bluuebunny/crossref_metadata_2025_split huggingface dataset:
In vivo single-molecule imaging of syntaxin1A reveals polyphosphoinositide- and activity-dependent trapping in presynaptic nanoclusters
Authors: Bademosi Adekunle T. , Lauwers Elsa , Padmanabhan Pranesh , Odierna Lorenzo , Chai Ye Jin , Papadopulos Andreas , Goodhill Geoffrey J. , Verstreken Patrik , van Swinderen Bruno , Meunier Frédéric A. 
Published: January 2017

AbstractSyntaxin1A is organized in nanoclusters that are critical for the docking and priming of secretory vesicles from neurosecretory cells. Whether and how these nanoclusters are affected by neurotransmitter release in nerve terminals from a living organism is unknown. Here we imaged photoconvertible syntaxin1A-mEos2 in the motor nerve terminal ofDrosophilalarvae by single-particle tracking photoactivation localization microscopy. Opto- and thermo-genetic neuronal stimulation increased syntaxin1A-mEos2 mobility, and reduced the size and molecular density of nanoclusters, suggesting an activity-dependent release of syntaxin1A from the confinement of nanoclusters. Syntaxin1A mobility was increased by mutating its polyphosphoinositide-binding site or preventing SNARE complex assembly via co-expression of tetanus toxin light chain. In contrast, syntaxin1A mobility was reduced by preventing SNARE complex disassembly. Our data demonstrate that polyphosphoinositide favours syntaxin1A trapping, and show that SNARE complex disassembly leads to syntaxin1A dissociation from nanoclusters. Lateral diffusion and trapping of syntaxin1A in nanoclusters therefore dynamically regulate neurotransmitter release.
JAK/STAT controls organ size and fate specification by regulating morphogen production and signalling
Authors: Recasens-Alvarez Carles , Ferreira Ana , Milán Marco 
Published: January 2017

AbstractA stable pool of morphogen-producing cells is critical for the development of any organ or tissue. Here we present evidence that JAK/STAT signalling in the Drosophila wing promotes the cycling and survival of Hedgehog-producing cells, thereby allowing the stable localization of the nearby BMP/Dpp-organizing centre in the developing wing appendage. We identify the inhibitor of apoptosis dIAP1 and Cyclin A as two critical genes regulated by JAK/STAT and contributing to the growth of the Hedgehog-expressing cell population. We also unravel an early role of JAK/STAT in guaranteeing Wingless-mediated appendage specification, and a later one in restricting the Dpp-organizing activity to the appendage itself. These results unveil a fundamental role of the conserved JAK/STAT pathway in limb specification and growth by regulating morphogen production and signalling, and a function of pro-survival cues and mitogenic signals in the regulation of the pool of morphogen-producing cells in a developing organ.
An allosteric conduit facilitates dynamic multisite substrate recognition by the SCFCdc4 ubiquitin ligase
Authors: Csizmok Veronika , Orlicky Stephen , Cheng Jing , Song Jianhui , Bah Alaji , Delgoshaie Neda , Lin Hong , Mittag Tanja , Sicheri Frank , Chan Hue Sun , Tyers Mike , Forman-Kay Julie D. 
Published: January 2017

AbstractThe ubiquitin ligase SCFCdc4 mediates phosphorylation-dependent elimination of numerous substrates by binding one or more Cdc4 phosphodegrons (CPDs). Methyl-based NMR analysis of the Cdc4 WD40 domain demonstrates that Cyclin E, Sic1 and Ash1 degrons have variable effects on the primary Cdc4WD40 binding pocket. Unexpectedly, a Sic1-derived multi-CPD substrate (pSic1) perturbs methyls around a previously documented allosteric binding site for the chemical inhibitor SCF-I2. NMR cross-saturation experiments confirm direct contact between pSic1 and the allosteric pocket. Phosphopeptide affinity measurements reveal negative allosteric communication between the primary CPD and allosteric pockets. Mathematical modelling indicates that the allosteric pocket may enhance ultrasensitivity by tethering pSic1 to Cdc4. These results suggest negative allosteric interaction between two distinct binding pockets on the Cdc4WD40 domain may facilitate dynamic exchange of multiple CPD sites to confer ultrasensitive dependence on substrate phosphorylation.
Death receptor 6 contributes to autoimmunity in lupus-prone mice
Authors: Fujikura Daisuke , Ikesue Masahiro , Endo Tsutomu , Chiba Satoko , Higashi Hideaki , Uede Toshimitsu 
Published: January 2017

