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The etiology of Parkinson's disease (PD) is complex and the mechanism is unclear. It has become a top priority to find common factors that induce and affect PD pathology. We explored the key role of hypoxia in promoting the pathological propagation of α-synuclein (α-syn) and the progression of PD.We performed PD modeling by conducting intracranial stereotaxic surgery in the unilateral striatum of mice. We then measured protein aggregation in vitro. The rotarod and pole tests were employed next to measure the damage of the phenotype. Pathological deposition and autophagy were also observed by immunofluorescence staining and protein levels measured by western blotting.We demonstrated that short-term hypoxia activated phosphorylated (p)-α-syn in mice. We confirmed that p-α-syn was more readily formed aggregates than α-syn in vitro. Furthermore, we found that hypoxia promoted the activation and propagation of endogenous α-syn, contributing to the earlier degeneration of dopaminergic neurons in the substantia nigra and the deposition of p-α-syn in our animal model. Finally, autophagy inhibition contributed to the above pathologies.Hypoxia was shown to accelerate the pathological progression and damage phenotype in PD model mice. The results provided a promising research target for determining common interventions for PD in the future.

Olfactory dysfunction, one of the earliest non-motor symptoms of Parkinson disease (PD), is accompanied by abnormal deposition of SNCA/α-synuclein in the olfactory bulb (OB). The macroautophagy/autophagy-lysosome pathway (ALP) plays an important role in degrading pathological SNCA and modulating this pathway may be a promising treatment strategy. P2RX4 (purinergic receptor P2X, ligand-gated ion channel 4), a member of the purinergic receptor X family, is a key molecule regulating ALP. Piperine (PIP) is a Chinese medicine with anti-inflammatory and anti-oxidant effects. The present study investigated the neuroprotective effects of PIP on SNCA overexpression-induced PD cell and mouse models. We found that PIP oral administration (25, 50 and 100 mg/kg) for 6 weeks attenuated olfactory deficits and delayed motor deficits in Thy 1-SNCA transgenic mice overexpressing human SNCA. This was accompanied by a degradation of pathological SNCA in OB. In addition, PIP improved cell viability and promoted degradation of human SNCA in SK-N-SH cells. These protective effects were exerted via autophagy flux promotion by enhancing autophagosome-lysosome membrane fusion. Furthermore, tandem mass tag proteomics analyses showed that P2RX4 plays an important role in PIP treatment-induced activation of autophagy flux. These findings demonstrate that PIP exerts neuroprotective effects in PD models via promotion of autophagy flux and may be an effective agent for PD treatment.Abbreviations: 6-OHDA, 6-hydroxydopamine; ALP, autophagy-lysosome pathway; BafA1, bafilomycin A1; CoQ10, coenzyme Q10; DMSO: dimethyl sulfoxide; HPLC, high-performance liquid chromatography; IVE, ivermectin; LDH, lactate dehydrogenase; MAP1LC3/LC3-II, lipid-conjugated microtubule-associated protein 1 light chain 3; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mRFP-GFP, tandem monomeric red fluorescent protein-green fluorescent protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; OB, olfactory bulb; P2RX4, purinergic receptor P2X, ligand-gated ion channel 4; PD, Parkinson disease; PBS: phosphate-buffered saline; PI: propidium iodide; PIP, piperine; PLG, piperlongumine; p-SNCA, SNCA phosphorylated at Ser129; Rap, rapamycin; RT-PCR: quantitative real-time PCR; SNARE, soluble N-ethylmaleimide-sensitive factor-attachment protein receptor; SNCA/α-synuclein, synuclein, alpha; STX17, syntaxin17; TG, transgenic; TH, tyrosine hydroxylase; UPS, ubiquitin-proteasome system; WT, wild-type.

Olfactory dysfunction, one of the earliest non-motor symptoms of Parkinson disease (PD), is accompanied by abnormal deposition of SNCA/α-synuclein in the olfactory bulb (OB). The macroautophagy/autophagy-lysosome pathway (ALP) plays an important role in degrading pathological SNCA and modulating this pathway may be a promising treatment strategy. P2RX4 (purinergic receptor P2X, ligand-gated ion channel 4), a member of the purinergic receptor X family, is a key molecule regulating ALP. Piperine (PIP) is a Chinese medicine with anti-inflammatory and anti-oxidant effects. The present study investigated the neuroprotective effects of PIP on SNCA overexpression-induced PD cell and mouse models. We found that PIP oral administration (25, 50 and 100 mg/kg) for 6 weeks attenuated olfactory deficits and delayed motor deficits in Thy 1

