bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of STAT1 protects hair cells from ototoxicity through modulation of STAT3, c-Jun, Akt, and autophagy factors
Authors: Levano S , Bodmer D 
Published: December 2015

AbstractHair cell damage is a side effect of cisplatin and aminoglycoside use. The inhibition or attenuation of this process is a target of many investigations. There is growing evidence that STAT1 deficiency decreases cisplatin-mediated ototoxicity; however, the role of STAT function and the molecules that act in gentamicin-mediated toxicity have not been fully elucidated. We used mice lacking STAT1 to investigate the effect of STAT1 ablation in cultured organs treated with cisplatin and gentamicin. Here we show that ablation of STAT1 decreased cisplatin toxicity and attenuated gentamicin-mediated hair cell damage. More TUNEL-positive hair cells were observed in explants of wild-type mice than that of STAT1−/− mice. Although cisplatin increased serine phosphorylation of STAT1 in wild-type mice and diminished STAT3 expression in wild-type and STAT1−/− mice, gentamicin increased tyrosine phosphorylation of STAT3 in STAT1−/− mice. The early inflammatory response was manifested in the upregulation of TNF-α and IL-6 in cisplatin-treated explants of wild-type and STAT1−/− mice. Expression of the anti-inflammatory cytokine IL-10 was altered in cisplatin-treated explants, upregulated in wild-type explants, and downregulated in STAT1−/− explants. Cisplatin and gentamicin triggered the activation of c-Jun. Activation of Akt was observed in gentamicin-treated explants from STAT1−/− mice. Increased levels of the autophagy proteins Beclin-1 and LC3-II were observed in STAT1−/− explants. These data suggest that STAT1 is a central player in mediating ototoxicity. Gentamicin and cisplatin activate different downstream factors to trigger ototoxicity. Although cisplatin and gentamicin triggered inflammation and activated apoptotic factors, the absence of STAT1 allowed the cells to overcome the effects of these drugs.
Effects of PI3K inhibitor NVP-BKM120 on overcoming drug resistance and eliminating cancer stem cells in human breast cancer cells
Authors: Hu Y , Guo R , Wei J , Zhou Y , Ji W , Liu J , Zhi X , Zhang J 
Published: December 2015

AbstractThe multidrug resistance (MDR) phenotype often accompanies activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, which renders a survival signal to withstand cytotoxic anticancer drugs and enhances cancer stem cell (CSC) characteristics. As a result, PI3K/AKT-blocking approaches have been proposed as antineoplastic strategies, and inhibitors of PI3K/AKT are currently being trailed clinically in breast cancer patients. However, the effects of PI3K inhibitors on MDR breast cancers have not yet been elucidated. In the present study, the tumorigenic properties of three MDR breast cancer cell lines to a selective inhibitor of PI3K, NVP-BKM120 (BKM120), were assessed. We found that BKM120 showed a significant cytotoxic activity on MDR breast cancer cells both in vitro and in vivo. When doxorubicin (DOX) was combined with BKM120, strong synergistic antiproliferative effect was observed. BKM120 activity induced the blockage of PI3K/AKT signaling and NF-κB expression, which in turn led to activate caspase-3/7 and caspase-9 and changed the expression of several apoptosis-related gene expression. Furthermore, BKM120 effectively eliminated CSC subpopulation and reduced sphere formation of these drug-resistant cells. Our findings indicate that BKM120 partially overcomes the MDR phenotype in chemoresistant breast cancer through cell apoptosis induction and CSC abolishing, which appears to be mediated by the inhibition of the PI3K/AKT/NF-κB axis. This offers a strong rationale to explore the therapeutic strategy of using BKM120 alone or in combination for chemotherapy-nonresponsive breast cancer patients.
Cigarette toxicity triggers Leber’s hereditary optic neuropathy by affecting mtDNA copy number, oxidative phosphorylation and ROS detoxification pathways
Authors: Giordano L , Deceglie S , d'Adamo P , Valentino M L , La Morgia C , Fracasso F , Roberti M , Cappellari M , Petrosillo G , Ciaravolo S , Parente D , Giordano C , Maresca A , Iommarini L , Del Dotto V , Ghelli A M , Salomao S R , Berezovsky A , Belfort R , Sadun A A , Carelli V , Loguercio Polosa P , Cantatore P 
Published: December 2015

