bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRAF2 protects against cerebral ischemia-induced brain injury by suppressing necroptosis
Authors: Li Jie , Zhang Jingyu , Zhang Yusuo , Wang Zichuang , Song Yanmei , Wei Shanwen , He Meijun , You Shoujiang , Jia Jia , Cheng Jian 
Published: April 2019

AbstractNecroptosis contributes to ischemia-induced brain injury. Tumor necrosis factor (TNF) receptor associated factor 2 (TRAF2) has been reported to suppress necroptotic cell death under several pathological conditions. In this study, we investigated the role of TRAF2 in experimental stroke using a mouse middle cerebral artery occlusion (MCAO) model and in vitro cellular models. TRAF2 expression in the ischemic brain was assessed with western blot and real-time RT-PCR. Gene knockdown of TRAF2 by lentivirus was utilized to investigate the role of TRAF2 in stroke outcomes. The expression of TRAF2 was significantly induced in the ischemic brain at 24 h after reperfusion, and neurons and microglia were two of the cellular sources of TRAF2 induction. Striatal knockdown of TRAF2 increased infarction size, cell death, microglial activation and the expression of pro-inflammatory markers at 24 h after reperfusion. TRAF2 expression and necroptosis were induced in mouse primary microglia treated with conditioned medium collected from neurons subject to oxygen and glucose deprivation (OGD) and in TNFα-treated mouse hippocampal neuronal HT-22 cells in the presence of the pan-caspase inhibitor Z-VAD. In addition, TRAF2 knockdown exacerbated microglial cell death and neuronal cell death under these conditions. Moreover, pre-treatment with a specific necroptosis inhibitor necrostatin-1 (nec-1) suppressed the cell death exacerbated by TRAF2 knockdown in the brain following MCAO, indicating that TRAF2 impacted ischemic brain damage through necroptosis mechanism. Taken together, our results demonstrate that TRAF2 is a novel regulator of cerebral ischemic injury.
Blockade of HMGB1 signaling pathway by ethyl pyruvate inhibits tumor growth in diffuse large B-cell lymphoma
Authors: Zhang Tian , Guan Xu-Wen , Gribben John G. , Liu Feng-Ting , Jia Li 
Published: April 2019

AbstractHigh mobility group box 1 (HMGB1) protein in the tumor microenvironment actively contributes to tumor progression but its role in diffuse large B-cell lymphoma (DLBCL) is unknown. The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade of HMGB1 signaling pathway could inhibit tumorigenesis. We report that HMGB1 promotes proliferation of DLBCL cells by activation of AKT, extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3) and SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase (Src). Ethyl pyruvate (EP), an anti-inflammatory agent, inhibits HMGB1 active release from DLBCL cells and significantly inhibited proliferation of DLBCL cells in vitro. Treatment with EP significantly prevented and inhibited tumor growth in vivo and prolonged DLBCL-bearing mice survival. EP significantly downregulated HMGB1 expression and phosphorylation of Src and ERK1/2 in mice lymphoma tissue. EP induced accumulation of the cell cycle inhibitor p27 but downregulated expression of cyclin-dependent kinase 2 (CDK2). Increased nuclear translocation of p27 interacted with CDK2 and cyclin A, which led to blockade of cell cycle progression at the G1 to S phase transition. In conclusion, we demonstrated for the first time that blockade of HMGB1-mediated signaling pathway by EP effectively inhibited DLBCL tumorigenesis and disease progression.
A space–time tradeoff for implementing a function with master equation dynamics
Authors: Wolpert David H. , Kolchinsky Artemy , Owen Jeremy A. 
Published: April 2019

