bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi‐instrument Observations of Mesoscale Enhancement of Subauroral Polarization Stream Associated With an Injection
Authors: Wang Zihan , Zou Shasha , Shepherd Simon G. , Liang Jun , Gjerloev Jesper W. , Ruohoniemi J. Michael , Kunduri Bharat , Wygant John R. 
Published: March 2019

AbstractSubauroral polarization streams (SAPS) prefer geomagnetically disturbed conditions and strongly correlate with geomagnetic indexes. However, the temporal evolution of SAPS and its relationship with dynamic and structured ring current and particle injection are still not well understood. In this study, we performed detailed analysis of temporal evolution of SAPS during a moderate storm on 18 May 2013 using conjugate observations of SAPS from the Van Allen Probes (VAP) and the Super Dual Auroral Radar Network (SuperDARN). The large‐scale SAPS (LS‐SAPS) formed during the main phase of this storm and decayed due to the northward turning of the interplanetary magnetic field. A mesoscale (approximately several hundreds of kilometers zonally) enhancement of SAPS was observed by SuperDARN at 0456 UT. In the conjugate magnetosphere, a large SAPS electric field (∼8 mV/m) pointing radially outward, a local magnetic field dip, and a dispersionless ion injection were observed simultaneously by VAP‐A at L shell = 3.5 and MLT = 20. The particle injection observed by VAP‐A is likely associated with the particle injection observed by the Geostationary Operational Environmental Satellite 15 near 20 MLT. Magnetic perturbations observed by the ground magnetometers and flow reversals observed by SuperDARN reveal that this mesoscale enhancement of SAPS developed near the Harang reversal and before the substorm onset. The observed complex signatures in both space and ground can be explained by a two‐loop current wedge generated by the perturbed plasma pressure gradient and the diamagnetic effect of the structured ring current following particle injection.
Targeting c-MET by Tivantinib through synergistic activation of JNK/c-jun pathway in cholangiocarcinoma
Authors: Wei Kai , Li Mao , Zöller Margot , Wang Meng , Mehrabi Arianeb , Hoffmann Katrin 
Published: March 2019

AbstractClinical treatment options for human cholangiocarcinoma (CC) are limited. c-MET, a high-affinity receptor for hepatocyte growth factor (HGF), is deregulated in many cancers. Its role in cholangiocarcinogenesis remains unclear. In current study, 23 corresponding tumor- and non-tumor tissues, taken from patients with intrahepatic (iCC) and perihilar cholangiocarcinoma (pCC), who underwent liver resection, were analyzed. The relationship of clinicopathological features and c-MET, as well as c-jun N-terminal kinase (JNK) was evaluated. The anti-tumor effects of Tivantinib, a small-molecule inhibitor with potent activity against the c-MET kinase, was investigated in three human CC cell lines, namely HUCC-T1, TFK-1, and EGI-1. In comparison with the results obtained in non-tumor tissue samples, c-MET was overexpressed in 91.3 % of tumor tissues (p < 0.01). The JNK expression was higher in tumor tissue compared with the corresponding non-tumor tissue sample in 17.4% patients (p < 0.01). The inhibition of aberrant c-MET expression in human CC cell lines was achieved by blocking the phosphorylation of c-MET with Tivantinib. Notable losses in cell viability and colony-forming capability were detected (p < 0.01). Synergistic activation of the JNK/c-jun pathway was demonstrated after Tivantinib treatment. Knockdown of the JNK by siRNA or competitive binding of c-MET receptor by stimulation with HGF-antagonized anti-tumor effects of Tivantinib was observed. Our data suggest that inhibition of c-MET could be a possible alternative approach for the treatment of human CC, for which Tivantinib may an effective inhibitor. The synergistic activation of the JNK/c-jun pathway contributed to the elevated apoptosis in CC cells via treatment with Tivantinib.
Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog
Authors: Yao Nan , Wang Chenran , Hu Nan , Li Yingjie , Liu Mingqun , Lei Yuhe , Chen Minfeng , Chen Liping , Chen Chen , Lan Ping , Chen Weimin , Chen Zhesheng , Fu Dengrui , Ye Wencai , Zhang Dongmei 
Published: March 2019

