bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted inhibition of the COP9 signalosome for treatment of cancer
Authors: Schlierf Anita , Altmann Eva , Quancard Jean , Jefferson Anne B. , Assenberg René , Renatus Martin , Jones Matthew , Hassiepen Ulrich , Schaefer Michael , Kiffe Michael , Weiss Andreas , Wiesmann Christian , Sedrani Richard , Eder Jörg , Martoglio Bruno
Published: October 2016

The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin–proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy.
Single-molecule imaging reveals modulation of cell wall synthesis dynamics in live bacterial cells
Authors: Lee Timothy K. , Meng Kevin , Shi Handuo , Huang Kerwyn Casey
Published: October 2016

The peptidoglycan cell wall is an integral organelle critical for bacterial cell shape and stability. Proper cell wall construction requires the interaction of synthesis enzymes and the cytoskeleton, but it is unclear how the activities of individual proteins are coordinated to preserve the morphology and integrity of the cell wall during growth. To elucidate this coordination, we used single-molecule imaging to follow the behaviours of the two major peptidoglycan synthases in live, elongating Escherichia coli cells and after perturbation. We observed heterogeneous localization dynamics of penicillin-binding protein (PBP) 1A, the synthase predominantly associated with cell wall elongation, with individual PBP1A molecules distributed between mobile and immobile populations. Perturbations to PBP1A activity, either directly through antibiotics or indirectly through PBP1A’s interaction with its lipoprotein activator or other synthases, shifted the fraction of mobile molecules. Our results suggest that multiple levels of regulation control the activity of enzymes to coordinate peptidoglycan synthesis.
Genetic variation at the 8q24.21 renal cancer susceptibility locus affects HIF binding to a MYC enhancer
Authors: Grampp Steffen , Platt James L. , Lauer Victoria , Salama Rafik , Kranz Franziska , Neumann Viviana K. , Wach Sven , Stöhr Christine , Hartmann Arndt , Eckardt Kai-Uwe , Ratcliffe Peter J. , Mole David R. , Schödel Johannes
Published: October 2016

Clear cell renal cell carcinoma (ccRCC) is characterized by loss of function of the von Hippel–Lindau tumour suppressor (VHL) and unrestrained activation of hypoxia-inducible transcription factors (HIFs). Genetic and epigenetic determinants have an impact on HIF pathways. A recent genome-wide association study on renal cancer susceptibility identified single-nucleotide polymorphisms (SNPs) in an intergenic region located between the oncogenes MYC and PVT1. Here using assays of chromatin conformation, allele-specific chromatin immunoprecipitation and genome editing, we show that HIF binding to this regulatory element is necessary to trans-activate MYC and PVT1 expression specifically in cells of renal tubular origins. Moreover, we demonstrate that the risk-associated polymorphisms increase chromatin accessibility and activity as well as HIF binding to the enhancer. These findings provide further evidence that genetic variation at HIF-binding sites modulates the oncogenic transcriptional output of the VHL–HIF axis and provide a functional explanation for the disease-associated effects of SNPs in ccRCC.
In-depth analysis of chloride treatments for thin-film CdTe solar cells
Authors: Major J. D. , Al Turkestani M. , Bowen L. , Brossard M. , Li C. , Lagoudakis P. , Pennycook S. J. , Phillips L. J. , Treharne R. E. , Durose K.
Published: October 2016

CdTe thin-film solar cells are now the main industrially established alternative to silicon-based photovoltaics. These cells remain reliant on the so-called chloride activation step in order to achieve high conversion efficiencies. Here, by comparison of effective and ineffective chloride treatments, we show the main role of the chloride process to be the modification of grain boundaries through chlorine accumulation, which leads an increase in the carrier lifetime. It is also demonstrated that while improvements in fill factor and short circuit current may be achieved through use of the ineffective chlorides, or indeed simple air annealing, voltage improvement is linked directly to chlorine incorporation at the grain boundaries. This suggests that focus on improved or more controlled grain boundary treatments may provide a route to achieving higher cell voltages and thus efficiencies.
Evolution from the plasmon to exciton state in ligand-protected atomically precise gold nanoparticles
Authors: Zhou Meng , Zeng Chenjie , Chen Yuxiang , Zhao Shuo , Sfeir Matthew Y. , Zhu Manzhou , Jin Rongchao
Published: October 2016

The evolution from the metallic (or plasmonic) to molecular state in metal nanoparticles constitutes a central question in nanoscience research because of its importance in revealing the origin of metallic bonding and offering fundamental insights into the birth of surface plasmon resonance. Previous research has not been able to probe the transition due to the unavailability of atomically precise nanoparticles in the 1–3 nm size regime. Herein, we investigate the transition by performing ultrafast spectroscopic studies on atomically precise thiolate-protected Au25, Au38, Au144, Au333, Au∼520 and Au∼940 nanoparticles. Our results clearly map out three distinct states: metallic (size larger than Au333, that is, larger than 2.3 nm), transition regime (between Au333 and Au144, that is, 2.3–1.7 nm) and non-metallic or excitonic state (smaller than Au144, that is, smaller than 1.7 nm). The transition also impacts the catalytic properties as demonstrated in both carbon monoxide oxidation and electrocatalytic oxidation of alcohol.
Laser recrystallization and inscription of compositional microstructures in crystalline SiGe-core fibres
Authors: Coucheron David A. , Fokine Michael , Patil Nilesh , Breiby Dag Werner , Buset Ole Tore , Healy Noel , Peacock Anna C. , Hawkins Thomas , Jones Max , Ballato John , Gibson Ursula J.
Published: October 2016

