bluuebunny/crossref_metadata_2025_split huggingface dataset:
Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma
Authors: Beug Shawn T. , Beauregard Caroline E. , Healy Cristin , Sanda Tarun , St-Jean Martine , Chabot Janelle , Walker Danielle E. , Mohan Aditya , Earl Nathalie , Lun Xueqing , Senger Donna L. , Robbins Stephen M. , Staeheli Peter , Forsyth Peter A. , Alain Tommy , LaCasse Eric C. , Korneluk Robert G. 
Published: February 2017

AbstractSmall-molecule inhibitor of apoptosis (IAP) antagonists, called Smac mimetic compounds (SMCs), sensitize tumours to TNF-α-induced killing while simultaneously blocking TNF-α growth-promoting activities. SMCs also regulate several immunomodulatory properties within immune cells. We report that SMCs synergize with innate immune stimulants and immune checkpoint inhibitor biologics to produce durable cures in mouse models of glioblastoma in which single agent therapy is ineffective. The complementation of activities between these classes of therapeutics is dependent on cytotoxic T-cell activity and is associated with a reduction in immunosuppressive T-cells. Notably, the synergistic effect is dependent on type I IFN and TNF-α signalling. Furthermore, our results implicate an important role for TNF-α-producing cytotoxic T-cells in mediating the anti-cancer effects of immune checkpoint inhibitors when combined with SMCs. Overall, this combinatorial approach could be highly effective in clinical application as it allows for cooperative and complimentary mechanisms in the immune cell-mediated death of cancer cells.
Hormetic heat stress and HSF-1 induce autophagy to improve survival and proteostasis in C. elegans
Authors: Kumsta Caroline , Chang Jessica T. , Schmalz Jessica , Hansen Malene 
Published: February 2017

AbstractStress-response pathways have evolved to maintain cellular homeostasis and to ensure the survival of organisms under changing environmental conditions. Whereas severe stress is detrimental, mild stress can be beneficial for health and survival, known as hormesis. Although the universally conserved heat-shock response regulated by transcription factor HSF-1 has been implicated as an effector mechanism, the role and possible interplay with other cellular processes, such as autophagy, remains poorly understood. Here we show that autophagy is induced in multiple tissues of Caenorhabditis elegans following hormetic heat stress or HSF-1 overexpression. Autophagy-related genes are required for the thermoresistance and longevity of animals exposed to hormetic heat shock or HSF-1 overexpression. Hormetic heat shock also reduces the progressive accumulation of PolyQ aggregates in an autophagy-dependent manner. These findings demonstrate that autophagy contributes to stress resistance and hormesis, and reveal a requirement for autophagy in HSF-1-regulated functions in the heat-shock response, proteostasis and ageing.
Abrupt cooling over the North Atlantic in modern climate models
Authors: Sgubin Giovanni , Swingedouw Didier , Drijfhout Sybren , Mary Yannick , Bennabi Amine 
Published: February 2017

AbstractObservations over the 20th century evidence no long-term warming in the subpolar North Atlantic (SPG). This region even experienced a rapid cooling around 1970, raising a debate over its potential reoccurrence. Here we assess the risk of future abrupt SPG cooling in 40 climate models from the fifth Coupled Model Intercomparison Project (CMIP5). Contrary to the long-term SPG warming trend evidenced by most of the models, 17.5% of the models (7/40) project a rapid SPG cooling, consistent with a collapse of the local deep-ocean convection. Uncertainty in projections is associated with the models’ varying capability in simulating the present-day SPG stratification, whose realistic reproduction appears a necessary condition for the onset of a convection collapse. This event occurs in 45.5% of the 11 models best able to simulate the observed SPG stratification. Thus, due to systematic model biases, the CMIP5 ensemble as a whole underestimates the chance of future abrupt SPG cooling, entailing crucial implications for observation and adaptation policy.
Large positive in-plane magnetoresistance induced by localized states at nanodomain boundaries in graphene
Authors: Wu Han-Chun , Chaika Alexander N. , Hsu Ming-Chien , Huang Tsung-Wei , Abid Mourad , Abid Mohamed , Aristov Victor Yu , Molodtsova Olga V. , Babenkov Sergey V. , Niu Yuran , Murphy Barry E. , Krasnikov Sergey A. , Lübben Olaf , Liu Huajun , Chun Byong Sun , Janabi Yahya T. , Molotkov Sergei N. , Shvets Igor V. , Lichtenstein Alexander I. , Katsnelson Mikhail I. , Chang Ching-Ray 
Published: February 2017