In this research, a water-soluble ultraviolet (UV) absorber (PEI-H) was synthesized by grafting polyethyleneimine (PEI) with 2,4-dihydroxybenzophenone (UV-0). UV-resistant and superhydrophobic coating was fabricated upon cotton fabric by sequentially depositing PEI-H, silica sol (SiO2) and hexadecyltrimethoxysilane via layer-by-layer assembly and dip-coating. The surface morphology, chemical composition, water-repellence, UV resistance property, durability against washing and abrasion test, air permeability as well as safety of the obtained fabric were investigated. It found that the obtained cotton fabric exhibited superior UV-resistant property with UPF value more than 800 which was attributed to the synergistic effect between organic UV absorber (UV-0) and inorganic UV shielding agent (SiO2). Meanwhile, it also possessed superhydrophobicity, self-cleaning and anti-fouling properties with water contact angle of 154°. In addition, the multifunctional fabric after 20 washing times or 300 abrasion times remained excellent hydrophobicity and the corresponding UPF values were still 400+, showing an outstanding durability. Importantly, the obtained fabric was absolutely safe for human body.

A hybrid UV absorber (SiO2-H) was successfully synthesized by functionalizing nanosilica (SiO2) with 2,4-dihydroxybenzophenone and then was introduced onto the surface of cotton fabric by sequentially depositing in poly (diallyl dimethyl ammonium chloride) (PDDA) aqueous solution and SiO2-H suspension via layer-by-layer assembly method. The SiO2-H particles imparted excellent ultraviolet (UV) resistance property to the cotton fabric, while forming nano- and micro structure on the surface of cotton fabric, making the fabric superhydrophobic after the modification with hexadecyltrimethoxy silane (HDTMS). The surface morphology, wetting behavior, UV resistance and physical properties of cotton fabrics were studied. According to the results, the modified cotton fabric not only showed strong UV-resistant ability with Ultraviolet Protection Factor (UPF) value as high as 500, but also displayed superhydrophobicty with WCA of 153 ± 1°. Moreover, the durability of multifunctional surface was examined by laundering and abrasion tests. The modified fabrics still maintained hydrophobic property and excellent UV resistance after 300 abrasion or 20 laundering cycles, demonstrating outstanding durability.

In this paper, superhydrophobic and antibacterial fabric is fabricated via the sequential deposition of polydopamine (PDA), quaternized nanosilica particles and hexadecyltrimethoxy silane (HDTMS). The epoxypropyl dodecyl dimethyl ammonium chloride (EPDDAC)-modified silica particles simultaneously contributed to the antibacterial activity and generated a rough surface on the textiles. According to the results, the obtained fabric showed excellent superhydrophobicity, good washability, and high antibacterial activity against Escherichia coli and Staphylococcus aureus.

Shelterin, a protective complex at telomeres, plays essential roles in cancer. In addition to maintain telomere integrity, shelterin functions in various survival pathways. However, the detailed mechanisms of shelterin regulation in cancer remain elusive. Here, we perform a comprehensive analysis of shelterin in 9125 tumor samples across 33 cancer types using multi-omic data from The Cancer Genome Atlas, and validate some findings in Chinese Glioma Genome Atlas and cancer cell lines from Cancer Cell Line Encyclopedia. In the genomic landscape, we identify the amplification of TRF1 and POT1, co-amplification/deletion of TRF2–RAP1–TPP1 as the dominant alteration events. Clustering analysis based on shelterin expression reveals three cancer clusters with different degree of genome instability. To measure overall shelterin activity in cancer, we derive a shelterin score based on shelterin expression. Pathway analysis shows shelterin is positively correlated with E2F targets, while is negatively correlated with p53 pathway. Importantly, shelterin links to tumor immunity and predicts response to PD-1 blockade immune therapy. In-depth miRNA analysis reveals a miRNA–shelterin interaction network, with p53 regulated miRNAs targeting multiple shelterin components. We also identify a significant amount of lncRNAs regulating shelterin expression. In addition, we find shelterin expression could be used to predict patient survival in 24 cancer types. Finally, by mining the connective map database, we discover a number of potential drugs that might target shelterin. In summary, this study provides broad molecular signatures for further functional and therapeutic studies of shelterin, and also represents a systemic approach to characterize key protein complex in cancer.