Glass fibres with silicon cores have emerged as a versatile platform for all-optical processing, sensing and microscale optoelectronic devices. Using SiGe in the core extends the accessible wavelength range and potential optical functionality because the bandgap and optical properties can be tuned by changing the composition. However, silicon and germanium segregate unevenly during non-equilibrium solidification, presenting new fabrication challenges, and requiring detailed studies of the alloy crystallization dynamics in the fibre geometry. We report the fabrication of SiGe-core optical fibres, and the use of CO2 laser irradiation to heat the glass cladding and recrystallize the core, improving optical transmission. We observe the ramifications of the classic models of solidification at the microscale, and demonstrate suppression of constitutional undercooling at high solidification velocities. Tailoring the recrystallization conditions allows formation of long single crystals with uniform composition, as well as fabrication of compositional microstructures, such as gratings, within the fibre core.
GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth
Authors: Bayin N S , Frenster J D , Kane J R , Rubenstein J , Modrek A S , Baitalmal R , Dolgalev I , Rudzenski K , Scarabottolo L , Crespi D , Redaelli L , Snuderl M , Golfinos J G , Doyle W , Pacione D , Parker E C , Chi A S , Heguy A , MacNeil D J , Shohdy N , Zagzag D , Placantonakis D G
Published: October 2016

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1α (Hif1α)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.
Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells
Authors: Vouri M , Croucher D R , Kennedy S P , An Q , Pilkington G J , Hafizi S
Published: October 2016

Acquired resistance to conventional and targeted therapies is becoming a major hindrance in cancer management. It is increasingly clear that cancer cells are able to evolve and rewire canonical signalling pathways to their advantage, thus evading cell death and promoting cell invasion. The Axl receptor tyrosine kinase (RTK) has been shown to modulate acquired resistance to EGFR-targeted therapies in both breast and lung cancers. Glioblastoma multiforme (GBM) is a highly infiltrative and invasive form of brain tumour with little response to therapy. Both Axl and EGFR have been identified as major players in gliomagenesis and invasiveness. However, the mechanisms underlying a potential signalling crosstalk between EGFR and Axl RTKs are unknown. The purpose of this study was to investigate this novel and unconventional interaction among RTKs of different families in human GBM cells. With the use of western blotting, in vitro kinase activity, co-immunoprecipitation and bimolecular fluorescence complementation assays, we show that EGF stimulates activation of Axl kinase and that there is a hetero-interaction between the two RTKs. Through small interfering RNA knockdown and quantitative PCR screening, we identified distinct gene expression patterns in GBM cells that were specifically regulated by signalling from EGFR-EGFR, Axl–Axl and EGFR-Axl RTK parings. These included genes that promote invasion, which were activated only via the EGFR-Axl axis (MMP9), while EGFR-EGFR distinctly regulated the cell cycle and Axl–Axl regulated invasion. Our findings provide critical insights into the role of EGFR-Axl hetero-dimerisation in cancer cells and reveal regulation of cell invasion via Axl as a novel function of EGFR signalling.
A database of human exposomes and phenomes from the US National Health and Nutrition Examination Survey
Authors: Patel Chirag J. , Pho Nam , McDuffie Michael , Easton-Marks Jeremy , Kothari Cartik , Kohane Isaac S. , Avillach Paul
Published: October 2016

The National Health and Nutrition Examination Survey (NHANES) is a population survey implemented by the Centers for Disease Control and Prevention (CDC) to monitor the health of the United States whose data is publicly available in hundreds of files. This Data Descriptor describes a single unified and universally accessible data file, merging across 255 separate files and stitching data across 4 surveys, encompassing 41,474 individuals and 1,191 variables. The variables consist of phenotype and environmental exposure information on each individual, specifically (1) demographic information, physical exam results (e.g., height, body mass index), laboratory results (e.g., cholesterol, glucose, and environmental exposures), and (4) questionnaire items. Second, the data descriptor describes a dictionary to enable analysts find variables by category and human-readable description. The datasets are available on DataDryad and a hands-on analytics tutorial is available on GitHub. Through a new big data platform, BD2K Patient Centered Information Commons (http://pic-sure.org), we provide a new way to browse the dataset via a web browser (https://nhanes.hms.harvard.edu) and provide application programming interface for programmatic access.
A German-language replication study analysing the role of figurative speech in reasoning
Authors: Christmann Ursula , Göhring Anne-Louise
Published: October 2016

