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1. chinaXiv:201605.01806 [pdf]

Polymer-Ag Nanocomposites with Enhanced Antimicrobial Activity against Bacterial Infection

Mei, Lin; Lu, Zhentan; Zhang, Xinge; Li, Chaoxing; Jia, Yanxia; Jia, Yanxia
Subjects: Biology >> Biophysics

Herein, a nontoxic nanocomposite is synthesized by reduction of silver nitrate in the presence of a cationic polymer displaying strong antimicrobial activity against bacterial infection. These nanocomposites with a large concentration of positive charge promote their adsorption to bacterial membranes through electrostatic interaction. Moreover, the synthesized nanocomposites with polyvalent and synergistic antimicrobial effects can effectively kill both Gram-positive and Gram-negative bacteria without the emergence of bacterial resistance. Morphological changes obtained by transmission electron microscope observation show that these nanocomposites can cause leakage and chaos of intracellular contents. Analysis of the antimicrobial mechanism confirms that the lethal action of nanocomposites against the bacteria started with disruption of the bacterial membrane, subsequent cellular internalization of the nanopartides, and inhibition of intracellular enzymatic activity. This novel antimicrobial material with good cytocompatibility promotes healing of infected wounds in diabetic rats, and has a promising future in the treatment of other infectious diseases.

submitted time 2016-05-18 Hits3735Downloads1746 Comment 0

2. chinaXiv:201605.01804 [pdf]

An Iron-Containing Dodecameric Heptosyltransferase Family Modifies Bacterial Autotransporters in Pathogenesis

Lu, Qiuhe; Yao, Qing; Xu, Yue; Li, Lin; Li, Shan; Gao, Wenqing; Niu, Miao; Chen, She; Shao, Feng; Xu, Yue; Liu, Yanhua; Liu, Xiaoyun; Liu, Yanhua; Liu, Xiaoyun; Sharon, Michal; Ben-Nissan, Gili; Zamyatina, Alla; Shao, Feng; Shao, Feng
Subjects: Biology >> Biophysics

Autotransporters deliver virulence factors to the bacterial surface by translocating an effector passenger domain through a membrane-anchored barrel structure. Although passenger domains are diverse, those found in enteric bacteria autotransporters, including AIDA-I in diffusely adhering Escherichia coli (DAEC) and TibA in enterotoxigenic E. coli, are commonly glycosylated. We show that AIDA-I is heptosylated within the bacterial cytoplasm by autotransporter adhesin heptosyltransferase (AAH) and its paralogue AAH2. AIDA-I heptosylation determines DAEC adhesion to host cells. AAH/AAH2 define a bacterial autotransporter heptosyltransferase (BAHT) family that contains ferric ion and adopts a dodecamer assembly. Structural analyses of the heptosylated TibA passenger domain reveal 35 heptose conjugates forming patterned and solenoid-like arrays on the surface of a beta helix. Additionally, CARC, the AIDA-like autotransporter from Citrobacter rodentium, is essential for colonization in mice and requires heptosylation by its cognate BAHT. Our study establishes a bacterial glycosylation system that regulates virulence and is essential for pathogenesis.

submitted time 2016-05-18 Hits3577Downloads1637 Comment 0

3. chinaXiv:201605.01735 [pdf]

PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype

Duan, Shunlei; Yuan, Guohong; Ren, Ruotong; Xu, Xiuling; Fu, Lina; Li, Ying; Yang, Jiping; Zhang, Weiqi; Liu, Guang-Hui; Liu, Xiaomeng; Li, Jingyi; Tang, Fuchou; Ren, Ruotong; Bai, Ruijun; Liu, Guang-Hui; Ren, Ruotong; Bai, Ruijun; Qu, Jing; Zhang, Weizhou; Wu, Jun
Subjects: Biology >> Biophysics

PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficientmice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.

submitted time 2016-05-15 Hits4008Downloads1797 Comment 0

4. chinaXiv:201605.01733 [pdf]

Structural Basis of the Differential Function of the Two C. elegans Atg8 Homologs, LGG-1 and LGG-2, in Autophagy

Wu, Fan; Qi, Xin; Zhao, Hong-Yu; Wang, Zheng; Zhang, Hui; Ren, Jin-Qi; Feng, Wei; Hu, Jun-Jie; Zhang, Hong; Watanabe, Yasunori; Fujioka, Yuko; Noda, Nobuo N.; Guo, Xiang-Yang; Fang, Tian-Cheng; Wang, Peng; Shen, Yu-Xian
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