AbstractExpansion of autoreactive follicular helper T (Tfh) cells is tightly restricted to prevent induction of autoantibody-dependent immunological diseases, such as systemic lupus erythematosus (SLE). Here we show expression of an orphan immune regulator, death receptor 6 (DR6/TNFRSF21), on a population of Tfh cells that are highly expanded in lupus-like disease progression in mice. Genome-wide screening reveals an interaction between syndecan-1 and DR6 resulting in immunosuppressive functions. Importantly, syndecan-1 is expressed specifically on autoreactive germinal centre (GC) B cells that are critical for maintenance of Tfh cells. Syndecan-1 expression level on GC B cells is associated with Tfh cell expansion and disease progression in lupus-prone mouse strains. In addition, Tfh cell suppression by DR6-specific monoclonal antibody delays disease progression in lupus-prone mice. These findings suggest that the DR6/syndecan-1 axis regulates aberrant GC reactions and could be a therapeutic target for autoimmune diseases such as SLE.
Purely antiferromagnetic magnetoelectric random access memory
Authors: Kosub Tobias , Kopte Martin , Hühne Ruben , Appel Patrick , Shields Brendan , Maletinsky Patrick , Hübner René , Liedke Maciej Oskar , Fassbender Jürgen , Schmidt Oliver G. , Makarov Denys 
Published: January 2017

AbstractMagnetic random access memory schemes employing magnetoelectric coupling to write binary information promise outstanding energy efficiency. We propose and demonstrate a purely antiferromagnetic magnetoelectric random access memory (AF-MERAM) that offers a remarkable 50-fold reduction of the writing threshold compared with ferromagnet-based counterparts, is robust against magnetic disturbances and exhibits no ferromagnetic hysteresis losses. Using the magnetoelectric antiferromagnet Cr2O3, we demonstrate reliable isothermal switching via gate voltage pulses and all-electric readout at room temperature. As no ferromagnetic component is present in the system, the writing magnetic field does not need to be pulsed for readout, allowing permanent magnets to be used. Based on our prototypes, we construct a comprehensive model of the magnetoelectric selection mechanisms in thin films of magnetoelectric antiferromagnets, revealing misfit induced ferrimagnetism as an important factor. Beyond memory applications, the AF-MERAM concept introduces a general all-electric interface for antiferromagnets and should find wide applicability in antiferromagnetic spintronics.
Relaxation oscillations and hierarchy of feedbacks in MAPK signaling
Authors: Kochańczyk Marek , Kocieniewski Paweł , Kozłowska Emilia , Jaruszewicz-Błońska Joanna , Sparta Breanne , Pargett Michael , Albeck John G. , Hlavacek William S. , Lipniacki Tomasz 
Published: January 2017

AbstractWe formulated a computational model for a MAPK signaling cascade downstream of the EGF receptor to investigate how interlinked positive and negative feedback loops process EGF signals into ERK pulses of constant amplitude but dose-dependent duration and frequency. A positive feedback loop involving RAS and SOS, which leads to bistability and allows for switch-like responses to inputs, is nested within a negative feedback loop that encompasses RAS and RAF, MEK, and ERK that inhibits SOS via phosphorylation. This negative feedback, operating on a longer time scale, changes switch-like behavior into oscillations having a period of 1 hour or longer. Two auxiliary negative feedback loops, from ERK to MEK and RAF, placed downstream of the positive feedback, shape the temporal ERK activity profile but are dispensable for oscillations. Thus, the positive feedback introduces a hierarchy among negative feedback loops, such that the effect of a negative feedback depends on its position with respect to the positive feedback loop. Furthermore, a combination of the fast positive feedback involving slow-diffusing membrane components with slower negative feedbacks involving faster diffusing cytoplasmic components leads to local excitation/global inhibition dynamics, which allows the MAPK cascade to transmit paracrine EGF signals into spatially non-uniform ERK activity pulses.
The Three-Herb Formula Shuang-Huang-Lian stabilizes mast cells through activation of mitochondrial calcium uniporter
Authors: Gao Yuan , Hou Rui , Fei Qiaoling , Fang Lei , Han Yixin , Cai Runlan , Peng Cheng , Qi Yun 
Published: January 2017