AbstractLeber’s hereditary optic neuropathy (LHON), the most frequent mitochondrial disease, is associated with mitochondrial DNA (mtDNA) point mutations affecting Complex I subunits, usually homoplasmic. This blinding disorder is characterized by incomplete penetrance, possibly related to several genetic modifying factors. We recently reported that increased mitochondrial biogenesis in unaffected mutation carriers is a compensatory mechanism, which reduces penetrance. Also, environmental factors such as cigarette smoking have been implicated as disease triggers. To investigate this issue further, we first assessed the relationship between cigarette smoke and mtDNA copy number in blood cells from large cohorts of LHON families, finding that smoking was significantly associated with the lowest mtDNA content in affected individuals. To unwrap the mechanism of tobacco toxicity in LHON, we exposed fibroblasts from affected individuals, unaffected mutation carriers and controls to cigarette smoke condensate (CSC). CSC decreased mtDNA copy number in all cells; moreover, it caused significant reduction of ATP level only in mutated cells including carriers. This implies that the bioenergetic compensation in carriers is hampered by exposure to smoke derivatives. We also observed that in untreated cells the level of carbonylated proteins was highest in affected individuals, whereas the level of several detoxifying enzymes was highest in carriers. Thus, carriers are particularly successful in reactive oxygen species (ROS) scavenging capacity. After CSC exposure, the amount of detoxifying enzymes increased in all cells, but carbonylated proteins increased only in LHON mutant cells, mostly from affected individuals. All considered, it appears that exposure to smoke derivatives has a more deleterious effect in affected individuals, whereas carriers are the most efficient in mitigating ROS rather than recovering bioenergetics. Therefore, the identification of genetic modifiers that modulate LHON penetrance must take into account also the exposure to environmental triggers such as tobacco smoke.
Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition
Authors: Doeppner T R , Kaltwasser B , Schlechter J , Jaschke J , Kilic E , Bähr M , Hermann D M , Weise J 
Published: December 2015

AbstractAlthough cellular prion protein (PrPc) has been suggested to have physiological roles in neurogenesis and angiogenesis, the pathophysiological relevance of both processes remain unknown. To elucidate the role of PrPc in post-ischemic brain remodeling, we herein exposed PrPc wild type (WT), PrPc knockout (PrP−/−) and PrPc overexpressing (PrP+/+) mice to focal cerebral ischemia followed by up to 28 days reperfusion. Improved neurological recovery and sustained neuroprotection lasting over the observation period of 4 weeks were observed in ischemic PrP+/+ mice compared with WT mice. This observation was associated with increased neurogenesis and angiogenesis, whereas increased neurological deficits and brain injury were noted in ischemic PrP−/− mice. Proteasome activity and oxidative stress were increased in ischemic brain tissue of PrP−/− mice. Pharmacological proteasome inhibition reversed the exacerbation of brain injury induced by PrP−/−, indicating that proteasome inhibition mediates the neuroprotective effects of PrPc. Notably, reduced proteasome activity and oxidative stress in ischemic brain tissue of PrP+/+ mice were associated with an increased abundance of hypoxia-inducible factor 1α and PACAP-38, which are known stimulants of neural progenitor cell (NPC) migration and trafficking. To elucidate effects of PrPc on intracerebral NPC homing, we intravenously infused GFP+ NPCs in ischemic WT, PrP−/− and PrP+/+ mice, showing that brain accumulation of GFP+ NPCs was greatly reduced in PrP−/− mice, but increased in PrP+/+ animals. Our results suggest that PrPc induces post-ischemic long-term neuroprotection, neurogenesis and angiogenesis in the ischemic brain by inhibiting proteasome activity.
Giant negative magnetoresistance induced by the chiral anomaly in individual Cd3As2 nanowires
Authors: Li Cai-Zhen , Wang Li-Xian , Liu Haiwen , Wang Jian , Liao Zhi-Min , Yu Da-Peng 
Published: December 2015