Multicellular organisms have multiple homologs of the yeast ATG8 gene, but the differential roles of these homologs in autophagy during development remain largely unknown. Here we investigated structure/function relationships in the two C. elegans Atg8 homologs, LGG-1 and LGG-2. lgg-1 is essential for degradation of protein aggregates, while lgg-2 has cargo-specific and developmental-stage-specific roles in aggregate degradation. Crystallography revealed that the N-terminal tails of LGG-1 and LGG-2 adopt the closed and open form, respectively. LGG-1 and LGG-2 interact differentially with autophagy substrates and Atg proteins, many of which carry a LIR motif. LGG-1 and LGG-2 have structurally distinct substrate binding pockets that prefer different residues in the interacting LIR motif, thus influencing binding specificity. Lipidated LGG-1 and LGG-2 possess distinct membrane tethering and fusion activities, which may result from the N-terminal differences. Our study reveals the differential function of two ATG8 homologs in autophagy during C. elegans development.

submitted time 2016-05-15 Hits10995Downloads1614 Comment 0

5. chinaXiv:201605.01529 [pdf]

A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Zhang, Weiqi; Wang, Ping; Zhou, Junzhi; Ren, Ruotong; Xu, Xiuling; Yuan, Tingting; Yang, Jiping; Li, Ying; Guan, Dee; Pan, Huize; Duan, Shunlei; Ding, Zhichao; Chen, Chang; Yang, Fuquan; Liu, Guang-Hui; Li, Jingyi; Liu, Xiaomeng; Tang, Fuchou; Suzuki, Keiichiro; Ocampo, Alejandro
Subjects: Biology >> Biophysics

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1 alpha and nuclear lamina-heterochromatin anchoring protein LAP2 beta. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

submitted time 2016-05-12 Hits2512Downloads1362 Comment 0

6. chinaXiv:201605.01528 [pdf]

Visible Thrombolysis Acceleration of a Nanomachine Powered by Light-Driving F0F1-ATPase Motor

Duan, Xiaoxia; Yue, Jiachang; Liu, Lifeng; Jiang, Weijian; Liu, Lifeng; Liu, Lifeng; Jiang, Weijian
Subjects: Biology >> Biophysics

We report on thrombolysis acceleration of a nanomachine powered by light-driving delta-subunit-free F0F1-ATPase motor. It is composed of a mechanical device, locating device, energy storage device, and propeller. The rotory delta-subunit-free F0F1-ATPase motor acts as a mechanical device, which was obtained by reconstructing an original chromatophore extracted from Rhodospirillum rubrum. We found that the bioactivity of the F0F1-ATPase motor improved greatly after reconstruction. The zeta potential of the nanomachine is about -23.4 mV. Cytotoxicity induced by the nanomachine was measured using cell counting kit (CCK)-8 assay. The A549 cells incubated with different fractional concentrations of the nanomachine within 48 h did not show obvious cytotoxicity. The locating device helps the nanomachine bind to the thrombi. Energy was easily stored by exposing the nanomachine to 600-nm-wavelength irradiation, which promoted activity of the motor. The rotation of the long propeller accelerated thrombolysis of a blood clot in vitro in the presence of urokinase (UK). This result was based on visual inspection and confirmed by a series of tests.

submitted time 2016-05-12 Hits1660Downloads964 Comment 0

7. chinaXiv:201605.01525 [pdf]

Three-dimensional super-resolution protein localization correlated with vitrified cellular context

Liu, Bei; Xue, Yanhong; Zhao, Wei; Chen, Yan; Fan, Chunyan; Gu, Lusheng; Zhang, Yongdeng; Zhang, Xiang; Sun, Lei; Huang, Xiaojun; Ding, Wei; Sun, Fei; Ji, Wei; Xu, Tao; Liu, Bei; Gu, Lusheng; Zhang, Yongdeng; Xu, Tao; Zhao, Wei; Chen, Yan
Subjects: Biology >> Biophysics

We demonstrate the use of cryogenic super-resolution correlative light and electron microscopy (csCLEM) to precisely determine the spatial relationship between proteins and their native cellular structures. Several fluorescent proteins (FPs) were found to be photoswitchable and emitted far more photons under our cryogenic imaging condition, resulting in higher localization precision which is comparable to ambient super-resolution imaging. Vitrified specimens were prepared by high pressure freezing and cryo-sectioning to maintain a near-native state with better fluorescence preservation. A 2-3-fold improvement of resolution over the recent reports was achieved due to the photon budget performance of screening out Dronpa and optimized imaging conditions, even with thin sections which is at a disadvantage when calculate the structure resolution from label density. We extended csCLEM to mammalian cells by introducing cryo-sectioning and observed good correlation of a mitochondrial protein with the mitochondrial outer membrane at nanometer resolution in three dimensions.

submitted time 2016-05-12 Hits2064Downloads1221 Comment 0

8. chinaXiv:201605.01520 [pdf]

Effect of UBXD8 Deletion on Lipid Metabolism in Skeletal Muscle Cells

Zou Fei; Diao Zhi-Qing; Xu Shi-Meng; Liu Ping-Sheng; Liang Bie; Zhang Hong-Chao; Wei Xuan
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