AbstractMast cells (MCs) are key effector cells of IgE-FcεRI- or MrgprX2-mediated signaling event. Shuang-Huang-Lian (SHL), a herbal formula from Chinese Pharmacopoeia, has been clinically used in type I hypersensitivity. Our previous study demonstrated that SHL exerted a non-negligible effect on MC stabilization. Herein, we sought to elucidate the molecular mechanisms of the prominent anti-allergic ability of SHL. MrgprX2- and IgE-FcεRI-mediated MC activationin vitroandin vivomodels were developed by using compound 48/80 (C48/80) and shrimp tropomyosin (ST), respectively. Our data showed that SHL markedly dampened C48/80- or ST-induced MC degranulationin vitroandin vivo. Mechanistic study indicated that cytosolic Ca2+(Ca2+[c]) level decreased rapidly and sustainably after SHL treatment, and then returned to homeostasis when SHL was withdrawn. Moreover, SHL decreases Ca2+[c]levels mainly through enhancing the mitochondrial Ca2+(Ca2+[m]) uptake. After genetically silencing or pharmacologic inhibiting mitochondrial calcium uniporter (MCU), the effect of SHL on the Ca2+[c]level and MC degranulation was significantly weakened. Simultaneously, the activation of SHL on Ca2+[m]uptake was completely lost. Collectively, by activating MCU, SHL decreases Ca2+[c]level to stabilize MCs, thus exerting a remarkable anti-allergic activity, which could have considerable influences on clinical practice and research.
Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype
Authors: Xue Nina , Zhou Qin , Ji Ming , Jin Jing , Lai Fangfang , Chen Ju , Zhang Mengtian , Jia Jing , Yang Huarong , Zhang Jie , Li Wenbin , Jiang Jiandong , Chen Xiaoguang 
Published: January 2017

AbstractGlioblastoma is an aggressive tumor that is associated with distinctive infiltrating microglia/macrophages populations. Previous studies demonstrated that chlorogenic acid (5-caffeoylquinic acid, CHA), a phenolic compound with low molecular weight, has an anti-tumor effect in multiple malignant tumors. In the present study, we focused on the macrophage polarization to investigate the molecular mechanisms behind the anti-glioma response of CHA in vitro and in vivo. We found that CHA treatment increased the expression of M1 markers induced by LPS/IFNγ, including iNOS, MHC II (I-A/I-E subregions) and CD11c, and reduced the expression of M2 markers Arg and CD206 induced by IL-4, resulting in promoting the production of apoptotic-like cancer cells and inhibiting the growth of tumor cells by co-culture experiments. The activations of STAT1 and STAT6, which are two crucial signaling events in M1 and M2-polarization, were significantly promoted and suppressed by CHA in macrophages, respectively. Furthermore, In G422 xenograft mice, CHA increased the proportion of CD11c-positive M1 macrophages and decreased the distribution of CD206-positive M2 macrophages in tumor tissue, consistent with the reduction of tumor weight observed in CHA-treated mice. Overall these findings indicated CHA as a potential therapeutic approach to reduce glioma growth through promoting M1-polarized macrophage and inhibiting M2 phenotypic macrophage.
Targeted RNA-Seq profiling of splicing pattern in the DMD gene: exons are mostly constitutively spliced in human skeletal muscle
Authors: Bougé Anne-Laure , Murauer Eva , Beyne Emmanuelle , Miro Julie , Varilh Jessica , Taulan Magali , Koenig Michel , Claustres Mireille , Tuffery-Giraud Sylvie 
Published: January 2017

AbstractWe have analysed the splicing pattern of the human Duchenne Muscular Dystrophy (DMD) transcript in normal skeletal muscle. To achieve depth of coverage required for the analysis of this lowly expressed gene in muscle, we designed a targeted RNA-Seq procedure that combines amplification of the full-length 11.3 kb DMD cDNA sequence and 454 sequencing technology. A high and uniform coverage of the cDNA sequence was obtained that allowed to draw up a reliable inventory of the physiological alternative splicing events in the muscular DMD transcript. In contrast to previous assumptions, we evidenced that most of the 79 DMD exons are constitutively spliced in skeletal muscle. Only a limited number of 12 alternative splicing events were identified, all present at a very low level. These include previously known exon skipping events but also newly described pseudoexon inclusions and alternative 3′ splice sites, of which one is the first functional NAGNAG splice site reported in the DMD gene. This study provides the first RNA-Seq-based reference of DMD splicing pattern in skeletal muscle and reports on an experimental procedure well suited to detect condition-specific differences in this low abundance transcript that may prove useful for diagnostic, research or RNA-based therapeutic applications.
In situ heavy ion irradiation studies of nanopore shrinkage and enhanced radiation tolerance of nanoporous Au
Authors: Li Jin , Fan C. , Ding J. , Xue S. , Chen Y. , Li Q. , Wang H. , Zhang X. 
Published: January 2017

