bluuebunny/crossref_metadata_2025 huggingface dataset:
Specific mutations in the D1–D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors
Authors: Bastola Prabhakar , Wang Feng , Schaich Matthew A , Gan Taiping , Freudenthal Bret D , Chou Tsui-Fen , Chien Jeremy
Published: November 2017

Valosin-containing protein (VCP), together with several partner proteins, extracts ubiquitinated client proteins from E3 ligase complex and facilitates their degradation through ubiquitin–proteasome system. Therefore, it plays an important role in regulating protein quality control and various cellular pathways. Recent studies also identified VCP as a lineage-specific essential gene in ovarian cancer. An orally bioavailable VCP inhibitor, CB-5083, is currently in Phase I clinical trials because it shows therapeutic effects in multiple tumor xenograft models. However, the mechanism of resistance to CB-5083 is unknown. Here, we characterized molecular mechanism of resistance to CB-5083. Using incremental exposure to CB-5083, we established CB-5083-resistant ovarian cancer cells that showed five- to six-fold resistancein vitrocompared with parental cells. Genomic and complementary DNA sequencing of theVCPcoding region revealed a pattern of co-selected mutations: (1) missense mutations at codon 470 in one copy resulting in increased ATPase activity and (2) nonsense or frameshift mutations at codon 606 or codon 616 in another copy causing the loss of allele-specific expression. Unbiased molecular docking studies showed codon 470 as a putative binding site for CB-5083. Furthermore, the analysis of somatic mutations in cancer genomes from the Cancer Genome Atlas (TCGA) indicated that codon 616 contains hotspot mutations inVCP. Thus, identification of these mutations associated within vitroresistance to VCP inhibitors may be useful as potential theranostic markers while screening for patients to enroll in clinical trials. VCP has emerged as a viable therapeutic target for several cancer types, and therefore targeting such hyperactive VCP mutants should aid in improving the therapeutic outcome in cancer patients.
Prototype chemical synapse chip for spatially patterned neurotransmitter stimulation of the retina ex vivo
Authors: Rountree Corey M. , Raghunathan Ashwin , Troy John B. , Saggere Laxman
Published: November 2017

Biomimetic stimulation of the retina with neurotransmitters, the natural agents of communication at chemical synapses, could be more effective than electrical stimulation for treating blindness from photoreceptor degenerative diseases. Recent studies have demonstrated the feasibility of neurotransmitter stimulation by injecting glutamate, a primary retinal neurotransmitter, into the retina at isolated single sites. Here, we demonstrate spatially patterned multisite stimulation of the retina with glutamate, offering the first experimental evidence for applicability of this strategy for translating visual patterns into afferent neural signals. To accomplish pattern stimulation, we fabricated a special microfluidic device comprising an array of independently addressable microports connected to tiny on-chip glutamate reservoirs via microchannels. The device prefilled with glutamate was interfaced with explanted rat retinas placed over a multielectrode array (MEA) with the retinal ganglion cells (RGC) contacting the electrodes and photoreceptor surface contacting the microports. By independently and simultaneously activating a subset of the microports with modulated pressure pulses, small boluses of glutamate were convectively injected at multiple sites in alphabet patterns over the photoreceptor surface. We found that the glutamate-driven RGC responses recorded through the MEA system were robust and spatially laid out in patterns strongly resembling the injection patterns. The stimulations were also highly localized with spatial resolutions comparable to or better than electrical retinal prostheses. Our findings suggest that surface stimulation of the retina with neurotransmitters in pixelated patterns of visual images is feasible and an artificial chemical synapse chip based on this approach could potentially circumvent the limitations of electrical retinal prostheses.
Optical focal plane based on MEMS light lead-in for geometric camera calibration
Authors: Li Jin , Liu Zilong
Published: November 2017

The focal plane of a collimator used for the geometric calibration of an optical camera is a key element in the calibration process. The traditional focal plane of the collimator has only a single aperture light lead-in, resulting in a relatively unreliable calibration accuracy. Here we demonstrate a multi-aperture micro-electro-mechanical system (MEMS) light lead-in device that is located at the optical focal plane of the collimator used to calibrate the geometric distortion in cameras. Without additional volume or power consumption, the random errors of this calibration system are decreased by the multi-image matrix. With this new construction and a method for implementing the system, the reliability of high-accuracy calibration of optical cameras is guaranteed.
Stimulated left DLPFC-nucleus accumbens functional connectivity predicts the anti-depression and anti-anxiety effects of rTMS for depression
Authors: Du Lian , Liu Huan , Du Wanyi , Chao Fenglei , Zhang Lei , Wang Kejian , Huang Chunxia , Gao Yuan , Tang Yong
Published: November 2017

Not all depression patients effectively respond to repeated transcranial magnetic stimulation (rTMS). We tested whether the intrinsic functional connectivity (FC) strength between the stimulated left dorsolateral prefrontal cortex (DLPFC) and left nucleus accumbens (NAcc) might predict effects of rTMS. Twenty-two medication-naïve depression patients received rTMS on left DLPFC for 2 weeks and underwent baseline functional magnetic resonance imaging (fMRI). We compared the amplitude of the low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) in the stimulated target (the cortex region directly stimulated by rTMS) located in the left DLPFC, and the left NAcc, as well as the intrinsic FC of the DLPFC–NAcc between early improvers and non-improvers. We evaluated the association between the baseline brain imaging features (ALFF, ReHo, and FC) and improvements in depression and anxiety symptoms. We found that the pretreatment ALFF and ReHo in the stimulated DLPFC and left NAcc did not significantly differ between the subgroups. The early improvers displayed increased negative FC strength between the stimulated DLPFC and left NAcc with respect to non-improvers. The stimulated DLPFC–NAcc FC strength negatively correlated with improved depressive and anxious symptoms. This study is the first to demonstrate that the resting-state FC of the stimulated DLPFC–NAcc, rather than regional brain activity or local synchronization in the stimulated target, might predict the anti-depression and anti-anxiety effects of rTMS for depression.
ProBDNF/p75NTR/sortilin pathway is activated in peripheral blood of patients with alcohol dependence
Authors: Zhou Li , Xiong Jing , Ruan Chun-Sheng , Ruan Ye , Liu Dennis , Bao Jian-Jun , Zhou Xin-Fu
Published: November 2017

