bluuebunny/crossref_metadata_2025_split huggingface dataset:
TWO HUNTERS, A MILKMAID AND THE FRENCH ‘REVOLUTIONARY’ CANON
Authors: DOE JULIA 
Published: October 2018

ABSTRACTLarge-scale programming studies of French Revolutionary theatre confirm that the most frequently staged opera of the 1790s was not one of the politically charged, compositionally progressive works that have come to define the era for posterity, but rather a pastoral comedy from mid-century:Les deux chasseurs et la laitière(1763), with a score by Egidio Duni to a libretto by Louis Anseaume. This article draws upon both musical and archival evidence to establish an extended performance history ofLes deux chasseurs, and a more nuanced explanation for its enduring hold on the French lyric stage. I consider the pragmatic, legal and aesthetic factors contributing to the comedy's widespread adaptability, including its cosmopolitan musical idiom, scenographic simplicity and ready familiarity amongst consumers of printed music. More broadly, I address the advantages and limitations of corpus-based analysis with respect to delineating the operatic canon. In late eighteenth-century Paris, observers were already beginning to identify a chasm between their theatre-going experiences and the reactions of critics: Was a true piece of ‘Revolutionary’ theatre one that was heralded as emblematic of its time, or one, likeLes deux chasseurs, that was so frequently seen that it hardly elicited a mention in the printed record?
Oceanic Heat Delivery to the Antarctic Continental Shelf: Large‐Scale, Low‐Frequency Variability
Authors: Palóczy André , Gille Sarah T. , McClean Julie L. 
Published: October 2018

AbstractOnshore penetration of oceanic water across the Antarctic continental slope (ACS) plays a major role in global sea level rise by delivering heat to the Antarctic marginal seas, thus contributing to the basal melting of ice shelves. Here the time‐mean (Φmean) and eddy (Φeddy) components of the heat transport (Φ) across the 1,000‐m isobath along the entire ACS are investigated using a 0.1∘ global coupled ocean/sea ice simulation based on the Los Alamos Parallel Ocean Program (POP) and sea ice (Community Ice CodE) models. Comparison with in situ hydrography shows that the model successfully represents the basic water mass structure, with a warm bias in the Circumpolar Deep Water layer. Segments of on‐shelf Φ, with lengths of O(100–1,000 km), are found along the ACS. The circumpolar integral of the annually averaged Φ is O(20 TW), with Φeddy always on‐shelf, while Φmean fluctuates between on‐shelf and off‐shelf. Stirring along isoneutral surfaces is often the dominant process by which eddies transport heat across the ACS, but advection of heat by both mean flow‐topography interactions and eddies can also be significant depending on the along‐ and across‐slope location. The seasonal and interannual variability of the circumpolarly integrated Φmean is controlled by convergence of Ekman transport within the ACS. Prominent warming features at the bottom of the continental shelf (consistent with observed temperature trends) are found both during high‐Southern Annular Mode and high‐Niño 3.4 periods, suggesting that climate modes can modulate the heat transfer from the Southern Ocean to the ACS across the entire Antarctic margin.
The Global Mode‐2 M2 Internal Tide
Authors: Zhao Zhongxiang 
Published: October 2018