According to the metaphorical framing model, the use of metaphors in discussing an issue influences recipients’ understanding and assessment of that issue. In a recent study, participants read a text referring to a city’s crime problem either as a beast or a virus and then proposed counter-measures for that problem. Participants’ suggestions differed depending on the metaphor they had read. This replication matched the original procedure regarding the content of the rhetorical figures (beast vs virus), the topic under focus (crime) and the measurement of the dependent variable (open-end format to collect participants’ proposals). The procedure differed from the original with respect to language (German instead of English) and by including the formal type of rhetorical figure (metaphor or simile) as a factor. A systematic influence of the content of the figure on subjects’ proposals was observed. Presenting the rhetorical figure as a metaphor or a simile had no effect. Taken together, we were able to replicate the main effect of the original study. Metaphors do indeed frame reasoning.
αβ T cell receptor germline CDR regions moderate contact with MHC ligands and regulate peptide cross-reactivity
Authors: Attaf Meriem , Holland Stephan J. , Bartok Istvan , Dyson Julian
Published: October 2016

αβ T cells respond to peptide epitopes presented by major histocompatibility complex (MHC) molecules. The role of T cell receptor (TCR) germline complementarity determining regions (CDR1 and 2) in MHC restriction is not well understood. Here, we examine T cell development, MHC restriction and antigen recognition where germline CDR loop structure has been modified by multiple glycine/alanine substitutions. Surprisingly, loss of germline structure increases TCR engagement with MHC ligands leading to excessive loss of immature thymocytes. MHC restriction is, however, strictly maintained. The peripheral T cell repertoire is affected similarly, exhibiting elevated cross-reactivity to foreign peptides. Our findings are consistent with germline TCR structure optimising T cell cross-reactivity and immunity by moderating engagement with MHC ligands. This strategy may operate alongside co-receptor imposed MHC restriction, freeing germline TCR structure to adopt this novel role in the TCR-MHC interface.
New Insecticidal Agents from Halogenation/Acylation of the Furyl-Ring of Fraxinellone
Authors: Guo Yong , Yang Ruige , Xu Hui
Published: October 2016

Introduction of the halogen atom or the acyl group at the C-ring of fraxinellone was investigated. Some unexpected halogenation products were obtained with the different chlorination/bromination reagents, and their possible reaction mechanisms were also proposed. Seven key steric structures of 2a’, 2b, 2b’, 2c’, 3a, 3b, and one isomer (5’α-Cl) of 2a were further confirmed by single-crystal X-ray diffraction. Especially compounds 2a, 2a’, 3a and 3c exhibited more potent insecticidal activity than toosendanin. Some structure-activity relationships of tested compounds were also described.
One-step solvothermal deposition of ZnO nanorod arrays on a wood surface for robust superamphiphobic performance and superior ultraviolet resistance
Authors: Yao Qiufang , Wang Chao , Fan Bitao , Wang Hanwei , Sun Qingfeng , Jin Chunde , Zhang Hong
Published: October 2016

In the present paper, uniformly large-scale wurtzite-structured ZnO nanorod arrays (ZNAs) were deposited onto a wood surface through a one-step solvothermal method. The as-prepared samples were characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetry (TG), and differential thermal analysis (DTA). ZNAs with a diameter of approximately 85 nm and a length of approximately 1.5 μm were chemically bonded onto the wood surface through hydrogen bonds. The superamphiphobic performance and ultraviolet resistance were measured and evaluated by water or oil contact angles (WCA or OCA) and roll-off angles, sand abrasion tests and an artificially accelerated ageing test. The results show that the ZNA-treated wood demonstrates a robust superamphiphobic performance under mechanical impact, corrosive liquids, intermittent and transpositional temperatures, and water spray. Additionally, the as-prepared wood sample shows superior ultraviolet resistance.
Two identified looming detectors in the locust: ubiquitous lateral connections among their inputs contribute to selective responses to looming objects
Authors: Rind F. Claire , Wernitznig Stefan , Pölt Peter , Zankel Armin , Gütl Daniel , Sztarker Julieta , Leitinger Gerd
Published: October 2016

In locusts, two lobula giant movement detector neurons (LGMDs) act as looming object detectors. Their reproducible responses to looming and their ethological significance makes them models for single neuron computation. But there is no comprehensive picture of the neurons that connect directly to each LGMD. We used high-through-put serial block-face scanning-electron-microscopy to reconstruct the network of input-synapses onto the LGMDs over spatial scales ranging from single synapses and small circuits, up to dendritic branches and total excitatory input. Reconstructions reveal that many trans-medullary-afferents (TmAs) connect the eye with each LGMD, one TmA per facet per LGMD. But when a TmA synapses with an LGMD it also connects laterally with another TmA. These inter-TmA synapses are always reciprocal. Total excitatory input to the LGMD 1 and 2 comes from 131,000 and 186,000 synapses reaching densities of 3.1 and 2.6 synapses per μm2 respectively. We explored the computational consequences of reciprocal synapses between each TmA and 6 others from neighbouring columns. Since any lateral interactions between LGMD inputs have always been inhibitory we may assume these reciprocal lateral connections are most likely inhibitory. Such reciprocal inhibitory synapses increased the LGMD’s selectivity for looming over passing objects, particularly at the beginning of object approach.
Implementations of two-photon four-qubit Toffoli and Fredkin gates assisted by nitrogen-vacancy centers
Authors: Wei Hai-Rui , Zhu Pei-Jin
Published: October 2016