AbstractHigh energy particle radiations induce severe microstructural damage in metallic materials. Nanoporous materials with a giant surface-to-volume ratio may alleviate radiation damage in irradiated metallic materials as free surface are defect sinks. Here we show, by using in situ Kr ion irradiation in a transmission electron microscope at room temperature, that nanoporous Au indeed has significantly improved radiation tolerance comparing with coarse-grained, fully dense Au. In situ studies show that nanopores can absorb and eliminate a large number of radiation-induced defect clusters. Meanwhile, nanopores shrink (self-heal) during radiation, and their shrinkage rate is pore size dependent. Furthermore, the in situ studies show dose-rate-dependent diffusivity of defect clusters. This study sheds light on the design of radiation-tolerant nanoporous metallic materials for advanced nuclear reactor applications.
Local alignment vectors reveal cancer cell-induced ECM fiber remodeling dynamics
Authors: Lee Byoungkoo , Konen Jessica , Wilkinson Scott , Marcus Adam I. , Jiang Yi 
Published: January 2017

AbstractInvasive cancer cells interact with the surrounding extracellular matrix (ECM), remodeling ECM fiber network structure by condensing, degrading, and aligning these fibers. We developed a novel local alignment vector analysis method to quantitatively measure collagen fiber alignment as a vector field using Circular Statistics. This method was applied to human non-small cell lung carcinoma (NSCLC) cell lines, embedded as spheroids in a collagen gel. Collagen remodeling was monitored using second harmonic generation imaging under normal conditions and when the LKB1-MARK1 pathway was disrupted through RNAi-based approaches. The results showed that inhibiting LKB1 or MARK1 in NSCLC increases the collagen fiber alignment and captures outward alignment vectors from the tumor spheroid, corresponding to high invasiveness of LKB1 mutant cancer cells. With time-lapse imaging of ECM micro-fiber morphology, the local alignment vector can measure the dynamic signature of invasive cancer cell activity and cell-migration-induced ECM and collagen remodeling and realigning dynamics.
Premature senescence of endothelial cells upon chronic exposure to TNFα can be prevented by N-acetyl cysteine and plumericin
Authors: Khan Shafaat Y. , Awad Ezzat M. , Oszwald Andre , Mayr Manuel , Yin Xiaoke , Waltenberger Birgit , Stuppner Hermann , Lipovac Markus , Uhrin Pavel , Breuss Johannes M. 
Published: January 2017

AbstractCellular senescence is characterized by a permanent cell-cycle arrest and a pro-inflammatory secretory phenotype, and can be induced by a variety of stimuli, including ionizing radiation, oxidative stress, and inflammation. In endothelial cells, this phenomenon might contribute to vascular disease. Plasma levels of the inflammatory cytokine tumor necrosis factor alpha (TNFα) are increased in age-related and chronic conditions such as atherosclerosis, rheumatoid arthritis, psoriasis, and Crohn’s disease. Although TNFα is a known activator of the central inflammatory mediator NF-κB, and can induce the intracellular generation of reactive oxygen species (ROS), the question whether TNFα can induce senescence has not been answered conclusively. Here, we investigated the effect of prolonged TNFα exposure on the fate of endothelial cells and found that such treatment induced premature senescence. Induction of endothelial senescence was prevented by the anti-oxidant N-acetyl cysteine, as well as by plumericin and PHA-408, inhibitors of the NF-κB pathway. Our results indicated that prolonged TNFα exposure could have detrimental consequences to endothelial cells by causing senescence and, therefore, chronically increased TNFα levels might possibly contribute to the pathology of chronic inflammatory diseases by driving premature endothelial senescence.
Disruption of cell adhesion by an antibody targeting the cell-adhesive intermediate (X-dimer) of human P-cadherin
Authors: Kudo Shota , Caaveiro Jose M. M. , Nagatoishi Satoru , Miyafusa Takamitsu , Matsuura Tadashi , Sudou Yukio , Tsumoto Kouhei 
Published: January 2017