AbstractMaster equations are commonly used to model the dynamics of physical systems, including systems that implement single-valued functions like a computer’s update step. However, many such functions cannot be implemented by any master equation, even approximately, which raises the question of how they can occur in the real world. Here we show how any function over some “visible” states can be implemented with master equation dynamics—if the dynamics exploits additional, “hidden” states at intermediate times. We also show that any master equation implementing a function can be decomposed into a sequence of “hidden” timesteps, demarcated by changes in what state-to-state transitions have nonzero probability. In many real-world situations there is a cost both for more hidden states and for more hidden timesteps. Accordingly, we derive a “space–time” tradeoff between the number of hidden states and the number of hidden timesteps needed to implement any given function.
Spin-current-mediated rapid magnon localisation and coalescence after ultrafast optical pumping of ferrimagnetic alloys
Authors: Iacocca E. , Liu T.-M. , Reid A. H. , Fu Z. , Ruta S. , Granitzka P. W. , Jal E. , Bonetti S. , Gray A. X. , Graves C. E. , Kukreja R. , Chen Z. , Higley D. J. , Chase T. , Le Guyader L. , Hirsch K. , Ohldag H. , Schlotter W. F. , Dakovski G. L. , Coslovich G. , Hoffmann M. C. , Carron S. , Tsukamoto A. , Kirilyuk A. , Kimel A. V. , Rasing Th. , Stöhr J. , Evans R. F. L. , Ostler T. , Chantrell R. W. , Hoefer M. A. , Silva T. J. , Dürr H. A. 
Published: April 2019

AbstractSub-picosecond magnetisation manipulation via femtosecond optical pumping has attracted wide attention ever since its original discovery in 1996. However, the spatial evolution of the magnetisation is not yet well understood, in part due to the difficulty in experimentally probing such rapid dynamics. Here, we find evidence of a universal rapid magnetic order recovery in ferrimagnets with perpendicular magnetic anisotropy via nonlinear magnon processes. We identify magnon localisation and coalescence processes, whereby localised magnetic textures nucleate and subsequently interact and grow in accordance with a power law formalism. A hydrodynamic representation of the numerical simulations indicates that the appearance of noncollinear magnetisation via optical pumping establishes exchange-mediated spin currents with an equivalent 100% spin polarised charge current density of 107 A cm−2. Such large spin currents precipitate rapid recovery of magnetic order after optical pumping. The magnon processes discussed here provide new insights for the stabilization of desired meta-stable states.
Spy&Go purification of SpyTag-proteins using pseudo-SpyCatcher to access an oligomerization toolbox
Authors: Khairil Anuar Irsyad N. A. , Banerjee Anusuya , Keeble Anthony H. , Carella Alberto , Nikov Georgi I. , Howarth Mark 
Published: April 2019

AbstractPeptide tags are a key resource, introducing minimal change while enabling a consistent process to purify diverse proteins. However, peptide tags often provide minimal benefit post-purification. We previously designed SpyTag, forming an irreversible bond with its protein partner SpyCatcher. SpyTag provides an easy route to anchor, bridge or multimerize proteins. Here we establish Spy&Go, enabling protein purification using SpyTag. Through rational engineering we generated SpyDock, which captures SpyTag-fusions and allows efficient elution. Spy&Go enabled sensitive purification of SpyTag-fusions from Escherichia coli, giving superior purity than His-tag/nickel-nitrilotriacetic acid. Spy&Go allowed purification of mammalian-expressed, N-terminal, C-terminal or internal SpyTag. As an oligomerization toolbox, we established a panel of SpyCatcher-linked coiled coils, so SpyTag-fusions can be dimerized, trimerized, tetramerized, pentamerized, hexamerized or heptamerized. Assembling oligomers for Death Receptor 5 stimulation, we probed multivalency effects on cancer cell death. Spy&Go, combined with simple oligomerization, should have broad application for exploring multivalency in signaling.
Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation
Authors: Dondelinger Yves , Delanghe Tom , Priem Dario , Wynosky-Dolfi Meghan A. , Sorobetea Daniel , Rojas-Rivera Diego , Giansanti Piero , Roelandt Ria , Gropengiesser Julia , Ruckdeschel Klaus , Savvides Savvas N. , Heck Albert J. R. , Vandenabeele Peter , Brodsky Igor E. , Bertrand Mathieu J. M. 
Published: April 2019