// Zhengfu He 1 , Xing Hu 2 , Weijin Liu 2 , Adrienne Dorrance 3 , Ramiro Garzon 3 , Peter J. Houghton 4 and Changxian Shen 3 1 Department of Thoracic Surgery, Sir Run Run Shaw Hospital, College of Medicine Zhejiang University, Hangzhou, Zhejiang Province, China 2 College of Biology and Food Engineering, Huaihua University, Huaihua, Hunan Province, China 3 Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA 4 The Greehey Children’s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA Correspondence to: Changxian Shen, email: shen.637@osu.edu Keywords: mammalian target of rapamycin (mTOR), deoxyribonucleotides (dNTPs), ribonucleotide reductase (RNR), p53, nutlin-3 Received: September 27, 2016 Accepted: April 11, 2017 Published: April 26, 2017 ABSTRACT Balanced deoxyribonucleotides pools are essential for cell survival and genome stability. Ribonucleotide reductase is the rate-limiting enzyme for the production of deoxyribonucleotides. We report here that p53 suppresses ribonucleotide reductase subunit 1 (RRM1) and 2 (RRM2) via inhibiting mammalian target of rapamycin complex 1 (mTORC1). In vitro , cancer cell lines and mouse embryonic fibroblast cells were treated with different concentrations of pharmacological inhibitors for different times. In vivo , rhabdomyosarcoma Rh30 cell tumor-bearing mice were treated with rapamycin or AZD8055. Protein levels and phosphorylation status were assessed by immunoblotting and mRNA levels were determined by real time RT-PCR. Pharmacological inhibition of mTORC1 with rapamycin, mTOR kinase with AZD8055 or protein kinase B with MK2206 resulted in decrease of RRM1 and RRM2 in Rh30 cells both in vitro and in mouse tumor xenografts. Moreover, eukaryotic translational initiation factor 4E-binding proteins 1 and 2 double knockout mouse embryonic fibroblast cells demonstrated an elevation of RRM1 and RRM2. Furthermore, down-regulation of mTOR-protein kinase B signaling or cyclin dependent kinase 4 led to decrease of RRM1 and RRM2 mRNAs. In addition, TP53 mutant cancer cells had elevation of RRM1 and RRM2, which was reduced by rapamycin. Importantly, human double minute 2 inhibitor nutlin-3 decreased RRM1 and RRM2 in TP53 wild type rhabdomyosarcoma Rh18 but not in TP53 mutated Rh30 cells. Our data demonstrated that mTOR enhances the cap-dependent protein translation and gene transcription of RRM1 and RRM2. Our findings might provide an additional mechanism by which p53 maintains genome stability.

PET non-woven fabrics and poly (ethylene glycol) dimethacrylate were added to strengthen tensile strength and chemical stability of PAN-MA separators. Besides, PET non-woven fabrics also act as the skeleton to sustain separators at high temperatures, and they can work at even 150 °C. Porous structures of PAN-MA separators are formed by phase inversion, and strengthened by PEGDMA which cross-link at high temperature without adding initiator. Effects of PEGDMA on tensile strength, porosity and ionic conductivity were studied and performances of separators modified by two kinds of molecular weight of PEGDMA were compared. As a result, a battery separator with ionic conductivity of 2.14 mS/cm, tensile strength of 26.7 MPa, porosity of 36.6% was obtained.

Polyethylene/paraffin oil blend sheets with different molecular weights of polyethylene were prepared by thermally induced phase separation. Isothermal and non-isothermal crystallization behaviors of blend sheets were investigated by differential scanning calorimetry (DSC). Isothermal DSC curves were analyzed by Avrami equation, whereas non-isothermal DSC curves were analyzed by Jeziorny method and Mo method. Effective activation energy (ΔE) of isothermal and non-isothermal crystallization was calculated by Friedman method. Under isothermal condition, value of n in Avrami equation hovered at 2.1, and lgZ increased with the decrease of crystallization temperature. lgZ and ΔE of blend sheets with a larger molecular weight of polyethylene was smaller than that of blend sheets with smaller molecular weight. Under non-isothermal condition, value of n obtained by Jeziorny method hovered at 2.4, close to n of isothermal condition. lgZ c increased with the increase of cooling rate and decrease of molecular weight of polyethylene. ΔE of different blend sheets were close to each other. Crystal structures of blend sheets formed under non-isothermal condition were analyzed by X-ray diffraction (XRD) analysis. XRD analysis showed that molecular weight of polyethylene and cooling rate had slight influence on crystal structure and crystallinity of polyethylene/paraffin oil blend sheet.

