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  • Articles  (280,341)
  • Springer Nature  (147,748)
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  • 1
    Publication Date: 2014-06-17
    Print ISSN: 1552-4450
    Electronic ISSN: 1552-4469
    Topics: Biology , Chemistry and Pharmacology
    Published by Springer Nature
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  • 2
  • 3
    Publication Date: 2014-02-26
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 4
    Publication Date: 2014-12-13
    Description: We estimate the contamination risks from the atmospheric dispersion of radionuclides released by severe nuclear power plant accidents using the ECHAM/Modular Earth Submodel System (MESSy) atmospheric chemistry (EMAC) atmospheric chemistry-general circulation model at high resolution (50 km). We present an overview of global risks and also a case study of nuclear power plants that are currently under construction, planned and proposed in the Eastern Mediterranean and Middle East, a region prone to earthquakes. We implemented continuous emissions from each location, making the simplifying assumption that all potential accidents release the same amount of radioactivity. We simulated atmospheric transport and decay, focusing on 137Cs and 131I as proxies for particulate and gaseous radionuclides, respectively. We present risk maps for potential surface layer concentrations, deposition and doses to humans from the inhalation exposure of 131I. The estimated risks exhibit seasonal variability, with the highest surface level concentrations of gaseous radionuclides in the Northern Hemisphere during winter.
    Electronic ISSN: 1996-1073
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by MDPI Publishing
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  • 5
    Publication Date: 2014-12-13
    Description: The long-lived pioneer species Pericopsis elata is one of the rare tropical timbers on the list of the Convention on International Trade of Endangered Species, supporting the need for accurate and reliable growth data. In one planted and one natural forest in the Democratic Republic of Congo, respectively four and 37 Pericopsis stem disks were collected. The tree-ring series of planted trees were used to confirm annual tree-ring formation. For the natural forest, a tree-ring chronology with 24 stem disks ranged from 1852 up to 2008. This chronology was compared with time-series of local precipitation, resulting in a significant correlation with the second half of the rainy season (September–November). This seasonal precipitation was related with sea surface temperatures of the West Indian Ocean. Higher precipitation during El Niño years corresponded with higher tree-ring indices but differences were not significant. In addition, pointer years were rare and did not have a consistent link with extreme climatic conditions. The existence of annual tree rings encourages further tree-ring analyses of P. elata and other flagship timber species in order to further document climate-growth responses and to provide the long-term framework that is needed for sustainable management planning.
    Electronic ISSN: 1999-4907
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by MDPI Publishing
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  • 6
    Publication Date: 2014-12-13
    Description: Current earthquake early warning (EEW) systems lack the ability to appropriately handle multiple concurrent earthquakes, which led to many false alarms during the 2011 Tohoku earthquake sequence in Japan. This paper uses a Bayesian probabilistic approach to handle multiple concurrent events for EEW. We implement the theory using a two-step algorithm. First, an efficient approximate Bayesian model class selection scheme is used to estimate the number of concurrent events. Then, the Rao-Blackwellized Importance Sampling method with a sequential proposal probability density function is used to estimate the earthquake parameters, that is hypocentre location, origin time, magnitude and local seismic intensity. A real data example based on 2 months data (2011 March 9–April 30) around the time of the 2011 M 9 Tohoku earthquake is studied to verify the proposed algorithm. Our algorithm results in over 90 per cent reduction in the number of incorrect warnings compared to the existing EEW system operating in Japan.
    Keywords: Seismology
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 7
    Publication Date: 2014-12-13
    Description: Admixture mapping has been enormously resourceful in identifying genetic variations linked to phenotypes, adaptation, and diseases. In this study through analysis of copy number variable regions (CNVRs), we report extensive restructuring in the genomes of the recently admixed African-Indian population (OG-W-IP) that inhabits a highly saline environment in Western India. The study included subjects from OG-W-IP (OG), five different Indian and three HapMap populations that were genotyped using Affymetrix version 6.0 arrays. Copy number variations (CNVs) detected using Birdsuite were used to define CNVRs. Population structure with respect to CNVRs was delineated using random forest approach. OG genomes have a surprising excess of CNVs in comparison to other studied populations. Individual ancestry proportions computed using STRUCTURE also reveals a unique genetic component in OGs. Population structure analysis with CNV genotypes indicates OG to be distant from both the African and Indian ancestral populations. Interestingly, it shows genetic proximity with respect to CNVs to only one Indian population IE-W-LP4, which also happens to reside in the same geographical region. We also observe a significant enrichment of molecular processes related to ion binding and receptor activity in genes encompassing OG-specific CNVRs. Our results suggest that retention of CNVRs from ancestral natives and de novo acquisition of CNVRs could accelerate the process of adaptation especially in an extreme environment. Additionally, this population would be enormously useful for dissecting genes and delineating the involvement of CNVs in salt adaptation.
    Electronic ISSN: 1759-6653
    Topics: Biology
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  • 8
    Publication Date: 2014-12-07
    Description: Article Superconductivity in the iron pnictides is believed to be related to quantum critical fluctuations. Putzke et al. observe unexpected anomalies in the critical fields of BaFe 2 (As 1−x P x ) 2 that emerge close to its magnetic critical point, which they argue is a generic feature of quantum critical superconductivity. Nature Communications doi: 10.1038/ncomms6679 Authors: C. Putzke, P. Walmsley, J. D. Fletcher, L. Malone, D. Vignolles, C. Proust, S. Badoux, P. See, H. E. Beere, D. A. Ritchie, S. Kasahara, Y. Mizukami, T. Shibauchi, Y. Matsuda, A. Carrington
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 9
    Publication Date: 2014-12-12
    Description: We present a catalogue of 2D, point spread function-corrected de Vacouleurs, Sérsic, de Vacouleurs+Exponential, and Sérsic+Exponential fits of ~7 x 10 5 spectroscopically selected galaxies drawn from the Sloan Digital Sky Survey (SDSS) Data Release 7. Fits are performed for the SDSS r band utilizing the fitting routine galfit and analysis pipeline pymorph . We compare these fits to prior catalogues. Fits are analysed using a physically motivated flagging system. The flags suggest that more than 90 per cent of two-component fits can be used for analysis. We show that the fits follow the expected behaviour for early and late galaxy types. The catalogues provide a robust set of structural and photometric parameters for future galaxy studies. We show that some biases remain in the measurements, e.g. the presence of bars significantly affect the bulge measurements although the bulge ellipticity may be used to separate barred and non-barred galaxies, and about 15 per cent of bulges of two-component fits are also affected by resolution. The catalogues are available in electronic format. We also provide an interface for generating postage stamp images of the 2D model and residual as well as the 1D profile. These images can be generated for a user-uploaded list of galaxies on demand.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 10
    Publication Date: 2014-12-13
    Description: Our aim is to explore general practitioners’ (GPs’) knowledge about EMF, and to assess whether different knowledge structures are related to the GPs’ concern about EMF. Random samples were drawn from lists of GPs in Germany in 2008. Knowledge about EMF was assessed by seven items. A latent class analysis was conducted to identify latent structures in GPs’ knowledge. Further, the GPs’ concern about EMF health risk was measured using a score comprising six items. The association between GPs’ concern about EMF and their knowledge was analysed using multiple linear regression. In total 435 (response rate 23.3%) GPs participated in the study. Four groups were identified by the latent class analysis: 43.1% of the GPs gave mainly correct answers; 23.7% of the GPs answered low frequency EMF questions correctly; 19.2% answered only the questions relating EMF with health risks, and 14.0% answered mostly “don’t know”. There was no association between GPs’ latent knowledge classes or between the number of correct answers given by the GPs and their EMF concern, whereas the number of incorrect answers was associated with EMF concern. Greater EMF concern in subjects with more incorrect answers suggests paying particular attention to misconceptions regarding EMF in risk communication.
    Print ISSN: 1661-7827
    Electronic ISSN: 1660-4601
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Published by MDPI Publishing
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  • 11
    Publication Date: 2014-12-13
    Description: This study aims to explore the efficiency of using online education as an intervention measure to prevent occupational hazards in a clinical nursing setting. The subjects were 320 female nursing staff from two hospitals in Taiwan. The questionnaire results indicated that the subjects primarily experienced human factor occupational hazards, as well as psychological and social hazards. Specifically, 73.1% and 69.8% of the subjects suffered from poor sleep quality and low back pain, respectively. After web-based learning, the experimental group had higher post-test scores than the control group in terms of knowledge, attitudes, and practices (KAP). However, there was only a significant difference (p 〈 0.05) in their knowledge about the prevention of occupational hazards. It is suggested that an online discussion may enhance nursing staff’s participation in web-based learning, and further facilitate their comments on negative factors. The findings can highly promote nursing staff’s attitudes and practices toward preventing occupational hazards through web-based learning.
    Print ISSN: 1661-7827
    Electronic ISSN: 1660-4601
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Published by MDPI Publishing
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  • 12
    Publication Date: 2014-12-13
    Description: Ambient particulate matters and temperature were reported to have additive effects over the respiratory disease hospital admissions and deaths. The purpose of this study is to discuss the interactive pulmonary toxicities of cold stress and fine particulate matter (PM2.5) exposure by estimating inflammation and oxidative stress responses. 48 Wistar male rats, matched by weight and age, were randomly assigned to six groups, which were treated with cold stress alone (0 °C, 10 °C, and 20 °C (Normal control)) and cold stresses plus PM2.5 exposures respectively. Cold stress alone groups were intratracheal instillation of 0.25 mL normal saline, while cold stress plus PM2.5 exposure groups were intratracheal instillation of 8 mg/0.25 mL PM2.5. These procedures were carried out for three times with an interval of 48 hours for each treatment. All rats were sacrificed after 48 hours of the third treatment. The bronchoalveolar lavage fluid (BALF) was collected for analyzing inflammatory cells and cytokines, and lung homogenate MDA was determined for oxidative stress estimation. Results showed higher level of total cell and neutrophil in the BALF of PM2.5 exposed groups (p 〈 0.05). Negative relationships between cold stress intensity and the level of tumor necrosis factor alpha (TNF-a), C-reactive protein (CRP) interleukin-6 (IL-6) and interleukin-8 (IL-8) in BALF were indicated in PM2.5 exposure groups. Exposure to cold stress alone caused significant increase of inflammatory cytokines and methane dicarboxylic aldehyde (MDA) and decline of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity only in 0 °C exposure group (p 〈 0.05). The two-way ANOVA found significant interactive effects between PM2.5 exposure and cold stress in the level of neutrophil, IL-6 and IL-8 and SOD activity (p 〈 0.05). These data demonstrated that inflammation and oxidative stress involved in the additive effect of PM2.5 exposure and cold stress on pulmonary toxicity, providing explanation for epidemiological studies on the health effect of ambient PM2.5 and cold stress.