AbstractThe mode‐2 M2 internal tide is observed from satellite altimetry. It is extracted in two steps: First, the mode‐2 component is separated from modes 1 and 3 by a bandpass filter with cutoff wavelengths of [0.85 1.35]×λ2, where λ2 is the mode‐2 wavelength; and second, three mode‐2 internal tidal waves are extracted by fitting plane waves in each 120 km by 120 km window. The satellite‐observed mode‐2 M2 internal tide underestimates its strength: It contains the phase‐locked component only, missing the time‐varying component; it contains the southbound/northbound component only, missing the eastbound/westbound component. The satellite results provide rich information on the global mode‐2 M2 internal tide. The results show that the mode‐2 M2 internal tide is ubiquitous in the ocean, and its sea surface height amplitudes are O (1 mm). The spatial patterns of mode‐1 and mode‐2 internal tides are very different. Mode 1 mainly originates at steep topographic features such as submarine ridges, but mode 2 is also generated at gentler topographic features such as abyssal seamounts and fracture zones. Mode‐1 beams propagate O (1,000 km), while mode‐2 beams can be tracked for O (100 km). Depth‐integrated energy and flux are calculated using sea surface height amplitudes and conversion functions built from the World Ocean Atlas 2013. The globally integrated energy of the mode‐2 M2 internal tide approximates to 8 PJ, about 22% of mode 1 (36.4 PJ). This work suggests that higher‐mode internal tides play an important role in the tidal energetics, in particular, over abyssal seamounts and fracture zones.
A polygenic p factor for major psychiatric disorders
Authors: Selzam Saskia , Coleman Jonathan R. I. , Caspi Avshalom , Moffitt Terrie E. , Plomin Robert 
Published: October 2018

AbstractIt has recently been proposed that a single dimension, called the p factor, can capture a person’s liability to mental disorder. Relevant to the p hypothesis, recent genetic research has found surprisingly high genetic correlations between pairs of psychiatric disorders. Here, for the first time, we compare genetic correlations from different methods and examine their support for a genetic p factor. We tested the hypothesis of a genetic p factor by applying principal component analysis to matrices of genetic correlations between major psychiatric disorders estimated by three methods—family study, genome-wide complex trait analysis, and linkage-disequilibrium score regression—and on a matrix of polygenic score correlations constructed for each individual in a UK-representative sample of 7 026 unrelated individuals. All disorders loaded positively on a first unrotated principal component, which accounted for 57, 43, 35, and 22% of the variance respectively for the four methods. Our results showed that all four methods provided strong support for a genetic p factor that represents the pinnacle of the hierarchical genetic architecture of psychopathology.
Seasonal modulation of deep slow-slip and earthquakes on the Main Himalayan Thrust
Authors: Panda Dibyashakti , Kundu Bhaskar , Gahalaut Vineet K. , Bürgmann Roland , Jha Birendra , Asaithambi Renuhaa , Yadav Rajeev Kumar , Vissa Naresh Krishna , Bansal Amit Kumar 
Published: October 2018

AbstractThe interaction between seasonally-induced non-tectonic and tectonic deformation along the Himalayan plate boundary remains debated. Here, we propose that tectonic deformation along this plate boundary can be significantly influenced by the deformation induced by the non-tectonic hydrological loading cycles. We explore seasonal mass oscillations by continental water storage in Southeast Asia and Himalayan arc region using continuous Global Positioning System measurements and satellite data from the Gravity Recovery and Climate Experiment. We suggest that the substantially higher transient displacements above the base of the seismogenic zone indicate a role of changes in aseismic slip rate on the deep megathrust that may be controlled by seasonal hydrological loading. We invoke modulation of aseismic slip on the megathrust down-dip of the seismogenic zone due to a fault resonance process induced by the seasonal stress changes. This process modulates mid-crustal ramp associated micro-seismicity and influences the timing of Central Himalayan earthquakes.
Ultra-long-acting removable drug delivery system for HIV treatment and prevention
Authors: Kovarova Martina , Benhabbour S. Rahima , Massud Ivana , Spagnuolo Rae Ann , Skinner Brianna , Baker Caroline E. , Sykes Craig , Mollan Katie R. , Kashuba Angela D. M. , García-Lerma J. Gerardo , Mumper Russell J. , Garcia J. Victor 
Published: October 2018

