bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Expansion 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

Magnetic 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

We 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

Mast 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

Glioblastoma 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

We 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.
Erratum: Emergence of human G2P[4] rotaviruses containing animal derived gene segments in the post-vaccine era
Authors: Zeller Mark , Nuyts Valerie , Heylen Elisabeth , Coster Sarah De , Conceição-Neto Nádia , Ranst Marc Van , Matthijnssens Jelle
Published: January 2017

Scientific Reports 6: Article number: 36841; published online: 14 November 2016; updated: 03 January 2017 The original version of this Article contained an error in the name of the first author Mark Zeller which was incorrectly given as Jelle Matthijnssens. This error has now been corrected in the PDF and HTML versions of this Article.
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

High 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

Invasive 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

Cellular 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

Human 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.
Correction: Corrigendum: A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion
Authors: Ikenoue Tsuneo , Terakado Yumi , Nakagawa Hayato , Hikiba Yohko , Fujii Tomoaki , Matsubara Daisuke , Noguchi Rei , Zhu Chi , Yamamoto Keisuke , Kudo Yotaro , Asaoka Yoshinari , Yamaguchi Kiyoshi , Ijichi Hideaki , Tateishi Keisuke , Fukushima Noriyoshi , Maeda Shin , Koike Kazuhiko , Furukawa Yoichi
Published: January 2017

Scientific Reports 6: Article number: 23899; published online: 01 April 2016; updated: 03 January 2017 This Article contains an error in the Figure legend of Figure 1. The correct Figure legend is given below: Figure 1. Generation of the mice with liver-specific KrasG12D expression and Pten deletion. (A) Strategy to generate the compound mice.
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

Neural 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

Most 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

Locating 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.
High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa
Authors: Ezquerra-Inchausti Maitane , Barandika Olatz , Anasagasti Ander , Irigoyen Cristina , López de Munain Adolfo , Ruiz-Ederra Javier
Published: January 2017

Retinitis pigmentosa is the most frequent group of inherited retinal dystrophies. It is highly heterogeneous, with more than 80 disease-causing genes 27 of which are known to cause autosomal dominant RP (adRP), having been identified. In this study a total of 29 index cases were ascertained based on a family tree compatible with adRP. A custom panel of 31 adRP genes was analysed by targeted next-generation sequencing using the Ion PGM platform in combination with Sanger sequencing. This allowed us to detect putative disease-causing mutations in 14 out of the 29 (48.28%) families analysed. Remarkably, around 38% of all adRP cases analysed showed mutations affecting the splicing process, mainly due to mutations in genes coding for spliceosome factors (SNRNP200 and PRPF8) but also due to splice-site mutations in RHO. Twelve of the 14 mutations found had been reported previously and two were novel mutations found in PRPF8 in two unrelated patients. In conclusion, our results will lead to more accurate genetic counselling and will contribute to a better characterisation of the disease. In addition, they may have a therapeutic impact in the future given the large number of studies currently underway based on targeted RNA splicing for therapeutic purposes.
The Molecular Structure of Human Red Blood Cell Membranes from Highly Oriented, Solid Supported Multi-Lamellar Membranes
Authors: Himbert Sebastian , Alsop Richard J. , Rose Markus , Hertz Laura , Dhaliwal Alexander , Moran-Mirabal Jose M. , Verschoor Chris P. , Bowdish Dawn M. E. , Kaestner Lars , Wagner Christian , Rheinstädter Maikel C.
Published: January 2017

We prepared highly oriented, multi-lamellar stacks of human red blood cell (RBC) membranes applied on silicon wafers. RBC ghosts were prepared by hemolysis and applied onto functionalized silicon chips and annealed into multi-lamellar RBC membranes. High resolution X-ray diffraction was used to determine the molecular structure of the stacked membranes. We present direct experimental evidence that these RBC membranes consist of nanometer sized domains of integral coiled-coil peptides, as well as liquid ordered (lo) and liquid disordered (ld) lipids. Lamellar spacings, membrane and hydration water layer thicknesses, areas per lipid tail and domain sizes were determined. The common drug aspirin was added to the RBC membranes and found to interact with RBC membranes and preferably partition in the head group region of the lo domain leading to a fluidification of the membranes, i.e., a thinning of the bilayers and an increase in lipid tail spacing. Our results further support current models of RBC membranes as patchy structures and provide unprecedented structural details of the molecular organization in the different domains.
Insensitivity to pain induced by a potent selective closed-state Nav1.7 inhibitor
Authors: Flinspach M. , Xu Q. , Piekarz A. D. , Fellows R. , Hagan R. , Gibbs A. , Liu Y. , Neff R. A. , Freedman J. , Eckert W. A. , Zhou M. , Bonesteel R. , Pennington M. W. , Eddinger K. A. , Yaksh T. L. , Hunter M. , Swanson R. V. , Wickenden A. D.
Published: January 2017

Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.
Evidence for a missing source of efficient ice nuclei
Authors: Du Rui , Du Pengrui , Lu Zedong , Ren Weishan , Liang Zongmin , Qin Saisai , Li Ziming , Wang Yaling , Fu Pingqing
Published: January 2017

It has been known for several decades that some bioaerosols, such as ice-nucleation-active (INA) bacteria, especially Pseudomonas syringae strains, may play a critical potential role in the formation of clouds and precipitation. We investigated bacterial and fungal ice nuclei (IN) in rainwater samples collected from the Hulunber temperate grasslands in North China. The median freezing temperatures (T50) for three years’ worth of unprocessed rain samples were greater than −10 °C based on immersion freezing testing. The heat and filtration treatments inactivated 7–54% and 2–89%, respectively, of the IN activity at temperatures warmer than −10 °C. We also determined the composition of the microbial community. The majority of observed Pseudomonas strains were distantly related to the verified ice-nucleating Pseudomonas strains, as revealed by phylogenetic analysis. Here, we show that there are submicron INA particles <220 nm in rainwater that are not identifiable as the known species of high-INA bacteria and fungi and there may be a new potential type of efficient submicroscale or nanoscale ice nucleator in the regional rainwater samplers. Our results suggest the need for a reinterpretation of the source of high-INA material in the formation of precipitation and contribute to the search for new methods of weather modification.
Polarized white light from hybrid organic/III-nitrides grating structures
Authors: Athanasiou M. , Smith R. M. , Ghataora S. , Wang T.
Published: January 2017

Highly polarised white light emission from a hybrid organic/inorganic device has been achieved. The hybrid devices are fabricated by means of combining blue InGaN-based multiple quantum wells (MQWs) with a one-dimensional (1D) grating structure and down-conversion F8BT yellow light emitting polymer. The 1D grating structure converts the blue emission from unpolarised to highly polarised; Highly polarised yellow emission has been achieved from the F8BT polymer filled and aligned along the periodic nano-channels of the grating structure as a result of enhanced nano-confinement. Optical polarization measurements show that our device demonstrates a polarization degree of up to 43% for the smallest nano-channel width. Furthermore, the hybrid device with such a grating structure allows us to achieve an optimum relative orientation between the dipoles in the donor (i.e., InGaN/GaN MQWs) and the diploes in the acceptor (i.e., the F8BT), maximizing the efficiency of non-radiative energy transfer (NRET) between the donor and the acceptor. Time–resolved micro photoluminescence measurements show a 2.5 times enhancement in the NRET efficiency, giving a maximal NRET efficiency of 90%. It is worth highlighting that the approach developed paves the way for the fabrication of highly polarized white light emitters.
Dendritic and Axonal Propagation Delays Determine Emergent Structures of Neuronal Networks with Plastic Synapses
Authors: Madadi Asl Mojtaba , Valizadeh Alireza , Tass Peter A.
Published: January 2017

Spike-timing-dependent plasticity (STDP) modifies synaptic strengths based on the relative timing of pre- and postsynaptic spikes. The temporal order of spikes turned out to be crucial. We here take into account how propagation delays, composed of dendritic and axonal delay times, may affect the temporal order of spikes. In a minimal setting, characterized by neglecting dendritic and axonal propagation delays, STDP eliminates bidirectional connections between two coupled neurons and turns them into unidirectional connections. In this paper, however, we show that depending on the dendritic and axonal propagation delays, the temporal order of spikes at the synapses can be different from those in the cell bodies and, consequently, qualitatively different connectivity patterns emerge. In particular, we show that for a system of two coupled oscillatory neurons, bidirectional synapses can be preserved and potentiated. Intriguingly, this finding also translates to large networks of type-II phase oscillators and, hence, crucially impacts on the overall hierarchical connectivity patterns of oscillatory neuronal networks.
miRsig: a consensus-based network inference methodology to identify pan-cancer miRNA-miRNA interaction signatures
Authors: Nalluri Joseph J. , Barh Debmalya , Azevedo Vasco , Ghosh Preetam
Published: January 2017