    Print ISSN: 1661-7827
    Electronic ISSN: 1660-4601
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Published by MDPI Publishing
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  • 13
    Publication Date: 2014-12-13
    Description: This paper presents a detailed description of an approach designed to investigate the application of the Health Impact Assessment (HIA) framework to assess the potential health impacts of climate change. A HIA framework has been combined with key climate change terminology and concepts. The fundamental premise of this framework is an understanding of the interactions between people, the environment and climate. The diversity and complexity of these interactions can hinder much needed action on the critical health issue of climate change. The objectives of the framework are to improve the methodology for understanding and assessing the risks associated with potential health impacts of climate change, and to provide decision-makers with information that can facilitate the development of effective adaptation plans. While the process presented here provides guidance with respect to this task it is not intended to be prescriptive. As such, aspects of the process can be amended to suit the scope and available resources of each project. A series of working tables has been developed to assist in the collation of evidence throughout the process. The framework has been tested in a number of locations including Western Australia, Solomon Islands, Vanuatu and Nauru.
    Print ISSN: 1661-7827
    Electronic ISSN: 1660-4601
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Published by MDPI Publishing
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  • 14
    Publication Date: 2014-12-12
    Description: Article microRNAs are short non-coding RNAs that post-transcriptionally regulate gene expression for which the identification of promoter and primary transcripts (pri-miRNAs) has been difficult. Here the authors describe microTSS, an algorithm that supports the precise identification of intergenic pri-miRNA transcription start sites. Nature Communications doi: 10.1038/ncomms6700 Authors: Georgios Georgakilas, Ioannis S. Vlachos, Maria D. Paraskevopoulou, Peter Yang, Yuhong Zhang, Aris N. Economides, Artemis G. Hatzigeorgiou
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 15
    Publication Date: 2014-12-12
    Description: Article Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. In this study, the authors use RNA sequencing analyses to characterize differences in the transcriptome between autistic and typically developing brains. Nature Communications doi: 10.1038/ncomms6748 Authors: Simone Gupta, Shannon E. Ellis, Foram N. Ashar, Anna Moes, Joel S. Bader, Jianan Zhan, Andrew B. West, Dan E. Arking
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 16
    Publication Date: 2014-12-12
    Description: Article Pulse oximetry is a non-invasive means for measuring blood oxygen saturation and pulse rate, with typical sensors based on rigid electronics. Here, the authors develop a pulse oximeter based solely on organic materials, allowing flexible devices and hence increasing the potential sensing locations on the body. Nature Communications doi: 10.1038/ncomms6745 Authors: Claire M. Lochner, Yasser Khan, Adrien Pierre, Ana C. Arias
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 17
    Publication Date: 2014-12-12
    Description: Article The straightforward and scalable synthesis and patterning of graphene-based nanomaterials remains a technological challenge. Here, the authors use a CO 2 infrared laser, under ambient conditions, to directly produce and pattern porous graphene films with three-dimensional networks from commercial polymer films. Nature Communications doi: 10.1038/ncomms6714 Authors: Jian Lin, Zhiwei Peng, Yuanyue Liu, Francisco Ruiz-Zepeda, Ruquan Ye, Errol L. G. Samuel, Miguel Jose Yacaman, Boris I. Yakobson, James M. Tour
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 18
    Publication Date: 2014-12-13
    Description: One of the most uncertain parameters in stepped spillway design is the length (from the crest) of boundary layer development. The normal velocity profiles responding to the steps as bed roughness are investigated in the developing non-aerated flow region. A detailed analysis of the logarithmic vertical velocity profiles on stepped spillways is conducted through experimental data to verify the computational code and numerical experiments to expand the data available. To determine development length, the hydraulic roughness and displacement thickness, along with the shear velocity, are needed. This includes determining displacement height d and surface roughness length z0 and the relationship of d and z0 to the step geometry. The results show that the hydraulic roughness height ks is the primary factor on which d and z0 depend. In different step height, step width, discharge and intake Froude number, the relations d/ks = 0.22–0.27, z0/ks = 0.06–0.1 and d/z0 = 2.2–4 result in a good estimate. Using the computational code and numerical experiments, air inception will occur over stepped spillway flow as long as the Bauer-defined boundary layer thickness is between 0.72 and 0.79.
    Electronic ISSN: 2073-4441
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by MDPI Publishing
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  • 19
    Publication Date: 2014-12-13
    Description: A regional-level and dimensionless analysis for designing a domestic rainwater harvesting system (DRWHS) was developed. To consider various combinations of water demand, storage capacity, effective roof area, and rainfall in DRWHS design, two dimensionless ratios were used, namely, demand fraction and storage fraction, along with a relationship between the two ratios. Firstly, Northern Taiwan was divided into four sub-regions through cluster analysis based on the average annual 10-day rainfall distribution at rainfall stations and administrative districts. Easy-to-use dimensionless curves between demand fraction and storage fraction were obtained for five rainwater supply reliabilities of the DRWHS for the four sub-regions. Based on the dimensionless curves, a nomogram was constructed for designing DRWHSs at a rainwater supply reliability of 95% in the sub-region I. Storage capacities determined from the dimensionless curves showed a close fit with those determined from simulated values, but were larger than the values estimated from the method presented in the Green Building Evaluation Manual in most situations. The methodology developed herein can be used effectively for the preliminary design of a DRWHS and for overcoming the difficulties faced in designing a DRWHS without rainfall data and with incomplete rainfall data.
    Electronic ISSN: 2073-4441
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by MDPI Publishing
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  • 20
    Publication Date: 2014-12-13
    Description: Article Plasmons in metallic nanostructures provide light enhancement that amplifies their nonlinear optical response. This study shows that graphene nanoislands also give rise to an amplified nonlinear polarizability that can be tuned electrically to surpass those of other nonlinear media by orders of magnitude. Nature Communications doi: 10.1038/ncomms6725 Authors: Joel D. Cox, F. Javier García de Abajo
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 21
    Publication Date: 2014-12-13
    Description: Article FAN1 is a structure-specific nuclease that plays a major role in eliminating highly cytotoxic interstrand DNA crosslinks. Here, Zhao et al . present several crystal structures of FAN1 in complex with DNA substrates and biochemical analyses that establish how FAN1 functions to resolve interstrand DNA crosslinks. Nature Communications doi: 10.1038/ncomms6726 Authors: Qi Zhao, Xiaoyu Xue, Simonne Longerich, Patrick Sung, Yong Xiong
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 22
    Publication Date: 2014-12-13
    Description: We present new narrow-band (Hα and [O  iii ]) images and optical spectrophotometry of H  ii regions for a gas-rich low-surface-brightness irregular galaxy, KKR 17. The central surface brightness of the galaxy is μ 0 ( B ) = 24.15 ± 0.03 mag s –2 . The galaxy was detected by the Arecibo Legacy Fast ALFA survey (ALFALFA). Its mass is dominated by neutral hydrogen (H  i ) gas. In contrast, both the stellar masses of the bright H  ii and diffuse stellar regions are small. In addition, the fit to the spectral energy distribution to each region shows the stellar populations of H  ii and diffuse regions are different. The bright H  ii region contains a large fraction of O-type stars, revealing recent strong star formation, whereas the diffuse region is dominated by median age stars with a typical age of ~600 Myr. Using McGaugh's abundance model, we found that the average metallicity of KKR 17 is 12 + (O/H) = 8.0 ± 0.1. The star-formation rate of KKR 17 is 0.21 ± 0.04 M  yr –1 , which is ~1/5 of our Milky Way's. Based on the analysis results for young stellar clusters in the H  ii region, the bright H  ii region has two sub-components with different velocities and metallicities. This may be caused by the outflow of massive stars or merging events. However, the mechanism triggering star formation in the H  ii region is still uncertain.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 23
    Publication Date: 2014-12-13
    Description: We review the results of the 1988 multiwavelength campaign on the late-type eclipsing binary YY Geminorum. Observations include: broad-band optical and near-infrared photometry, simultaneous optical and ultraviolet ( IUE ) spectroscopy, X-ray ( Ginga ) and radio (VLA) data. From models fitted to the optical light curves, fundamental physical parameters have been determined together with evidence for transient maculations (spots) located near quadrature longitudes and intermediate latitudes. Eclipses were observed at optical, ultraviolet and radio wavelengths. Significant drops in 6 cm radio emission near the phases of both primary and secondary eclipse indicate relatively compact radio emitting volumes that may lie between the binary components. IUE observations during secondary eclipse are indicative of a uniform chromosphere saturated with Mg  ii emission and an extended volume of Lyα emission. Profile fitting of high-dispersion Hα spectra confirms the chromospheric saturation and indicates significant Hα opacity to heights of a few per cent of the photospheric radius. There is evidence for an enhanced Hα emission region visible near phase 0.25–0.35 which may be associated with a large spot on the primary and with two small optical flares which were also observed at other wavelengths: one in microwave radiation and the other in X-rays. For both flares, L X / L opt is consistent with energy release in closed magnetic structures.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 24
    Publication Date: 2014-12-13
    Description: Article Spartan/DVC1 is a translesion synthesis regulator with important roles in cellular DNA damage tolerance. Here, the authors report that Spartan is essential for DNA lesion bypass and that Spartan insufficiency in mice causes chromosomal instability, cellular senescence and early onset of age-related phenotypes. Nature Communications doi: 10.1038/ncomms6744 Authors: Reeja S. Maskey, Myoung Shin Kim, Darren J. Baker, Bennett Childs, Liviu A. Malureanu, Karthik B. Jeganathan, Yuka Machida, Jan M. van Deursen, Yuichi J. Machida
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 25
    Publication Date: 2014-12-13
    Description: Article Carbon sequestration will be vital in mitigating future climate change, and understanding how CO 2 behaves in aquifers is important for developing technologies. Here, the authors suggest that silicate-rich rocks inhibit the transport of CO 2 , which may have consequences for future engineered storage facilities. Nature Communications doi: 10.1038/ncomms6743 Authors: S. S. S. Cardoso, J. T. H. Andres
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 26
    Publication Date: 2014-12-12
    Description: The inherent attenuation of a homogeneous viscous medium limits radiation propagation, thereby restricting the use of many high-frequency acoustic devices to only short-range applications. Here, we design and experimentally demonstrate an acoustic metamaterial localization cavity which is used for sound pressure level (SPL) gain using double coiled up space like structures thereby increasing the range of detection. This unique behavior occurs within a subwavelength cavity that is 1/10th of the wavelength of the incident acoustic wave, which provides up to a 13 dB SPL gain. We show that the amplification results from the Fabry-Perot resonance of the cavity, which has a simultaneously high effective refractive index and effective impedance. We also experimentally verify the SPL amplification in an underwater environment at higher frequencies using a sample with an identical unit cell size. The versatile scalability of the design shows promising applications in many areas, especially in acoustic imaging and underwater communication. Scientific Reports 4 doi: 10.1038/srep07421
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 27
    Publication Date: 2014-12-12