AbstractDirac electronic materials beyond graphene and topological insulators have recently attracted considerable attention. Cd3As2 is a Dirac semimetal with linear dispersion along all three momentum directions and can be viewed as a three-dimensional analogue of graphene. By breaking of either time-reversal symmetry or spatial inversion symmetry, the Dirac semimetal is believed to transform into a Weyl semimetal with an exotic chiral anomaly effect, however the experimental evidence of the chiral anomaly is still missing in Cd3As2. Here we show a large negative magnetoresistance with magnitude of −63% at 60 K and −11% at 300 K in individual Cd3As2 nanowires. The negative magnetoresistance can be modulated by gate voltage and temperature through tuning the density of chiral states at the Fermi level and the inter-valley scatterings between Weyl nodes. The results give evidence of the chiral anomaly effect and are valuable for understanding the Weyl fermions in Dirac semimetals.
Ternary structure reveals mechanism of a membrane diacylglycerol kinase
Authors: Li Dianfan , Stansfeld Phillip J. , Sansom Mark S. P. , Keogh Aaron , Vogeley Lutz , Howe Nicole , Lyons Joseph A. , Aragao David , Fromme Petra , Fromme Raimund , Basu Shibom , Grotjohann Ingo , Kupitz Christopher , Rendek Kimberley , Weierstall Uwe , Zatsepin Nadia A. , Cherezov Vadim , Liu Wei , Bandaru Sateesh , English Niall J. , Gati Cornelius , Barty Anton , Yefanov Oleksandr , Chapman Henry N. , Diederichs Kay , Messerschmidt Marc , Boutet Sébastien , Williams Garth J. , Marvin Seibert M. , Caffrey Martin 
Published: December 2015

AbstractDiacylglycerol kinase catalyses the ATP-dependent conversion of diacylglycerol to phosphatidic acid in the plasma membrane of Escherichia coli. The small size of this integral membrane trimer, which has 121 residues per subunit, means that available protein must be used economically to craft three catalytic and substrate-binding sites centred about the membrane/cytosol interface. How nature has accomplished this extraordinary feat is revealed here in a crystal structure of the kinase captured as a ternary complex with bound lipid substrate and an ATP analogue. Residues, identified as essential for activity by mutagenesis, decorate the active site and are rationalized by the ternary structure. The γ-phosphate of the ATP analogue is positioned for direct transfer to the primary hydroxyl of the lipid whose acyl chain is in the membrane. A catalytic mechanism for this unique enzyme is proposed. The active site architecture shows clear evidence of having arisen by convergent evolution.
Cdk1 orders mitotic events through coordination of a chromosome-associated phosphatase switch
Authors: Qian Junbin , Beullens Monique , Huang Jin , De Munter Sofie , Lesage Bart , Bollen Mathieu 
Published: December 2015

AbstractRepoMan is a scaffold for signalling by mitotic phosphatases at the chromosomes. During (pro)metaphase, RepoMan-associated protein phosphatases PP1 and PP2A-B56 regulate the chromosome targeting of Aurora-B kinase and RepoMan, respectively. Here we show that this task division is critically dependent on the phosphorylation of RepoMan by protein kinase Cyclin-dependent kinase 1 (Cdk1), which reduces the binding of PP1 but facilitates the recruitment of PP2A-B56. The inactivation of Cdk1 in early anaphase reverses this phosphatase switch, resulting in the accumulation of PP1-RepoMan to a level that is sufficient to catalyse its own chromosome targeting in a PP2A-independent and irreversible manner. Bulk-targeted PP1-RepoMan also inactivates Aurora B and initiates nuclear-envelope reassembly through dephosphorylation-mediated recruitment of Importin β. Bypassing the Cdk1 regulation of PP1-RepoMan causes the premature dephosphorylation of its mitotic-exit substrates in prometaphase. Hence, the regulation of RepoMan-associated phosphatases by Cdk1 is essential for the timely dephosphorylation of their mitotic substrates.
Paving the way to nanoionics: atomic origin of barriers for ionic transport through interfaces
Authors: Frechero M. A. , Rocci M. , Sánchez-Santolino G. , Kumar Amit , Salafranca J. , Schmidt Rainer , Díaz-Guillén M. R. , Durá O. J. , Rivera-Calzada A. , Mishra R. , Jesse Stephen , Pantelides S. T. , Kalinin Sergei V. , Varela M. , Pennycook S. J. , Santamaria J. , Leon C. 
Published: December 2015

AbstractThe blocking of ion transport at interfaces strongly limits the performance of electrochemical nanodevices for energy applications. The barrier is believed to arise from space-charge regions generated by mobile ions by analogy to semiconductor junctions. Here we show that something different is at play by studying ion transport in a bicrystal of yttria (9% mol) stabilized zirconia (YSZ), an emblematic oxide ion conductor. Aberration-corrected scanning transmission electron microscopy (STEM) provides structure and composition at atomic resolution, with the sensitivity to directly reveal the oxygen ion profile. We find that Y segregates to the grain boundary at Zr sites, together with a depletion of oxygen that is confined to a small length scale of around 0.5 nm. Contrary to the main thesis of the space-charge model, there exists no evidence of a long-range O vacancy depletion layer. Combining ion transport measurements across a single grain boundary by nanoscale electrochemical strain microscopy (ESM), broadband dielectric spectroscopy measurements and density functional calculations, we show that grain-boundary-induced electronic states act as acceptors, resulting in a negatively charged core. Besides the possible effect of the modified chemical bonding, this negative charge gives rise to an additional barrier for ion transport at the grain boundary.
Comparative transcriptome analysis of grapevine in response to copper stress
Authors: Leng Xiangpeng , Jia Haifeng , Sun Xin , Shangguan Lingfei , Mu Qian , Wang Baoju , Fang Jinggui 
Published: December 2015