AbstractRIPK1 regulates cell death and inflammation through kinase-dependent and -independent mechanisms. As a scaffold, RIPK1 inhibits caspase-8-dependent apoptosis and RIPK3/MLKL-dependent necroptosis. As a kinase, RIPK1 paradoxically induces these cell death modalities. The molecular switch between RIPK1 pro-survival and pro-death functions remains poorly understood. We identify phosphorylation of RIPK1 on Ser25 by IKKs as a key mechanism directly inhibiting RIPK1 kinase activity and preventing TNF-mediated RIPK1-dependent cell death. Mimicking Ser25 phosphorylation (S > D mutation) protects cells and mice from the cytotoxic effect of TNF in conditions of IKK inhibition. In line with their roles in IKK activation, TNF-induced Ser25 phosphorylation of RIPK1 is defective in TAK1- or SHARPIN-deficient cells and restoring phosphorylation protects these cells from TNF-induced death. Importantly, mimicking Ser25 phosphorylation compromises the in vivo cell death-dependent immune control of Yersinia infection, a physiological model of TAK1/IKK inhibition, and rescues the cell death-induced multi-organ inflammatory phenotype of the SHARPIN-deficient mice.
CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation
Authors: Krajewska Malgorzata , Dries Ruben , Grassetti Andrew V. , Dust Sofia , Gao Yang , Huang Hao , Sharma Bandana , Day Daniel S. , Kwiatkowski Nicholas , Pomaville Monica , Dodd Oliver , Chipumuro Edmond , Zhang Tinghu , Greenleaf Arno L. , Yuan Guo-Cheng , Gray Nathanael S. , Young Richard A. , Geyer Matthias , Gerber Scott A. , George Rani E. 
Published: April 2019

AbstractCyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and selectively affects the expression of genes involved in the DNA damage response (DDR) and mRNA processing. Yet, the mechanisms underlying such selectivity remain unclear. Here we show that CDK12 inhibition in cancer cells lacking CDK12 mutations results in gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlates with an increased number of intronic polyadenylation sites, a feature especially prominent among DDR genes. Phosphoproteomic analysis indicated that CDK12 directly phosphorylates pre-mRNA processing factors, including those regulating PCPA. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition primarily due to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.
Optimizing the conservation of migratory species over their full annual cycle
Authors: Schuster Richard , Wilson Scott , Rodewald Amanda D. , Arcese Peter , Fink Daniel , Auer Tom , Bennett Joseph. R. 
Published: April 2019

AbstractLimited knowledge of the distribution, abundance, and habitat associations of migratory species hinders effective conservation actions. We use Neotropical migratory birds as a model group to compare approaches to prioritize land conservation needed to support ≥30% of the global abundances of 117 species. Specifically, we compare scenarios from spatial optimization models to achieve conservation targets by: 1) area requirements for conserving >30% abundance of each species for each week of the year independently vs. combined; 2) including vs. ignoring spatial clustering of species abundance; and 3) incorporating vs. avoiding human-dominated landscapes. Solutions integrating information across the year require 56% less area than those integrating weekly abundances, with additional reductions when shared-use landscapes are included. Although incorporating spatial population structure requires more area, geographical representation among priority sites improves substantially. These findings illustrate that globally-sourced citizen science data can elucidate key trade-offs among opportunity costs and spatiotemporal representation of conservation efforts.
Towards reliable extreme weather and climate event attribution
Authors: Bellprat Omar , Guemas Virginie , Doblas-Reyes Francisco , Donat Markus G. 
Published: April 2019

AbstractClimate change is shaping extreme heat and rain. To what degree human activity has increased the risk of high impact events is of high public concern and still heavily debated. Recent studies attributed single extreme events to climate change by comparing climate model experiments where the influence of an external driver can be included or artificially suppressed. Many of these results however did not properly account for model errors in simulating the probabilities of extreme event occurrences. Here we show, exploiting advanced correction techniques from the weather forecasting field, that correcting properly for model probabilities alters the attributable risk of extreme events to climate change. This study illustrates the need to correct for this type of model error in order to provide trustworthy assessments of climate change impacts.
Mechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting
Authors: Okazaki Kei-ichi , Wöhlert David , Warnau Judith , Jung Hendrik , Yildiz Özkan , Kühlbrandt Werner , Hummer Gerhard 
Published: April 2019