    Description: Advanced macrolides, such as azithromycin (AZM) or clarithromycin (CLM), are antibiotics with immunomodulatory properties. Here we have sought to evaluate their in vitro influence on the activation of CD4+ T-cells. Isolated CD4+ T-cells were stimulated with agonistic anti-CD3/anti-CD28 monoclonal antibodies in the presence of 0.6 mg/L, 2.5 mg/L, 10 mg/L or 40 mg/L AZM or CLM. Cell proliferation, cytokine level in supernatants and cell viability was assessed. Intracellular signaling pathways were evaluated using reporter cell lines, FACS analysis, immunoblotting and in vitro kinase assays. AZM inhibited cell proliferation rate and cytokine secretion of CD4+ T-cells in a dose-dependent manner. Similarly, high concentrations of CLM (40 mg/L) also suppressed these T-cell functions. Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein, a downstream target of mTOR. This effect was also observed at 40 mg/L CLM. In vitro kinase studies using recombinant mTOR showed that AZM inhibited mTOR activity. In contrast to rapamycin, this inhibition was independent of FKBP12. We show for the first time that AZM and to a lesser extent CLM act as immunosuppressive agents on CD4+ T-cells by inhibiting mTOR activity. Our results might have implications for the clinical use of macrolides. Scientific Reports 4 doi: 10.1038/srep07438
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 28
    Publication Date: 2014-12-13
    Description: A solid-state nanopore platform with a low noise level and sufficient sensitivity to discriminate single-strand DNA (ssDNA) homopolymers of poly-A40 and poly-T40 using ionic current blockade sensing is proposed and demonstrated. The key features of this platform are (a) highly insulating dielectric substrates that are used to mitigate the effect of parasitic capacitance elements, which decrease the ionic current RMS noise level to sub-10 pA and (b) ultra-thin silicon nitride membranes with a physical thickness of 5 nm (an effective thickness of 2.4 nm estimated from the ionic current) are used to maximize the signal-to-noise ratio and the spatial depth resolution. The utilization of an ultra-thin membrane and a nanopore diameter as small as 1.5 nm allow the successful discrimination of 40 nucleotide ssDNA poly-A40 and poly-T40. Overall, we demonstrate that this platform overcomes several critical limitations of solid-state nanopores and opens the door to a wide range of applications in single-molecule-based detection and analysis. Scientific Reports 4 doi: 10.1038/srep07448
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 29
    Publication Date: 2014-12-13
    Description: Actions such as sharing food and cooperating to reach a common goal have played a fundamental role in the evolution of human societies. Despite the importance of such good actions, little is known about if and how they can spread from person to person to person. For instance, does being recipient of an altruistic act increase your probability of being cooperative with a third party? We have conducted an experiment on Amazon Mechanical Turk to test this mechanism using economic games. We have measured willingness to be cooperative through a standard Prisoner's dilemma and willingness to act altruistically using a binary Dictator game. In the baseline treatments, the endowments needed to play were given by the experimenters, as usual; in the control treatments, they came from a good action made by someone else. Across four different comparisons and a total of 572 subjects, we have never found a significant increase of cooperation or altruism when the endowment came from a good action. We conclude that good actions do not necessarily inspire good actions in others. While this is consistent with the theoretical prediction, it challenges the majority of other experimental studies. Scientific Reports 4 doi: 10.1038/srep07470
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 30
    Publication Date: 2014-12-13
    Description: EPAS1 involves in the hypoxic response and is suggested to be responsible for the genetic adaptation of high-altitude hypoxia in Tibetans. However, the detailed molecular mechanism remains unknown. In this study, a single nucleotide polymorphism rs56721780:G〉C and an insertion/deletion (indel) polymorphism −742 indel in the promoter region showed divergence between Tibetans and non-Tibetan lowlanders. rs56721780:G〉C regulated the transcription of EPAS1 by IKAROS family zinc finger 1 (IKZF1), which was identified as a new transcriptional repressor for EPAS1 gene. It demonstrated that the C allele of rs56721780:G〉C decreased the binding of IKZF1, leading to the attenuated transcriptional repression of EPAS1 gene. The insertion at −742 indel provided a new binding site for Sp1 and was related to the activation of EPAS1 promoter. Further functional analysis revealed that lysyl oxidase (LOX) gene, which was reported to be responsible for extracellular matrix protein cross-linking of amnion previously, was a direct target of EPAS1. The CC genotype at rs56721780:G〉C and the insertion genotype at −742 indel were found associated with higher EPAS1 and LOX expression levels in amnion, as well as higher birth weight of Tibetan newborns, suggesting that EPAS1 gene might play important roles in the development of amnion, fetus growth and high-altitude adaptation of Tibetans. Scientific Reports 4 doi: 10.1038/srep07465
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 31
    Publication Date: 2014-12-13
    Description: It has been recently reported that the reciprocity of real-life weighted networks is very pronounced, however its impact on dynamical processes is poorly understood. In this paper, we study random walks in a scale-free directed weighted network with a trap at the central hub node, where the weight of each directed edge is dominated by a parameter controlling the extent of network reciprocity. We derive two expressions for the mean first passage time (MFPT) to the trap, by using two different techniques, the results of which agree well with each other. We also analytically determine all the eigenvalues as well as their multiplicities for the fundamental matrix of the dynamical process, and show that the largest eigenvalue has an identical dominant scaling as that of the MFPT.We find that the weight parameter has a substantial effect on the MFPT, which behaves as a power-law function of the system size with the power exponent dependent on the parameter, signaling the crucial role of reciprocity in random walks occurring in weighted networks. Scientific Reports 4 doi: 10.1038/srep07460
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 32
    Publication Date: 2014-12-13
    Description: Most influenza pandemics have been caused by H1N1 viruses of purely or partially avian origin. Here, using Cox proportional hazard model, we attempt to identify the genetic variations in the whole genome of wild-type North American avian H1N1 influenza A viruses that are associated with their virulence in mice by residue variations, host origins of virus (Anseriformes-ducks or Charadriiformes-shorebirds), and host-residue interactions. In addition, through structural modeling, we predicted that several polymorphic sites associated with pathogenicity were located in structurally important sites, especially in the polymerase complex and NS genes. Our study introduces a new approach to identify pathogenic variations in wild-type viruses circulating in the natural reservoirs and ultimately to understand their infectious risks to humans as part of risk assessment efforts towards the emergence of future pandemic strains. Scientific Reports 4 doi: 10.1038/srep07455
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 33
    Publication Date: 2014-12-13
    Description: We propose a method to enhance the fuel cell efficiency with the simultaneous removal of toxic heavy metal ions. Carbon monoxide (CO), an intermediate of methanol oxidation that is primarily responsible for Pt catalyst deactivation, can be used as an in-situ reducing agent for hexavalent chromium (Cr (VI)) with reactivating the CO-poisoned Pt catalyst. Using electro-oxidation measurements, the oxidation of adsorbed CO molecules coupled with the concurrent conversion of Cr (VI) to Cr (III) was confirmed. This concept was also successfully applied to a methanol fuel cell to enhance its performance efficiency and to remove toxic Cr (VI) at the same time. Scientific Reports 4 doi: 10.1038/srep07450
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 34
    Publication Date: 2014-12-13
    Description: Alzheimer's disease (AD) is a lethal progressive neurological disorder affecting the memory. Recently, US Food and Drug Administration mitigated the standard for drug approval, allowing symptomatic drugs that only improve cognitive deficits to be allowed to accelerate on to clinical trials. Our study focuses on taurine, an endogenous amino acid found in high concentrations in humans. It has demonstrated neuroprotective properties against many forms of dementia. In this study, we assessed cognitively enhancing property of taurine in transgenic mouse model of AD. We orally administered taurine via drinking water to adult APP/PS1 transgenic mouse model for 6 weeks. Taurine treatment rescued cognitive deficits in APP/PS1 mice up to the age-matching wild-type mice in Y-maze and passive avoidance tests without modifying the behaviours of cognitively normal mice. In the cortex of APP/PS1 mice, taurine slightly decreased insoluble fraction of Aβ. While the exact mechanism of taurine in AD has not yet been ascertained, our results suggest that taurine can aid cognitive impairment and may inhibit Aβ-related damages. Scientific Reports 4 doi: 10.1038/srep07467
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 35
    Publication Date: 2014-12-13
    Description: Archaeal plasma membranes appear to be extremely durable and almost impermeable to water and ions, in contrast to the membranes of Bacteria and Eucaryota. Additionally, they remain liquid within a temperature range of 0–100°C. These are the properties that have most likely determined the evolutionary fate of Archaea, and it may be possible for bionanotechnology to adopt these from nature. In this work, we use molecular dynamics simulations to assess at the atomistic level the structure and dynamics of a series of model archaeal membranes with lipids that have tetraether chemical nature and “branched” hydrophobic tails. We conclude that the branched structure defines dense packing and low water permeability of archaeal-like membranes, while at the same time ensuring a liquid-crystalline state, which is vital for living cells. This makes tetraether lipid systems promising in bionanotechnology and material science, namely for design of new and unique membrane nanosystems. Scientific Reports 4 doi: 10.1038/srep07462
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
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  • 36
    Publication Date: 2014-12-13
    Description: Scientific Reports 4 doi: 10.1038/srep05692
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
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  • 37
    Publication Date: 2014-12-13
    Description: Typhoid fever poses significant burden on healthcare systems in Southeast Asia and other endemic countries. Several epidemiological and genomic studies have attributed pseudogenisation to be the major driving force for the evolution of Salmonella Typhi although its real potential remains elusive. In the present study, we analyzed genomes of S. Typhi from different parts of Southeast Asia and Oceania, comprising of isolates from outbreak, sporadic and carrier cases. The genomes showed high genetic relatedness with limited opportunity for gene acquisition as evident from pan-genome structure. Given that pseudogenisation is an active process in S. Typhi, we further investigated core and pan-genome profiles of functional and pseudogenes separately. We observed a decline in core functional gene content and a significant increase in accessory pseudogene content. Upon functional classification, genes encoding metabolic functions formed a major constituent of pseudogenes as well as core functional gene clusters with SNPs. Further, an in-depth analysis of accessory pseudogene content revealed the existence of heterogeneous complements of functional and pseudogenes among the strains. In addition, these polymorphic genes were also enriched in metabolism related functions. Thus, the study highlights the existence of heterogeneous strains in a population with varying metabolic potential and that S. Typhi possibly resorts to metabolic fine tuning for its adaptation. Scientific Reports 4 doi: 10.1038/srep07457
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
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  • 38
    Publication Date: 2014-12-13
    Description: Ultraviolet photodetectors have been fabricated from ZnO quantum dots/carbon nanodots hybrid films, and the introduction of carbon nanodots improves the performance of the photodetectors greatly. The photodetectors can be used to detect very weak ultraviolet signals (as low as 12 nW/cm2). The detectivity and noise equivalent power of the photodetector can reach 3.1 × 1017 cmHz1/2/W and 7.8 × 10−20 W, respectively, both of which are the best values ever reported for ZnO-based photodetectors. The mechanism for the high sensitivity of the photodetectors has been attributed to the enhanced carrier-separation at the ZnO/C interface. Scientific Reports 4 doi: 10.1038/srep07469
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 39
    Publication Date: 2014-12-13