It is desirable to implement an efficient quantum information process demanding fewer quantum resources. We designed two compact quantum circuits for determinately implementing four-qubit Toffoli and Fredkin gates on single-photon systems in both the polarization and spatial degrees of freedom (DoFs) via diamond nitrogen-vacancy (NV) centers in resonators. The gates are heralded by the electron spins associated with the diamond NV centers. In contrast to the ones with one DoF, our implementations reduce the quantum resource and are robust against the decoherence. Evaluations of fidelities and efficiencies of our gates show that our schemes may be implemented with current technology.
Retro-dimension-cue benefit in visual working memory
Authors: Ye Chaoxiong , Hu Zhonghua , Ristaniemi Tapani , Gendron Maria , Liu Qiang
Published: October 2016

In visual working memory (VWM) tasks, participants’ performance can be improved by a retro-object-cue. However, previous studies have not investigated whether participants’ performance can also be improved by a retro-dimension-cue. Three experiments investigated this issue. We used a recall task with a retro-dimension-cue in all experiments. In Experiment 1, we found benefits from retro-dimension-cues compared to neutral cues. This retro-dimension-cue benefit is reflected in an increased probability of reporting the target, but not in the probability of reporting the non-target, as well as increased precision with which this item is remembered. Experiment 2 replicated the retro-dimension-cue benefit and showed that the length of the blank interval after the cue disappeared did not influence recall performance. Experiment 3 replicated the results of Experiment 2 with a lower memory load. Our studies provide evidence that there is a robust retro-dimension-cue benefit in VWM. Participants can use internal attention to flexibly allocate cognitive resources to a particular dimension of memory representations. The results also support the feature-based storing hypothesis.
RNA sequencing analysis of human podocytes reveals glucocorticoid regulated gene networks targeting non-immune pathways
Authors: Jiang Lulu , Hindmarch Charles C. T. , Rogers Mark , Campbell Colin , Waterfall Christy , Coghill Jane , Mathieson Peter W. , Welsh Gavin I.
Published: October 2016

Glucocorticoids are steroids that reduce inflammation and are used as immunosuppressive drugs for many diseases. They are also the mainstay for the treatment of minimal change nephropathy (MCN), which is characterised by an absence of inflammation. Their mechanisms of action remain elusive. Evidence suggests that immunomodulatory drugs can directly act on glomerular epithelial cells or ‘podocytes’, the cell type which is the main target of injury in MCN. To understand the nature of glucocorticoid effects on non-immune cell functions, we generated RNA sequencing data from human podocyte cell lines and identified the genes that are significantly regulated in dexamethasone-treated podocytes compared to vehicle-treated cells. The upregulated genes are of functional relevance to cytoskeleton-related processes, whereas the downregulated genes mostly encode pro-inflammatory cytokines and growth factors. We observed a tendency for dexamethasone-upregulated genes to be downregulated in MCN patients. Integrative analysis revealed gene networks composed of critical signaling pathways that are likely targeted by dexamethasone in podocytes.
Asymptotic theory of time-varying social networks with heterogeneous activity and tie allocation
Authors: Ubaldi Enrico , Perra Nicola , Karsai Márton , Vezzani Alessandro , Burioni Raffaella , Vespignani Alessandro
Published: October 2016

The dynamic of social networks is driven by the interplay between diverse mechanisms that still challenge our theoretical and modelling efforts. Amongst them, two are known to play a central role in shaping the networks evolution, namely the heterogeneous propensity of individuals to i) be socially active and ii) establish a new social relationships with their alters. Here, we empirically characterise these two mechanisms in seven real networks describing temporal human interactions in three different settings: scientific collaborations, Twitter mentions, and mobile phone calls. We find that the individuals’ social activity and their strategy in choosing ties where to allocate their social interactions can be quantitatively described and encoded in a simple stochastic network modelling framework. The Master Equation of the model can be solved in the asymptotic limit. The analytical solutions provide an explicit description of both the system dynamic and the dynamical scaling laws characterising crucial aspects about the evolution of the networks. The analytical predictions match with accuracy the empirical observations, thus validating the theoretical approach. Our results provide a rigorous dynamical system framework that can be extended to include other processes shaping social dynamics and to generate data driven predictions for the asymptotic behaviour of social networks.
Optimal Universal Uncertainty Relations
Authors: Li Tao , Xiao Yunlong , Ma Teng , Fei Shao-Ming , Jing Naihuan , Li-Jost Xianqing , Wang Zhi-Xi
Published: October 2016

We study universal uncertainty relations and present a method called joint probability distribution diagram to improve the majorization bounds constructed independently in [Phys. Rev. Lett. 111, 230401 (2013)] and [J. Phys. A. 46, 272002 (2013)]. The results give rise to state independent uncertainty relations satisfied by any nonnegative Schur-concave functions. On the other hand, a remarkable recent result of entropic uncertainty relation is the direct-sum majorization relation. In this paper, we illustrate our bounds by showing how they provide a complement to that in [Phys. Rev. A. 89, 052115 (2014)].
Immune Responses to an Oral Cholera Vaccine in Internally Displaced Persons in South Sudan
Authors: Iyer Anita S. , Bouhenia Malika , Rumunu John , Abubakar Abdinasir , Gruninger Randon J. , Pita Jane , Lino Richard Lako , Deng Lul L. , Wamala Joseph F. , Ryan Edward T. , Martin Stephen , Legros Dominique , Lessler Justin , Sack David A. , Luquero Francisco J. , Leung Daniel T. , Azman Andrew S.
Published: October 2016