AbstractGraphene supports long spin lifetimes and long diffusion lengths at room temperature, making it highly promising for spintronics. However, making graphene magnetic remains a principal challenge despite the many proposed solutions. Among these, graphene with zig-zag edges and ripples are the most promising candidates, as zig-zag edges are predicted to host spin-polarized electronic states, and spin–orbit coupling can be induced by ripples. Here we investigate the magnetoresistance of graphene grown on technologically relevant SiC/Si(001) wafers, where inherent nanodomain boundaries sandwich zig-zag structures between adjacent ripples of large curvature. Localized states at the nanodomain boundaries result in an unprecedented positive in-plane magnetoresistance with a strong temperature dependence. Our work may offer a tantalizing way to add the spin degree of freedom to graphene.
Atomic structures of twin boundaries in hexagonal close-packed metallic crystals with particular focus on Mg
Authors: Pei Zongrui , Zhang Xie , Hickel Tilmann , Friák Martin , Sandlöbes Stefanie , Dutta Biswanath , Neugebauer Jörg 
Published: February 2017

AbstractWe have investigated twin boundaries in double-lattice hexagonal close-packed metallic materials, focusing on their atomic geometry. Combining accurate ab-initio methods and large-scale atomistic simulations we address the following two fundamental questions: (i) What are the possible intrinsic twin boundary structures in hcp crystals? (ii) Are these structures stable against small distortions? In order to help end a decade-long controversy over the experimental observations of the atomic structures of twin boundaries, we have determined the energetics, spectra, and transition mechanisms of the twin boundaries. Our results confirm that the mechanical stability controls structures which are observed.
TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury
Authors: Ding Xibing , Jin Shuqing , Tong Yao , Jiang Xi , Chen Zhixia , Mei Shuya , Zhang Liming , Billiar Timothy R. , Li Quan 
Published: February 2017

AbstractAcute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host’s innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4−/−and Myd88−/−mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system.
Method for Dual Viral Vector Mediated CRISPR-Cas9 Gene Disruption in Primary Human Endothelial Cells
Authors: Gong Haixia , Liu Menglin , Klomp Jeff , Merrill Bradley J. , Rehman Jalees , Malik Asrar B. 
Published: February 2017

AbstractHuman endothelial cells (ECs) are widely used to study mechanisms of angiogenesis, inflammation, and endothelial permeability. Targeted gene disruption induced by Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-CRISPR-Associated Protein 9 (Cas9) nuclease gene editing is potentially an important tool for definitively establishing the functional roles of individual genes in ECs. We showed that co-delivery of adenovirus encoding EGFP-tagged Cas9 and lentivirus encoding a single guide RNA (sgRNA) in primary human lung microvascular ECs (HLMVECs) disrupted the expression of the Tie2 gene and protein. Tie2 disruption increased basal endothelial permeability and prevented permeability recovery following injury induced by the inflammatory stimulus thrombin. Thus, gene deletion via viral co-delivery of CRISPR-Cas9 in primary human ECs provides a novel platform to investigate signaling mechanisms of normal and perturbed EC function without the need for clonal expansion.
NMR metabolic fingerprints of murine melanocyte and melanoma cell lines: application to biomarker discovery
Authors: Santana-Filho Arquimedes Paixão de , Jacomasso Thiago , Riter Daniel Suss , Barison Andersson , Iacomini Marcello , Winnischofer Sheila Maria Brochado , Sassaki Guilherme Lanzi 
Published: February 2017