    Description: Microglia represent rational but challenging targets for improving white matter integrity because of their dualistic protective and toxic roles. The present study examines the effect of Omega-3 polyunsaturated fatty acids (n-3 PUFAs) on microglial responses to myelin pathology in primary cultures and in the cuprizone mouse model of multiple sclerosis (MS), a devastating demyelination disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the two main forms of n-3 PUFAs in the brain, inhibited the release of nitric oxide and tumor necrosis factor-α from primary microglia upon IFN-γ and myelin stimulation. DHA and EPA also enhanced myelin phagocytosis in vitro. Therefore, n-3 PUFAs can inhibit inflammation while at the same time enhancing beneficial immune responses such as microglial phagocytosis. In vivo studies demonstrated that n-3 PUFA supplementation reduced cuprizone-induced demyelination and improved motor and cognitive function. The positive effects of n-3 PUFAs were accompanied by a shift in microglial polarization toward the beneficial M2 phenotype both in vitro and in vivo. These results suggest that n-3 PUFAs may be clinically useful as immunomodulatory agents for demyelinating diseases through a novel mechanism involving microglial phenotype switching. Scientific Reports 4 doi: 10.1038/srep07458
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 40
    Publication Date: 2014-12-13
    Description: With Fe2O3 as a proof-of-concept, free-standing nanomembrane structure is demonstrated to be highly advantageous to improve the performance of Li-ion batteries. The Fe2O3 nanomembrane electrodes exhibit ultra-long cycling life at high current rates with satisfactory capacity (808 mAh g−1 after 1000 cycles at 2 C and 530 mAh g−1 after 3000 cycles at 6 C) as well as repeatable high rate capability up to 50 C. The excellent performance benefits particularly from the unique structural advantages of the nanomembranes. The mechanical feature can buffer the strain of lithiation/delithiation to postpone the pulverization. The two-dimensional transport pathways in between the nanomembranes can promote the pseudo-capacitive type storage. The parallel-laid nanomembranes, which are coated by polymeric gel-like film and SEI layer with the electrolyte in between layers, electrochemically behave like numerous “mini-capacitors” to provide the pseudo-capacitance thus maintain the capacity at high rate. Scientific Reports 4 doi: 10.1038/srep07452
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 41
    Publication Date: 2014-12-13
    Description: Peptide deformylase (PDF) is a prokaryotic enzyme that catalyzes the deformylation of nascent peptides generated during protein synthesis and water molecules play a key role in these hydrolases. Using X-ray absorption near edge spectroscopy (XANES) and ab initio calculations we accurately probe the local atomic environment of the metal ion binding in the active site of PDF at different pH values and with different metal ions. This new approach is an effective way to monitor existing correlations among functions and structural changes. We show for the first time that the enzymatic activity depends on pH values and metal ions via the bond length of the nearest coordinating water (Wat1) to the metal ion. Combining experimental and theoretical data we may claim that PDF exhibits an enhanced enzymatic activity only when the distance of the Wat1 molecule with the metal ion falls in the limited range from 2.15 to 2.55 Å. Scientific Reports 4 doi: 10.1038/srep07453
    Electronic ISSN: 2045-2322
    Topics: Natural Sciences in General
    Published by Springer Nature
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  • 42
    Publication Date: 2014-12-14
    Description: Article The Microrchidia (Morc) family of GHKL ATPases are important repressors of transposons and other DNA-methylated and silent genes in A. thaliana . Here, the authors show that MORC1 is responsible for repression and methylation of specific classes of transposons in the mouse male germline. Nature Communications doi: 10.1038/ncomms6795 Authors: William A. Pastor, Hume Stroud, Kevin Nee, Wanlu Liu, Dubravka Pezic, Sergei Manakov, Serena A. Lee, Guillaume Moissiard, Natasha Zamudio, Déborah Bourc’his, Alexei A. Aravin, Amander T. Clark, Steven E. Jacobsen
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 43
    Publication Date: 2014-12-14
    Description: To make relevant predictions about observable emission, hydrodynamical simulation codes must employ schemes that account for radiative losses, but the large dimensionality of accurate radiative transfer schemes is often prohibitive. Stamatellos and collaborators introduced a scheme for smoothed particle hydrodynamics (SPH) simulations based on the notion of polytropic pseudo-clouds that uses only local quantities to estimate cooling rates. The computational approach is extremely efficient and works well in cases close to spherical symmetry, such as in star formation problems. Unfortunately, the method, which takes the local gravitational potential as an input, can be inaccurate when applied to non-spherical configurations, limiting its usefulness when studying discs or stellar collisions, among other situations of interest. Here, we introduce the ‘pressure scale height method,’ which incorporates the fluid pressure scaleheight into the determination of column densities and cooling rates, and show that it produces more accurate results across a wide range of physical scenarios while retaining the computational efficiency of the original method. The tested models include spherical polytropes as well as discs with specified density and temperature profiles. We focus on applying our techniques within an SPH code, although our method can be implemented within any particle-based Lagrangian or grid-based Eulerian hydrodynamic scheme. Our new method may be applied in a broad range of situations, including within the realm of stellar interactions, collisions, and mergers.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 44
    Publication Date: 2014-12-14
    Description: Article The induction of autophagy under stress conditions such as chemotherapy is a contributing factor towards resistance to anticancer therapy. Here, Zhang et al . identify the molecular chaperone clusterin as an adaptor that facilitates lipidation of LC3 and autophagosome biogenesis. Nature Communications doi: 10.1038/ncomms6775 Authors: Fan Zhang, Masafumi Kumano, Eliana Beraldi, Ladan Fazli, Caigan Du, Susan Moore, Poul Sorensen, Amina Zoubeidi, Martin E. Gleave
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 45
    Publication Date: 2014-12-16
    Description: Three ideal point-based multi-criteria decision methods (MCDM), i.e., iterative ideal point thresholding (IIPT), compromise programming (CP) and a newly-proposed CP variant, called balanced compromise programming (BCP), were applied to the Tabacay catchment in Ecuador with the aim of finding a distribution of land use types (LUT) that optimizes regional land performance. This performance was expressed in terms of several conflicting on-site ecosystem services (ESS), namely water conservation, soil protection, carbon storage and monetary income. IIPT selects the best performing LUT on a per-land unit basis, that is the assignment of a LUT to a land unit is completely independent with respect to other land units. CP and BCP, on the other hand, aim at optimizing the integrated regional performance. These methods produce a LUT distribution that is as close as possible to the absolute optimal performance that would be achieved when conflict among ESS is not considered. In general, similar results were obtained with CP and BCP. This was not the case when the results produced by these two methods were contrasted with IIPT. For most ESS under consideration, CP and BCP produced balanced results that were closer to the absolute optimal values when compared to IIPT. We conclude from our results that, when optimization of land performance at a regional scale is at stake, CP-derived models emerge as the preferable option over IIPT, especially when balanced solutions are a requirement.
    Electronic ISSN: 1999-4907
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by MDPI Publishing
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  • 46
    Publication Date: 2014-12-16
    Description: Current understanding of aspen fire ecology in western North America includes the paradoxical characterization that aspen-dominated stands, although often regenerated following fire, are “fire-proof”. We tested this idea by predicting potential fire behavior across a gradient of aspen dominance in northern Utah using the Forest Vegetation Simulator and the Fire and Fuels Extension. The wind speeds necessary for crowning (crown-to-crown fire spread) and torching (surface to crown fire spread) were evaluated to test the hypothesis that predicted fire behavior is influenced by the proportion of aspen in the stand. Results showed a strong effect of species composition on crowning, but only under moderate fire weather, where aspen-dominated stands were unlikely to crown or torch. Although rarely observed in actual fires, conifer-dominated stands were likely to crown but not to torch, an example of “hysteresis” in crown fire behavior. Results support the hypothesis that potential crown fire behavior varies across a gradient of aspen dominance and fire weather, where it was likely under extreme and severe fire weather, and unlikely under moderate and high fire weather. Furthermore, the “fire-proof” nature of aspen stands broke down across the gradient of aspen dominance and fire weather.
    Electronic ISSN: 1999-4907
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Published by MDPI Publishing
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  • 47
    Publication Date: 2014-12-17
    Description: Surface nuclear magnetic resonance (surface-NMR) is a promising technique for exploring shallow subsurface aquifer structures. Surface-NMR can be applied in environments that are characterized as a 1-D layered Earth. The technique utilizes a single loop and is referred to as magnetic resonance sounding. The technique referred to as magnetic resonance tomography (MRT) allows complex 2-D aquifer structures to be explored. Currently, MRT requires multiple loops and a roll along measurement scheme, which causes long survey time. We propose a loop layout using an elongated transmitter and an in-loop receiver arrays (ETRA) to conduct a 2-D survey with just one measurement. We present a comprehensive comparison between the new layout and the common approaches based on sensitivity and resolution analyses and show synthetic and field data. The results show that ETRA generates subsurface images at sufficient resolution with significantly lower survey times than other loop layouts.
    Keywords: Geomagnetism, Rock Magnetism and Palaeomagnetism
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 48
    Publication Date: 2014-12-17
    Description: Measurements of ground deformation can be used to identify and interpret geophysical processes occurring at volcanoes. Most studies rely on a single geodetic technique, or fit a geophysical model to the results of multiple geodetic techniques. Here we present a methodology that combines GPS, Total Station measurements and InSAR into a single reference frame to produce an integrated 3-D geodetic velocity surface without any prior geophysical assumptions. The methodology consists of five steps: design of the network, acquisition and processing of the data, spatial integration of the measurements, time series computation and finally the integration of spatial and temporal measurements. The most significant improvements of this method are (1) the reduction of the required field time, (2) the unambiguous detection of outliers, (3) an increased measurement accuracy and (4) the construction of a 3-D geodetic velocity field. We apply this methodology to ongoing motion on Arenal's western flank. Integration of multiple measurement techniques at Arenal volcano revealed a deformation field that is more complex than that described by individual geodetic techniques, yet remains consistent with previous studies. This approach can be applied to volcano monitoring worldwide and has the potential to be extended to incorporate other geodetic techniques and to study transient deformation.
    Keywords: Gravity, Geodesy and Tides
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 49
    Publication Date: 2014-12-16
    Description: In this study we evaluate the capabilities of three satellite sensors for assessing water composition and bottom depth in Lake Garda, Italy. A consistent physics-based processing chain was applied to Moderate Resolution Imaging Spectroradiometer (MODIS), Landsat-8 Operational Land Imager (OLI) and RapidEye. Images gathered on 10 June 2014 were corrected for the atmospheric effects with the 6SV code. The computed remote sensing reflectance (Rrs) from MODIS and OLI were converted into water quality parameters by adopting a spectral inversion procedure based on a bio-optical model calibrated with optical properties of the lake. The same spectral inversion procedure was applied to RapidEye and to OLI data to map bottom depth. In situ measurements of Rrs and of concentrations of water quality parameters collected in five locations were used to evaluate the models. The bottom depth maps from OLI and RapidEye showed similar gradients up to 7 m (r = 0.72). The results indicate that: (1) the spatial and radiometric resolutions of OLI enabled mapping water constituents and bottom properties; (2) MODIS was appropriate for assessing water quality in the pelagic areas at a coarser spatial resolution; and (3) RapidEye had the capability to retrieve bottom depth at high spatial resolution. Future work should evaluate the performance of the three sensors in different bio-optical conditions.
