Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells

BACKGROUND: The microtubule associated protein tau is the principle component of neurofibrillar tangles, which are a characteristic marker in the pathology of Alzheimer's disease; similar lesions are also observed after chronic alcohol abuse. Formaldehyde is a common environmental contaminant and also a metabolite of methanol. Although many studies have been done on methanol and formaldehyde intoxication, none of these address the contribution of protein misfolding to the pathological mechanism, in particular the effect of formaldehyde on protein conformation and polymerization. RESULTS: We found that unlike the typical globular protein BSA, the natively-unfolded structure of human neuronal tau was induced to misfold and aggregate in the presence of ~0.01% formaldehyde, leading to formation of amyloid-like deposits that appeared as densely staining granules by electron microscopy and atomic force microscopy, and bound the amyloid-specific dyes thioflavin T and Congo Red. The amyloid-like aggregates of tau were found to induce apoptosis in the neurotypic cell line SH-SY5Y and in rat hippocampal cells, as observed by Hoechst 33258 staining, assay of caspase-3 activity, and flow cytometry using Annexin V and Propidium Iodide staining. Further experiments showed that Congo Red specifically attenuated the caspase-3 activity induced by amyloid-like deposits of tau. CONCLUSION: The results suggest that low concentrations of formaldehyde can induce human tau protein to form neurotoxic aggregates, which could play a role in the induction of tauopathies

NOXA-Induced Alterations in the Bax/Smac Axis Enhance Sensitivity of Ovarian Cancer Cells to Cisplatin

Ovarian cancer is the most common cause of death from gynecologic malignancy. Deregulation of p53 and/or p73-associated apoptotic pathways contribute to the platinum-based resistance in ovarian cancer. NOXA, a pro-apoptotic BH3-only protein, is identified as a transcription target of p53 and/or p73. In this study, we found that genetic variants of Bcl-2 proteins exist among cisplatin-sensitive and -resistant ovarian cancer cells, and the responses of NOXA and Bax to cisplatin are regulated mainly by p53. We further evaluated the effect of NOXA on cisplatin. NOXA induced apoptosis and sensitized A2780s and SKOV3 cells to cisplatin in vitro and in vivo. The effects were mediated by elevated Bax expression, enhanced caspase activation, release of Cyt C and Smac into the cytosol. Furthermore, gene silencing of Bax or Smac significantly attenuated NOXA and/or cisplatin-induced apoptosis in chemosensitive A2780s cells, whereas overexpression of Bax or addition of Smac-N7 peptide significantly increased NOXA and/or cisplatin-induced apoptosis in chemoresistant SKOV3 cells. To our knowledge, these data suggest a new mechanism by which NOXA chemosensitized ovarian cancer cells to cisplatin by inducing alterations in the Bax/Smac axis. Taken together, our findings show that NOXA is potentially useful as a chemosensitizer in ovarian cancer therapy

Synthesis and applications of porous non-silica metal oxide submicrospheres

© 2016 Royal Society of Chemistry. Nowadays the development of submicroscale products of specific size and morphology that feature a high surface area to volume ratio, well-developed and accessible porosity for adsorbates and reactants, and are non-toxic, biocompatible, thermally stable and suitable as synergetic supports for precious metal catalysts is of great importance for many advanced applications. Complex porous non-silica metal oxide submicrospheres constitute an important class of materials that fulfill all these qualities and in addition, they are relatively easy to synthesize. This review presents a comprehensive appraisal of the methods used for the synthesis of a wide range of porous non-silica metal oxide particles of spherical morphology such as porous solid spheres, core-shell and yolk-shell particles as well as single-shell and multi-shell particles. In particular, hydrothermal and low temperature solution precipitation methods, which both include various structure developing strategies such as hard templating, soft templating, hydrolysis, or those taking advantage of Ostwald ripening and the Kirkendall effect, are reviewed. In addition, a critical assessment of the effects of different experimental parameters such as reaction time, reaction temperature, calcination, pH and the type of reactants and solvents on the structure of the final products is presented. Finally, the practical usefulness of complex porous non-silica metal oxide submicrospheres in sensing, catalysis, biomedical, environmental and energy-related applications is presented

Establishment of porcine and human expanded potential stem cells.

