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1. chinaXiv:201605.01740 [pdf]

Aberrantly upregulated TRAP1 is required for tumorigenesis of breast cancer

Zhang, Bo; Wei, Peng; Hao, Junfeng; Zhao, Lijing; Zhang, Fenglin; Wei, Taotao; Wang, Jing; Huang, Zhen; Wei, Peng; Liu, Ying; Tu, Yaping
Subjects: Biology >> Biophysics >> Oncology

Tumor necrosis factor receptor-associated protein 1 (TRAP1) is abnormally expressed in many cancers. In this study, we showed that TRAP1 is aberrantly upregulated in breast tumors compared to control tissues. TRAP1 knockdown downregulates mitochondrial aerobic respiratory, sensitizes cells to lethal stimuli, and inhibited tumor growth in MDA-MB-231 and MCF-7 breast cancer cells in vivo. TRAP1 overexpression, however, enhances the capacity to cope with stress conditions. These evidences suggested that TRAP1 is required for tumorigenesis. We also found that TRAP1 regulates the mitochondrial morphology. Relatively lower TRAP1 levels are associated with the rod-shaped mitochondrial phenotype in invasive and metastatic MDA-MB-231 breast cancer cells; on the contrary, higher TRAP1 levels are associated with the tubular network-shaped mitochondrial phenotype in non-invasive MCF-7 cells. Interestingly, the expression of TRAP1 in human breast cancer specimens inversely correlates with tumor grade. Overexpression of TRAP1 in MDA-MB-231 cells causes mitochondrial fusion, triggers mitochondria to form tubular networks, and suppresses cell migration and invasion in vitro and in vivo. These data link TRAP1-regulated mitochondrial dynamics and function with tumorigenesis of breast cancer and suggested that TRAP1 may therefore be a potential target for breast cancer drug development.

submitted time 2016-05-15 Hits4138Downloads1688 Comment 0

2. chinaXiv:201605.01737 [pdf]

Baicalin Inhibits the Lethality of Shiga-Like Toxin 2 in Mice

Dong, Jing; Zhang, Yong; Zhang, Yu; Deng, Xuming; Dong, Jing; Chen, Yutao; Wang, Quan; Li, Xuemei; Niu, Xiaodi; Yang, Cheng
Subjects: Biology >> Biophysics

Shiga-like toxins (Stxs), produced by pathogenic Escherichia coli, are a major virulence factor involved in severe diseases in human and animals. These toxins are ribosome-inactivating proteins, and treatment for diseases caused by them is not available. Therefore, there is an urgent need for agents capable of effectively targeting this lethal toxin. In this study, we identified baicalin, a flavonoid compound used in Chinese traditional medicine, as a compound against Shiga-like toxin 2 (Stx2). We found that baicalin significantly improves renal function and reduces Stx2-induced lethality in mice. Further experiments revealed that baicalin induces the formation of oligomers by the toxin by direct binding. We also identified the residues important for such interactions and analyzed their roles in binding baicalin by biophysical and biochemical analyses. Our results establish baicalin as a candidate compound for the development of therapeutics against diseases caused by Stxs.

submitted time 2016-05-15 Hits3391Downloads1404 Comment 0

3. chinaXiv:201605.01521 [pdf]

Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming

Yang, Xiaoyu; Wang, Shen; Sheng, Yi; Xu, Tao; Ma, Cong; Zhang, Mingshu; Zhang, Rongguang; Xu, Tao; Zou, Wenjuan; Kang, Lijun; Wu, Lijie; Zhang, Rongguang; Rizo, Josep; Xu, Tao
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

UNC-13-Munc13s have a central function in synaptic-vesicle priming through their MUN domains. However, it is unclear whether this function arises from the ability of the MUN domain to mediate the transition from the Munc18-1-closed syntaxin-1 complex to the SNARE complex in vitro. The crystal structure of the rat Munc13-1 MUN domain now reveals an elongated, arch-shaped architecture formed by a-helical bundles, with a highly conserved hydrophobic pocket in the middle. Mutation of two residues (NF) in this pocket abolishes the stimulation caused by the Munc13-1 MUN domain on SNARE-complex assembly and on SNARE-dependent proteoliposome fusion in vitro. Moreover, the same mutation in UNC-13 abrogates synaptic-vesicle priming in Caenorhabditis elegans neuromuscular junctions. These results support the notion that orchestration of syntaxin-1 opening and SNARE-complex assembly underlies the central role of UNC-13-Munc13s in synaptic-vesicle priming.