AbstractMelanoma is the most aggressive type of skin cancer and efforts to improve the diagnosis of this neoplasia are largely based on the use of cell lines. Metabolomics is currently undergoing great advancements towards its use to screening for disease biomarkers. Although NMR metabolomics includes both 1D and 2D methodologies, there is a lack of data in the literature regarding heteronuclear 2D NMR assignments of the metabolome from eukaryotic cell lines. The present study applied NMR-based metabolomics strategies to characterize aqueous and lipid extracts from murine melanocytes and melanoma cell lines with distinct tumorigenic potential, successfully obtaining fingerprints of the metabolites from the extracts of the cell lines by means of 2D NMR HSQC correlation maps. Relative amounts of the identified metabolites were compared between the 4 cell lines. Multivariate analysis of 1H NMR data was able not only to differentiate the melanocyte cell line from the tumorigenic ones but also distinguish among the 3 tumorigenic cell lines. We also investigated the effects of mitogenic agents, and found that they can markedly influence the metabolome of the melanocyte cell line, resembling the pattern of most proliferative cell lines.
MicroRNA-155 Controls Exosome Synthesis and Promotes Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma
Authors: Mikamori Manabu , Yamada Daisaku , Eguchi Hidetoshi , Hasegawa Shinichiro , Kishimoto Tomoya , Tomimaru Yoshito , Asaoka Tadafumi , Noda Takehiro , Wada Hiroshi , Kawamoto Koichi , Gotoh Kunihito , Takeda Yutaka , Tanemura Masahiro , Mori Masaki , Doki Yuichiro 
Published: February 2017

AbstractThe cancer drug gemcitabine (GEM) is a key drug for treating pancreatic ductal adenocarcinoma (PDAC), but PDAC cells develop chemoresistance after long-term administration. Since the tolerance was immediately spread to every PDAC tissue in a patient, it is assumed that some certain efficient mechanisms underlay in the development of chemoresistance. Changes in the levels of particular microRNAs or alterations in intercellular communication play a dominant role in chemoresistance development, and recent data also suggest that exosomes play an important role in this process. In this study, we revealed that the loop conferred chemoresistance in PDAC cells. The loop was as follows; 1, The long-term exposure of GEM increased miR-155 expression in PDAC cells. 2, The increase of miR-155 induced two different functions; exosome secretion and chemoresistance ability via facilitating the anti-apoptotic activity. 3, Exosome deliver the miR-155 into the other PDAC cells and induce the following function. The target therapy to miR-155 or the exosome secretion effectively attenuated the chemoresistance, and these results were validated with both clinical samples and in vivo experiments. This mechanism represents a novel therapeutic target in GEM treatment to PDAC.
PDI regulates seizure activity via NMDA receptor redox in rats
Authors: Kim Ji Yang , Ko Ah-Rhem , Hyun Hye-Won , Min Su-Ji , Kim Ji-Eun 
Published: February 2017

AbstractRedox modulation of cysteine residues is one of the post-translational modifications of N-methyl-D-aspartate receptor (NMDAR). Protein disulfide isomerases (PDI), an endoplasmic reticulum (ER) chaperone, plays a crucial role in catalyzing disulfide bond formation, reduction, and isomerization. In the present study, we found that PDI bound to NMDAR in the normal hippocampus, and that this binding was increased in chronic epileptic rats. In vitro thiol reductase assay revealed that PDI increased the amount of thiols on full-length recombinant NR1 protein. PDI siRNA, 5–5′-dithio-bis(2-nitrobenzoic acid) (DTNB), bacitracin and PDI antibody reduced seizure susceptibility in response to pilocarpine. In addition, PDI knockdown effectively ameliorated spontaneous seizure activity in chronic epileptic rats. Anticonvulsive effects of PDI siRNA were correlated to the reduction of the amount of free- and nitrosothiols on NMDAR, accompanied by the inhibition of PDI activity. However, PDI knockdown did not lead to alteration in basal neurotransmission or ER stress under physiological condition. These findings provide mechanistic insight into sulfhydration of disulfide bonds on NMDAR by PDI, and suggest that PDI may represent a target of potential therapeutics for epilepsy, which avoids a possible side effect on physiological receptor functionality.
Quick and inexpensive paraffin-embedding method for dynamic bone formation analyses
Authors: Porter Amy , Irwin Regina , Miller Josselyn , Horan Daniel J. , Robling Alexander G. , McCabe Laura R. 
Published: February 2017