AbstractGrapevine is one of the most economically important and widely cultivated fruit crop worldwide. With the industrialization and the popular application of cupric fungicides in grape industry, copper stress and copper pollution are also the factors affecting grape production and berry and wine quality. Here, 3,843 transcripts were significantly differently expressed genes in response to Cu stress by RNA-seq, which included 1,892 up-regulated and 1,951 down-regulated transcripts. During this study we found many known and novel Cu-induced and -repressed genes. Biological analysis of grape samples were indicated that exogenous Cu can influence chlorophylls metabolism and photosynthetic activities of grapevine. Most ROS detoxification systems, including antioxidant enzyme, stress-related proteins and secondary metabolites were strongly induced. Concomitantly, abscisic acid functioned as a negative regulator in Cu stress, in opposite action to ethylene, auxin, jasmonic acid and brassinolide. This study also identified a set of Cu stress specifically activated genes coding copper transporter, P1B-type ATPase, multidrug transporters. Overall, this work was carried out to gain insights into the copper-regulated and stress-responsive mechanisms in grapevine at transcriptome level. This research can also provide some genetic information that can help us in better vinery management and breeding Cu-resistant grape cultivars.
TRAIL-R2 Superoligomerization Induced by Human Monoclonal Agonistic Antibody KMTR2
Authors: Tamada Taro , Shinmi Daisuke , Ikeda Masahiro , Yonezawa Yasushi , Kataoka Shiro , Kuroki Ryota , Mori Eiji , Motoki Kazuhiro 
Published: December 2015

AbstractThe fully human monoclonal antibody KMTR2 acts as a strong direct agonist for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2), which is capable of inducing apoptotic cell death without cross-linking. To investigate the mechanism of direct agonistic activity induced by KMTR2, the crystal structure of the extracellular region of TRAIL-R2 and a Fab fragment derived from KMTR2 (KMTR2-Fab) was determined to 2.1 Å resolution. Two KMTR2-Fabs assembled with the complementarity-determining region 2 of the light chain via two-fold crystallographic symmetry, suggesting that the KMTR2-Fab assembly tended to enhance TRAIL-R2 oligomerization. A single mutation at Asn53 to Arg located at the two-fold interface in the KMTR2 resulted in a loss of its apoptotic activity, although it retained its antigen-binding activity. These results indicate that the strong agonistic activity, such as apoptotic signaling and tumor regression, induced by KMTR2 is attributed to TRAIL-R2 superoligomerization induced by the interdimerization of KMTR2.
Resistance to dual-gene Bt maize in Spodoptera frugiperda: selection, inheritance and cross-resistance to other transgenic events
Authors: Santos-Amaya Oscar F. , Rodrigues João V. C. , Souza Thadeu C. , Tavares Clébson S. , Campos Silverio O. , Guedes Raul N.C. , Pereira Eliseu J.G. 
Published: December 2015

AbstractTransgenic crop “pyramids” producing two or moreBacillus thuringiensis(Bt) toxins active against the same pest are used to delay evolution of resistance in insect pest populations. Laboratory and greenhouse experiments were performed with fall armyworm,Spodoptera frugiperda, to characterize resistance to Bt maize producing Cry1A.105 and Cry2Ab and test some assumptions of the “pyramid” resistance management strategy. Selection of a field-derived strain ofS. frugiperdaalready resistant to Cry1F maize with Cry1A.105 + Cry2Ab maize for ten generations produced resistance that allowed the larvae to colonize and complete the life cycle on these Bt maize plants. Greenhouse experiments revealed that the resistance was completely recessive (Dx = 0), incomplete, autosomal and without maternal effects or cross-resistance to the Vip3Aa20 toxin produced in other Bt maize events. This profile of resistance supports some of the assumptions of the pyramid strategy for resistance management. However, laboratory experiments with purified Bt toxin and plant leaf tissue showed that resistance to Cry1A.105 + Cry2Ab2 maize further increased resistance to Cry1Fa, which indicates that populations of fall armyworm have high potential for developing resistance to some currently available pyramided maize used against this pest, especially where resistance to Cry1Fa was reported in the field.
Relation of retinal blood flow and retinal oxygen extraction during stimulation with diffuse luminance flicker
Authors: Palkovits Stefan , Lasta Michael , Told Reinhard , Schmidl Doreen , Werkmeister René , Cherecheanu Alina Popa , Garhöfer Gerhard , Schmetterer Leopold 
Published: December 2015