Decoding the patterns of miRNA regulation in diseases are important to properly realize its potential in diagnostic, prog- nostic, and therapeutic applications. Only a handful of studies computationally predict possible miRNA-miRNA interactions; hence, such interactions require a thorough investigation to understand their role in disease progression. In this paper, we design a novel computational pipeline to predict the common signature/core sets of miRNA-miRNA interactions for different diseases using network inference algorithms on the miRNA-disease expression profiles; the individual predictions of these algorithms were then merged using a consensus-based approach to predict miRNA-miRNA associations. We next selected the miRNA-miRNA associations across particular diseases to generate the corresponding disease-specific miRNA-interaction networks. Next, graph intersection analysis was performed on these networks for multiple diseases to identify the common signature/core sets of miRNA interactions. We applied this pipeline to identify the common signature of miRNA-miRNA inter- actions for cancers. The identified signatures when validated using a manual literature search from PubMed Central and the PhenomiR database, show strong relevance with the respective cancers, providing an indirect proof of the high accuracy of our methodology. We developed miRsig, an online tool for analysis and visualization of the disease-specific signature/core miRNA-miRNA interactions, available at: http://bnet.egr.vcu.edu/miRsig.
PDLIM5 links kidney anion exchanger 1 (kAE1) to ILK and is required for membrane targeting of kAE1
Authors: Su Ya , Hiemstra Thomas F. , Yan Yahui , Li Juan , Karet Hannah I. , Rosen Lawrence , Moreno Pablo , Karet Frankl Fiona E.
Published: January 2017

Anion exchanger 1 (AE1) mediates Cl−/HCO3− exchange in erythrocytes and kidney intercalated cells where it functions to maintain normal bodily acid-base homeostasis. AE1’s C-terminal tail (AE1C) contains multiple potential membrane targeting/retention determinants, including a predicted PDZ binding motif, which are critical for its normal membrane residency. Here we identify PDLIM5 as a direct binding partner for AE1 in human kidney, via PDLIM5’s PDZ domain and the PDZ binding motif in AE1C. Kidney AE1 (kAE1), PDLIM5 and integrin-linked kinase (ILK) form a multiprotein complex in which PDLIM5 provides a bridge between ILK and AE1C. Depletion of PDLIM5 resulted in significant reduction in kAE1 at the cell membrane, whereas over-expression of kAE1 was accompanied by increased PDLIM5 levels, underscoring the functional importance of PDLIM5 for proper kAE1 membrane residency, as a crucial linker between kAE1 and actin cytoskeleton-associated proteins in polarized cells.
Nutrition affects insect susceptibility to Bt toxins
Authors: Deans Carrie A. , Behmer Spencer T. , Tessnow Ashley E. , Tamez-Guerra Patricia , Pusztai-Carey Marianne , Sword Gregory A.
Published: January 2017

Pesticide resistance represents a major challenge to global food production. The spread of resistance alleles is the primary explanation for observations of reduced pesticide efficacy over time, but the potential for gene-by-environment interactions (plasticity) to mediate susceptibility has largely been overlooked. Here we show that nutrition is an environmental factor that affects susceptibility to Bt toxins. Protein and carbohydrates are two key macronutrients for insect herbivores, and the polyphagous pest Helicoverpa zea self-selects and performs best on diets that are protein-biased relative to carbohydrates. Despite this, most Bt bioassays employ carbohydrate-biased rearing diets. This study explored the effect of diet protein-carbohydrate content on H. zea susceptibility to Cry1Ac, a common Bt endotoxin. We detected a 100-fold increase in LC50 for larvae on optimal versus carbohydrate-biased diets, and significant diet-mediated variation in survival and performance when challenged with Cry1Ac. Our results suggest that Bt resistance bioassays that use ecologically- and physiologically-mismatched diets over-estimate susceptibility and under-estimate resistance.
Low-temperature atomic layer epitaxy of AlN ultrathin films by layer-by-layer, in-situ atomic layer annealing
Authors: Shih Huan-Yu , Lee Wei-Hao , Kao Wei-Chung , Chuang Yung-Chuan , Lin Ray-Ming , Lin Hsin-Chih , Shiojiri Makoto , Chen Miin-Jang
Published: January 2017