AbstractBetulinic acid (BA) and its derivatives are a class of high-profile drug candidates, but their anticancer effects on resistant cancer have rarely been reported. Although a few studies indicated mitophagy is related with drug resistance, its role in different cancer types and anticancer agents treatment remains largely unclear. Here, we find that B5G1, a new derivative of BA, induces cell death in multidrug resistant cancer cells HepG2/ADM and MCF-7/ADR through mitochondrial-apoptosis pathway. B5G1 also triggers mitophagy independent on Atg5/Beclin 1. Further mechanistic study indicates that B5G1 upregulates PTEN-induced putative kinase 1 (PINK1) to recruit Parkin to mitochondria followed by ubiquitination of Mfn2 to initiate mitophagy. Inhibition of mitophagy by PINK1 siRNA, mdivi-1, or bafilomycin A1 (Baf A1) promotes B5G1-induced cell death. In addition, ROS production and mitochondrial damage in B5G1-treated HepG2/ADM cells cause mitochondrial apoptosis and mitophagy. In vivo study shown that B5G1 dramatically inhibits HepG2/ADM xenograft growth accompanied by apoptosis and mitophagy induction. Together, our results provide the first demonstration that B5G1, as a novel mitophagy inducer, has the potential to be developed into a drug candidate for treating multidrug resistant cancer.
RETRACTED ARTICLE: Involvement of autophagy in hypoxia-BNIP3 signaling to promote epidermal keratinocyte migration
Authors: Zhang Junhui , Zhang Can , Jiang Xupin , Li Lingfei , Zhang Dongxia , Tang Di , Yan Tiantian , Zhang Qiong , Yuan Hongping , Jia Jiezhi , Hu Jiongyu , Zhang Jiaping , Huang Yuesheng 
Published: March 2019

AbstractBNIP3 is an atypical BH3-only member of the Bcl-2 family with pro-death, pro-autophagic, and cytoprotective functions, depending on the type of stress and cellular context. Recently, we demonstrated that BNIP3 stimulates the migration of epidermal keratinocytes under hypoxia. In the present study found that autophagy and BNIP3 expression were concomitantly elevated in the migrating epidermis during wound healing in a hypoxia-dependent manner. Inhibition of autophagy through lysosome-specific chemicals (CQ and BafA1) or Atg5-targeted small-interfering RNAs greatly attenuated the hypoxia-induced cell migration, and knockdown of BNIP3 in keratinocytes significantly suppressed hypoxia-induced autophagy activation and cell migration, suggesting a positive role of BNIP3-induced autophagy in keratinocyte migration. Furthermore, these results indicated that the accumulation of reactive oxygen species (ROS) by hypoxia triggered the activation of p38 and JNK mitogen-activated protein kinase (MAPK) in human immortalized keratinocyte HaCaT cells. In turn, activated p38 and JNK MAPK mediated the activation of BNIP3-induced autophagy and the enhancement of keratinocyte migration. These data revealed a previously unknown mechanism that BNIP3-induced autophagy occurs through hypoxia-induced ROS-mediated p38 and JNK MAPK activation and supports the migration of epidermal keratinocytes during wound healing.
Diversifying the structure of zinc finger nucleases for high-precision genome editing
Authors: Paschon David E. , Lussier Stephanie , Wangzor Tenzin , Xia Danny F. , Li Patrick W. , Hinkley Sarah J. , Scarlott Nicholas A. , Lam Stephen C. , Waite Adam J. , Truong Lynn N. , Gandhi Nimisha , Kadam Bhakti N. , Patil Deepak P. , Shivak David A. , Lee Gary K. , Holmes Michael C. , Zhang Lei , Miller Jeffrey C. , Rebar Edward J. 
Published: March 2019

AbstractGenome editing for therapeutic applications often requires cleavage within a narrow sequence window. Here, to enable such high-precision targeting with zinc-finger nucleases (ZFNs), we have developed an expanded set of architectures that collectively increase the configurational options available for design by a factor of 64. These new architectures feature the functional attachment of the FokI cleavage domain to the amino terminus of one or both zinc-finger proteins (ZFPs) in the ZFN dimer, as well as the option to skip bases between the target triplets of otherwise adjacent fingers in each zinc-finger array. Using our new architectures, we demonstrate targeting of an arbitrarily chosen 28 bp genomic locus at a density that approaches 1.0 (i.e., efficient ZFNs available for targeting almost every base step). We show that these new architectures may be used for targeting three loci of therapeutic significance with a high degree of precision, efficiency, and specificity.
The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy
Authors: Wang Gui-Zhen , Zhang Li , Zhao Xin-Chun , Gao San-Hui , Qu Li-Wei , Yu Hong , Fang Wen-Feng , Zhou Yong-Chun , Liang Fan , Zhang Chen , Huang Yun-Chao , Liu Zhihua , Fu Yang-Xin , Zhou Guang-Biao 
Published: March 2019