Oncogenic transformation leads to dysregulated cell proliferation, nutrient deficiency, and hypoxia resulting in metabolic stress and increased DNA damage. In normal cells, such metabolic stress leads to inhibition of signaling through the mammalian Target of Rapamycin Complex 1 (mTORC1), reduction of protein translation, cell cycle arrest, and conservation of energy. In contrast, negative regulation of mTORC1 signaling by DNA damage is abrogated in many cancer cells, thus mTORC1 signaling remains active under microenvironmental conditions that potentially promote endogenous DNA damage. Here we report that mTORC1 signaling suppresses endogenous DNA damage and replication stress. Pharmacological inhibition of mTOR signaling resulted in phosphorylation of H2AX concomitant with the decrease of CHK1 levels both in cell culture and mouse rhadomyosarcoma xenografts. Further results demonstrated that mTORC1-S6K1 signaling controls transcription of CHK1 via Rb-E2F by upregulating cyclin D and E. Consistent with these results, downregulation of CHK1 by inhibition of mTOR kinase resulted in defects in the slow S phase progression following DNA damage. These results indicate that, under stressful conditions, maintained mTORC1 signaling in cancer cells promotes survival by suppressing endogenous DNA damage, and may control cell fate through the regulation of CHK1.

In this article, we report a novel method for the design and development of a polyaniline (PANI)/poly(ethylene terephthalate) (PET) conducting composite fabric based on in situ polymerization. With the aim of improving fabric–PANI adhesion and good fastness to washing, we took some special steps: the alkali reduction pretreatment of the PET fabric before the polymerization of aniline onto the fabric, the introduction of squeezing the laboratory padder on the fabric to push the reagent into the inner part of the fabric, and short immersion time of the aniline-absorbed fabric in oxidant solution. Factors affecting the conductivity and fastness to washing, including the alkali reduction percentage, the wet pickup of the reagent-absorbed fabric, the immersion time in oxidant solution, and the reaction time, are discussed. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 5775–5780, 2006

Polyaniline fibers were prepared with a continuous forming-drawn processing routine that better met practical production requirements. The continuous forming drawing of the fibers was conducted successfully with the following methods. A reducing agent was added to a polymer solution during the dissolution of a polyaniline emeraldine base in N-methyl-2-pyrrolidinone (NMP). After the entire wet-spinning process was finished, the fibers were reoxidized and doped to obtain electric conductivity. The as-spun fibers were predrawn at a low drawing ratio in a warm water bath before a plasticization drawing process on a hot plate. After the fibers were predrawn, some solvent was still kept in the fibers and used as a plasticizer of the fibers so that the plasticization drawing process would be performed successfully. The spinning conditions that affected the mechanical properties and conductivity of the fibers were the content of NMP in the coagulation bath, the coagulation-bath temperature, the warm-water-bath temperature, the predrawing ratio, the hot-plate temperature, the plasticization drawing ratio, and the reoxidation and protonation treatment time. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 93: 956–960, 2004

Survivin is an attractive target for anti-cancer drug development; however targeting it by small molecules or antibodies is difficult, as survivin is neither a kinase nor a cell surface protein. Protein transduction domain (PTD)-mediated macromolecular therapeutics provides an alternative avenue for targeting survivin.A plasmid expressing a dominant-negative survivin-T34A fused with the immunodeficiency virus protein transduction domain TAT was constructed. The fusion protein was expressed and purified from E. coli. The inhibition of proliferation and induction of apoptosis was tested in human lung carcinoma cell line A549 by directly adding survivin-T34A to the cell culture medium.Recombinant survivin-T34A was efficiently expressed and purified by affinity chromatography. It induced cell apoptosis as demonstrated by induction of caspase 3 activation and higher percentage of Annexin V staining, and inhibited cell proliferation as determined by cell number counting.This functional recombinant protein is promising for development of macromolecular therapeutics targeting survivin.

The PTEN (phosphatase and tensin homolog deleted on chromosome ten) tumor suppressor gene is mutated in a wide range of malignancies and recent studies have demonstrated that PTEN prevents tumorigenesis through multiple mechanisms. PTEN functions as a plasma-membrane lipid phosphatase that antagonizes the PI3K (phosphoinositide 3 kinase)-AKT pathway. PTEN physically and genetically interacts with the central genome guardian p53. PTEN also associates with the centromeric protein CENP-C to maintain centromere integrity and suppresses chromosomal instability from DNA double-strand breaks (DSBs) through transcriptional regulation of Rad51 (radiosensitive yeast mutant 51). Moreover PTEN controls the growth and proliferation of haematopoietic stem cells (HSC) and restrains cells from leukemia in an mTOR (mammalian target of rapamycin) dependent manner. Thus, restoring PTEN functions in cancer cells directly or indirectly holds great promise for cancer therapy.