Low-temperature epitaxial growth of AlN ultrathin films was realized by atomic layer deposition (ALD) together with the layer-by-layer, in-situ atomic layer annealing (ALA), instead of a high growth temperature which is needed in conventional epitaxial growth techniques. By applying the ALA with the Ar plasma treatment in each ALD cycle, the AlN thin film was converted dramatically from the amorphous phase to a single-crystalline epitaxial layer, at a low deposition temperature of 300 °C. The energy transferred from plasma not only provides the crystallization energy but also enhances the migration of adatoms and the removal of ligands, which significantly improve the crystallinity of the epitaxial layer. The X-ray diffraction reveals that the full width at half-maximum of the AlN (0002) rocking curve is only 144 arcsec in the AlN ultrathin epilayer with a thickness of only a few tens of nm. The high-resolution transmission electron microscopy also indicates the high-quality single-crystal hexagonal phase of the AlN epitaxial layer on the sapphire substrate. The result opens a window for further extension of the ALD applications from amorphous thin films to the high-quality low-temperature atomic layer epitaxy, which can be exploited in a variety of fields and applications in the near future.
Population genetics of the Manila clam (Ruditapes philippinarum) introduced in North America and Europe
Authors: Cordero David , Delgado Marina , Liu Baozhong , Ruesink Jennifer , Saavedra Carlos
Published: January 2017

Globally, the Manila clam (Ruditapes philippinarum) stands as the second most important bivalve species in fisheries and aquaculture. Native to the Pacific coast of Asia, it is now well-established in North America and Europe, where its on-going management reflects local economic interests. The historic record of transfers spans the 20th century and suggests sequential movement from Japan to North America, as a hitch-hiker on oysters, and then intentional introduction in Europe, but global genetic data are missing. We have studied mitochondrial DNA and microsatellite markers in nine populations from Asia, North America and Europe. The results from the two types of markers indicated a good concordance of present-day genetic structure with the reported history of clam transfers across continents, and no evidence of relevant concealed introductions from continental Asia in Europe and North America. However, European populations showed a loss of genetic variability and significant genetic differentiation as compared to their American counterparts. Our study shows that in spite of the increasing ease for species to spread out of their native range, in the case of the Manila clam this has not resulted in new invasion waves in the two studied continents.
Comparative genome analyses of Mycobacterium avium reveal genomic features of its subspecies and strains that cause progression of pulmonary disease
Authors: Uchiya Kei-ichi , Tomida Shuta , Nakagawa Taku , Asahi Shoki , Nikai Toshiaki , Ogawa Kenji
Published: January 2017

Pulmonary disease caused by nontuberculous mycobacteria (NTM) is increasing worldwide.Mycobacterium aviumis the most clinically significant NTM species in humans and animals, and comprises four subspecies:M. aviumsubsp.avium(MAA),M. aviumsubsp.silvaticum(MAS),M. aviumsubsp.paratuberculosis(MAP), andM. aviumsubsp.hominissuis(MAH). To improve our understanding of the genetic landscape and diversity ofM. aviumand its role in disease, we performed a comparative genome analysis of 79 M. aviumstrains. Our analysis demonstrated that MAH is an open pan-genome species. Phylogenetic analysis based on single nucleotide variants showed that MAH had the highest degree of sequence variability among the subspecies, and MAH strains isolated in Japan and those isolated abroad possessed distinct phylogenetic features. Furthermore, MAP strains, MAS and MAA strains isolated from birds, and many MAH strains that cause the progression of pulmonary disease were grouped in each specific cluster. Comparative genome analysis revealed the presence of genetic elements specific to each lineage, which are thought to be acquired via horizontal gene transfer during the evolutionary process, and identified potential genetic determinants accounting for the pathogenic and host range characteristics ofM. avium.
Soluble OX40L and JAG1 Induce Selective Proliferation of Functional Regulatory T-Cells Independent of canonical TCR signaling
Authors: Kumar Prabhakaran , Alharshawi Khaled , Bhattacharya Palash , Marinelarena Alejandra , Haddad Christine , Sun Zuoming , Chiba Shigeru , Epstein Alan L. , Prabhakar Bellur S.
Published: January 2017