AbstractWhether tobacco carcinogens enable exposed cells immune escape resulting in carcinogenesis, and why patients who smoke respond better to immunotherapies than non-smokers, remains poorly understood. Here we report that cigarette smoke and the carcinogen benzo(a)pyrene (BaP) induce PD-L1 expression on lung epithelial cells in vitro and in vivo, which is mediated by aryl hydrocarbon receptor (AhR). Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer. In 37 patients treated with anti-PD-1 antibody pembrolizumab, 13/16 (81.3%) patients who achieve partial response or stable disease express high levels of AhR, whereas 12/16 (75%) patients with progression disease exhibit low levels of AhR in tumor tissues. AhR inhibitors exert significant antitumor activity and synergize with anti-PD-L1 antibody in lung cancer mouse models. These results demonstrate that tobacco smoke enables lung epithelial cells to escape from adaptive immunity to promote tumorigenesis, and AhR predicts the response to immunotherapy and represents an attractive therapeutic target.
Neurotrophin receptor tyrosine kinases regulated with near-infrared light
Authors: Leopold Anna V. , Chernov Konstantin G. , Shemetov Anton A. , Verkhusha Vladislav V. 
Published: March 2019

AbstractOptical control over the activity of receptor tyrosine kinases (RTKs) provides an efficient way to reversibly and non-invasively map their functions. We combined catalytic domains of Trk (tropomyosin receptor kinase) family of RTKs, naturally activated by neurotrophins, with photosensory core module of DrBphP bacterial phytochrome to develop opto-kinases, termed Dr-TrkA and Dr-TrkB, reversibly switchable on and off with near-infrared and far-red light. We validated Dr-Trk ability to reversibly light-control several RTK pathways, calcium level, and demonstrated that their activation triggers canonical Trk signaling. Dr-TrkA induced apoptosis in neuroblastoma and glioblastoma, but not in other cell types. Absence of spectral crosstalk between Dr-Trks and blue-light-activatable LOV-domain-based translocation system enabled intracellular targeting of Dr-TrkA independently of its activation, additionally modulating Trk signaling. Dr-Trks have several superior characteristics that make them the opto-kinases of choice for regulation of RTK signaling: high activation range, fast and reversible photoswitching, and multiplexing with visible-light-controllable optogenetic tools.
Unraveling the mysterious failure of Cu/SAPO-34 selective catalytic reduction catalysts
Authors: Wang Aiyong , Chen Ying , Walter Eric D. , Washton Nancy M. , Mei Donghai , Varga Tamas , Wang Yilin , Szanyi János , Wang Yong , Peden Charles H. F. , Gao Feng 
Published: March 2019

AbstractCommercial Cu/SAPO-34 selective catalytic reduction (SCR) catalysts have experienced unexpected and quite perplexing failure. Understanding the causes at an atomic level is vital for the synthesis of more robust Cu/SAPO-34 catalysts. Here we show, via application of model catalysts with homogeneously dispersed isolated Cu ions, that Cu transformations resulting from low-temperature hydrothermal aging and ambient temperature storage can be semi-quantitatively probed with 2-dimensional pulsed electron paramagnetic resonance. Coupled with kinetics, additional material characterizations and DFT simulations, we propose the following catalyst deactivation steps: (1) detachment of Cu(II) ions from cationic positions in the form of Cu(OH)2; (2) irreversible hydrolysis of the SAPO-34 framework forming terminal Al species; and (3) interaction between Cu(OH)2and terminal Al species forming SCR inactive, Cu-aluminate like species. Especially significant is that these reactions are greatly facilitated by condensed water molecules under wet ambient conditions, causing low temperature failure of the commercial Cu/SAPO-34 catalysts.
Framework nucleic acids as programmable carrier for transdermal drug delivery
Authors: Wiraja Christian , Zhu Ying , Lio Daniel Chin Shiuan , Yeo David C. , Xie Mo , Fang Weina , Li Qian , Zheng Mengjia , Van Steensel Maurice , Wang Lihua , Fan Chunhai , Xu Chenjie 
Published: March 2019