Alcohol dependence is a worldwide problem with a great social and economic burden in many countries. A number of studies have suggested that BDNF (mature BDNF) and its precursor (proBDNF) play important roles in the alcohol dependence. However, what roles of the mBDNF/proBDNF pathways play during the pathological process of alcohol dependence are not clearly understood. In our clinical study, peripheral blood was sampled from 30 male patients with alcohol dependence and 50 healthy males (as control). The protein levels of proBDNF, p75NTR, sortilin, mBDNF, TrkB and mRNA levels ofBDNF,p75NTR,sortilin, andTrkBwere detected in the peripheral blood in our study. We found that the protein levels of proBDNF and p75NTR were increased, but not the sortilin protein level; while the TrkB protein level was decreased in the alcohol dependence patients compared with healthy controls. Moreover, the mRNA levels ofp75NTRandsortilinfrom the lymphocytes were slightly increased; whileBDNFandTrkBwere significantly decreased. The ELISA results of mBDNF and TrkB were declined in the alcohol dependence group. The levels of mBDNF and TrkB were negatively correlated with the average amount of daily ethanol consumption, and the levels of proBDNF, p75NTR and sortilin were positively correlated with the average amount of ethanol consumption per day. The ratio of proBDNF to mBDNF was altered in alcohol dependence patients. The balance between the proBDNF/p75NTR and mBDNF/TrkB signalling pathways appeared dysregulated in alcohol dependence. Our results suggested that both pathways may participate in the complex processes of alcohol dependence.
Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes
Authors: Zhu Jingjing , Powis de Tenbossche Céline G. , Cané Stefania , Colau Didier , van Baren Nicolas , Lurquin Christophe , Schmitt-Verhulst Anne-Marie , Liljeström Peter , Uyttenhove Catherine , Van den Eynde Benoit J.
Published: November 2017

Despite impressive clinical success, cancer immunotherapy based on immune checkpoint blockade remains ineffective in many patients due to tumoral resistance. Here we use the autochthonous TiRP melanoma model, which recapitulates the tumoral resistance signature observed in human melanomas. TiRP tumors resist immunotherapy based on checkpoint blockade, cancer vaccines or adoptive T-cell therapy. TiRP tumors recruit and activate tumor-specific CD8+T cells, but these cells then undergo apoptosis. This does not occur with isogenic transplanted tumors, which are rejected after adoptive T-cell therapy. Apoptosis of tumor-infiltrating lymphocytes can be prevented by interrupting the Fas/Fas-ligand axis, and is triggered by polymorphonuclear-myeloid-derived suppressor cells, which express high levels of Fas-ligand and are enriched in TiRP tumors. Blocking Fas-ligand increases the anti-tumor efficacy of adoptive T-cell therapy in TiRP tumors, and increases the efficacy of checkpoint blockade in transplanted tumors. Therefore, tumor-infiltrating lymphocytes apoptosis is a relevant mechanism of immunotherapy resistance, which could be blocked by interfering with the Fas/Fas-ligand pathway.
Identification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer’s disease
Authors: Mann Aman P. , Scodeller Pablo , Hussain Sazid , Braun Gary B. , Mölder Tarmo , Toome Kadri , Ambasudhan Rajesh , Teesalu Tambet , Lipton Stuart A. , Ruoslahti Erkki
Published: November 2017

Cerebrovascular changes occur in Alzheimer’s disease (AD). Using in vivo phage display, we searched for molecular markers of the neurovascular unit, including endothelial cells and astrocytes, in mouse models of AD. We identified a cyclic peptide, CDAGRKQKC (DAG), that accumulates in the hippocampus of hAPP-J20 mice at different ages. Intravenously injected DAG peptide homes to neurovascular unit endothelial cells and to reactive astrocytes in mouse models of AD. We identified connective tissue growth factor (CTGF), a matricellular protein that is highly expressed in the brain of individuals with AD and in mouse models, as the target of the DAG peptide. We also showed that exogenously delivered DAG homes to the brain in mouse models of glioblastoma, traumatic brain injury, and Parkinson’s disease. DAG may potentially be used as a tool to enhance delivery of therapeutics and imaging agents to sites of vascular changes and astrogliosis in diseases associated with neuroinflammation.
Symmetry control of nanorod superlattice driven by a governing force
Authors: Liang Yujia , Xie Yong , Chen Dongxue , Guo Chuanfei , Hou Shuai , Wen Tao , Yang Fengyou , Deng Ke , Wu Xiaochun , Smalyukh Ivan I. , Liu Qian
Published: November 2017