AbstractNon-adherence to medication is an important health care problem, especially in the treatment of chronic conditions. Injectable long-acting (LA) formulations of antiretrovirals (ARVs) represent a viable alternative to improve adherence to HIV/AIDS treatment and prevention. However, the LA-ARV formulations currently in clinical trials cannot be removed after administration even if adverse events occur. Here we show an ultra-LA removable system that delivers drug for up to 9 months and can be safely removed to stop drug delivery. We use two pre-clinical models for HIV transmission and treatment, non-human primates (NHP) and humanized BLT (bone marrow/liver/thymus) mice and show a single dose of subcutaneously administered ultra-LA dolutegravir effectively delivers the drug in both models and show suppression of viremia and protection from multiple high-dose vaginal HIV challenges in BLT mice. This approach represents a potentially effective strategy for the ultra-LA drug delivery with multiple possible therapeutic applications.
Synergy between intrinsically disordered domains and structured proteins amplifies membrane curvature sensing
Authors: Zeno Wade F. , Baul Upayan , Snead Wilton T. , DeGroot Andre C. M. , Wang Liping , Lafer Eileen M. , Thirumalai D. , Stachowiak Jeanne C. 
Published: October 2018

AbstractThe ability of proteins to sense membrane curvature is essential to cellular function. All known sensing mechanisms rely on protein domains with specific structural features such as wedge-like amphipathic helices and crescent-shaped BAR domains. Yet many proteins that contain these domains also contain large intrinsically disordered regions. Here we report that disordered domains are themselves potent sensors of membrane curvature. Comparison of Monte Carlo simulations with in vitro and live-cell measurements demonstrates that the polymer-like behavior of disordered domains found in endocytic proteins drives them to partition preferentially to convex membrane surfaces, which place fewer geometric constraints on their conformational entropy. Further, proteins containing both structured curvature sensors and disordered regions are more than twice as curvature sensitive as their respective structured domains alone. These findings demonstrate an entropic mechanism of curvature sensing that is independent of protein structure and illustrate how structured and disordered domains can synergistically enhance curvature sensitivity.
An efficient and multiple target transgenic RNAi technique with low toxicity in Drosophila
Authors: Qiao Huan-Huan , Wang Fang , Xu Rong-Gang , Sun Jin , Zhu Ruibao , Mao Decai , Ren Xingjie , Wang Xia , Jia Yu , Peng Ping , Shen Da , Liu Lu-Ping , Chang Zhijie , Wang Guirong , Li Shao , Ji Jun-Yuan , Liu Qingfei , Ni Jian-Quan 
Published: October 2018

AbstractBeing relatively simple and practical, Drosophila transgenic RNAi is the technique of top priority choice to quickly study genes with pleiotropic functions. However, drawbacks have emerged over time, such as high level of false positive and negative results. To overcome these shortcomings and increase efficiency, specificity and versatility, we develop a next generation transgenic RNAi system. With this system, the leaky expression of the basal promoter is significantly reduced, as well as the heterozygous ratio of transgenic RNAi flies. In addition, it has been first achieved to precisely and efficiently modulate highly expressed genes. Furthermore, we increase versatility which can simultaneously knock down multiple genes in one step. A case illustration is provided of how this system can be used to study the synthetic developmental effect of histone acetyltransferases. Finally, we have generated a collection of transgenic RNAi lines for those genes that are highly homologous to human disease genes.
Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma
Authors: Kahn Suzana A. , Wang Xin , Nitta Ryan T. , Gholamin Sharareh , Theruvath Johanna , Hutter Gregor , Azad Tej D. , Wadi Lina , Bolin Sara , Ramaswamy Vijay , Esparza Rogelio , Liu Kun-Wei , Edwards Michael , Swartling Fredrik J. , Sahoo Debashis , Li Gordon , Wechsler-Reya Robert J. , Reimand Jüri , Cho Yoon-Jae , Taylor Michael D. , Weissman Irving L. , Mitra Siddhartha S. , Cheshier Samuel H. 
Published: October 2018

AbstractMedulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.
Genetic and mechanistic basis for APOBEC3H alternative splicing, retrovirus restriction, and counteraction by HIV-1 protease
Authors: Ebrahimi Diako , Richards Christopher M. , Carpenter Michael A. , Wang Jiayi , Ikeda Terumasa , Becker Jordan T. , Cheng Adam Z. , McCann Jennifer L. , Shaban Nadine M. , Salamango Daniel J. , Starrett Gabriel J. , Lingappa Jairam R. , Yong Jeongsik , Brown William L. , Harris Reuben S. 
Published: October 2018