Regulatory T-cells (Tregs) play a pivotal role in maintaining peripheral tolerance. Increasing Treg numbers/functions has been shown to ameliorate autoimmune diseases. However, common Treg expansion approaches use T-Cell Receptor (TCR)-mediated stimulation which also causes proliferation of effector T-cells (Teff). To overcome this limitation, purified patient-specific Tregs are expanded ex vivo and transfused. Although promising, this approach is not suitable for routine clinical use. Therefore, an alternative approach to selectively expand functional Tregs in vivo is highly desired. We report a novel TCR-independent strategy for the selective proliferation of Foxp3+Tregs (without Teff proliferation), by co-culturing CD4+ T-cells with OX40 L+Jagged(JAG)-1+ bone marrow-derived DCs differentiated with GM-CSF or treating them with soluble OX40 L and JAG1 in the presence of exogenous IL-2. Tregs expanded using soluble OX40 L and JAG1 were of suppressive phenotype and delayed the onset of diabetes in NOD mice. Ligation of OX40 L and JAG1 with their cognate-receptors OX40 and Notch3, preferentially expressed on Tregs but not on Teff cells, was required for selective Treg proliferation. Soluble OX40L-JAG1-induced NF-κB activation as well as IL-2-induced STAT5 activation were essential for the proliferation of Tregs with sustained Foxp3 expression. Altogether, these findings demonstrate the utility of soluble OX40 L and JAG1 to induce TCR-independent Treg proliferation.
Personalised proteome analysis by means of protein microarrays made from individual patient samples
Authors: Syafrizayanti  , Lueong Smiths S. , Di Cuixia , Schaefer Jonas V. , Plückthun Andreas , Hoheisel Jörg D.
Published: January 2017

DNA sequencing has advanced to a state that permits studying the genomes of individual patients as nearly a matter of routine. Towards analysing a tissue’s protein content in a similar manner, we established a method for the production of microarrays that represent full-length proteins as they are encoded in individual specimens, exhibiting the particular variations, such as mutations or splice variations, present in these samples. From total RNA isolates, each transcript is copied to a specific location on the array by an on-chip polymerase elongation reaction, followed by in situ cell-free transcription and translation. These microarrays permit parallel analyses of variations in protein structure and interaction that are specific to particular samples.
Induced pluripotent stem cell generation from a man carrying a complex chromosomal rearrangement as a genetic model for infertility studies
Authors: Mouka Aurélie , Izard Vincent , Tachdjian Gérard , Brisset Sophie , Yates Frank , Mayeur Anne , Drévillon Loïc , Jarray Rafika , Leboulch Philippe , Maouche-Chrétien Leila , Tosca Lucie
Published: January 2017

Despite progress in human reproductive biology, the cause of male infertility often remains unknown, due to the lack of appropriate and convenient in vitro models of meiosis. Induced pluripotent stem cells (iPSCs) derived from the cells of infertile patients could provide a gold standard model for generating primordial germ cells and studying their development and the process of spermatogenesis. We report the characterization of a complex chromosomal rearrangement (CCR) in an azoospermic patient, and the successful generation of specific-iPSCs from PBMC-derived erythroblasts. The CCR was characterized by karyotype, fluorescence in situ hybridization and oligonucleotide-based array-comparative genomic hybridization. The CCR included five breakpoints and was caused by the inverted insertion of a chromosome 12 segment into the short arm of one chromosome 7 and a pericentric inversion of the structurally rearranged chromosome 12. Gene mapping of the breakpoints led to the identification of a candidate gene, SYCP3. Erythroblasts from the patient were reprogrammed with Sendai virus vectors to generate iPSCs. We assessed iPSC pluripotency by RT-PCR, immunofluorescence staining and teratoma induction. The generation of specific-iPSCs from patients with a CCR provides a valuable in vitro genetic model for studying the mechanisms by which chromosomal abnormalities alter meiosis and germ cell development.
Modifying effect of mouse double minute-2 promoter variants on risk of recurrence for patients with squamous cell carcinoma of oropharynx
Authors: Zhang Yang , Sturgis Erich M. , Li Yuncheng , Wei Qingyi , Huang Zhigang , Li Guojun
Published: January 2017