Nanoparticle self-assembly promises scalable fabrication of composite materials with unique properties, but symmetry control of assembled structures remains a challenge. By introducing a governing force in the assembly process, we develop a strategy to control assembly symmetry. As a demonstration, we realize the tetragonal superlattice of octagonal gold nanorods, breaking through the only hexagonal symmetry of the superlattice so far. Surprisingly, such sparse tetragonal superstructure exhibits much higher thermostability than its close-packed hexagonal counterpart. Multiscale modeling reveals that the governing force arises from hierarchical molecular and colloidal interactions. This force dominates the interactions involved in the assembly process and determines the superlattice symmetry, leading to the tetragonal superlattice that becomes energetically favorable over its hexagonal counterpart. This strategy might be instructive for designing assembly of various nanoparticles and may open up a new avenue for realizing diverse assembly structures with pre-engineered properties.
Phospholipid flippase ATP11C is endocytosed and downregulated following Ca2+-mediated protein kinase C activation
Authors: Takatsu Hiroyuki , Takayama Masahiro , Naito Tomoki , Takada Naoto , Tsumagari Kazuya , Ishihama Yasushi , Nakayama Kazuhisa , Shin Hye-Won
Published: November 2017

We and others showed that ATP11A and ATP11C, members of the P4-ATPase family, translocate phosphatidylserine (PS) and phosphatidylethanolamine from the exoplasmic to the cytoplasmic leaflets at the plasma membrane. PS exposure on the outer leaflet of the plasma membrane in activated platelets, erythrocytes, and apoptotic cells was proposed to require the inhibition of PS-flippases, as well as activation of scramblases. Although ATP11A and ATP11C are cleaved by caspases in apoptotic cells, it remains unclear how PS-flippase activity is regulated in non-apoptotic cells. Here we report that the PS-flippase ATP11C, but not ATP11A, is sequestered from the plasma membrane via clathrin-mediated endocytosis upon Ca2+-mediated PKC activation. Importantly, we show that a characteristic di-leucine motif (SVRPLL) in the C-terminal cytoplasmic region of ATP11C becomes functional upon PKC activation. Moreover endocytosis of ATP11C is induced by Ca2+-signaling via Gq-coupled receptors. Our data provide the first evidence for signal-dependent regulation of mammalian P4-ATPase.
A thermostable Cas9 with increased lifetime in human plasma
Authors: Harrington Lucas B. , Paez-Espino David , Staahl Brett T. , Chen Janice S. , Ma Enbo , Kyrpides Nikos C. , Doudna Jennifer A.
Published: November 2017

CRISPR-Cas9 is a powerful technology that has enabled genome editing in a wide range of species. However, the currently developed Cas9 homologs all originate from mesophilic bacteria, making them susceptible to degradation and unsuitable for applications requiring cleavage at elevated temperatures. Here, we show that the Cas9 protein from the thermophilic bacterium Geobacillus stearothermophilus (GeoCas9) catalyzes RNA-guided DNA cleavage at elevated temperatures. GeoCas9 is active at temperatures up to 70 °C, compared to 45 °C for Streptococcus pyogenes Cas9 (SpyCas9), which expands the temperature range for CRISPR-Cas9 applications. We also found that GeoCas9 is an effective tool for editing mammalian genomes when delivered as a ribonucleoprotein (RNP) complex. Together with an increased lifetime in human plasma, the thermostable GeoCas9 provides the foundation for improved RNP delivery in vivo and expands the temperature range of CRISPR-Cas9.
Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology
Authors: Hammam Kahina , Saez-Ayala Magali , Rebuffet Etienne , Gros Laurent , Lopez Sophie , Hajem Berengere , Humbert Martine , Baudelet Emilie , Audebert Stephane , Betzi Stephane , Lugari Adrien , Combes Sebastien , Letard Sebastien , Casteran Nathalie , Mansfield Colin , Moussy Alain , De Sepulveda Paulo , Morelli Xavier , Dubreuil Patrice
Published: November 2017

Masitinib, a highly selective protein kinase inhibitor, can sensitise gemcitabine-refractory cancer cell lines when used in combination with gemcitabine. Here we report a reverse proteomic approach that identifies the target responsible for this sensitisation: the deoxycytidine kinase (dCK). Masitinib, as well as other protein kinase inhibitors, such as imatinib, interact with dCK and provoke an unforeseen conformational-dependent activation of this nucleoside kinase, modulating phosphorylation of nucleoside analogue drugs. This phenomenon leads to an increase of prodrug phosphorylation of most of the chemotherapeutic drugs activated by this nucleoside kinase. The unforeseen dual activity of protein kinase inhibition/nucleoside kinase activation could be of great therapeutic benefit, through either reducing toxicity of therapeutic agents by maintaining effectiveness at lower doses or by counteracting drug resistance initiated via down modulation of dCK target.
Novel genetically encoded fluorescent probes enable real-time detection of potassium in vitro and in vivo
Authors: Bischof Helmut , Rehberg Markus , Stryeck Sarah , Artinger Katharina , Eroglu Emrah , Waldeck-Weiermair Markus , Gottschalk Benjamin , Rost Rene , Deak Andras T. , Niedrist Tobias , Vujic Nemanja , Lindermuth Hanna , Prassl Ruth , Pelzmann Brigitte , Groschner Klaus , Kratky Dagmar , Eller Kathrin , Rosenkranz Alexander R. , Madl Tobias , Plesnila Nikolaus , Graier Wolfgang F. , Malli Roland
Published: November 2017