Despite recent large-scale cholera outbreaks, little is known about the immunogenicity of oral cholera vaccines (OCV) in African populations, particularly among those at highest cholera risk. During a 2015 preemptive OCV campaign among internally displaced persons in South Sudan, a year after a large cholera outbreak, we enrolled 37 young children (1–5 years old), 67 older children (6–17 years old) and 101 adults (≥18 years old), who received two doses of OCV (Shanchol) spaced approximately 3 weeks apart. Cholera-specific antibody responses were determined at days 0, 21 and 35 post-immunization. High baseline vibriocidal titers (>80) were observed in 21% of the participants, suggesting recent cholera exposure or vaccination. Among those with titers ≤80, 90% young children, 73% older children and 72% adults seroconverted (≥4 fold titer rise) after the 1st OCV dose; with no additional seroconversion after the 2nd dose. Post-vaccination immunological endpoints did not differ across age groups. Our results indicate Shanchol was immunogenic in this vulnerable population and that a single dose alone may be sufficient to achieve similar short-term immunological responses to the currently licensed two-dose regimen. While we found no evidence of differential response by age, further immunologic and epidemiologic studies are needed.
Supernova: A Versatile Vector System for Single-Cell Labeling and Gene Function Studies in vivo
Authors: Luo Wenshu , Mizuno Hidenobu , Iwata Ryohei , Nakazawa Shingo , Yasuda Kosuke , Itohara Shigeyoshi , Iwasato Takuji
Published: October 2016

Here we describe “Supernova” series of vector systems that enable single-cell labeling and labeled cell-specific gene manipulation, when introduced by in utero electroporation (IUE) or adeno-associated virus (AAV)-mediated gene delivery. In Supernova, sparse labeling relies on low TRE leakage. In a small population of cells with over-threshold leakage, initial tTA-independent weak expression is enhanced by tTA/TRE-positive feedback along with a site-specific recombination system (e.g., Cre/loxP, Flpe/FRT). Sparse and bright labeling by Supernova with little background enables the visualization of the morphological details of individual neurons in densely packed brain areas such as the cortex and hippocampus, both during development and in adulthood. Sparseness levels are adjustable. Labeled cell-specific gene knockout was accomplished by introducing Cre/loxP-based Supernova vectors into floxed mice. Furthermore, by combining with RNAi, TALEN, and CRISPR/Cas9 technologies, IUE-based Supernova achieved labeled cell-specific gene knockdown and editing/knockout without requiring genetically altered mice. Thus, Supernova system is highly extensible and widely applicable for single-cell analyses in complex organs, such as the mammalian brain.
Functionalized magnetic nanowires for chemical and magneto-mechanical induction of cancer cell death
Authors: Martínez-Banderas Aldo Isaac , Aires Antonio , Teran Francisco J. , Perez Jose Efrain , Cadenas Jael F. , Alsharif Nouf , Ravasi Timothy , Cortajarena Aitziber L. , Kosel Jürgen
Published: October 2016

Exploiting and combining different properties of nanomaterials is considered a potential route for next generation cancer therapies. Magnetic nanowires (NWs) have shown good biocompatibility and a high level of cellular internalization. We induced cancer cell death by combining the chemotherapeutic effect of doxorubicin (DOX)-functionalized iron NWs with the mechanical disturbance under a low frequency alternating magnetic field. (3-aminopropyl)triethoxysilane (APTES) and bovine serum albumin (BSA) were separately used for coating NWs allowing further functionalization with DOX. Internalization was assessed for both formulations by confocal reflection microscopy and inductively coupled plasma-mass spectrometry. From confocal analysis, BSA formulations demonstrated higher internalization and less agglomeration. The functionalized NWs generated a comparable cytotoxic effect in breast cancer cells in a DOX concentration-dependent manner, (~60% at the highest concentration tested) that was significantly different from the effect produced by free DOX and non-functionalized NWs formulations. A synergistic cytotoxic effect is obtained when a magnetic field (1 mT, 10 Hz) is applied to cells treated with DOX-functionalized BSA or APTES-coated NWs, (~70% at the highest concentration). In summary, a bimodal method for cancer cell destruction was developed by the conjugation of the magneto-mechanical properties of iron NWs with the effect of DOX producing better results than the individual effects.
Conditions Optimizing and Application of Laccase-mediator System (LMS) for the Laccase-catalyzed Pesticide Degradation
Authors: Jin Xiaoting , Yu Xiangyang , Zhu Guangyan , Zheng Zuntao , Feng Fayun , Zhang Zhiyong
Published: October 2016