    Electronic ISSN: 1424-8220
    Topics: Chemistry and Pharmacology , Electrical Engineering, Measurement and Control Technology
    Published by MDPI Publishing
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  • 50
    Publication Date: 2014-12-16
    Description: From a holistic view, this paper addresses a perspective of coordinated development of economy, society, and environment for regional sustainability assessment. Firstly, a comprehensive indicator system for co-evaluating the level of economic, social, and environmental subsystems is presented based on a holistic understanding of regional sustainability. Then, a coordinated development index model focusing on the level of coordination among the subsystems as well as their comprehensive development level is established. Furthermore, an empirical study of all the provinces and municipalities is conducted by collecting the panel data from 2004 to 2010. The result shows that: (1) the coordinated developments of the most developed and the most underdeveloped regions stay stable while the regions with medium development level possess more fluctuant trends during the study years; (2) regional disparities are indicated according to the grading of CDI (the coordinated development index), which are further analyzed to be related to the local economic development patterns; (3) the conditions and causes of economic, social, and environmental development in real situations under different grades of CDI are discussed through detailed case studies of typical regions, which indicate specific suggestions of sustainable development for regions in the same pattern.
    Electronic ISSN: 2071-1050
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Published by MDPI Publishing
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  • 51
    Publication Date: 2014-12-16
    Description: As the largest solid waste (SW) generator in the world, China is facing serious pollution issues induced by increasing quantities of SW. The sustainability assessment of SW management is very important for designing relevant policy for further improving the overall efficiency of solid waste management (SWM). By focusing on industrial solid waste (ISW) and municipal solid waste (MSW), the paper investigated the sustainability performance of SWM by applying decoupling analysis, and further identified the main drivers of SW change in China by adopting Logarithmic Mean Divisia Index (LMDI) model. The results indicate that China has made a great achievement in SWM which was specifically expressed as the increase of ISW utilized amount and harmless disposal ratio of MSW, decrease of industrial solid waste discharged (ISWD), and absolute decoupling of ISWD from economic growth as well. However, China has a long way to go to achieve the goal of sustainable management of SW. The weak decoupling, even expansive negative decoupling of ISW generation and MSW disposal suggests that China needs timely technology innovation and rational institutional arrangement to reduce SW intensity from the source and promote classification and recycling. The factors of investment efficiency and technology are the main determinants of the decrease in SW, inversely, economic growth has increased SW discharge. The effects of investment intensity showed a volatile trend over time but eventually decreased SW discharged. Moreover, the factors of population and industrial structure slightly increased SW.
    Electronic ISSN: 2071-1050
    Topics: Energy, Environment Protection, Nuclear Power Engineering
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  • 52
    Publication Date: 2014-12-16
    Description: This paper aims to construct conservation laws for a Benjamin–Bona–Mahony equation with variable coefficients, which is a third-order partial differential equation. This equation does not have a Lagrangian and so we transform it to a fourth-order partial differential equation, which has a Lagrangian. The Noether approach is then employed to construct the conservation laws. It so happens that the derived conserved quantities fail to satisfy the divergence criterion and so one needs to make adjustments to the derived conserved quantities in order to satisfy the divergence condition. The conservation laws are then expressed in the original variable. Finally, a conservation law is used to obtain exact solution of a special case of the Benjamin–Bona–Mahony equation.
    Electronic ISSN: 2073-8994
    Topics: Mathematics , Physics
    Published by MDPI Publishing
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  • 53
    Publication Date: 2014-12-16
    Description: The sensorimotor system (SMS) plays an important role in sports and in every day movement. Several tools for assessment and training have been designed. Many of them are directed to specific populations, and have major shortcomings due to the training effect or safety. The aim of the present study was to design and assess a dynamic sensorimotor test and training device that can be adjusted for all levels of performance. The novel pneumatic-driven mechatronic device can guide the trainee, allow independent movements or disrupt the individual with unpredicted perturbations while standing on a platform. The test-reliability was evaluated using intraclass correlation coefficient (ICC). Subjects were required to balance their center of pressure (COP) in a target circle (TITC). The time in TITC and the COP error (COPe) were recorded for analysis. The results of 22 males and 14 females (23.7 ± 2.6 years) showed good to excellent test–retest reliability. The newly designed Active Balance System (ABS) was then compared with the Biodex Balance System SD® (BBS). The results of 15 females, 14 males (23.4 ± 1.6 years) showed modest correlation in static and acceptable correlation in dynamic conditions, suggesting that ABS could be a reliable and comparable tool for dynamic balance assessments.
    Electronic ISSN: 1424-8220
    Topics: Chemistry and Pharmacology , Electrical Engineering, Measurement and Control Technology
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  • 54
    Publication Date: 2014-12-17
    Description: Climate change will increase the frequency and magnitude of extreme weather events and create risks that will impact health care facilities. Health care facilities will need to assess climate change risks and adopt adaptive management strategies to be resilient, but guidance tools are lacking. In this study, a toolkit was developed for health care facility officials to assess the resiliency of their facility to climate change impacts. A mixed methods approach was used to develop climate change resiliency indicators to inform the development of the toolkit. The toolkit consists of a checklist for officials who work in areas of emergency management, facilities management and health care services and supply chain management, a facilitator’s guide for administering the checklist, and a resource guidebook to inform adaptation. Six health care facilities representing three provinces in Canada piloted the checklist. Senior level officials with expertise in the aforementioned areas were invited to review the checklist, provide feedback during qualitative interviews and review the final toolkit at a stakeholder workshop. The toolkit helps health care facility officials identify gaps in climate change preparedness, direct allocation of adaptation resources and inform strategic planning to increase resiliency to climate change.
    Print ISSN: 1661-7827
    Electronic ISSN: 1660-4601
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
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  • 55
    Publication Date: 2014-12-17
    Description: The World Health Organization defines social determinants of health as “complex, integrated, and overlapping social structures and economic systems” that are responsible for most health inequities. Similar to the individual-level risk factors such as behavioral and biological risk factors that influence disease, we consider social determinants of health such as the distribution of income, wealth, influence and power as risk factors for risk of disease. We operationally define health inequity in a disease within a population due to a risk factor that is unfair and avoidable as the difference between the disease outcome with and without the risk factor in the population. We derive expressions for difference in health inequity between two populations due to a risk factor that is unfair and avoidable for a given disease. The difference in heath inequity between two population groups due to a risk factor increases with increasing difference in relative risks and the difference in prevalence of the risk factor in the two populations. The difference in health inequity could be larger than the difference in health outcomes between the two populations in some situations. Compared to health disparities which are typically measured and monitored using absolute or relative disparities of health outcomes, the methods presented in this manuscript provide a different, yet complementary, picture because they parse out the contributions of unfair and avoidable risk factors.
    Print ISSN: 1661-7827
    Electronic ISSN: 1660-4601
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
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  • 56
    Publication Date: 2014-12-17
    Description: Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice The ISME Journal 9, 1 (January 2015). doi:10.1038/ismej.2014.99 Authors: Jingjing Wang, Huang Tang, Chenhong Zhang, Yufeng Zhao, Muriel Derrien, Emilie Rocher, Johan ET van-Hylckama Vlieg, Katherine Strissel, Liping Zhao, Martin Obin & Jian Shen
    Print ISSN: 1751-7362
    Electronic ISSN: 1751-7370
    Topics: Biology
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  • 57
    Publication Date: 2014-12-17
    Description: From community approaches to single-cell genomics: the discovery of ubiquitous hyperhalophilic Bacteroidetes generalists The ISME Journal 9, 16 (January 2015). doi:10.1038/ismej.2014.95 Authors: María Gomariz, Manuel Martínez-García, Fernando Santos, Francisco Rodriguez, Salvador Capella-Gutiérrez, Toni Gabaldón, Ramon Rosselló-Móra, Inmaculada Meseguer & Josefa Antón
    Print ISSN: 1751-7362
    Electronic ISSN: 1751-7370
    Topics: Biology
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  • 58
    Publication Date: 2014-12-17
    Description: Interpreting 16S metagenomic data without clustering to achieve sub-OTU resolution The ISME Journal 9, 68 (January 2015). doi:10.1038/ismej.2014.117 Authors: Mikhail Tikhonov, Robert W Leach & Ned S Wingreen
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  • 59
    Publication Date: 2014-12-17
    Description: Life on the edge: functional genomic response of Ignicoccus hospitalis to the presence of Nanoarchaeum equitans The ISME Journal 9, 101 (January 2015). doi:10.1038/ismej.2014.112 Authors: Richard J Giannone, Louie L Wurch, Thomas Heimerl, Stanton Martin, Zamin Yang, Harald Huber, Reinhard Rachel, Robert L Hettich & Mircea Podar
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    Electronic ISSN: 1751-7370
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  • 60
    Publication Date: 2014-12-17
    Description: Quorum sensing enhancement of the stress response promotes resistance to quorum quenching and prevents social cheating The ISME Journal 9, 115 (January 2015). doi:10.1038/ismej.2014.98 Authors: Rodolfo García-Contreras, Leslie Nuñez-López, Ricardo Jasso-Chávez, Brian W Kwan, Javier A Belmont, Adrián Rangel-Vega, Toshinari Maeda & Thomas K Wood
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  • 61
    Publication Date: 2014-12-17
    Description: Microbial dormancy improves development and experimental validation of ecosystem model The ISME Journal 9, 226 (January 2015). doi:10.1038/ismej.2014.120 Authors: Gangsheng Wang, Sindhu Jagadamma, Melanie A Mayes, Christopher W Schadt, J Megan Steinweg, Lianhong Gu & Wilfred M Post
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  • 62
    Publication Date: 2014-12-17
    Description: Growth form defines physiological photoprotective capacity in intertidal benthic diatoms The ISME Journal 9, 32 (January 2015). doi:10.1038/ismej.2014.105 Authors: Alexandre Barnett, Vona Méléder, Lander Blommaert, Bernard Lepetit, Pierre Gaudin, Wim Vyverman, Koen Sabbe, Christine Dupuy & Johann Lavaud
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  • 63
    Publication Date: 2014-12-17
    Description: The niche of an invasive marine microbe in a subtropical freshwater impoundment The ISME Journal 9, 256 (January 2015). doi:10.1038/ismej.2014.103 Authors: K David Hambright, Jessica E Beyer, James D Easton, Richard M Zamor, Anne C Easton & Thayer C Hallidayschult
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  • 64
    Publication Date: 2014-12-17
    Description: The subgingival microbiome of clinically healthy current and never smokers The ISME Journal 9, 268 (January 2015). doi:10.1038/ismej.2014.114 Authors: Matthew R Mason, Philip M Preshaw, Haikady N Nagaraja, Shareef M Dabdoub, Anis Rahman & Purnima S Kumar
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  • 65
    Publication Date: 2014-12-17
    Description: Improved annotation of antibiotic resistance determinants reveals microbial resistomes cluster by ecology The ISME Journal 9, 207 (January 2015). doi:10.1038/ismej.2014.106 Authors: Molly K Gibson, Kevin J Forsberg & Gautam Dantas
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  • 66
    Publication Date: 2014-12-17
    Description: Predominant pathogen competition and core microbiota divergence in chronic airway infection The ISME Journal 9, 217 (January 2015). doi:10.1038/ismej.2014.124 Authors: Geraint B Rogers, Christopher J van der Gast & David J Serisier
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  • 67
    Publication Date: 2014-12-17
    Description: Genome-wide analysis of Sphingomonas wittichii RW1 behaviour during inoculation and growth in contaminated sand The ISME Journal 9, 150 (January 2015). doi:10.1038/ismej.2014.101 Authors: Silvia K Moreno-Forero & Jan Roelof van der Meer
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  • 68
    Publication Date: 2014-12-17
    Description: In this research, structural-functional integrated cement-based materials were prepared by employing cement paste and a microencapsulated phase change material (MPCM) manufactured using urea-formaldehyde resin as the shell and paraffin as the core material. The encapsulation ratio of the MPCM could reach up to 91.21 wt%. Thermal energy storage cement pastes (TESCPs) incorporated with different MPCM contents (5%, 10%, 15%, 20% and 25% by weight of cement) were developed, and their thermal and mechanical properties were studied. The results showed that the total energy storage capacity of the hardened cement specimens with MPCM increased by up to 3.9-times compared with that of the control cement paste. The thermal conductivity at different temperature levels (35–36 °C, 55–56 °C and 72–74 °C) decreased with the increase of MPCM content, and the decrease was the highest when the temperature level was 55–56 °C. Moreover, the compressive strength, flexural strength and density of hardened cement paste decreased with the increase in MPCM content linearly. Among the evaluated properties, the compressive strength of TESCPs had a larger and faster degradation with the increase of MPCM content.