Changes in intra- and extracellular potassium ion (K+) concentrations control many important cellular processes and related biological functions. However, our current understanding of the spatiotemporal patterns of physiological and pathological K+ changes is severely limited by the lack of practicable detection methods. We developed K+-sensitive genetically encoded, Förster resonance energy transfer-(FRET) based probes, called GEPIIs, which enable quantitative real-time imaging of K+ dynamics. GEPIIs as purified biosensors are suitable to directly and precisely quantify K+ levels in different body fluids and cell growth media. GEPIIs expressed in cells enable time-lapse and real-time recordings of global and local intracellular K+ signals. Hitherto unknown Ca2+-triggered, organelle-specific K+ changes were detected in pancreatic beta cells. Recombinant GEPIIs also enabled visualization of extracellular K+ fluctuations in vivo with 2-photon microscopy. Therefore, GEPIIs are relevant for diverse K+ assays and open new avenues for live-cell K+ imaging.
Purcell-enhanced quantum yield from carbon nanotube excitons coupled to plasmonic nanocavities
Authors: Luo Yue , Ahmadi Ehsaneh D. , Shayan Kamran , Ma Yichen , Mistry Kevin S. , Zhang Changjian , Hone James , Blackburn Jeffrey L. , Strauf Stefan
Published: November 2017

Single-walled carbon nanotubes (SWCNTs) are promising absorbers and emitters to enable novel photonic applications and devices but are also known to suffer from low optical quantum yields. Here we demonstrate SWCNT excitons coupled to plasmonic nanocavity arrays reaching deeply into the Purcell regime with Purcell factors (FP) up to FP = 180 (average FP = 57), Purcell-enhanced quantum yields of 62% (average 42%), and a photon emission rate of 15 MHz into the first lens. The cavity coupling is quasi-deterministic since the photophysical properties of every SWCNT are enhanced by at least one order of magnitude. Furthermore, the measured ultra-narrow exciton linewidth (18 μeV) reaches the radiative lifetime limit, which is promising towards generation of transform-limited single photons. To demonstrate utility beyond quantum light sources we show that nanocavity-coupled SWCNTs perform as single-molecule thermometers detecting plasmonically induced heat at cryogenic temperatures in a unique interplay of excitons, phonons, and plasmons at the nanoscale.
Cooperative polariton dynamics in feedback-coupled cavities
Authors: Yao Bimu , Gui Y. S. , Rao J. W. , Kaur S. , Chen X. S. , Lu W. , Xiao Y. , Guo H. , Marzlin K. -P. , Hu C. -M.
Published: November 2017

The emerging field of cavity spintronics utilizes the cavity magnon polariton (CMP) induced by magnon Rabi oscillations. In contrast to a single-spin quantum system, such a cooperative spin dynamics in the linear regime is governed by the classical physics of harmonic oscillators. It makes the magnon Rabi frequency independent of the photon Fock state occupation, and thereby restricts the quantum application of CMP. Here we show that a feedback cavity architecture breaks the harmonic-oscillator restriction. By increasing the feedback photon number, we observe an increase in the Rabi frequency, accompanied with the evolution of CMP to a cavity magnon triplet and a cavity magnon quintuplet. We present a theory that explains these features. Our results reveal the physics of cooperative polariton dynamics in feedback-coupled cavities, and open up new avenues for exploiting the light–matter interactions.
Theory, simulations and the design of functionalized nanoparticles for biomedical applications: A Soft Matter Perspective
Authors: Angioletti-Uberti Stefano
Published: November 2017

Functionalised nanoparticles for biomedical applications represents an incredibly exciting and rapidly growing field of research. Considering the complexity of the nano–bio interface, an important question is to what extent can theory and simulations be used to study these systems in a realistic, meaningful way. In this review, we will argue for a positive answer to this question. Approaching the issue from a “Soft Matter” perspective, we will consider those properties of functionalised nanoparticles that can be captured within a classical description. We will thus not concentrate on optical and electronic properties, but rather on the way nanoparticles’ interactions with the biological environment can be tuned by functionalising their surface and exploited in different contexts relevant to applications. In particular, we wish to provide a critical overview of theoretical and computational coarse-grained models, developed to describe these interactions and present to the readers some of the latest results in this fascinating area of research.
Involvement of galanin and galanin receptor 1 in nociceptive modulation in the central nucleus of amygdala in normal and neuropathic rats
Authors: Li Shi-Yang , Huo Mei-Ling , Wu Xu-Yang , Huang Yu-Qing , Wang Lei , Zhang Xin , Jiang Yan-Mei , Zhang Meng-Lin , Wang Lin-Lin , Yu Long-Chuan
Published: November 2017

The present study was performed to explore the role of galanin and galanin receptor 1 (GalR 1) in nociceptive modulation in the central nucleus of amygdala (CeA) in normal rats and rats with neuropathy, and the involvement of GalR 1 and PKC was also investigated. The hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulations were increased in a dose-dependent manner after intra-CeA injection of galanin in both normal rats and rats with neuropathy. The increased HWLs were significantly attenuated by intra-CeA injection of galanin receptor antagonist M40, indicating an involvement of galanin receptor in nociceptive modulation in CeA. Furthermore, intra-CeA administration of the GalR 1 agonist M 617 induced increases in HWLs in normal rats, suggesting that GalR 1 may be involved in galanin-induce antinociception in CeA. Additionally, intra-CeA injection of the PKC inhibitor inhibited galanin-induced antinociception, showing an involvement of PKC in galanin-induced antinociception in CeA of normal rats. Moreover, there was a significant increase in GalR1 content in CeA in rats with neuropathy than that in normal rats. These results illustrated that galanin induced antinociception in CeA in normal rats and rats with neuropathy, and there is an up-regulation of GalR1 expression in rats with neuropathy.
Clinical Potential of an Enzyme-based Novel Therapy for Cocaine Overdose
Authors: Zhang Ting , Zheng Xirong , Zhou Ziyuan , Chen Xiabin , Jin Zhenyu , Deng Jing , Zhan Chang-Guo , Zheng Fang
Published: November 2017