submitted time 2016-05-12 Hits11187Downloads1759 Comment 0

4. chinaXiv:201605.01511 [pdf]

Spatiotemporal Detection and Analysis of Exocytosis Reveal Fusion 'Hotspots'' Organized by the Cytoskeleton in Endocrine Cells

Yuan, Tianyi; Chen, Liangyi; Yuan, Tianyi; Chen, Liangyi; Lu, Jingze; Zhang, Jinzhong; Zhang, Yongdeng
Subjects: Biology >> Biophysics

Total internal reflection fluorescence microscope has often been used to study the molecular mechanisms underlying vesicle exocytosis. However, the spatial occurrence of the fusion events within a single cell is not frequently explored due to the lack of sensitive and accurate computer-assisted programs to analyze large image data sets. Here, we have developed an image analysis platform for the nonbiased identification of different types of vesicle fusion events with high accuracy in different cell types. By performing spatiotemporal analysis of stimulus-evoked exocytosis in insulin-secreting INS-1 cells, we statistically prove that individual vesicle fusion events are clustered at hotspots. This spatial pattern disappears upon the disruption of either the actin or the microtubule network; this disruption also severely inhibits evoked exocytosis. By demonstrating that newcomer vesicles are delivered from the cell interior to the surface membrane for exocytosis, we highlight a previously unappreciated mechanism in which the cytoskeleton-dependent transportation of secretory vesicles organizes exocytosis hotspots in endocrine cells.

submitted time 2016-05-12 Hits1524Downloads866 Comment 0

5. chinaXiv:201605.01488 [pdf]

Crystal structures of the PsbS protein essential for photoprotection in plants

Fan, Minrui; Li, Mei; Liu, Zhenfeng; Cao, Peng; Pan, Xiaowei; Zhang, Hongmei; Zhao, Xuelin; Zhang, Jiping; Chang, Wenrui; Fan, Minrui
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

The photosystem II protein PsbS has an essential role in qE-type nonphotochemical quenching, which protects plants from photodamage under excess light conditions. qE is initiated by activation of PsbS by low pH, but the mechanism of PsbS action remains elusive. Here we report the low-pH crystal structures of PsbS from spinach in its free form and in complex with the qE inhibitor N, N'-dicyclohexylcarbodiimide (DCCD), revealing that PsbS adopts a unique folding pattern, and, unlike other members of the light-harvesting-complex superfamily, it is a noncanonical pigment-binding protein. Structural and biochemical evidence shows that both active and inactive PsbS form homodimers in the thylakoid membranes, and DCCD binding disrupts the lumenal intermolecular hydrogen bonds of the active PsbS dimer. Activation of PsbS by low pH during qE may involve a conformational change associated with altered lumenal intermolecular interactions of the PsbS dimer.

submitted time 2016-05-12 Hits2278Downloads1306 Comment 0

6. chinaXiv:201605.01463 [pdf]

NMR structure and function of Helicoverpa armigera sterol carrier protein-2, an important insecticidal target from the cotton bollworm

Ma, Haihao; Ma, Yuemin; Liu, Kaiyu; Peng, Jianxin; Peng, Rong; Liu, Xuehui; Xu, Pingyong; Dyer, David H.; Lan, Que; Hong, Huazhu
Subjects: Biology >> Biophysics