    Electronic ISSN: 1996-1944
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Published by MDPI Publishing
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  • 69
    Publication Date: 2014-12-17
    Description: We measure and quantify properties of galactic outflows and diffuse gas at z ≥ 1 in cosmological hydrodynamical simulations. Our novel subresolution model, Multi-Phase Particle Integrator (MUPPI), implements supernova feedback using fully local gas properties, where the wind velocity and mass loading are not given as input. We find the following trends at z  = 2 by analysing central galaxies having a stellar mass higher than 10 9 M . The outflow velocity and mass outflow rate ( $\dot{M}_{\rm out}$ ) exhibit positive correlations with galaxy mass and with the star formation rate (SFR). However, most of the relations present a large scatter. The outflow mass loading factor () is between 0.2 and 10. The comparison effective model generates a constant outflow velocity, and a negative correlation of with halo mass. The number fraction of galaxies where outflow is detected decreases at lower redshifts, but remains more than 80 per cent over z  = 1–5. The outflow velocity correlation with SFR becomes flatter at z  = 1, and displays a negative correlation with halo mass in massive galaxies. Our study demonstrates that both the MUPPI and effective models produce significant outflows at ~1/10 of the virial radius; at the same time shows that the properties of outflows generated can be different from the input speed and mass loading in the effective model. Our MUPPI model, using local properties of gas in the subresolution recipe, is able to develop galactic outflows whose properties correlate with global galaxy properties , and consistent with observations.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 70
    Publication Date: 2014-12-17
    Description: Article The kinase LRRK2 is implicated in Parkinson’s disease progression and is known to be phosphorylated. Chia et al. show that this phosphorylation is mediated by the kinase CK1a, and is required for the recruitment of LRRK2 to Golgi-derived vesicles, suggesting a role for this protein in Golgi maintenance. Nature Communications doi: 10.1038/ncomms6827 Authors: Ruth Chia, Sara Haddock, Alexandra Beilina, Iakov N. Rudenko, Adamantios Mamais, Alice Kaganovich, Yan Li, Ravindran Kumaran, Michael A. Nalls, Mark R. Cookson
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 71
    Publication Date: 2014-12-17
    Description: Article Synaptotagmin-1 (syt-1) triggers fast synchronous neurotransmission mediated by fusion of synaptic vesicles with presynaptic membranes. Here Lin et al. use inter-membrane FRET combined with DNA rulers as calibration standards to quantify Ca 2+ -induced changes in membrane distances mediated by syt-1. Nature Communications doi: 10.1038/ncomms6859 Authors: Chao-Chen Lin, Jan Seikowski, Angel Pérez-Lara, Reinhard Jahn, Claudia Höbartner, Peter Jomo Walla
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 72
    Publication Date: 2014-12-17
    Description: Article Loss of olfactory function is one of the many symptoms of the ciliopathy Bardet–Biedl syndrome. Williams et al . show that Bardet–Biedl proteins are components of intraflagellar transport particles within cilia, and directly visualize their trafficking in native mammalian olfactory neurons. Nature Communications doi: 10.1038/ncomms6813 Authors: Corey L. Williams, Jeremy C. McIntyre, Stephen R. Norris, Paul M. Jenkins, Lian Zhang, Qinglin Pei, Kristen Verhey, Jeffrey R. Martens
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 73
    Publication Date: 2014-12-17
    Description: Article Immune cell pro-inflammatory gene expression is suppressed following prolonged stimulation. Using a chemoproteomic approach, the authors show that methyltransferase G9a forms a protein complex that promotes the transcriptional repressor activity of c-Myc to repress inflammation-induced gene expression. Nature Communications doi: 10.1038/ncomms6733 Authors: Cui Liu, Yanbao Yu, Feng Liu, Xin Wei, John A. Wrobel, Harsha P. Gunawardena, Li Zhou, Jian Jin, Xian Chen
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 74
    Publication Date: 2014-12-17
    Description: Nature Reviews Microbiology 13, 2 (2015). doi:10.1038/nrmicro3408 Author: Andrea Du Toit The bacterial actin homologue MreB forms membrane-associated filaments and is integral for determining rod cell shape, which is suggested to be due to its role in assembling the enzymes involved in cell wall synthesis. However, the factors that determine MreB membrane localization and its interactions
    Print ISSN: 1740-1526
    Electronic ISSN: 1740-1534
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 75
    Publication Date: 2014-12-17
    Description: Nature Reviews Microbiology 13, 42 (2015). doi:10.1038/nrmicro3380 Authors: Jessica M. A. Blair, Mark A. Webber, Alison J. Baylay, David O. Ogbolu & Laura J. V. Piddock Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and
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    Topics: Biology , Medicine
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  • 76
    Publication Date: 2014-12-17
    Description: Nature Reviews Microbiology 13, 58 (2015). doi:10.1038/nrmicro3405 Authors: W. Paul Duprex, Ron A. M. Fouchier, Michael J. Imperiale, Marc Lipsitch & David A. Relman According to the WHO, dual use research of concern (DURC) is “life sciences research that is intended for benefit, but which might easily be misapplied to do harm”. Recent studies, particularly those on influenza viruses, have led to renewed attention on DURC, as there is
    Print ISSN: 1740-1526
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    Topics: Biology , Medicine
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  • 77
    Publication Date: 2014-12-17
    Description: Nature Reviews Microbiology 13, 28 (2015). doi:10.1038/nrmicro3367 Authors: Amie J. Eisfeld, Gabriele Neumann & Yoshihiro Kawaoka Influenza A viral ribonucleoprotein (vRNP) complexes comprise the eight genomic negative-sense RNAs, each of which is bound to multiple copies of the vRNP and a trimeric viral polymerase complex. The influenza virus life cycle centres on the vRNPs, which in turn rely on host cellular
    Print ISSN: 1740-1526
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    Topics: Biology , Medicine
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  • 78
    Publication Date: 2014-12-17
    Description: Article Increased expression of MITF transcription factor is thought to promote melanoma progression and kinase inhibitor resistance. Here Muller et al . show that MITF loss is also common in melanomas and confers kinase inhibitor resistance due to upregulation of AXL and other receptor tyrosine kinases. Nature Communications doi: 10.1038/ncomms6712 Authors: Judith Müller, Oscar Krijgsman, Jennifer Tsoi, Lidia Robert, Willy Hugo, Chunying Song, Xiangju Kong, Patricia A. Possik, Paulien D. M. Cornelissen-Steijger, Marnix H Geukes Foppen, Kristel Kemper, Colin R. Goding, Ultan McDermott, Christian Blank, John Haanen, Thomas G. Graeber, Antoni Ribas, Roger S. Lo, Daniel S. Peeper
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
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  • 79
    Publication Date: 2014-12-17
    Description: Nature Reviews Microbiology 13, 4 (2015). doi:10.1038/nrmicro3410 Author: Yvonne Bordon An enteric RNA virus can substitute for commensal bacteria and support immune maturation and intestinal homeostasis.
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    Electronic ISSN: 1740-1534
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 80
    Publication Date: 2014-12-17
    Description: The advent in high-throughput-sequencing (HTS) technologies has revolutionized conventional biodiversity research by enabling parallel capture of DNA sequences possessing species-level diagnosis. However, polymerase chain reaction (PCR)-based implementation is biased by the efficiency of primer binding across lineages of organisms. A PCR-free HTS approach will alleviate this artefact and significantly improve upon the multi-locus method utilizing full mitogenomes. Here we developed a novel multiplex sequencing and assembly pipeline allowing for simultaneous acquisition of full mitogenomes from pooled animals without DNA enrichment or amplification. By concatenating assemblies from three de novo assemblers, we obtained high-quality mitogenomes for all 49 pooled taxa, with 36 species 〉15 kb and the remaining 〉10 kb, including 20 complete mitogenomes and nearly all protein coding genes (99.6%). The assembly quality was carefully validated with Sanger sequences, reference genomes and conservativeness of protein coding genes across taxa. The new method was effective even for closely related taxa, e.g. three Drosophila spp., demonstrating its broad utility for biodiversity research and mito-phylogenomics. Finally, the in silico simulation showed that by recruiting multiple mito-loci, taxon detection was improved at a fixed sequencing depth. Combined, these results demonstrate the plausibility of a multi-locus mito-metagenomics approach as the next phase of the current single-locus metabarcoding method.
    Keywords: Genomics
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  • 81
    Publication Date: 2014-12-17
    Description: The efficacy and the mutation spectrum of genome editing methods can vary substantially depending on the targeted sequence. A simple, quick assay to accurately characterize and quantify the induced mutations is therefore needed. Here we present TIDE, a method for this purpose that requires only a pair of PCR reactions and two standard capillary sequencing runs. The sequence traces are then analyzed by a specially developed decomposition algorithm that identifies the major induced mutations in the projected editing site and accurately determines their frequency in a cell population. This method is cost-effective and quick, and it provides much more detailed information than current enzyme-based assays. An interactive web tool for automated decomposition of the sequence traces is available. TIDE greatly facilitates the testing and rational design of genome editing strategies.