It is a grand challenge to develop a truly effective medication for treatment of cocaine overdose. The current available, practical emergence treatment for cocaine overdose includes administration of a benzodiazepine anticonvulsant agent (e.g. diazepam) and/or physical cooling with an aim to relieve the symptoms. The inherent difficulties of antagonizing physiological effects of drugs in the central nervous system have led to exploring protein-based pharmacokinetic approaches using biologics like vaccines, monoclonal antibodies, and enzymes. However, none of the pharmacokinetic agents has demonstrated convincing preclinical evidence of clinical potential for drug overdose treatment without a question mark on the timing used in the animal models. Here we report the use of animal models, including locomotor activity, protection, and rescue experiments in rats, of drug toxicity treatment with clinically relevant timing for the first time. It has been demonstrated that an efficient cocaine-metabolizing enzyme developed in our previous studies can rapidly reverse the cocaine toxicity whenever the enzyme is given to a living rat, demonstrating promising clinical potential of an enzyme-based novel therapy for cocaine overdose as a successful example in comparison with the commonly used diazepam.
A viscous quantum hydrodynamics model based on dynamic density functional theory
Authors: Diaw Abdourahmane , Murillo Michael S.
Published: November 2017

Dynamic density functional theory (DDFT) is emerging as a useful theoretical technique for modeling the dynamics of correlated systems. We extend DDFT to quantum systems for application to dense plasmas through a quantum hydrodynamics (QHD) approach. The DDFT-based QHD approach includes correlations in the the equation of state self-consistently, satisfies sum rules and includes irreversibility arising from collisions. While QHD can be used generally to model non-equilibrium, heterogeneous plasmas, we employ the DDFT-QHD framework to generate a model for the electronic dynamic structure factor, which offers an avenue for measuring hydrodynamic properties, such as transport coefficients via x-ray Thomson scattering.
Spatially Resolved Thermometry of Resistive Memory Devices
Authors: Yalon Eilam , Deshmukh Sanchit , Muñoz Rojo Miguel , Lian Feifei , Neumann Christopher M. , Xiong Feng , Pop Eric
Published: November 2017

The operation of resistive and phase-change memory (RRAM and PCM) is controlled by highly localized self-heating effects, yet detailed studies of their temperature are rare due to challenges of nanoscale thermometry. Here we show that the combination of Raman thermometry and scanning thermal microscopy (SThM) can enable such measurements with high spatial resolution. We report temperature-dependent Raman spectra of HfO2, TiO2 and Ge2Sb2Te5 (GST) films, and demonstrate direct measurements of temperature profiles in lateral PCM devices. Our measurements reveal that electrical and thermal interfaces dominate the operation of such devices, uncovering a thermal boundary resistance of 28 ± 8 m2K/GW at GST-SiO2 interfaces and an effective thermopower 350 ± 50 µV/K at GST-Pt interfaces. We also discuss possible pathways to apply Raman thermometry and SThM techniques to nanoscale and vertical resistive memory devices.
On Economic Complexity and the Fitness of Nations
Authors: Morrison Greg , Buldyrev Sergey V. , Imbruno Michele , Doria Arrieta Omar Alonso , Rungi Armando , Riccaboni Massimo , Pammolli Fabio
Published: November 2017

Complex economic systems can often be described by a network, with nodes representing economic entities and edges their interdependencies, while network centrality is often a good indicator of importance. Recent publications have implemented a nonlinear iterative Fitness-Complexity (FC) algorithm to measure centrality in a bipartite trade network, which aims to represent the ‘Fitness’ of national economies as well as the ‘Complexity’ of the products being traded. In this paper, we discuss this methodological approach and conclude that further work is needed to identify stable and reliable measures of fitness and complexity. We provide theoretical and numerical evidence for the intrinsic instability in the nonlinear definition of the FC algorithm. We perform an in-depth evaluation of the algorithm’s rankings in two real world networks at the country level: the global trade network, and the patent network in different technological domains. In both networks, we find evidence of the instabilities predicted theoretically, and show that ‘complex’ products or patents tend often to be those that countries rarely produce, rather than those that are intrinsically more difficult to produce.
Publisher Correction: PP2A inhibition from LB100 therapy enhances daunorubicin cytotoxicity in secondary acute myeloid leukemia via miR-181b-1 upregulation
Authors: Hu Chao , Yu Mengxia , Ren Yanling , Li Kongfei , Maggio Dominic M. , Mei Chen , Ye Li , Wei Juying , Jin Jie , Zhuang Zhengping , Tong Hongyan
Published: November 2017

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.
Ferroelectric thin film acoustic devices with electrical multiband switching ability
Authors: Ptashnik Sergey V. , Mikhailov Anatoliy K. , Yastrebov Alexander V. , Petrov Peter K. , Liu Wei , Alford Neil McN , Hirsch Soeren , Kozyrev Andrey B.
Published: November 2017