AbstractWe have developed a straightforward method that uses paraffin-embedded bone for undemineralized thin sectioning, which is amenable to subsequent dynamic bone formation measurements. Bone has stiffer material properties than paraffin, and therefore has hereforto usually been embedded in plastic blocks, cured and sectioned with a tungsten carbide knife to obtain mineralized bone sections for dynamic bone formation measures. This process is expensive and requires special equipment, experienced personnel, and time for the plastic to penetrate the bone and cure. Our method utilizes a novel way to prepare mineralized bone that increases its compliance so that it can be embedded and easily section in paraffin blocks. The approach is simple, quick, and costs less than 10% of the price for plastic embedded bone sections. While not effective for static bone measures, this method allows dynamic bone analyses to be readily performed in laboratories worldwide which might not otherwise have access to traditional (plastic) equipment and expertise.
A one-week 5-choice serial reaction time task to measure impulsivity and attention in adult and adolescent mice
Authors: Remmelink Esther , Chau Uyen , Smit August B. , Verhage Matthijs , Loos Maarten 
Published: February 2017

AbstractMany psychiatric disorders emerge during adolescence. The study of executive functions in animal models of these disorders critically requires short-duration tasks measuring these functions before the animal ages. Here, a novel 5-choice serial reaction time task (5-CSRTT) protocol is presented, to measure attention and impulsivity within one week, without scheduled food deprivation and with little animal handling. Mice were allowed 24-h/day task access from their home-cage, during which they could self-pace task progression and earn unlimited food rewards depending on task performance. Manipulation of task parameters in this self-paced 5-CSRTT protocol (SP-5C) affected attentional performance and impulsivity to a similar extent as previously observed in the 5-CSRTT. Task activity followed intrinsic circadian rhythm, distinctive for the SP-5C protocol, with task performance stable over the day. The sensitivity of the SP-5C protocol to detect strain differences between C57BL/6J, DBA/2 J, BXD16 and BXD62 mice was demonstrated as well as its suitability for testing adolescent mice. Acute administration of the muscarinic acetylcholine receptor antagonist scopolamine impaired attentional performance, providing initial pharmacological validation of the task. The SP-5C substantially shortens the assessment of impulsivity and attention, increases test efficiency and enables the assessment of adolescent mouse models of psychiatric disorders.
Comparative proteomic analysis of horseweed (Conyza canadensis) biotypes identifies candidate proteins for glyphosate resistance
Authors: González-Torralva Fidel , Brown Adrian P. , Chivasa Stephen 
Published: February 2017

AbstractEmergence of glyphosate-resistant horseweed (Conyza canadensis) biotypes is an example of how unrelenting use of a single mode of action herbicide in agricultural weed control drives genetic adaptation in targeted species. While in other weeds glyphosate resistance arose from target site mutation or target gene amplification, the resistance mechanism in horseweed uses neither of these, being instead linked to reduced herbicide uptake and/or translocation. The molecular components underpinning horseweed glyphosate-resistance remain unknown. Here, we used anin vitroleaf disc system for comparative analysis of proteins extracted from control and glyphosate-treated tissues of glyphosate-resistant and glyphosate-susceptible biotypes. Analysis of shikimic acid accumulation,ABC-transportergene expression, and cell death were used to select a suitable glyphosate concentration and sampling time for enriching proteins pivotal to glyphosate resistance. Protein gel analysis and mass spectrometry identified mainly chloroplast proteins differentially expressed between the biotypes before and after glyphosate treatment. Chloroplasts are the organelles in which the shikimate pathway, which is targeted by glyphosate, is located. Calvin cycle enzymes and proteins of unknown function were among the proteins identified. Our study provides candidate proteins that could be pivotal in engendering resistance and implicates chloroplasts as the primary sites driving glyphosate-resistance in horseweed.
Ubiquitin C-terminal hydrolase37 regulates Tcf7 DNA binding for the activation of Wnt signalling
Authors: Han Wonhee , Lee Hyeyoon , Han Jin-Kwan 
Published: February 2017

