis: a double-blind controlled pilot study

<p>Abstract</p> <p>Background</p> <p>In planning a randomized controlled trial of acupuncture, we conducted a pilot study using validated outcome measures to assess the feasibility of the protocol, and to obtain preliminary data on efficacy and tolerability of 3 different forms of acupuncture treatment as an adjunct for the treatment of chronic pain in patients with Rheumatoid arthritis (RA).</p> <p>Methods</p> <p>The study employs a randomized, prospective, double-blind, placebo-controlled trial to evaluate the effect of electroacupuncture (EA), traditional Chinese acupuncture (TCA) and sham acupuncture (Sham) in patients with RA. All patients received 20 sessions over a period of 10 weeks. Six acupuncture points were chosen. Primary outcome is the changes in the pain score. Secondary outcomes included the changes in the ACR core disease measures, DAS 28 score and the number of patients who achieved ACR 20 at week 10.</p> <p>Results</p> <p>From 80 eligible patients, 36 patients with mean age of 58 ± 10 years and disease duration of 9.3 ± 6.4 years were recruited. Twelve patients were randomized to each group. Twelve, 10 and 7 patients from the EA, TCA and Sham group respectively completed the study at 20 weeks (p < 0.03); all except one of the premature dropouts were due to lack of efficacy. At week 10, the pain score remained unchanged in all 3 groups. The number of tender joints was significantly reduced for the EA and TCA groups. Physician's global score was significantly reduced for the EA group and patient's global score was significantly reduced for the TCA group. All the outcomes except patient's global score remained unchanged in the Sham group.</p> <p>Conclusion</p> <p>This pilot study has allowed a number of recommendations to be made to facilitate the design of a large-scale trial, which in turn will help to clarify the existing evidence base on acupuncture for RA.</p> <p>Trial registration</p> <p>ClinicalTrials.gov NCT00404443</p