    Keywords: Targeted gene modification
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  • 82
    Publication Date: 2014-12-17
    Description: NMR chemical shift predictions based on empirical methods are nowadays indispensable tools during resonance assignment and 3D structure calculation of proteins. However, owing to the very limited statistical data basis, such methods are still in their infancy in the field of nucleic acids, especially when non-canonical structures and nucleic acid complexes are considered. Here, we present an ab initio approach for predicting proton chemical shifts of arbitrary nucleic acid structures based on state-of-the-art fragment-based quantum chemical calculations. We tested our prediction method on a diverse set of nucleic acid structures including double-stranded DNA, hairpins, DNA/protein complexes and chemically-modified DNA. Overall, our quantum chemical calculations yield highly/very accurate predictions with mean absolute deviations of 0.3–0.6 ppm and correlation coefficients ( r 2 ) usually above 0.9. This will allow for identifying misassignments and validating 3D structures. Furthermore, our calculations reveal that chemical shifts of protons involved in hydrogen bonding are predicted significantly less accurately. This is in part caused by insufficient inclusion of solvation effects. However, it also points toward shortcomings of current force fields used for structure determination of nucleic acids. Our quantum chemical calculations could therefore provide input for force field optimization.
    Keywords: Nucleic acid structure, Protein-nucleic acid interaction
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  • 83
    Publication Date: 2014-12-17
    Description: Bicyclic oxazaphospholidine monomers were used to prepare a series of phosphorothioate (PS)-modified gapmer antisense oligonucleotides (ASOs) with control of the chirality of each of the PS linkages within the 10-base gap. The stereoselectivity was determined to be 98% for each coupling. The objective of this work was to study how PS chirality influences biophysical and biological properties of the ASO including binding affinity ( T m ), nuclease stability, activity in vitro and in vivo , RNase H activation and cleavage patterns (both human and E. coli ) in a gapmer context. Compounds that had nine or more Sp-linkages in the gap were found to be poorly active in vitro , while compounds with uniform Rp-gaps exhibited activity very similar to that of the stereo-random parent ASOs. Conversely, when tested in vivo , the full Rp-gap compound was found to be quickly metabolized resulting in low activity. A total of 31 ASOs were prepared with control of the PS chirally of each linkage within the gap in an attempt to identify favorable Rp/Sp positions. We conclude that a mix of Rp and Sp is required to achieve a balance between good activity and nuclease stability.
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  • 84
    Publication Date: 2014-12-17
    Description: In an isogenic cell population, phenotypic heterogeneity among individual cells is common and critical for survival of the population under different environment conditions. DNA modification is an important epigenetic factor that can regulate phenotypic heterogeneity. The single molecule real-time (SMRT) sequencing technology provides a unique platform for detecting a wide range of DNA modifications, including N6-methyladenine (6-mA), N4-methylcytosine (4-mC) and 5-methylcytosine (5-mC). Here we present qDNAmod, a novel bioinformatic tool for genome-wide quantitative profiling of intercellular heterogeneity of DNA modification from SMRT sequencing data. It is capable of estimating proportion of isogenic haploid cells, in which the same loci of the genome are differentially modified. We tested the reliability of qDNAmod with the SMRT sequencing data of Streptococcus pneumoniae strain ST556. qDNAmod detected extensive intercellular heterogeneity of DNA methylation (6-mA) in a clonal population of ST556. Subsequent biochemical analyses revealed that the recognition sequences of two type I restriction–modification (R-M) systems are responsible for the intercellular heterogeneity of DNA methylation initially identified by qDNAmod. qDNAmod thus represents a valuable tool for studying intercellular phenotypic heterogeneity from genome-wide DNA modification.
    Keywords: Nucleic acid modification, Computational Methods
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  • 85
    Publication Date: 2014-12-17
    Description: Combinatorial transcription factor (TF) binding is essential for cell-type-specific gene regulation. However, much remains to be learned about the mechanisms of TF interactions, including to what extent constrained spacing and orientation of interacting TFs are critical for regulatory element activity. To examine the relative prevalence of the ‘enhanceosome’ versus the ‘TF collective’ model of combinatorial TF binding, a comprehensive analysis of TF binding site sequences in large scale datasets is necessary. We developed a motif-pair discovery pipeline to identify motif co-occurrences with preferential distance(s) between motifs in TF-bound regions. Utilizing a compendium of 289 mouse haematopoietic TF ChIP-seq datasets, we demonstrate that haematopoietic-related motif-pairs commonly occur with highly conserved constrained spacing and orientation between motifs. Furthermore, motif clustering revealed specific associations for both heterotypic and homotypic motif-pairs with particular haematopoietic cell types. We also showed that disrupting the spacing between motif-pairs significantly affects transcriptional activity in a well-known motif-pair—E-box and GATA, and in two previously unknown motif-pairs with constrained spacing—Ets and Homeobox as well as Ets and E-box. In this study, we provide evidence for widespread sequence-specific TF pair interaction with DNA that conforms to the ‘enhanceosome’ model, and furthermore identify associations between specific haematopoietic cell-types and motif-pairs.
    Keywords: Computational Methods
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  • 86
    Publication Date: 2014-12-17
    Description: In silico tools have been developed to predict variants that may have an impact on pre-mRNA splicing. The major limitation of the application of these tools to basic research and clinical practice is the difficulty in interpreting the output. Most tools only predict potential splice sites given a DNA sequence without measuring splicing signal changes caused by a variant. Another limitation is the lack of large-scale evaluation studies of these tools. We compared eight in silico tools on 2959 single nucleotide variants within splicing consensus regions (scSNVs) using receiver operating characteristic analysis. The Position Weight Matrix model and MaxEntScan outperformed other methods. Two ensemble learning methods, adaptive boosting and random forests, were used to construct models that take advantage of individual methods. Both models further improved prediction, with outputs of directly interpretable prediction scores. We applied our ensemble scores to scSNVs from the Catalogue of Somatic Mutations in Cancer database. Analysis showed that predicted splice-altering scSNVs are enriched in recurrent scSNVs and known cancer genes. We pre-computed our ensemble scores for all potential scSNVs across the human genome, providing a whole genome level resource for identifying splice-altering scSNVs discovered from large-scale sequencing studies.
    Keywords: RNA characterisation and manipulation, Computational Methods
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  • 87
    Publication Date: 2014-12-17
    Description: In mammals, RNA interference is primarily a post-transcriptional mechanism. Evidence has accumulated for additional role in transcriptional gene silencing (TGS) but the question for a good paradigm for small interfering antigene RNA (agRNA)-induced chromatin modification remains unanswered. Here, we show that SETDB1, a histone H3-lysine 9 (H3K9)-specific methyltransferase, cooperates with Argonaute-2 (AGO2) and plays an essential role in agRNA-induced TGS. The androgen receptor ( AR ) gene was transcriptionally silenced by agRNA targeted to its promoter, and we show that this repression was mitigated by knockdown of SETDB1 or AGO2 . Chromatin immunoprecipitation demonstrated that agRNA-driven AGO2 was first targeted to the AR promoter, followed by SETDB1. SIN3A and HDAC1/2, the components of the SIN3-HDAC complex, immunoprecipitated with SETDB1, and localized at the agRNA-targeted promoter. Agreeing with the presence of SETDB1, trimethyl-H3K9 was enriched in the AR promoter. Both EZH2 and trimethyl-H3K27 were also present in the targeted locus; accordingly, EZH2 immunoprecipitated with SETDB1. DNA methylation level was not significantly changed, suggesting the absence of de novo methylating activity in agRNA-induced AR promoter. Our results demonstrate that SETDB1, together with AGO2, plays an essential role in TGS through recruiting chromatin remodeler and/or other modifiers, consequently creating a repressive chromatin milieu at the targeted promoter.
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  • 88
    Publication Date: 2014-12-17
    Description: LEF/TCFs direct the final step in Wnt/β-catenin signalling by recruiting β-catenin to genes for activation of transcription. Ancient, non-vertebrate TCFs contain two DNA binding domains, a High Mobility Group box for recognition of the Wnt Response Element (WRE; 5'-CTTTGWWS-3') and the C-clamp domain for recognition of the GC-rich Helper motif (5'-RCCGCC-3'). Two vertebrate TCFs (TCF-1/TCF7 and TCF-4/TCF7L2) use the C-clamp as an alternatively spliced domain to regulate cell-cycle progression, but how the C-clamp influences TCF binding and activity genome-wide is not known. Here, we used a doxycycline inducible system with ChIP-seq to assess how the C-clamp influences human TCF1 binding genome-wide. Metabolic pulse-labeling of nascent RNA with 4'Thiouridine was used with RNA-seq to connect binding to the Wnt transcriptome. We find that the C-clamp enables targeting to a greater number of gene loci for stronger occupancy and transcription regulation. The C-clamp uses Helper sites concurrently with WREs for gene targeting, but it also targets TCF1 to sites that do not have readily identifiable canonical WREs. The coupled ChIP-seq/4'Thiouridine-seq analysis identified new Wnt target genes, including additional regulators of cell proliferation. Thus, C-clamp containing isoforms of TCFs are potent transcriptional regulators with an expanded transcriptome directed by C-clamp-Helper site interactions.
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  • 89
    Publication Date: 2014-12-17
    Description: Chromatin modifiers and histone modifications are components of a chromatin-signaling network involved in transcription and its regulation. The interactions between chromatin modifiers and histone modifications are often unknown, are based on the analysis of few genes or are studied in vitro . Here, we apply computational methods to recover interactions between chromatin modifiers and histone modifications from genome-wide ChIP-Seq data. These interactions provide a high-confidence backbone of the chromatin-signaling network. Many recovered interactions have literature support; others provide hypotheses about yet unknown interactions. We experimentally verified two of these predicted interactions, leading to a link between H4K20me1 and members of the Polycomb Repressive Complexes 1 and 2. Our results suggest that our computationally derived interactions are likely to lead to novel biological insights required to establish the connectivity of the chromatin-signaling network involved in transcription and its regulation.
    Keywords: Genomics
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  • 90
    Publication Date: 2014-12-17
    Description: As the biomedical impact of small RNAs grows, so does the need to understand competing structural alternatives for regions of functional interest. Suboptimal structure analysis provides significantly more RNA base pairing information than a single minimum free energy prediction. Yet computational enhancements like Boltzmann sampling have not been fully adopted by experimentalists since identifying meaningful patterns in this data can be challenging. Profiling is a novel approach to mining RNA suboptimal structure data which makes the power of ensemble-based analysis accessible in a stable and reliable way. Balancing abstraction and specificity, profiling identifies significant combinations of base pairs which dominate low-energy RNA secondary structures. By design, critical similarities and differences are highlighted, yielding crucial information for molecular biologists. The code is freely available via http://gtfold.sourceforge.net/profiling.html .