Design principles of a new class of microwave thin film bulk acoustic resonators with multiband resonance frequency switching ability are presented. The theory of the excitation of acoustic eigenmodes in multilayer ferroelectric structures is considered, and the principle of selectivity for resonator with an arbitrary number of ferroelectric layers is formulated. A so called “criterion function” is suggested that allows to determine the conditions for effective excitation at one selected resonance mode with suppression of other modes. The proposed theoretical approach is verifiedusing thepreexisting experimental data published elsewhere. Finally, the possible application of the two ferroelectric layers structures for switchable microwave overtone resonators, binary and quadrature phase-shift keying modulators are discussed. These devices could play a pivotal role in the miniaturization of microwave front-end antenna circuits.
Three dimensional printed polylactic acid-hydroxyapatite composite scaffolds for prefabricating vascularized tissue engineered bone: An in vivo bioreactor model
Authors: Zhang Haifeng , Mao Xiyuan , Zhao Danyang , Jiang Wenbo , Du Zijing , Li Qingfeng , Jiang Chaohua , Han Dong
Published: November 2017

The repair of large bone defects with complex geometries remains a major clinical challenge. Here, we explored the feasibility of fabricating polylactic acid-hydroxyapatite (PLA-HA) composite scaffolds. These scaffolds were constructed from vascularized tissue engineered bone using an in vivo bioreactor (IVB) strategy with three-dimensional printing technology. Specifically, a rabbit model was established to prefabricate vascularized tissue engineered bone in two groups. An experimental group (EG) was designed using a tibial periosteum capsule filled with 3D printed (3DP) PLA-HA composite scaffolds seeded with bone marrow stromal cells (BMSCs) and crossed with a vascular bundle. 3DP PLA-HA scaffolds were also combined with autologous BMSCs and transplanted to tibial periosteum without blood vessel as a control group (CG). After four and eight weeks, neovascularisation and bone tissues were analysed by studying related genes, micro-computed tomography (Micro-CT) and histological examinations between groups. The results showed that our method capably generated vascularized tissue engineered bone in vivo. Furthermore, we observed significant differences in neovascular and new viable bone formation in the two groups. In this study, we demonstrated the feasibility of generating large vascularized bone tissues in vivo with 3DP PLA-HA composite scaffolds.
Cis-SNPs Set Testing and PrediXcan Analysis for Gene Expression Data using Linear Mixed Models
Authors: Zeng Ping , Wang Ting , Huang Shuiping
Published: November 2017

Understanding the functional mechanism of SNPs identified in GWAS on complex diseases is currently a challenging task. The studies of expression quantitative trait loci (eQTL) have shown that regulatory variants play a crucial role in the function of associated SNPs. Detecting significant genes (called eGenes) in eQTL studies and analyzing the effect sizes of cis-SNPs can offer important implications on the genetic architecture of associated SNPs and interpretations of the molecular basis of diseases. We applied linear mixed models (LMM) to the gene expression level and constructed likelihood ratio tests (LRT) to test for eGene in the Geuvadis data. We identified about 11% genes as eGenes in the Geuvadis data and found some eGenes were enriched in approximately independent linkage disequilibrium (LD) blocks (e.g. MHC). We further performed PrediXcan analysis for seven diseases in the WTCCC data with weights estimated using LMM and identified 64, 5, 21 and 1 significant genes (p < 0.05 after Bonferroni correction) associated with T1D, CD, RA and T2D. We found most of the significant genes of T1D and RA were also located within the MHC region. Our results provide strong evidence that gene expression plays an intermediate role for the associated variants in GWAS.
Progesterone attenuates temporomandibular joint inflammation through inhibition of NF-κB pathway in ovariectomized rats
Authors: Xue Xin-Tong , Kou Xiao-Xing , Li Chen-Shuang , Bi Rui-Yun , Meng Zhen , Wang Xue-Dong , Zhou Yan-Heng , Gan Ye-Hua
Published: November 2017

Sex hormones may contribute to the symptomatology of female-predominant temporomandibular disorders (TMDs) inflammatory pain. Pregnant women show less symptoms of TMDs than that of non-pregnant women. Whether progesterone (P4), one of the dominant sex hormones that regulates multiple biological functions, is involved in symptoms of TMDs remains to be explored. Freund’s complete adjuvant were used to induce joint inflammation. We evaluated the behavior-related and histologic effects of P4 and the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the synovial membrane. Primary TMJ synoviocytes were treated with TNF-α or IL-1β with the combination of P4. Progesterone receptor antagonist RU-486 were further applied. We found that P4 replacement attenuated TMJ inflammation and the nociceptive responses in a dose-dependent manner in the ovariectomized rats. Correspondingly, P4 diminished the DNA-binding activity of NF-κB and the transcription of its target genes in a dose-dependent manner in the synovial membrane of TMJ. Furthermore, P4 treatment showed decreased mRNA expression of proinflammatory cytokines, and partially reversed TNF-α and IL-1β induced transcription of proinflammatory cytokines in the primary synoviocytes. Moreover, progesterone receptor antagonist RU-486 partially reversed the effects of P4 on NF-κB pathway. In conclusion, progesterone ameliorated TMJ inflammation through inhibition of NF-κB pathway.
Crystalline Soda Can Metamaterial exhibiting Graphene-like Dispersion at subwavelength scale
Authors: Yves Simon , Lemoult Fabrice , Fink Mathias , Lerosey Geoffroy
Published: November 2017