The cotton bollworm, Helicoverpa armigera, has developed strong resistance to many insecticides. Sterol Carrier Protein-2 (SCP-2) is an important non-specific lipid transfer protein in insects and appears to be a potential new target. In order to elucidate the structure and function of Helicoverpa armigera SCP-2 (HaSCP-2), NMR spectroscopy, docking simulations, mutagenesis and bioassays were performed. HaSCP-2 composed of five alpha-helices and four stranded beta-sheets. The folds of alpha-helices and beta-sheets interacted together to form a hydrophobic cavity with putative entrance and exit openings, which served as a tunnel for accommodating and transporting of lipids. Several sterols and fatty acids could interact with HaSCP-2 via important hydrophobic sites, which could be potential targets for insecticides. Mutagenesis experiments indicated Y51, F53, F89, F110, I117 and Q131 may be the key functional sites. HaSCP-2 showed high cholesterol binding activity and SCP-2 inhibitors (SCPIs) could inhibit the biological activity of HaSCP-2. SCPI-treated larvae at young stage showed a significant decrease of cholesterol uptake in vivo. Our study describes for the first time a NMR structure of SCP-2 in lepidopteran H. armigera and reveals its important function in cholesterol uptake, which facilitates the screening of effective insecticides targeting the insect cholesterol metabolism.

submitted time 2016-05-12 Hits1538Downloads873 Comment 0

7. chinaXiv:201605.01418 [pdf]

Linear-dendrimer type methoxy-poly (ethylene glycol)-b-poly (epsilon-caprolactone) copolymer micelles for the delivery of curcumin

Song, Zhimei; Zhu, Wenxia; Yang, Fengying; Liu, Na; Feng, Runliang; Zhu, Wenxia; Song, Jiarong; Wei, Peng
Subjects: Biology >> Biophysics

Purpose: To improve curcumin's pharmacokinetic, in vitro cytotoxicity and release property. Methods: A novel linear-dendrimer methoxy-poly (ethylene glycol)-b-poly (epsilon-caprolactone) copolymer was synthesized through O-alkylation, basic hydrolysis and ring-opening polymerization reaction with methoxy-poly (ethylene glycol), epichlorohydrin and epsilon-caprolactone as raw materials. Its structure was characterized by 1 H-NMR and GPC. The copolymer's hemolysis and micellar encapsulation for curcumin by thin-film hydration were studied. Curcumin-loaded micelles were evaluated by use of in vitro release, FT-IR and X-ray diffraction. Curcumin-loaded micelles' in vitro cytotoxic activities against Hela and HT-29 cells were done, and its pharmacokinetic parameters were also carried out. Results: Curcumin was encapsulated into the micelles with 92.54% of entrapment efficiency and 12.84% of drug loading in amorphous forms. The dissolubility of nanoparticulate curcumin was 1.70 x 10(5) times higher than that of curcumin in water. The obtained copolymer showed no hemolysis. In vitro drug release study indicated that, in all cases, the kinetics was adjusted well to the Makoid-Banakar model (R-abj(2) = 0.9984). In addition, data were analyzed by the Korsmeyer-Peppas model, n values were 0.43, indicating that the drug release was accomplished by the combination diffusion and polymer chain relaxation. The cytotoxicity experiment indicated that the nanoparticulate curcumin kept up its potent anti-cancer activities. The pharmacokinetic results showed that the MRT0-infinity, t(1/2z) and AUC(0-infinity) of Curcumin-loaded micelles were 1.64, 6.54 and 4.67 times higher than that of CUR control solution. Conclusions: The copolymeric micelles loading curcumin might act as a delivery vehicle for CUR.

submitted time 2016-05-12 Hits1827Downloads1021 Comment 0

8. chinaXiv:201605.01382 [pdf]

A Unique Human Norovirus Lineage with a Distinct HBGA Binding Interface

Liu, Wu; Chen, Yutao; Yang, Yang; Li, Xuemei; Rao, Zihe; Jiang, Xi; Xia, Ming; Tan, Ming; Jiang, Xi; Tan, Ming
Subjects: Biology >> Biophysics

Norovirus (NoV) causes epidemic acute gastroenteritis in humans, whereby histo-blood group antigens (HBGAs) play an important role in host susceptibility. Each of the two major genogroups (GI and GII) of human NoVs recognizes a unique set of HBGAs through a distinct binding interface that is conserved within a genogroup, indicating a distinct evolutionary path for each genogroup. Here, we characterize a Lewis a (Le(a)) antigen binding strain (OIF virus) in the GII. 21 genotype that does not share the conserved GII binding interface, revealing a new evolution lineage with a distinct HBGA binding interface. Sequence alignment showed that the major residues contributing to the new HBGA binding interface are conserved among most members of the GII. 21, as well as a closely related GII. 13 genotype. In addition, we found that glycerol inhibits OIF binding to HBGAs, potentially allowing production of cheap antivirals against human NoVs. Taken together, our results reveal a new evolutionary lineage of NoVs selected by HBGAs, a finding that is important for understanding the diversity and widespread nature of NoVs.