    Keywords: Nucleic acid structure, Computational Methods
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  • 91
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    Oxford University Press
    Publication Date: 2014-12-17
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  • 92
    Publication Date: 2014-12-17
    Description: The stress-sensitive restriction-modification (RM) system CglI from Corynebacterium glutamicum and the homologous NgoAVII RM system from Neisseria gonorrhoeae FA1090 are composed of three genes: a DNA methyltransferase (M.CglI and M.NgoAVII), a putative restriction endonuclease (R.CglI and R.NgoAVII, or R-proteins) and a predicted DEAD-family helicase/ATPase (N.CglI and N.NgoAVII or N-proteins). Here we report a biochemical characterization of the R- and N-proteins. Size-exclusion chromatography and SAXS experiments reveal that the isolated R.CglI, R.NgoAVII and N.CglI proteins form homodimers, while N.NgoAVII is a monomer in solution. Moreover, the R.CglI and N.CglI proteins assemble in a complex with R 2 N 2 stoichiometry. Next, we show that N-proteins have ATPase activity that is dependent on double-stranded DNA and is stimulated by the R-proteins. Functional ATPase activity and extensive ATP hydrolysis (~170 ATP/s/monomer) are required for site-specific DNA cleavage by R-proteins. We show that ATP-dependent DNA cleavage by R-proteins occurs at fixed positions (6–7 nucleotides) downstream of the asymmetric recognition sequence 5'-GCCGC-3'. Despite similarities to both Type I and II restriction endonucleases, the CglI and NgoAVII enzymes may employ a unique catalytic mechanism for DNA cleavage.
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  • 93
    Publication Date: 2014-12-17
    Description: Emerging evidence points to roles for tRNA modifications and tRNA abundance in cellular stress responses. While isolated instances of stress-induced tRNA degradation have been reported, we sought to assess the effects of stress on tRNA levels at a systems level. To this end, we developed a next-generation sequencing method that exploits the paucity of ribonucleoside modifications at the 3'-end of tRNAs to quantify changes in all cellular tRNA molecules. Application of this tRNA-seq method to Saccharomyces cerevisiae identified all 76 expressed unique tRNA species out of 295 coded in the yeast genome, including all isoacceptor variants, with highly precise relative (fold-change) quantification of tRNAs. In studies of stress-induced changes in tRNA levels, we found that oxidation (H 2 O 2 ) and alkylation (methylmethane sulfonate, MMS) stresses induced nearly identical patterns of up- and down-regulation for 58 tRNAs. However, 18 tRNAs showed opposing changes for the stresses, which parallels our observation of signature reprogramming of tRNA modifications caused by H 2 O 2 and MMS. Further, stress-induced degradation was limited to only a small proportion of a few tRNA species. With tRNA-seq applicable to any organism, these results suggest that translational control of stress response involves a contribution from tRNA abundance.
    Keywords: Nucleic acid modification, Transcriptome Mapping - Monitoring Gene Expression
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  • 94
    Publication Date: 2014-12-17
    Description: During meiosis programmed DNA double-strand breaks (DSBs) are repaired by homologous recombination using the sister chromatid or the homologous chromosome (homolog) as a template. This repair results in crossover (CO) and non-crossover (NCO) recombinants. Only CO formation between homologs provides the physical linkages guiding correct chromosome segregation, which are essential to produce healthy gametes. The factors that determine the CO/NCO decision are still poorly understood. Using Schizosaccharomyces pombe as a model we show that the Rad51/Dmc1-paralog complexes Rad55-Rad57 and Rdl1-Rlp1-Sws1 together with Swi5-Sfr1 play a major role in antagonizing both the FANCM-family DNA helicase/translocase Fml1 and the RecQ-type DNA helicase Rqh1 to limit hybrid DNA formation and promote Mus81-Eme1-dependent COs. A common attribute of these protein complexes is an ability to stabilize the Rad51/Dmc1 nucleoprotein filament, and we propose that it is this property that imposes constraints on which enzymes gain access to the recombination intermediate, thereby controlling the manner in which it is processed and resolved.
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  • 95
    Publication Date: 2014-12-17
    Description: To study target sequence specificity, selectivity, and reaction kinetics of Streptococcus pyogenes Cas9 activity, we challenged libraries of random variant targets with purified Cas9::guide RNA complexes in vitro . Cleavage kinetics were nonlinear, with a burst of initial activity followed by slower sustained cleavage. Consistent with other recent analyses of Cas9 sequence specificity, we observe considerable (albeit incomplete) impairment of cleavage for targets mutated in the PAM sequence or in ‘seed’ sequences matching the proximal 8 bp of the guide. A second target region requiring close homology was located at the other end of the guide::target duplex (positions 13–18 relative to the PAM). Sequences flanking the guide+PAM region had measurable (albeit modest) effects on cleavage. In addition, the first-base Guanine constraint commonly imposed by gRNA expression systems has little effect on overall cleavage efficiency. Taken together, these studies provide an in vitro understanding of the complexities of Cas9–gRNA interaction and cleavage beyond the general paradigm of site determination based on the ‘seed’ sequence and PAM.
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  • 96
    Publication Date: 2014-12-17
    Description: Transcripts possessing a 5'-triphosphate are a hallmark of viral transcription and can trigger the host antiviral response. 5'-triphosphates are also found on common host transcripts transcribed by RNA polymerase III (RNAP III), yet how these transcripts remain non-immunostimulatory is incompletely understood. Most microRNAs (miRNAs) are 5'-monophosphorylated as a result of sequential endonucleolytic processing by Drosha and Dicer from longer RNA polymerase II (RNAP II)-transcribed primary transcripts. In contrast, bovine leukemia virus (BLV) expresses subgenomic RNAP III transcripts that give rise to miRNAs independent of Drosha processing. Here, we demonstrate that each BLV pre-miRNA is directly transcribed by RNAP III from individual, compact RNAP III type II genes. Thus, similar to manmade RNAP III-generated short hairpin RNAs (shRNAs), the BLV pre-miRNAs are initially 5'-triphosphorylated. Nonetheless, the derivative 5p miRNAs and shRNA-generated 5p small RNAs (sRNAs) possess a 5'-monophosphate. Our enzymatic characterization and small RNA sequencing data demonstrate that BLV 5p miRNAs are co-terminal with 5'-triphosphorylated miRNA precursors (pre-miRNAs). Thus, these results identify a 5'-tri-phosphatase activity that is involved in the biogenesis of BLV miRNAs and shRNA-generated sRNAs. This work advances our understanding of retroviral miRNA and shRNA biogenesis and may have implications regarding the immunostimulatory capacity of RNAP III transcripts.
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  • 97
    Publication Date: 2014-12-17
    Description: Within the field of synthetic biology, a rational design of genetic parts should include a causal understanding of their input-output responses—the so-called transfer function—and how to tune them. However, a commonly adopted strategy is to fit data to Hill-shaped curves without considering the underlying molecular mechanisms. Here we provide a novel mathematical formalization that allows prediction of the global behavior of a synthetic device by considering the actual information from the involved biological parts. This is achieved by adopting an enzymology-like framework, where transfer functions are described in terms of their input affinity constant and maximal response. As a proof of concept, we characterize a set of Lux homoserine-lactone-inducible genetic devices with different levels of Lux receptor and signal molecule. Our model fits the experimental results and predicts the impact of the receptor's ribosome-binding site strength, as a tunable parameter that affects gene expression. The evolutionary implications are outlined.
    Keywords: Synthetic Biology and Assembly Cloning, Computational Methods
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  • 98
    Publication Date: 2014-12-17
    Description: The restriction endonuclease (REase) NgoAVII is composed of two proteins, R.NgoAVII and N.NgoAVII, and shares features of both Type II restriction enzymes and Type I/III ATP-dependent restriction enzymes (see accompanying paper Zaremba et al. , 2014). Here we present crystal structures of the R.NgoAVII apo-protein and the R.NgoAVII C-terminal domain bound to a specific DNA. R.NgoAVII is composed of two domains: an N-terminal nucleolytic PLD domain; and a C-terminal B3-like DNA-binding domain identified previously in BfiI and EcoRII REases, and in plant transcription factors. Structural comparison of the B3-like domains of R.NgoAVII, EcoRII, BfiI and the plant transcription factors revealed a conserved DNA-binding surface comprised of N- and C-arms that together grip the DNA. The C-arms of R.NgoAVII, EcoRII, BfiI and plant B3 domains are similar in size, but the R.NgoAVII N-arm which makes the majority of the contacts to the target site is much longer. The overall structures of R.NgoAVII and BfiI are similar; however, whilst BfiI has stand-alone catalytic activity, R.NgoAVII requires an auxiliary cognate N.NgoAVII protein and ATP hydrolysis in order to cleave DNA at the target site. The structures we present will help formulate future experiments to explore the molecular mechanisms of intersubunit crosstalk that control DNA cleavage by R.NgoAVII and related endonucleases.
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  • 99
    Publication Date: 2014-12-17
    Description: Distinct translational initiation mechanisms between prokaryotes and eukaryotes limit the exploitation of prokaryotic riboswitch repertoire for regulatory RNA circuit construction in mammalian application. Here, we explored programmed ribosomal frameshifting (PRF) as the regulatory gene expression platform for engineered ligand-responsive RNA devices in higher eukaryotes. Regulation was enabled by designed ligand-dependent conformational rearrangements of the two cis-acting RNA motifs of opposite activity in -1 PRF. Particularly, RNA elements responsive to trans-acting ligands can be tailored to modify co-translational RNA refolding dynamics of a hairpin upstream of frameshifting site to achieve reversible and adjustable -1 PRF attenuating activity. Combined with a ligand-responsive stimulator, synthetic RNA devices for synergetic translational-elongation control of gene expression can be constructed. Due to the similarity between co-transcriptional RNA hairpin folding and co-translational RNA hairpin refolding, the RNA-responsive ligand repertoire provided in prokaryotic systems thus becomes accessible to gene-regulatory circuit construction for synthetic biology application in mammalian cells.
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  • 100
    Publication Date: 2014-12-17
    Description: Cutaneous photosensitization is a common side effect of drug treatment and can be associated with an increased skin cancer risk. The immunosuppressant azathioprine, the fluoroquinolone antibiotics and vemurafenib—a BRAF inhibitor used to treat metastatic melanoma—are all recognized clinical photosensitizers. We have compared the effects of UVA radiation on cultured human cells treated with 6-thioguanine (6-TG, a DNA-embedded azathioprine surrogate), the fluoroquinolones ciprofloxacin and ofloxacin and vemurafenib. Despite widely different structures and modes of action, each of these drugs potentiated UVA cytotoxicity. UVA photoactivation of 6-TG, ciprofloxacin and ofloxacin was associated with the generation of singlet oxygen that caused extensive protein oxidation. In particular, these treatments were associated with damage to DNA repair proteins that reduced the efficiency of nucleotide excision repair. Although vemurafenib was also highly phototoxic to cultured cells, its effects were less dependent on singlet oxygen. Highly toxic combinations of vemurafenib and UVA caused little protein carbonylation but were nevertheless inhibitory to nucleotide excision repair. Thus, for three different classes of drugs, photosensitization by at least two distinct mechanisms is associated with reduced protection against potentially mutagenic and carcinogenic DNA damage.
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