AbstractHuman APOBEC3H (A3H) is a single-stranded DNA cytosine deaminase that inhibits HIV-1. Seven haplotypes (I–VII) and four splice variants (SV154/182/183/200) with differing antiviral activities and geographic distributions have been described, but the genetic and mechanistic basis for variant expression and function remains unclear. Using a combined bioinformatic/experimental analysis, we find that SV200 expression is specific to haplotype II, which is primarily found in sub-Saharan Africa. The underlying genetic mechanism for differential mRNA splicing is an ancient intronic deletion [del(ctc)] within A3H haplotype II sequence. We show that SV200 is at least fourfold more HIV-1 restrictive than other A3H splice variants. To counteract this elevated antiviral activity, HIV-1 protease cleaves SV200 into a shorter, less restrictive isoform. Our analyses indicate that, in addition to Vif-mediated degradation, HIV-1 may use protease as a counter-defense mechanism against A3H in >80% of sub-Saharan African populations.
Bacterial coinfection restrains antiviral CD8 T-cell response via LPS-induced inhibitory NK cells
Authors: Straub Tobias , Freudenberg Marina A. , Schleicher Ulrike , Bogdan Christian , Gasteiger Georg , Pircher Hanspeter 
Published: October 2018

AbstractInfection of specific pathogen-free mice with lymphocytic choriomeningitis virus (LCMV) is a widely used model to study antiviral T-cell immunity. Infections in the real world, however, are often accompanied by coinfections with unrelated pathogens. Here we show that in mice, systemic coinfection withE. colisuppresses the LCMV-specific cytotoxic T-lymphocyte (CTL) response and virus elimination in a NK cell- and TLR2/4-dependent manner. Soluble TLR4 ligand LPS also induces NK cell-mediated negative CTL regulation during LCMV infection. NK cells in LPS-treated mice suppress clonal expansion of LCMV-specific CTLs by a NKG2D- or NCR1-independent but perforin-dependent mechanism. These results suggest a TLR4-mediated immunoregulatory role of NK cells during viral-bacterial coinfections.
Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control
Authors: Brosch Mario , Kattler Kathrin , Herrmann Alexander , von Schönfels Witigo , Nordström Karl , Seehofer Daniel , Damm Georg , Becker Thomas , Zeissig Sebastian , Nehring Sophie , Reichel Fabian , Moser Vincent , Thangapandi Raghavan Veera , Stickel Felix , Baretton Gustavo , Röcken Christoph , Muders Michael , Matz-Soja Madlen , Krawczak Michael , Gasparoni Gilles , Hartmann Hella , Dahl Andreas , Schafmayer Clemens , Walter Jörn , Hampe Jochen 
Published: October 2018

AbstractA deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver.
Ice rule fragility via topological charge transfer in artificial colloidal ice
Authors: Libál András , Lee Dong Yun , Ortiz-Ambriz Antonio , Reichhardt Charles , Reichhardt Cynthia J. O. , Tierno Pietro , Nisoli Cristiano 
Published: October 2018

AbstractArtificial particle ices are model systems of constrained, interacting particles. They have been introduced theoretically to study ice-manifolds emergent from frustration, along with domain wall and grain boundary dynamics, doping, pinning-depinning, controlled transport of topological defects, avalanches, and memory effects. Recently such particle-based ices have been experimentally realized with vortices in nano-patterned superconductors or gravitationally trapped colloids. Here we demonstrate that, although these ices are generally considered equivalent to magnetic spin ices, they can access a novel spectrum of phenomenologies that are inaccessible to the latter. With experiments, theory and simulations we demonstrate that in mixed coordination geometries, entropy-driven negative monopoles spontaneously appear at a density determined by the vertex-mixture ratio. Unlike its spin-based analogue, the colloidal system displays a “fragile ice” manifold, where local energetics oppose the ice rule, which is instead enforced through conservation of the global topological charge. The fragile colloidal ice, stabilized by topology, can be spontaneously broken by topological charge transfer.
Enhanced validation of antibodies for research applications
Authors: Edfors Fredrik , Hober Andreas , Linderbäck Klas , Maddalo Gianluca , Azimi Alireza , Sivertsson Åsa , Tegel Hanna , Hober Sophia , Szigyarto Cristina Al-Khalili , Fagerberg Linn , von Feilitzen Kalle , Oksvold Per , Lindskog Cecilia , Forsström Björn , Uhlen Mathias 
Published: October 2018