submitted time 2016-05-12 Hits2195Downloads1208 Comment 0

9. chinaXiv:201605.01361 [pdf]

A Novel Transgenic Mouse Line for Tracing MicroRNA-155-5p Activity In Vivo

Phiwpan, Krung; Guo, Jie; Zhang, Wei; Hu, Tanyu; Zhang, Jianhua; Zhou, Xuyu; Phiwpan, Krung; Hu, Tanyu; Boruah, Bhargavi M.
Subjects: Biology >> Biophysics

MicroRNA-155 (miR-155) plays significant role in various physiological processes involving both innate and adaptive immunity. miR-155 expression level changes dynamically during various immune responses. However, current approaches for miR-155 detection at the RNA level do not precisely reflect the real-time activity. Herein, we generated a transgenic mouse line (R26-DTR-155T) for determination of miR-155-5p activity in vivo by inserting miR-155-5p target sequence downstream of a reporter transgene comprising Diphtheria Toxin Receptor and TagBlue fluorescence protein. Using this approach, R26-DTR-155T mice were able to measure variation in levels of miR-155-5p activity in specific cell types of interest. The DTR expression levels were inversely correlated with the endogenous miR-155 expression pattern as detected by quantitative RT-PCR. Our data demonstrate a novel transgenic mouse line which could be useful for tracing miR-155-5p activity in specific cell types through measurement of miR-155-5p activity at single cell level.

submitted time 2016-05-11 Hits1794Downloads1002 Comment 0

10. chinaXiv:201605.01275 [pdf]

Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression

Kong, Ruirui; Wen, Pushuai; Liu, Jianghong; Zhu, Li; Wu, Jane Y.; Yi, Fengshuang; Ren, Jinqi; Feng, Wei; Yi, Fengshuang; Chen, Xiaoping; Wu, Jane Y.; Li, Xiaofei; Nie, Yongzhan; Wu, Kaichun; Fan, Daiming; Zhu, Li; Nie, Yongzhan; Wu, Kaichun; Fan, Daiming; Zhu, Li
Subjects: Biology >> Biophysics

Emerging evidence indicates that the neuronal guidance molecule SLIT plays a role in tumor suppression, as SLIT-encoding genes are inactivated in several types of cancer, including lung cancer; however, it is not clear how SLIT functions in lung cancer. Here, our data show that SLIT inhibits cancer cell migration by activating RhoA and that myosin 9b (Myo9b) is a ROBO-interacting protein that suppresses RhoA activity in lung cancer cells. Structural analyses revealed that the RhoGAP domain of Myo9b contains a unique patch that specifically recognizes RhoA. We also determined that the ROBO Intracellular domain interacts with the Myo9b RhoGAP domain and inhibits its activity; therefore, SLIT-dependent activation of RhoA is mediated by ROBO inhibition of Myo9b. In a murine model, compared with control lung cancer cells, SLIT-expressing cells had a decreased capacity for tumor formation and lung metastasis. Evaluation of human lung cancer and adjacent nontumor tissues revealed that Myo9b is upregulated in the cancer tissue. Moreover, elevated Myo9b expression was associated with lung cancer progression and poor prognosis. Together, our data identify Myo9b as a key player in lung cancer and as a ROBO-interacting protein in what is, to the best of our knowledge, a newly defined SLIT/ROBO/Myo9b/RhoA signaling pathway that restricts lung cancer progression and metastasis. Additionally, our work suggests that targeting the SLIT/ROBO/Myo9b/RhoA pathway has potential as a diagnostic and therapeutic strategy for lung cancer.

submitted time 2016-05-11 Hits1877Downloads1069 Comment 0

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