AbstractDNA nanostructures are promising drug carriers with their intrinsic biocompatibility, uniformity and versatility. However, rapid serum disintegration leads to low bioavailability at targeted sites following systemic administration, hindering their biomedical applications. Here we demonstrate transdermal delivery of framework nucleic acids (FNAs) through topical applications. By designing FNAs with distinct shapes and sizes, we interrogate their penetration on mice and human skin explant. Skin histology reveals size-dependent penetration, with FNAs ≤75 nm effectively reaching dermis layer. 17 nm-tetrahedral FNAs show greatest penetration to 350 µm from skin periphery. Importantly, structural integrity is maintained during the skin penetration. Employing a mouse melanoma model, topical application of doxorubicin-loaded FNAs accommodates ≥2-fold improvement in drug accumulation and tumor inhibition relative to topically-applied free doxorubicin, or doxorubicin loaded in liposomes and polymeric nanoparticles. Programmable penetration with minimal systemic biodistribution underlines FNA potential as localized transdermal drug delivery carriers.
Subtyping of circulating exosome-bound amyloid β reflects brain plaque deposition
Authors: Lim Carine Z. J. , Zhang Yan , Chen Yu , Zhao Haitao , Stephenson Mary C. , Ho Nicholas R. Y. , Chen Yuan , Chung Jaehoon , Reilhac Anthonin , Loh Tze Ping , Chen Christopher L. H. , Shao Huilin 
Published: March 2019

AbstractDespite intense interests in developing blood measurements of Alzheimer’s disease (AD), the progress has been confounded by limited sensitivity and poor correlation to brain pathology. Here, we present a dedicated analytical platform for measuring different populations of circulating amyloid β (Aβ) proteins – exosome-bound vs. unbound – directly from blood. The technology, termed amplified plasmonic exosome (APEX), leverages in situ enzymatic conversion of localized optical deposits and double-layered plasmonic nanostructures to enable sensitive, multiplexed population analysis. It demonstrates superior sensitivity (~200 exosomes), and enables diverse target co-localization in exosomes. Employing the platform, we find that prefibrillar Aβ aggregates preferentially bind with exosomes. We thus define a population of Aβ as exosome-bound (Aβ42+ CD63+) and measure its abundance directly from AD and control blood samples. As compared to the unbound or total circulating Aβ, the exosome-bound Aβ measurement could better reflect PET imaging of brain amyloid plaques and differentiate various clinical groups.
In-situ aerosol nanoparticle characterization by small angle X-ray scattering at ultra-low volume fraction
Authors: Bauer P. S. , Amenitsch H. , Baumgartner B. , Köberl G. , Rentenberger C. , Winkler P. M. 
Published: March 2019

AbstractState-of-the-art aerosol nanoparticle techniques all have one feature in common: for analysis they remove the nanoparticles from their original environment. Therefore, physical and chemical properties of the particles might be changed or cannot be measured correctly. To overcome these shortcomings, we apply synchrotron based small angle X-ray scattering (SAXS) as an in-situ measurement technique. Contrasting other aerosol studies using SAXS, we focus on particle concentrations which allow direct comparison to common aerosol nanoparticle analyzers. To this end, we analyze aerosol nanoparticles at ambient pressure and concentrations of slightly above ~106 cm−3. A differential mobility particle sizer (DMPS) is operated in parallel. We find that SAXS enables measurement of the primary particles and the aggregates, whereas the DMPS detects only aggregates. We conclude that in-situ nanoparticle characterization with ultra-low volume fractions of ~10–10 is feasible with SAXS. Our technique opens up a doorway to the in-situ analysis of aerosol nanoparticles under atmospheric conditions.
Time-space-resolved origami hierarchical electronics for ultrasensitive detection of physical and chemical stimuli
Authors: Zhang Min , Sun Jiaxing Jeccy , Khatib Muhammad , Lin Zi-Yang , Chen Zi-Han , Saliba Walaa , Gharra A’laa , Horev Yehu David , Kloper Viki , Milyutin Yana , Huynh Tan-Phat , Brandon Simon , Shi Guoyue , Haick Hossam 
Published: March 2019

AbstractRecent years have witnessed thriving progress of flexible and portable electronics, with very high demand for cost-effective and tailor-made multifunctional devices. Here, we report on an ingenious origami hierarchical sensor array (OHSA) written with a conductive ink. Thanks to origami as a controllable hierarchical framework for loading ink material, we have demonstrated that OHSA possesses unique time-space-resolved, high-discriminative pattern recognition (TSR-HDPR) features, qualifying it as a smart sensing device for simultaneous sensing and distinguishing of complex physical and chemical stimuli, including temperature, relative humidity, light and volatile organic compounds (VOCs). Of special importance, OSHA has shown very high sensitivity in differentiating between structural isomers and chiral enantiomers of VOCs – opening a door for wide variety of unique opportunities in several length scales.
Characterization of the hemodynamic response function in white matter tracts for event-related fMRI
Authors: Li Muwei , Newton Allen T. , Anderson Adam W. , Ding Zhaohua , Gore John C. 
Published: March 2019