AbstractHuman P-cadherin is a cell adhesion protein of the family of classical cadherins, the overexpression of which is correlated with poor prognosis in various types of cancer. Antibodies inhibiting cell-cell adhesion mediated by P-cadherin show clear therapeutic effect, although the mechanistic basis explaining their effectiveness is still unclear. Based on structural, physicochemical, and functional analyses, we have elucidated the molecular mechanism of disruption of cell adhesion by antibodies targeting human P-cadherin. Herein we have studied three different antibodies, TSP5, TSP7, and TSP11, each recognizing a different epitope on the surface of the cell-adhesive domain (EC1). Although all these three antibodies recognized human P-cadherin with high affinity, only TSP7 disrupted cell adhesion. Notably, we demonstrated that TSP7 abolishes cell adhesion by disabling the so-called X-dimer (a kinetic adhesive intermediate), in addition to disrupting the strand-swap dimer (the final thermodynamic state). The inhibition of the X-dimer was crucial for the overall inhibitory effect, raising the therapeutic value of a kinetic intermediary not only for preventing, but also for reversing, cell adhesion mediated by a member of the classical cadherin family. These findings should help to design more innovative and effective therapeutic solutions targeting human P-cadherin.
Speed hysteresis and noise shaping of traveling fronts in neural fields: role of local circuitry and nonlocal connectivity
Authors: Capone Cristiano , Mattia Maurizio 
Published: January 2017

AbstractNeural field models are powerful tools to investigate the richness of spatiotemporal activity patterns like waves and bumps, emerging from the cerebral cortex. Understanding how spontaneous and evoked activity is related to the structure of underlying networks is of central interest to unfold how information is processed by these systems. Here we focus on the interplay between local properties like input-output gain function and recurrent synaptic self-excitation of cortical modules, and nonlocal intermodular synaptic couplings yielding to define a multiscale neural field. In this framework, we work out analytic expressions for the wave speed and the stochastic diffusion of propagating fronts uncovering the existence of an optimal balance between local and nonlocal connectivity which minimizes the fluctuations of the activation front propagation. Incorporating an activity-dependent adaptation of local excitability further highlights the independent role that local and nonlocal connectivity play in modulating the speed of propagation of the activation and silencing wavefronts, respectively. Inhomogeneities in space of local excitability give raise to a novel hysteresis phenomenon such that the speed of waves traveling in opposite directions display different velocities in the same location. Taken together these results provide insights on the multiscale organization of brain slow-waves measured during deep sleep and anesthesia.
Effect of particle volume fraction on the settling velocity of volcanic ash particles: insights from joint experimental and numerical simulations
Authors: Del Bello Elisabetta , Taddeucci Jacopo , de’ Michieli Vitturi Mattia , Scarlato Piergiorgio , Andronico Daniele , Scollo Simona , Kueppers Ulrich , Ricci Tullio 
Published: January 2017

AbstractMost of the current ash transport and dispersion models neglect particle-fluid (two-way) and particle-fluid plus particle-particle (four-way) reciprocal interactions during particle fallout from volcanic plumes. These interactions, a function of particle concentration in the plume, could play an important role, explaining, for example, discrepancies between observed and modelled ash deposits. Aiming at a more accurate prediction of volcanic ash dispersal and sedimentation, the settling of ash particles at particle volume fractions (ϕp) ranging 10−7-10−3 was performed in laboratory experiments and reproduced by numerical simulations that take into account first the two-way and then the four-way coupling. Results show that the velocity of particles settling together can exceed the velocity of particles settling individually by up to 4 times for ϕp ~ 10−3. Comparisons between experimental and simulation results reveal that, during the sedimentation process, the settling velocity is largely enhanced by particle-fluid interactions but partly hindered by particle-particle interactions with increasing ϕp. Combining the experimental and numerical results, we provide an empirical model allowing correction of the settling velocity of particles of any size, density, and shape, as a function of ϕp. These corrections will impact volcanic plume modelling results as well as remote sensing retrieval techniques for plume parameters.
Testing the controllability of contextual cuing of visual search
Authors: Luque David , Vadillo Miguel A. , Lopez Francisco J. , Alonso Rafael , Shanks David R. 
Published: January 2017

AbstractLocating a target among distractors improves when the configuration of distractors consistently cues the target’s location across search trials, an effect called contextual cuing of visual search (CC). The important issue of whether CC is automatic has previously been studied by asking whether it can occur implicitly (outside awareness). Here we ask the novel question: is CC of visual search controllable? In 3 experiments participants were exposed to a standard CC procedure during Phase 1. In Phase 2, they localized a new target, embedded in configurations (including the previous target) repeated from Phase 1. Despite robust contextual cuing, congruency effects – which would imply the orientation of attention towards the old target in repeated configurations – were found in none of the experiments. The results suggest that top-down control can be exerted over contextually-guided visual search.