Graphene, a honeycomb lattice of carbon atoms ruled by tight-binding interaction, exhibits extraordinary electronic properties due to the presence of Dirac cones within its band structure. These intriguing singularities have naturally motivated the discovery of their classical analogues. In this work, we present a general and direct procedure to reproduce the peculiar physics of graphene within a very simple acoustic metamaterial: a double lattice of soda cans resonating at two different frequencies. The first triangular sub-lattice generates a bandgap at low frequency, which induces a tight-binding coupling between the resonant defects of the second honeycomb one, hence allowing us to obtain a graphene-like band structure. We prove the relevance of this approach by showing that both numerical and experimental dispersion relations exhibit the requested Dirac cone. We also demonstrate the straightforward monitoring of the coupling strength within the crystal of resonant defects. This work shows that crystalline metamaterials are very promising candidates to investigate tantalizing solid-state physics phenomena with classical waves.
Divergent effects of Wnt/β-catenin signaling modifiers on the preservation of human limbal epithelial progenitors according to culture condition
Authors: Lee Hyun Jung , Wolosin J. Mario , Chung So-Hyang
Published: November 2017

Wnt signaling plays an important role in the regulation of self-renewal in stem cells. Here we investigated the effect of CHIR99021, the primary transducer of the Wnt signaling canonical pathway, and IWP2, a wide action Wnt signal blocker, on the growth and differentiation of the limbal epithelial progenitor cells when these cells are cultured in two different, common culture approaches, outgrowth from limbal biopsy explants and isolated cell seeded in low calcium medium. Consistent with their expected effects, irrespective of the culture system, IWP2 decreased total β-catenin while CHIR99021 increased it in nuclear localization. However, IWP2 increased stem/progenitor cell marker (p63α and ABCG2) content and clonogenic capacity in the explants but had opposite effects on isolated cells. CHIR99021 reduced the growth rate, stem/progenitor cell marker content and clonogenic capacity in the explants but also had the opposite effect on the isolated cells. These results show that the outcome of Wnt/β-catenin signaling modification is dependent on the culture systems. Transplantation of limbal epithelial sheets from explant cultures is one of the standard treatments of limbal stem cell deficiency. Our study shows that Wnt-associated activity has a strong negative impact on stem/progenitor cell preservation in limbal explant cultures.
The positive effects of Xueshuan Xinmai tablets on brain functional connectivity in acute ischemic stroke: a placebo controlled randomized trial
Authors: Wei Dongfeng , Xie Daojun , Li He , Chen Yaojing , Qi Di , Wang Yujiao , Zhang Yangjun , Chen Kewei , Li Chuanfu , Zhang Zhanjun
Published: November 2017

Through a placebo controlled randomized study, the purpose of this report was to investigate the effects of Xueshuan Xinmai tablets (XXMT) on neurologic deficits, quality of life and brain functional connectivity in acute ischemic stroke patients and to explore the mechanism of action of XXMT. In total, 44 acute ischemic stroke patients were randomly divided to the XXMT treatment group (n = 22) or the placebo group (n = 22) in a 2-week trial. Before and after the treatment, the neurological assessment and functional magnetic resonance imaging examinations were carried out. Compared to the placebo group, the scores of the National Institutes of Health Stroke Scale (NIHSS) and Stroke-Specific Quality of Life Scale (SSQOL) significantly improved in the treatment group. In addition, XXMT-treated patients demonstrated significantly enhanced functional connectivity within the default mode, frontal-parietal, and motor control networks. Furthermore, the changed connectivity in the left precuneus was positively correlated to the improvement of NIHSS and SSQOL scores. The present study indicated that XXMT treatment significantly improved the neurologic deficit and quality of life of acute ischemic stroke patients and that the therapeutic effect may be based on the modulation of XXMT on the functional connectivity of brain networks.
Biological assessments of multifunctional hydrogel-decorated implantable neural cuff electrode for clinical neurology application
Authors: Kim Han-Jun , Heo Dong Nyoung , Lee Yi Jae , Lee Sang Jin , Kang Ji Yoon , Lee Soo Hyun , Kwon II Keun , Do Sun Hee
Published: November 2017

The implantable cuff electrode is an effective neuroprosthetic device in current nerve tissue engineering. However, biocompatibility and stability are still a serious dispute in terms of in vivo function and continuous monitoring. In this regard, assessing the host’s biological response to biomaterials is one of the key factors of chronic implantation. In this article, we analyzed the peripheral nerve specific-biological responses to the application of multi-functional hydrogel-coated electrodes. The surface of the cuff electrode was modified using a multifunctional hydrogel composed of PEG hydrogel, cyclosporin A(CsA)-microsphere(MS) and electrodeposited PEDOT:PSS. Through our approach, we have found that the multifunctional hydrogel coatings improve the neural electrode function, such as peak-to-peak amplitude increase. Additionally, the multifunctional hydrogel coated electrodes exhibited improved biocompatibility, such as reduced apoptotic properties and increased axonal myelination. Furthermore, 12 genes (BDNF, Gfra1, IL-6, Sox 10, S100B, P75
NTR
, GAP43, MBP, MPZ, NrCAM, NE-FL, CB1) were upregulated at 5 weeks post-implant. Finally, double immunofluorescence revealed the effect of endocannabinoid system on neuroprotective properties and tissue remodeling of peripheral nerves during cuff electrode implantation. These results clearly confirmed that multifunctional hydrogel coatings could improve electrode function and biocompatibility by enhancing neuroprotective properties, which may provide a valuable paradigm for clinical neurology application.
High-brightness laser imaging with tunable speckle reduction enabled by electroactive micro-optic diffusers
Authors: Farrokhi Hamid , Rohith Thazhe Madam , Boonruangkan Jeeranan , Han Seunghwoi , Kim Hyunwoong , Kim Seung-Woo , Kim Young-Jin
Published: November 2017