AbstractAccurate estimates of the BOLD hemodynamic response function (HRF) are crucial for the interpretation and analysis of event-related functional MRI data. To date, however, there have been no comprehensive measurements of the HRF in white matter (WM) despite increasing evidence that BOLD signals in WM change after a stimulus. We performed an event-related cognitive task (Stroop color-word interference) to measure the HRF in selected human WM pathways. The task was chosen in order to produce robust, distributed centers of activity throughout the cortex. To measure the HRF in WM, fiber tracts were reconstructed between each pair of activated cortical areas. We observed clear task-specific HRFs with reduced magnitudes, delayed onsets and prolonged initial dips in WM tracts compared with activated grey matter, thus calling for significant changes to current standard models for accurately characterizing the HRFs in WM and for modifications of standard methods of analysis of functional imaging data.
Systematic comparison of respiratory syncytial virus-induced memory B cell responses in two anatomical compartments
Authors: Shehata Laila , Wieland-Alter Wendy F. , Maurer Daniel P. , Chen Eunice , Connor Ruth I. , Wright Peter F. , Walker Laura M. 
Published: March 2019

AbstractRespiratory syncytial virus (RSV) is a leading cause of hospitalization in infants and young children. Although it is widely agreed that an RSV vaccine should induce both mucosal and systemic antibody responses, little is known about the B cell response to RSV in mucosa-associated lymphoid tissues. Here, we analyze this response by isolating 806 RSV F-specific antibodies from paired adenoid and peripheral blood samples from 4 young children. Overall, the adenoid-derived antibodies show higher binding affinities and neutralization potencies compared to antibodies isolated from peripheral blood. Approximately 25% of the neutralizing antibodies isolated from adenoids originate from a unique population of IgM+and/or IgD+memory B cells that contain a high load of somatic mutations but lack expression of classical memory B cell markers. Altogether, the results provide insight into the local B cell response to RSV and have implications for the development of vaccines that stimulate potent mucosal responses.
Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins
Authors: Miliara Xeni , Tatsuta Takashi , Berry Jamie-Lee , Rouse Sarah L. , Solak Kübra , Chorev Dror S. , Wu Di , Robinson Carol V. , Matthews Stephen , Langer Thomas 
Published: March 2019

AbstractConserved lipid transfer proteins of the Ups/PRELI family regulate lipid accumulation in mitochondria by shuttling phospholipids in a lipid-specific manner across the intermembrane space. Here, we combine structural analysis, unbiased genetic approaches in yeast and molecular dynamics simulations to unravel determinants of lipid specificity within the conserved Ups/PRELI family. We present structures of human PRELID1–TRIAP1 and PRELID3b–TRIAP1 complexes, which exert lipid transfer activity for phosphatidic acid and phosphatidylserine, respectively. Reverse yeast genetic screens identify critical amino acid exchanges that broaden and swap their lipid specificities. We find that amino acids involved in head group recognition and the hydrophobicity of flexible loops regulate lipid entry into the binding cavity. Molecular dynamics simulations reveal different membrane orientations of PRELID1 and PRELID3b during the stepwise release of lipids. Our experiments thus define the structural determinants of lipid specificity and the dynamics of lipid interactions by Ups/PRELI proteins.
Band gap closure, incommensurability and molecular dissociation of dense chlorine
Authors: Dalladay-Simpson Philip , Binns Jack , Peña-Alvarez Miriam , Donnelly Mary-Ellen , Greenberg Eran , Prakapenka Vitali , Chen Xiao-Jia , Gregoryanz Eugene , Howie Ross T. 
Published: March 2019

AbstractDiatomic elemental solids are highly compressible due to the weak interactions between molecules. However, as the density increases the intra- and intermolecular distances become comparable, leading to a range of phenomena, such as structural transformation, molecular dissociation, amorphization, and metallisation. Here we report, following the crystallization of chlorine at 1.15(30) GPa into an ordered orthorhombic structure (oC8), the existence of a mixed-molecular structure (mC8, 130(10)–241(10) GPa) and the concomitant observation of a continuous band gap closure, indicative of a transformation into a metallic molecular form around 200(10) GPa. The onset of dissociation of chlorine is identified by the observation of the incommensurate structure (i-oF4) above 200(10) GPa, before finally adopting a monatomic form (oI2) above 256(10) GPa.