AbstractNa+/H+ antiporters exchange sodium ions and protons on opposite sides of lipid membranes. The electroneutral Na+/H+ antiporter NhaP from archaea Pyrococcus abyssi (PaNhaP) is a functional homolog of the human Na+/H+ exchanger NHE1, which is an important drug target. Here we resolve the Na+ and H+ transport cycle of PaNhaP by transition-path sampling. The resulting molecular dynamics trajectories of repeated ion transport events proceed without bias force, and overcome the enormous time-scale gap between seconds-scale ion exchange and microseconds simulations. The simulations reveal a hydrophobic gate to the extracellular side that opens and closes in response to the transporter domain motion. Weakening the gate by mutagenesis makes the transporter faster, suggesting that the gate balances competing demands of fidelity and efficiency. Transition-path sampling and a committor-based reaction coordinate optimization identify the essential motions and interactions that realize conformational alternation between the two access states in transporter function.
Non-stationary coherent quantum many-body dynamics through dissipation
Authors: Buča Berislav , Tindall Joseph , Jaksch Dieter 
Published: April 2019

AbstractThe assumption that quantum systems relax to a stationary state in the long-time limit underpins statistical physics and much of our intuitive understanding of scientific phenomena. For isolated systems this follows from the eigenstate thermalization hypothesis. When an environment is present the expectation is that all of phase space is explored, eventually leading to stationarity. Notable exceptions are decoherence-free subspaces that have important implications for quantum technologies and have so far only been studied for systems with a few degrees of freedom. Here we identify simple and generic conditions for dissipation to prevent a quantum many-body system from ever reaching a stationary state. We go beyond dissipative quantum state engineering approaches towards controllable long-time non-stationarity typically associated with macroscopic complex systems. This coherent and oscillatory evolution constitutes a dissipative version of a quantum time crystal. We discuss the possibility of engineering such complex dynamics with fermionic ultracold atoms in optical lattices.
Reconstructing missing complex networks against adversarial interventions
Authors: Xue Yuankun , Bogdan Paul 
Published: April 2019

AbstractInteractions within complex network components define their operational modes, collective behaviors and global functionality. Understanding the role of these interactions is limited by either sensing methodologies or intentional adversarial efforts that sabotage the network structure. To overcome the partial observability and infer with good fidelity the unobserved network structures (latent subnetworks that are not random samples of the full network), we propose a general causal inference framework for reconstructing network structures under unknown adversarial interventions. We explore its applicability in both biological and social systems to recover the latent structures of human protein complex interactions and brain connectomes, as well as to infer the camouflaged social network structure in a simulated removal process. The demonstrated effectiveness establishes its good potential for capturing hidden information in much broader research domains.
Atomically defined angstrom-scale all-carbon junctions
Authors: Tan Zhibing , Zhang Dan , Tian Han-Rui , Wu Qingqing , Hou Songjun , Pi Jiuchan , Sadeghi Hatef , Tang Zheng , Yang Yang , Liu Junyang , Tan Yuan-Zhi , Chen Zhao-Bin , Shi Jia , Xiao Zongyuan , Lambert Colin , Xie Su-Yuan , Hong Wenjing 
Published: April 2019

AbstractFull-carbon electronics at the scale of several angstroms is an expeimental challenge, which could be overcome by exploiting the versatility of carbon allotropes. Here, we investigate charge transport through graphene/single-fullerene/graphene hybrid junctions using a single-molecule manipulation technique. Such sub-nanoscale electronic junctions can be tuned by band gap engineering as exemplified by various pristine fullerenes such as C60, C70, C76 and C90. In addition, we demonstrate further control of charge transport by breaking the conjugation of their π systems which lowers their conductance, and via heteroatom doping of fullerene, which introduces transport resonances and increase their conductance. Supported by our combined density functional theory (DFT) calculations, a promising future of tunable full-carbon electronics based on numerous sub-nanoscale fullerenes in the large family of carbon allotropes is anticipated.
Functional Screening Identifies MicroRNAs as Multi-Cellular Regulators of Heart Failure
Authors: Verjans Robin , Derks Wouter J. A. , Korn Kerstin , Sönnichsen Birte , van Leeuwen Rick E. W. , Schroen Blanche , van Bilsen Marc , Heymans Stephane 
Published: April 2019