High coherence of lasers is desirable in high-speed, high-resolution, and wide-field imaging. However, it also causes unavoidable background speckle noise thus degrades the image quality in traditional microscopy and more significantly in interferometric quantitative phase imaging (QPI). QPI utilizes optical interference for high-precision measurement of the optical properties where the speckle can severely distort the information. To overcome this, we demonstrated a light source system having a wide tunability in the spatial coherence over 43% by controlling the illumination angle, scatterer’s size, and the rotational speed of an electroactive-polymer rotational micro-optic diffuser. Spatially random phase modulation was implemented for the lower speckle imaging with over a 50% speckle reduction without a significant degradation in the temporal coherence. Our coherence control technique will provide a unique solution for a low-speckle, full-field, and coherent imaging in optically scattering media in the fields of healthcare sciences, material sciences and high-precision engineering.
A Light-Activated Antimicrobial Surface Is Active Against Bacterial, Viral and Fungal Organisms
Authors: Walker Tim , Canales Melisa , Noimark Sacha , Page Kristopher , Parkin Ivan , Faull Jane , Bhatti Manni , Ciric Lena
Published: November 2017

Evidence has shown that environmental surfaces play an important role in the transmission of nosocomial pathogens. Deploying antimicrobial surfaces in hospital wards could reduce the role environmental surfaces play as reservoirs for pathogens. Herein we show a significant reduction in viable counts ofStaphylococcus epidermidis,Saccharomyces cerevisiae, and MS2 Bacteriophage after light treatment of a medical grade silicone incorporating crystal violet, methylene blue and 2 nm gold nanoparticles. Furthermore, a migration assay demonstrated that in the presence of light, growth of the fungus-like organismPythium ultimumand the filamentous fungusBotrytis cinereawas inhibited. Atomic Force Microscopy showed significant alterations to the surface ofS.epidermidis, and electron microscopy showed cellular aggregates connected by discrete surface linkages. We have therefore demonstrated that the embedded surface has a broad antimicrobial activity under white light and that the surface treatment causes bacterial envelope damage and cell aggregation.
Exploration and recency as the main proximate causes of probability matching: a reinforcement learning analysis
Authors: Feher da Silva Carolina , Victorino Camila Gomes , Caticha Nestor , Baldo Marcus Vinícius Chrysóstomo
Published: November 2017

Research has not yet reached a consensus on why humans match probabilities instead of maximise in a probability learning task. The most influential explanation is that they search for patterns in the random sequence of outcomes. Other explanations, such as expectation matching, are plausible, but do not consider how reinforcement learning shapes people’s choices. We aimed to quantify how human performance in a probability learning task is affected by pattern search and reinforcement learning. We collected behavioural data from 84 young adult participants who performed a probability learning task wherein the majority outcome was rewarded with 0.7 probability, and analysed the data using a reinforcement learning model that searches for patterns. Model simulations indicated that pattern search, exploration, recency (discounting early experiences), and forgetting may impair performance. Our analysis estimated that 85% (95% HDI [76, 94]) of participants searched for patterns and believed that each trial outcome depended on one or two previous ones. The estimated impact of pattern search on performance was, however, only 6%, while those of exploration and recency were 19% and 13% respectively. This suggests that probability matching is caused by uncertainty about how outcomes are generated, which leads to pattern search, exploration, and recency.
Characterization of the Optical Properties of Turbid Media by Supervised Learning of Scattering Patterns
Authors: Hassaninia Iman , Bostanabad Ramin , Chen Wei , Mohseni Hooman
Published: November 2017

Fabricated tissue phantoms are instrumental in optical in-vitro investigations concerning cancer diagnosis, therapeutic applications, and drug efficacy tests. We present a simple non-invasive computational technique that, when coupled with experiments, has the potential for characterization of a wide range of biological tissues. The fundamental idea of our approach is to find a supervised learner that links the scattering pattern of a turbid sample to its thickness and scattering parameters. Once found, this supervised learner is employed in an inverse optimization problem for estimating the scattering parameters of a sample given its thickness and scattering pattern. Multi-response Gaussian processes are used for the supervised learning task and a simple setup is introduced to obtain the scattering pattern of a tissue sample. To increase the predictive power of the supervised learner, the scattering patterns are filtered, enriched by a regressor, and finally characterized with two parameters, namely, transmitted power and scaled Gaussian width. We computationally illustrate that our approach achieves errors of roughly 5% in predicting the scattering properties of many biological tissues. Our method has the potential to facilitate the characterization of tissues and fabrication of phantoms used for diagnostic and therapeutic purposes over a wide range of optical spectrum.
Hydrogen adsorption on doped MoS2 nanostructures
Authors: Hakala Mikko , Kronberg Rasmus , Laasonen Kari
Published: November 2017

Electrochemical devices for efficient production of hydrogen as energy carrier rely still largely on rare platinum group metal catalysts. Chemically and structurally modified metal dichalcogenide MoS2 is a promising substitute for these critical raw materials at the cathode side where the hydrogen evolution reaction takes place. For precise understanding of structure and hydrogen adsorption characteristics in chemically modified MoS2 nanostructures, we perform comprehensive density functional theory calculations on transition metal (Fe, Co, Ni, Cu) doping at the experimentally relevant MoS2 surfaces at substitutional Mo-sites. Clear benefits of doping the basal plane are found, whereas at the Mo- and S-edges complex modifications at the whole edge are observed. New insight into doping-enhanced activity is obtained and guidance is given for further experiments. We study a machine learning model to facilitate the screening of suitable structures and find a promising level of prediction accuracy with minimal structural input.