A high capacity of laccase from Trametes versicolor capable of degrading pesticides has been revealed. The conditions for degrading of five selected pesticides including chlorpyrifos, chlorothalonil, pyrimethanil, atrazine and isoproturon with the purified laccases from Trametes versicolor were optimized. The results showed that the optimum conditions for the highest activity were pH at 5.0 and temperature at 25 °C. The best mediators were violuric acid for pyrimethanil and isoproturon, vanillin for chlorpyrifos, and acetosyringone and HBT for chlorothalonil and atrazine, respectively. The laccase was found to be stable at a pH range from 5.0 to 7.0 and temperature from 25 to 30 °C. It was observed that each pesticide required a different laccase mediator concentration typically between 4.0–6.0 mmol/L. In the experiment, the degradation rates of pyrimethanil and isoproturon were significantly faster than those of chlorpyrifos, chlorothalonil and atrazine. For example, it was observed that pyrimethanil and isoproturon degraded up to nearly 100% after 24 hours while the other three pesticides just reached up 90% of degradation after 8 days of incubation.
Genetic analysis of innate immunity in Behcet’s disease identifies an association with IL-37 and IL-18RAP
Authors: Tan Handan , Deng Bolin , Yu Hongsong , Yang Yi , Ding Lin , Zhang Qi , Qin Jieying , Kijlstra Aize , Chen Rui , Yang Peizeng
Published: October 2016

Interleukin-1 (IL-1) and the IL-1 receptor (IL-1R) family play an important role in the pathogenesis of inflammatory diseases. This study aimed to investigate the association between single nucleotide polymorphisms (SNP) of IL-1 and IL-1R family genes with Vogt-Koyanagi-Harada (VKH) and Behcet’s disease (BD) in Han Chinese. The case-control study was divided into two stages and included 419 VKH cases, 1063 BD cases and 1872 healthy controls. The MassARRAY platform (Sequenom), iPLEX Gold Assay and TaqMan SNP assays were used to score genotypes of 24 SNPs. The expression of IL-37 and IL-18Rap was measured by ELISA and real-time PCR in genotyped healthy individuals. A significantly lower frequency of the AG genotype, and a higher frequency of the GG genotype and G allele of IL-37/rs3811047 were observed in BD as compared to controls. AA genotype and A allele frequency of IL-18RAP/rs2058660 was significantly decreased in BD as compared to controls. Functional studies performed in healthy controls showed that rs3811047 AG genotype carriers had a higher IL-37 gene expression in peripheral blood mononuclear cells (PBMCs) than GG carriers. GG carriers showed a higher cytokine expression as compared to AG carriers. No association was detected between the tested SNPs and VKH.
Involvement of P2X7 receptor signaling on regulating the differentiation of Th17 cells and type II collagen-induced arthritis in mice
Authors: Fan Zhi-Dan , Zhang Ya-Yuan , Guo Yi-Hong , Huang Na , Ma Hui-Hui , Huang Hui , Yu Hai-Guo
Published: October 2016

Interleukin (IL)-17 producing T helper (Th17) cells are major effector cells in the pathogenesis of rheumatoid arthritis (RA). The P2X7 receptor (P2X7R) has emerged as a potential site in the regulation of inflammation in RA but little is known of its functional role on the differentiation of Th17 cells. This study investigates thein vitroandin vivoeffects of P2X7R on Th17 cell differentiation during type II collagen (CII) induced experimental arthritis model. In CII-treated dendritic cells (DCs) and DC/CD4+T coculture system, pretreatment with pharmacological antagonists of P2X7R (Suramin and A-438079) caused strong inhibition of production of Th17-promoting cytokines (IL-1β, TGF-β1, IL-23p19 and IL-6). Exposure to CII induced the elevation of mRNAs encoding retinoic acid receptor-related orphan receptor α and γt, which were abolished by pretreatment with P2X7R antagonists. Furthermore, blocking P2X7R signaling abolished the CII-mediated increase in IL-17A. Blockade of P2X7R remarkably inhibited hind paw swelling and ameliorated pathological changes in ankle joint of the collagen-induced arthritis mice. Thus, we demonstrated a novel function for P2X7R signaling in regulating CII-induced differentiation of Th17 cells. P2X7R signaling facilitates the development of the sophisticated network of DC-derived cytokines that favors a Th17 phenotype.
Estimating individual optimal sleep duration and potential sleep debt
Authors: Kitamura Shingo , Katayose Yasuko , Nakazaki Kyoko , Motomura Yuki , Oba Kentaro , Katsunuma Ruri , Terasawa Yuri , Enomoto Minori , Moriguchi Yoshiya , Hida Akiko , Mishima Kazuo
Published: October 2016

In this study, we hypothesized that dynamics of sleep time obtained over consecutive days of extended sleep in a laboratory reflect an individual’s optimal sleep duration (OSD) and that the difference between OSD and habitual sleep duration (HSD) at home represents potential sleep debt (PSD). We found that OSD varies among individuals and PSD showed stronger correlation with subjective/objective sleepiness than actual sleep time, interacting with individual’s vulnerability of sleep loss. Furthermore, only 1 h of PSD takes four days to recover to their optimal level. Recovery from PSD was also associated with the improvement in glycometabolism, thyrotropic activity and hypothalamic-pituitary-adrenocortical axis. Additionally, the increase (rebound) in total sleep time from HSD at the first extended sleep would be a simple indicator of PSD. These findings confirmed self-evaluating the degree of sleep debt at home as a useful clinical marker. To establish appropriate sleep habits, it is necessary to evaluate OSD, vulnerability to sleep loss, and sleep homeostasis characteristics on an individual basis.
Stretching human mesenchymal stromal cells on stiffness-customized collagen type I generates a smooth muscle marker profile without growth factor addition
Authors: Rothdiener Miriam , Hegemann Miriam , Uynuk-Ool Tatiana , Walters Brandan , Papugy Piruntha , Nguyen Phong , Claus Valentin , Seeger Tanja , Stoeckle Ulrich , Boehme Karen A. , Aicher Wilhelm K. , Stegemann Jan P. , Hart Melanie L. , Kurz Bodo , Klein Gerd , Rolauffs Bernd
Published: October 2016