AbstractThere is a need for standardized validation methods for antibody specificity and selectivity. Recently, five alternative validation pillars were proposed to explore the specificity of research antibodies using methods with no need for prior knowledge about the protein target. Here, we show that these principles can be used in a streamlined manner for enhanced validation of research antibodies in Western blot applications. More than 6,000 antibodies were validated with at least one of these strategies involving orthogonal methods, genetic knockdown, recombinant expression, independent antibodies, and capture mass spectrometry analysis. The results show a path forward for efforts to validate antibodies in an application-specific manner suitable for both providers and users.
C16-ceramide is a natural regulatory ligand of p53 in cellular stress response
Authors: Fekry Baharan , Jeffries Kristen A. , Esmaeilniakooshkghazi Amin , Szulc Zdzislaw M. , Knagge Kevin J. , Kirchner David R. , Horita David A. , Krupenko Sergey A. , Krupenko Natalia I. 
Published: October 2018

AbstractCeramides are important participants of signal transduction, regulating fundamental cellular processes. Here we report the mechanism for activation of p53 tumor suppressor by C16-ceramide. C16-ceramide tightly binds within the p53 DNA-binding domain (Kd ~ 60 nM), in close vicinity to the Box V motif. This interaction is highly selective toward the ceramide acyl chain length with its C10 atom being proximal to Ser240 and Ser241. Ceramide binding stabilizes p53 and disrupts its complex with E3 ligase MDM2 leading to the p53 accumulation, nuclear translocation and activation of the downstream targets. This mechanism of p53 activation is fundamentally different from the canonical p53 regulation through protein–protein interactions or posttranslational modifications. The discovered mechanism is triggered by serum or folate deprivation implicating it in the cellular response to nutrient/metabolic stress. Our study establishes C16-ceramide as a natural small molecule activating p53 through the direct binding.
SWI/SNF catalytic subunits’ switch drives resistance to EZH2 inhibitors in ARID1A-mutated cells
Authors: Wu Shuai , Fatkhutdinov Nail , Fukumoto Takeshi , Bitler Benjamin G. , Park Pyoung Hwa , Kossenkov Andrew V. , Trizzino Marco , Tang Hsin-Yao , Zhang Lin , Gardini Alessandro , Speicher David W. , Zhang Rugang 
Published: October 2018

AbstractInactivation of the subunits of SWI/SNF complex such as ARID1A is synthetically lethal with inhibition of EZH2 activity. However, mechanisms of de novo resistance to EZH2 inhibitors in cancers with inactivating SWI/SNF mutations are unknown. Here we show that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 drives resistance to EZH2 inhibitors in ARID1A-mutated cells. SMARCA4 loss upregulates anti-apoptotic genes in the EZH2 inhibitor-resistant cells. EZH2 inhibitor-resistant ARID1A-mutated cells are hypersensitive to BCL2 inhibitors such as ABT263. ABT263 is sufficient to overcome resistance to an EZH2 inhibitor. In addition, ABT263 synergizes with an EZH2 inhibitor in vivo in ARID1A-inactivated ovarian tumor mouse models. Together, these data establish that the switch of the SWI/SNF catalytic subunits from SMARCA4 to SMARCA2 underlies the acquired resistance to EZH2 inhibitors. They suggest BCL2 inhibition alone or in combination with EZH2 inhibition represents urgently needed therapeutic strategy for ARID1A-mutated cancers.