Functional mouse double minute-2 (MDM2) promoter variants may alter MDM2 expression and thus affect radiotherapy response and prognosis of squamous cell carcinoma of oropharynx (SCCOP). Thus we assessed association of 2 functional MDM2 promoter variants with recurrence risk of SCCOP. The disease-free survival (DFS) of patients with MDM2rs2279744 TT or MDM2rs937283 AA genotypes was significantly reduced compared with that of patients with corresponding GT/GG or AG/GG genotypes. Multivariable analysis showed patients with TT or AA genotypes had a significantly higher risk of SCCOP recurrence than those with corresponding GT/GG or AG/GG genotypes did. Furthermore, patients with combined risk genotypes of the 2 polymorphisms had significantly worse DFS and a higher recurrence risk than patients with fewer combined risk genotypes did (Ptrend < 0.001). Compared with patients with 0 risk genotypes, patients with 1 or 2 risk genotypes had an approximately 3- or 11-fold increased risk of SCCOP recurrence, respectively. Notably, for both individual and combined polymorphisms, the above similar recurrence risks were particularly higher among patients with human papilloma virus (HPV)-positive tumors. Taken together, our findings suggest that MDM2 promoter variants individually, or more likely jointly, play a role in determining the risk of recurrence of SCCOP, particularly HPV-positive SCCOP.
How a single particle simultaneously modifies the physical reality of two distant others: a quantum nonlocality and weak value study
Authors: de Lima Bernardo Bertúlio , Canabarro Askery , Azevedo Sérgio
Published: January 2017

The concept of wave-particle duality, which is a key element of quantum theory, has been remarkably found to manifest itself in several experimental realizations as in the famous double-slit experiment. In this specific case, a single particle seems to travel through two separated slits simultaneously. Nevertheless, it is never possible to measure it in both slits, which naturally appears as a manifestation of the collapse postulate. In this respect, one could as well ask if it is possible to “perceive” the presence of the particle at the two slits simultaneously, once its collapse could be avoided. In this article, we use the recently proposed entanglement mediation protocol to provide a positive answer to this question. It is shown that a photon which behaves like a wave, i.e., which seems to be present in two distant locations at the same time, can modify two existing physical realities in these locations. Calculations of the “weak trace” left by such photon also enforce the validity of the present argumentation.
The Impact of Gastric Atrophy on the Incidence of Diabetes
Authors: Yu Tse-Ya , Wei Jung-Nan , Kuo Chun-Heng , Liou Jyh-Ming , Lin Mao-Shin , Shih Shyang-Rong , Hua Cyue-Huei , Hsein Yenh-Chen , Hsu Ya-Wen , Chuang Lee-Ming , Lee Mei-Kuei , Hsiao Ching-Hsiang , Wu Ming-Shiang , Li Hung-Yuan
Published: January 2017

Gastric atrophy results in lower plasma ghrelin, higher gastrin secretion, a change in gut microbiota, and altered dietary nutrient absorption, which may be associated with the incidence of diabetes. Helicobacter pylori (H. pylori) infection is a major cause of gastric atrophy and is associated with diabetes in some reports. Since there is no study which investigates the impact of gastric atrophy on diabetes, we conduct a prospective cohort study to examine the relationship between H. pylori infection, gastric atrophy, and incident diabetes. In this study, subjects with gastric atrophy had a lower risk of incident diabetes, compared to those without gastric atrophy. The extent of gastric atrophy, measured by serum pepsinogen (PG) I/II ratio, was correlated with age, H. pylori IgG titer, HOMA2-IR, and HOMA2%B. When gastric atrophy is more extensive, presented as a lower serum PG I/II ratio, the risk of incident diabetes is lower. On the other hand, there was no significant association between H. pylori infection and the incidence of diabetes. In conclusion, the presence and the extent of gastric atrophy, but not H. pylori infection, are associated with incident diabetes. Further studies are needed to investigate the detailed mechanisms and the potential applications of the findings to guide diabetes screening and treatment strategies.