Using matrix elasticity and cyclic stretch have been investigated for inducing mesenchymal stromal cell (MSC) differentiation towards the smooth muscle cell (SMC) lineage but not in combination. We hypothesized that combining lineage-specific stiffness with cyclic stretch would result in a significantly increased expression of SMC markers, compared to non-stretched controls. First, we generated dense collagen type I sheets by mechanically compressing collagen hydrogels. Atomic force microscopy revealed a nanoscale stiffness range known to support myogenic differentiation. Further characterization revealed viscoelasticity and stable biomechanical properties under cyclic stretch with >99% viable adherent human MSC. MSCs on collagen sheets demonstrated a significantly increased mRNA but not protein expression of SMC markers, compared to on culture flasks. However, cyclic stretch of MSCs on collagen sheets significantly increased both mRNA and protein expression of α-smooth muscle actin, transgelin, and calponin versus plastic and non-stretched sheets. Thus, lineage-specific stiffness and cyclic stretch can be applied together for inducing MSC differentiation towards SMCs without the addition of recombinant growth factors or other soluble factors. This represents a novel stimulation method for modulating the phenotype of MSCs towards SMCs that could easily be incorporated into currently available methodologies to obtain a more targeted control of MSC phenotype.
Rayleigh scattering in few-mode optical fibers
Authors: Wang Zhen , Wu Hao , Hu Xiaolong , Zhao Ningbo , Mo Qi , Li Guifang
Published: October 2016

The extremely low loss of silica fibers has enabled the telecommunication revolution, but single-mode fiber-optic communication systems have been driven to their capacity limits. As a means to overcome this capacity crunch, space-division multiplexing (SDM) using few-mode fibers (FMF) has been proposed and demonstrated. In single-mode optical fibers, Rayleigh scattering serves as the dominant mechanism for optical loss. However, to date, the role of Rayleigh scattering in FMFs remains elusive. Here we establish and experimentally validate a general model for Rayleigh scattering in FMFs. Rayleigh backscattering not only sets the intrinsic loss limit for FMFs but also provides the theoretical foundation for few-mode optical time-domain reflectometry, which can be used to probe perturbation-induced mode-coupling dynamics in FMFs. We also show that forward inter-modal Rayleigh scattering ultimately sets a fundamental limit on inter-modal-crosstalk for FMFs. Therefore, this work not only has implications specifically for SDM systems but also broadly for few-mode fiber optics and its applications in amplifiers, lasers, and sensors in which inter-modal crosstalk imposes a fundamental performance limitation.
Altered mitochondrial DNA copy number contributes to human cancer risk: evidence from an updated meta-analysis
Authors: Hu Liwen , Yao Xinyue , Shen Yi
Published: October 2016

Accumulating epidemiological evidence indicates that the quantitative changes in human mitochondrial DNA (mtDNA) copy number could affect the genetic susceptibility of malignancies in a tumor-specific manner, but the results are still elusive. To provide a more precise estimation on the association between mtDNA copy number and risk of diverse malignancies, a meta-analysis was conducted by calculating the pooled odds ratios (OR) and the 95% confidence intervals (95% CI). A total of 36 case-control studies involving 11,847 cases and 15,438 controls were finally included in the meta-analysis. Overall analysis of all studies suggested no significant association between mtDNA content and cancer risk (OR = 1.044, 95% CI = 0.866–1.260, P = 0.651). Subgroup analyses by cancer types showed an obvious positive association between mtDNA content and lymphoma and breast cancer (OR = 1.645, 95% CI = 1.117–2.421, P = 0.012; OR = 1.721, 95% CI = 1.130–2.622, P = 0.011, respectively), and a negative association for hepatic carcinoma. Stratified analyses by other confounding factors also found increased cancer risk in people with drinking addiction. Further analysis using studies of quartiles found that populations with the highest mtDNA content may be under more obvious risk of melanoma and that Western populations were more susceptible than Asians.
Tumour growth environment modulates Chk1 signalling pathways and Chk1 inhibitor sensitivity
Authors: Massey Andrew J.
Published: October 2016