UBXD8 is a membrane protein that mediates endoplasmic reticulum-associated protein ubiquitination and degradation by interacting with p97NCP. Recently, lipid droplet proteomic studies show the lipid droplet localization of UBXD8. Besides, UBXD8 is also involved in triglyceride metabolism. However, the molecular mechanism by which UBXD8 regulates triglyceride metabolism is still obscure. Here we knocked out UBXD8 in mouse C2C12 myoblasts by CRISPR/Cas9. We selected 2 UBXD8 knockout (KO) clone cell lines from 26 possible KO clones. UBXD8 KO did not change the lipid droplet proteins expression pattern. However, UBXD8 KO led to the accumulation of neutral lipid. Furthermore, our data show that UBXD8 KO could alleviate palmitate-induced insulin resistance and rescue palmitate-induced apoptosis which was characterized by PARP splicing. In addition, the phenotype of palmitate-induced insulin resistance and apoptosis was reappeared after overexpressing UBXD8 in UBXD8 KO cells. These data suggested that UBXD8 plays an important role in lipid metabolism and its abnormity related insulin signal and apoptosis.

submitted time 2016-05-12 Hits11074Downloads2111 Comment 0

9. chinaXiv:201605.01519 [pdf]

Biochemical and structural characterization of a novel ubiquitin-conjugating enzyme E2 from Agrocybe aegeria reveals Ube2w family-specific properties

Qi, Chao; Li, De-Feng; Feng, Lei; Hou, Yanjie; Wang, Da-Cheng; Qi, Chao; Sun, Hui; Liu, Wei
Subjects: Biology >> Biophysics

Ubiquitination is a post-translational modification that is involved in myriad cellar regulation and disease pathways. The ubiquitin-conjugating enzyme (E2) is an important player in the ubiquitin transfer pathway. Although many E2 structures are available, not all E2 families have known structures, and three-dimensional structures from fungal organisms other than yeast are lacking. We report here the crystal structure of UbcA1, which is a novel ubiquitin-conjugating enzyme identified from the edible and medicinal mushroom Agrocybe aegerita and displays potential antitumor properties. The protein belongs to the Ube2w family and shows similar biochemical characteristics to human Ube2w, including monomer-dimer equilibrium in solution, alpha-NH2 ubiquitin-transfer activity and a mechanism to recognize backbone atoms of intrinsically disordered N-termini in substrates. Its structure displays a unique C-terminal conformation with an orientation of helix alpha 3 that is completely different from the reported E2 structures but similar to a recently reported NMR ensemble of Ube2w. A mutagenesis study on this novel enzyme revealed that an intact C-terminus is significant for protein dimerization and enzymatic activity. As the first crystallized full-length protein of this family, UbcA1 may supersede the truncated X-ray structure of Ube2w (PDB entry 2A7L) as the representative structure of the Ube2w family.

submitted time 2016-05-12 Hits2476Downloads1307 Comment 0

10. chinaXiv:201605.01518 [pdf]

Homoharringtonine induces apoptosis and inhibits STAT3 via IL-6/JAK1/STAT3 signal pathway in Gefitinib-resistant lung cancer cells

Cao, Wei; Zhang, Ran; Zhu, Xianbing; Mei, Lin; Chen, Hongbo; Zhang, Hongling; Huang, Laiqiang; Cao, Wei; Liu, Ying; Zhang, Ran; Wang, Teng; Zhu, Xianbing; Mei, Lin; Chen, Hongbo; Zhang, Hongling; Huang, Laiqiang; Cao, Wei; Liu, Ying; Zhang, Ran; Wang, Teng
Subjects: Biology >> Biophysics

Tyrosine kinase inhibitors (TKIs) are mostly used in non-small cell lung cancer (NSCLC) treatment. Unfortunately, treatment with Gefitinib for a period of time will result in drug resistance and cause treatment failure in clinic. Therefore, exploring novel compounds to overcome this resistance is urgently required. Here we investigated the antitumor effect of homoharringtonine (HHT), a natural compound extracted from Cephalotaxus harringtonia, on Gefitinib-resistant NSCLC cell lines in vitro and in vivo. NCI-H1975 cells with EGFR T790M mutation are more sensitive to HHT treatment compared with that of A549 cells with wild type EGFR. HHT inhibited cells growth, cell viability and colony formation, as well as induced cell apoptosis through mitochondria pathway. Furthermore, we explored the mechanism of HHT inhibition on NSCLC cells. Higher level of interleukin-6 (IL-6) existed in lung cancer patients and mutant EGFR and TGF beta signal requires the upregulation of IL-6 through the gp130/JAK pathway to overactive STAT3, an oncogenic protein which has been considered as a potential target for cancer therapy. HHT reversiblely inhibited IL-6-induced STAT3 Tyrosine 705 phosphorylation and reduced anti-apoptotic proteins expression. Gefitinib-resistant NSCLC xenograft tests also confirmed the antitumor effect of HHT in vivo. Consequently, HHT has the potential in Gefitinib-resistant NSCLC treatment.

submitted time 2016-05-12 Hits2366Downloads1241 Comment 0

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