AbstractHeart failure (HF) is the leading cause of death in the Western world. Pathophysiological processes underlying HF development, including cardiac hypertrophy, fibrosis and inflammation, are controlled by specific microRNAs (miRNAs). Whereas most studies investigate miRNA function in one particular cardiac cell type, their multicellular function is poorly investigated. The present study probed 194 miRNAs –differentially expressed in cardiac inflammatory disease – for regulating cardiomyocyte size, cardiac fibroblasts collagen content, and macrophage polarization. Of the tested miRNAs, 13%, 26%, and 41% modulated cardiomyocyte size, fibroblast collagen production, and macrophage polarization, respectively. Seventeen miRNAs affected all three cellular processes, including miRNAs with established (miR-210) and unknown roles in cardiac pathophysiology (miR-145-3p). These miRNAs with a multi-cellular function commonly target various genes. In-depth analysis in vitro of previously unstudied miRNAs revealed that the observed phenotypical alterations concurred with changes in transcript and protein levels of hypertrophy-, fibrosis- and inflammation-related genes. MiR-145-3p and miR-891a-3p were identified to regulate the fibrotic response, whereas miR-223-3p, miR-486-3p, and miR-488-5p modulated macrophage activation and polarisation. In conclusion, miRNAs are multi-cellular regulators of different cellular processes underlying cardiac disease. We identified previously undescribed roles of miRNAs in hypertrophy, fibrosis, and inflammation, and attribute new cellular effects to various well-known miRNAs.
Stimulated Ionic Telegraph Noise in Filamentary Memristive Devices
Authors: Brivio Stefano , Frascaroli Jacopo , Covi Erika , Spiga Sabina 
Published: April 2019

AbstractRandom telegraph noise is a widely investigated phenomenon affecting the reliability of the reading operation of the class of memristive devices whose operation relies on formation and dissolution of conductive filaments. The trap and the release of electrons into and from defects surrounding the filament produce current fluctuations at low read voltages. In this work, telegraphic resistance variations are intentionally stimulated through pulse trains in HfO2-based memristive devices. The stimulated noise results from the re-arrangement of ionic defects constituting the filament responsible for the switching. Therefore, the stimulated noise has an ionic origin in contrast to the electronic nature of conventional telegraph noise. The stimulated noise is interpreted as raising from a dynamic equilibrium establishing from the tendencies of ionic drift and diffusion acting on the edges of conductive filament. We present a model that accounts for the observed increase of noise amplitude with the average device resistance. This work provides the demonstration and the physical foundation for the intentional stimulation of ionic telegraph noise which, on one hand, affects the programming operations performed with trains of identical pulses, as for neuromorphic computing, and on the other hand, it can open opportunities for applications relying on stochastic processes in nanoscaled devices.
Unveiling novel targets of paclitaxel resistance by single molecule long-read RNA sequencing in breast cancer
Authors: Lian Bi , Hu Xin , Shao Zhi-ming 
Published: April 2019

AbstractRNA sequencing has become one of the most common technology to study transcriptomes in cancer, whereas its length limits its application on alternative splicing (AS) events and novel isoforms. Firstly, we applied single molecule long-read RNA sequencing (Iso-seq) and de novo assembly with short-read RNA sequencing (RNA-seq) in both wild type (231-WT) and paclitaxel resistant type (231-PTX) of human breast cancer cell MDA-MBA-231. The two sequencing technology provide both the accurate transcript sequences and the deep transcript coverage. Then we combined shor-read and long-read RNA-seq to analyze alternative events and novel isoforms. Last but not the least, we selected BAK1 as our candidate target to verify our analysis. Our results implied that improved characterization of cancer genomic function may require the application of the single molecule long-read RNA sequencing to get the deeper and more precise view to transcriptional level. Our results imply that improved characterization of cancer genomic function may require the application of the single molecule long-read RNA sequencing to get the deeper and more precise view to transcriptional level.