Clinical development of Chk1 inhibitors is currently focussed on evaluating activity as monotherapy and as potentiators of chemotherapy. To aid translation of pre-clinical studies, we sought to understand the effects of the tumour growth environment on Chk1 signalling and sensitivity to small molecule Chk1 inhibition. Spheroid culture altered Chk1 signalling to a more xenograft like state but decreased sensitivity to Chk1 inhibition. Growth in low serum did not alter DDR signalling but increased the sensitivity of A2058 and U2OS tumour cells to Chk1 inhibition. An analysis of the expression levels of replication associated proteins identified a correlation between Cdc6 and pChk1 (S296) as well as total Chk1 in xenograft derived samples and between Cdc6 and total Chk1 in anchorage-dependent growth derived protein samples. No apparent correlation between Chk1 or Cdc6 expression and sensitivity to Chk1 inhibition in vitro was observed. A database analysis revealed upregulation of CDC6 mRNA expression in tumour compared to normal tissue and a correlation between CDC6 and CHEK1 mRNA expression in human cancers. We suggest that Cdc6 overexpression in human tumours requires a concomitant increase in Chk1 to counterbalance the deleterious effects of origin hyperactivation-induced DNA damage.
Magnesium diboride coated bulk niobium: a new approach to higher acceleration gradient
Authors: Tan Teng , Wolak M. A. , Xi X. X. , Tajima T. , Civale L.
Published: October 2016

Bulk niobium Superconducting Radio-Frequency cavities are a leading accelerator technology. Their performance is limited by the cavity loss and maximum acceleration gradient, which are negatively affected by vortex penetration into the superconductor when the peak magnetic field at the cavity wall surface exceeds the vortex penetration field (Hvp). It has been proposed that coating the inner wall of an SRF cavity with superconducting thin films increases Hvp. In this work, we utilized Nb ellipsoid to simulate an inverse SRF cavity and investigate the effect of coating it with magnesium diboride layer on the vortex penetration field. A significant enhancement of Hvp was observed. At 2.8 K, Hvp increased from 2100 Oe for an uncoated Nb ellipsoid to 2700 Oe for a Nb ellipsoid coated with ~200 nm thick MgB2 thin film. This finding creates a new route towards achieving higher acceleration gradient in SRF cavity accelerator beyond the theoretical limit of bulk Nb.
Adipose tissue hyperplasia with enhanced adipocyte-derived stem cell activity in Tc1(C8orf4)-deleted mice
Authors: Jang Hayoung , Kim Minsung , Lee Soyoung , Kim Jungtae , Woo Dong-Cheol , Kim Kyung Won , Song Kyuyoung , Lee Inchul
Published: October 2016

Adipose tissue hyperplasia with increased number of adipocytes is implicated in a protective rather than deleterious effect on obesity-associated metabolic disorder. It is poorly understood how the adipose tissue cellularity is regulated. Tc1 is a gene of vertebrates that regulates diverse downstream genes. Young Tc1-deleted mice fed on standard chow diet show expanded adipose tissue with smaller adipocytes in size compared to wild type controls, representing adipose tissue hyperplasia. Tc1−/− mice show enhanced glucose tolerance and reduced serum lipids. Adipocyte-derived stem cells (ADSCs) from Tc1−/− mice show enhanced proliferative and adipogenic capacity compared to wild type controls, suggesting that the adipose hyperplasia is regulated at the stem cell level. PPARγ and CEBPα are up-regulated robustly in Tc1−/− ADSCs upon induction for adipogenesis. Wisp2 and Dlk1, inhibitors of adipogenesis, are down-regulated in Tc1−/− ADSCs compared to controls. Tc1-transfected NIH3T3 cells show higher β-catenin reporter signals than vector transfected controls, suggesting a role of canonical Wnt signaling in the Tc1-dependent adipose regulation. Our data support that Tc1 is a novel regulator for adipose stem cells. Adipose tissue hyperplasia may be implicated in the metabolic regulation of Tc1−/− mice.
Clinical Charateristics and Outcome of Pyogenic Liver Abscess with Different Size: 15-Year Experience from a Single Center
Authors: Du Zhao-Qing , Zhang Li-Na , Lu Qiang , Ren Yi-Fan , Lv Yi , Liu Xue-Min , Zhang Xu-Feng
Published: October 2016

The standard therapeutic protocols of pyogenic liver abscess (PLA) have not been well established yet. We investigated the clinical characteristics, disease progression, choices of treatments and outcomes of PLA with different size. 410 cases of patients with PLA were enrolled retrospectively from 2000 to 2014, and were grouped as small abscess (≤5 cm, n = 125), large abscess (5 cm to 10 cm, n = 218) and giant abscess (>10 cm, n = 36). The most common bacteria were Klebsiella pneumonia (22%) and Escherichia coli (11%) by pus culture, and Escherichia coli (36.7%), gram-positive coccus,(36.7%) and Klebsiella pneumonia (33.3%) by blood culture. 115 patients (28.0%) received antibiotics treatment alone, 161 patients (39.3%) received percutaneous drainage (PD) and 134 patients (32.7%) underwent surgical incision and drainage (SD). The size of abscess was correlated with leukocytes increase, albumin decrease, and time duration for body temperature normalization (all p < 0.05). Antibiotics treatment alone, PD and SD was mainly used in patients with small abscess (42.4%), large abscess (44.0%) and giant abscess (47.2%), respectively. For patients with giant abscess, SD group (n = 17) had higher morbidity than PD group (n = 14) (76.4% vs. 35.7%, p = 0.022). PD might achieve the same curative rate as SD in giant abscess, but with less trauma, lower morbidity and shorter hospital stay.