AbstractThe Tcf/Lef family of transcription factors mediates the Wnt/β-catenin pathway that is involved in a wide range of biological processes, including vertebrate embryogenesis and diverse pathogenesis. Post-translational modifications, including phosphorylation, sumoylation and acetylation, are known to be important for the regulation of Tcf/Lef proteins. However, the importance of ubiquitination and ubiquitin-mediated regulatory mechanisms for Tcf/Lef activity are still unclear. Here, we newly show that ubiquitin C-terminal hydrolase 37 (Uch37), a deubiquitinase, interacts with Tcf7 (formerly named Tcf1) to activate Wnt signalling. Biochemical analyses demonstrated that deubiquitinating activity of Uch37 is not involved in Tcf7 protein stability but is required for the association of Tcf7 to target gene promoter in both Xenopus embryo and human liver cancer cells. In vivo analyses further revealed that Uch37 functions as a positive regulator of the Wnt/β-catenin pathway downstream of β-catenin stabilization that is required for the expression of ventrolateral mesoderm genes during Xenopus gastrulation. Our study provides a new mechanism for chromatin occupancy of Tcf7 and uncovers the physiological significance of Uch37 during early vertebrate development by regulating the Wnt/β-catenin pathway.
Heterogeneous Nucleation of Trichloroethylene Ozonation Products in the Formation of New Fine Particles
Authors: Wang Ning , Sun Xiaomin , Chen Jianmin , Li Xiang 
Published: February 2017

AbstractFree radicals in atmosphere have played an important role in the atmospheric chemistry. The chloro-Criegee free radicals are produced easily in the decomposition of primary ozonide (POZ) of the trichloroethylene, and can react with O2, NO, NO2, SO2 and H2O subsequently. Then the inorganic salts, polar organic nitrogen and organic sulfur compounds, oxygen-containing heterocyclic intermediates and polyhydroxy compounds can be obtained. The heterogeneous nucleation of oxidation intermediates in the formation of fine particles is investigated using molecular dynamics simulation. The detailed nucleation processes are reported. According to molecular dynamics simulation, the nucleation with a diameter of 2 nm is formed in the Organic Compounds-(NH4)2SO4-H2O system. The spontaneous nucleation is an important process in the formation of fine particles in atmosphere. The model study gives a good example from volatile organic compounds to new fine particles.
A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties
Authors: Zaini Mohamad A. , Müller Christine , Ackermann Tobias , Reinshagen Jeanette , Kortman Gertrud , Pless Ole , Calkhoven Cornelis F. 
Published: February 2017

AbstractAn important part of the beneficial effects of calorie restriction (CR) on healthspan and lifespan is mediated through regulation of protein synthesis that is under control of the mechanistic target of rapamycin complex 1 (mTORC1). As one of its activities, mTORC1 stimulates translation into the metabolic transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) isoform Liver-specific Inhibitory Protein (LIP). Regulation of LIP expression strictly depends on a translation re-initiation event that requires a conserved cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA. We showed before that suppression of LIP in mice, reflecting reduced mTORC1-signaling at the C/EBPβ level, results in CR-type of metabolic improvements. Hence, we aim to find possibilities to pharmacologically down-regulate LIP in order to induce CR-mimetic effects. We engineered a luciferase-based cellular reporter system that acts as a surrogate for C/EBPβ-mRNA translation, emulating uORF-dependent C/EBPβ-LIP expression under different translational conditions. By using the reporter system in a high-throughput screening (HTS) strategy we identified drugs that reduce LIP. The drug Adefovir Dipivoxil passed all counter assays and increases fatty acid β-oxidation in a hepatoma cell line in a LIP-dependent manner. Therefore, these drugs that suppress translation into LIP potentially exhibit CR-mimetic properties.