AbstractCerebral and retinal blood flow are dependent on local neuronal activity. Several studies quantified the increase in cerebral blood flow and oxygen consumption during activity. In the present study we investigated the relation between changes in retinal blood flow and oxygen extraction during stimulation with diffuse luminance flicker and the influence of breathing gas mixtures with different fractions of O2 (FiO2; 100% 15% and 12%). Twenty-four healthy subjects were included. Retinal blood flow was studied by combining measurement of vessel diameters using the Dynamic Vessel Analyser with measurements of blood velocity using laser Doppler velocimetry. Oxygen saturation was measured using spectroscopic reflectometry and oxygen extraction was calculated. Flicker stimulation increased retinal blood flow (57.7 ± 17.8%) and oxygen extraction (34.6 ± 24.1%; p < 0.001 each). During 100% oxygen breathing the response of retinal blood flow and oxygen extraction was increased (p < 0.01 each). By contrast, breathing gas mixtures with 12% and 15% FiO2 did not alter flicker–induced retinal haemodynamic changes. The present study indicates that at a comparable increase in blood flow the increase in oxygen extraction in the retina is larger than in the brain. During systemic hyperoxia the blood flow and oxygen extraction responses to neural stimulation are augmented. The underlying mechanism is unknown.
Physical Modeling of Gate-Controlled Schottky Barrier Lowering of Metal-Graphene Contacts in Top-Gated Graphene Field-Effect Transistors
Authors: Mao Ling-Feng , Ning Huansheng , Huo Zong-Liang , Wang Jin-Yan 
Published: December 2015

AbstractA new physical model of the gate controlled Schottky barrier height (SBH) lowering in top-gated graphene field-effect transistors (GFETs) under saturation bias condition is proposed based on the energy conservation equation with the balance assumption. The theoretical prediction of the SBH lowering agrees well with the experimental data reported in literatures. The reduction of the SBH increases with the increasing of gate voltage and relative dielectric constant of the gate oxide, while it decreases with the increasing of oxide thickness, channel length and acceptor density. The magnitude of the reduction is slightly enhanced under high drain voltage. Moreover, it is found that the gate oxide materials with large relative dielectric constant (>20) have a significant effect on the gate controlled SBH lowering, implying that the energy relaxation of channel electrons should be taken into account for modeling SBH in GFETs.
Autophagic degradation of aquaporin-2 is an early event in hypokalemia-induced nephrogenic diabetes insipidus
Authors: Khositseth Sookkasem , Uawithya Panapat , Somparn Poorichaya , Charngkaew Komgrid , Thippamom Nattakan , Hoffert Jason D. , Saeed Fahad , Michael Payne D. , Chen Shu-Hui , Fenton Robert A. , Pisitkun Trairak 
Published: December 2015

AbstractHypokalemia (low serum potassium level) is a common electrolyte imbalance that can cause a defect in urinary concentrating ability, i.e., nephrogenic diabetes insipidus (NDI), but the molecular mechanism is unknown. We employed proteomic analysis of inner medullary collecting ducts (IMCD) from rats fed with a potassium-free diet for 1 day. IMCD protein quantification was performed by mass spectrometry using a label-free methodology. A total of 131 proteins, including the water channel AQP2, exhibited significant changes in abundance, most of which were decreased. Bioinformatic analysis revealed that many of the down-regulated proteins were associated with the biological processes of generation of precursor metabolites and energy, actin cytoskeleton organization and cell-cell adhesion. Targeted LC-MS/MS and immunoblotting studies further confirmed the down regulation of 18 selected proteins. Electron microscopy showed autophagosomes/autophagolysosomes in the IMCD cells of rats deprived of potassium for only 1 day. An increased number of autophagosomes was also confirmed by immunofluorescence, demonstrating co-localization of LC3 and Lamp1 with AQP2 and several other down-regulated proteins in IMCD cells. AQP2 was also detected in autophagosomes in IMCD cells of potassium-deprived rats by immunogold electron microscopy. Thus, enhanced autophagic degradation of proteins, most notably including AQP2, is an early event in hypokalemia-induced NDI.