We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Enhanced Fenton Catalytic Efficiency of γ‑Cu–Al₂O₃ by σ‑Cu²⁺–Ligand Complexes from Aromatic Pollutant Degradation

Mesoporous Cu-doped γ-Al₂O₃ (γ-Cu–Al₂O₃) was prepared via an evaporation-induced self-assembly process, in which Cu^+/2+ was co-incorporated into mesoporous γ-Al₂O₃ by chemical bonding of Al–O–Cu. The catalyst was found to be highly effective and stable for the degradation and mineralization of aromatic pollutants, as demonstrated with bisphenol A, 2,4-dichlorophenoxyacetic acid, ibuprofen, diphenhydramine, and phenytoin in the presence of H₂O₂ under neutral pH conditions. In addition, the high utilization efficiency of H₂O₂ was maintained at approximately 90% prior to the disappearance of the initial aromatic pollutants. On the basis of all of the characterization results, the pollutant degradation processes predominantly occurred on the surface of the catalyst due to the formation of σ-Cu–ligand complexes between the phenolic OH group and the surface Cu. In the reaction system, in addition to the unselective oxidation by ^•OH, H₂O₂ directly attacked the σ-Cu²⁺-complexes aromatic ring with the phenolic OH group, which resulted in the formation of ^•OH and HO-adduct radicals that were oxidized to hydroxylation products by reduction of Cu²⁺ in the σ-Cu²⁺-complexes to Cu⁺. The process prevented Cu²⁺ from oxidizing H₂O₂ to form HO₂^•/O₂^•– or O₂, and enhanced the Cu⁺/Cu²⁺ cycle, the formation of ^•OH, and the utilization efficiency of H₂O₂. Therefore, an extraordinarily high degradation and mineralization of the aromatic pollutants was observed

Exposure history, post-exposure prophylaxis use, and clinical characteristics of human rabies cases in China, 2006-2012

Rabies is still a public health threat in China. Evaluating the exposure history, clinical characteristics, and post-exposure prophylaxis (PEP) of the cases could help in identifying approaches to reducing the number of these preventable deaths. We analysed data collected from 10,971 case-investigations conducted in China from 2006 to 2012. Most cases (n�=�7,947; 92.0%) were caused by animal bites; 5,800 (55.8%) and 2,974 (28.6%) exposures were from domestic and free-roaming dogs, respectively. Only 278 (4.8%) of these domestic dogs had previously received rabies vaccination. Among all cases, 5,927 (59.7%) cases had category III wounds, 1,187 (11.7%) cases initiated the rabies PEP vaccination and 234 (3.9%) cases with category III wounds received rabies immunoglobulin. In our adjusted logistic regression model, male cases (adjusted odds ratio [aOR]�=�1.25, 95% confidence interval [CI]: 1.09-1.44) and farmers (aOR�=�1.39, 95% CI: 1.10-1.77) and person older than 55 years (aOR�=�1.48, 95% CI: 1.01-2.17) were less likely than females and persons in other occupations or younger than 15 years to initiate PEP vaccination. The median incubation period was 66 days (interquartile range (IQR): 33-167 days). To reduce the number of human deaths due to rabies, rabies prevention campaigns targeting males and farmers and older people should be conducted. Increasing routine rabies vaccination among domestic dogs will be essential in the long term.</p

Robust Sub-nanomolar Library Preparation for High Throughput Next Generation Sequencing

Abstract Background Current library preparation protocols for Illumina HiSeq and MiSeq DNA sequencers require ≥2 nM initial library for subsequent loading of denatured cDNA onto flow cells. Such amounts are not always attainable from samples having a relatively low DNA or RNA input; or those for which a limited number of PCR amplification cycles is preferred (less PCR bias and/or more even coverage). A well-tested sub-nanomolar library preparation protocol for Illumina sequencers has however not been reported. The aim of this study is to provide a much needed working protocol for sub-nanomolar libraries to achieve outcomes as informative as those obtained with the higher library input (≥ 2 nM) recommended by Illumina’s protocols. Results Extensive studies were conducted to validate a robust sub-nanomolar (initial library of 100 pM) protocol using PhiX DNA (as a control), genomic DNA (Bordetella bronchiseptica and microbial mock community B for 16S rRNA gene sequencing), messenger RNA, microRNA, and other small noncoding RNA samples. The utility of our protocol was further explored for PhiX library concentrations as low as 25 pM, which generated only slightly fewer than 50% of the reads achieved under the standard Illumina protocol starting with > 2 nM. Conclusions A sub-nanomolar library preparation protocol (100 pM) could generate next generation sequencing (NGS) results as robust as the standard Illumina protocol. Following the sub-nanomolar protocol, libraries with initial concentrations as low as 25 pM could also be sequenced to yield satisfactory and reproducible sequencing results