bluuebunny/crossref_metadata_2025 huggingface dataset:
Feeding ecology of three sympatric species of stingrays on a tropical mudflat
Authors: Lim Kean Chong , Chong Ving Ching , Lim Phaik-Eem , Yurimoto Tatsuya , Loh Kar Hoe
Published: October 2018

Periodic fish ingressions into intertidal areas during high tide are known to occur on tropical mudflats. This study aimed to elucidate the feeding ground function of coastal mudflats for three common stingray species in the Klang Strait, Malaysia. Stingrays (disc width range from 5.65–54.50 cm) sampled over 17 months using a large barrier net (~2 ha enclosure) at two sampling sites were examined for their diet composition, prey frequency and prey volume according to predator species and maturity. The index of relative importance and Schoener's index of diet overlap were calculated. The three stingray species fed on relatively similar prey items which varied in size and contribution.Brevitrygon heterurafed on the widest range of prey taxa (28) whereasHemitrygon bennetti(22) andTelatrygon biasa(17) showed higher prey specialization. The Penaeidae (dominantlyMetapenaeus brevicornisandM. affinis) were the most important food item in the stingray diet which also included Actinopterygii, Amphipoda, Brachyura and Calanoida. The stingray diet showed an ontogenetic shift, with young stingrays tending to be generalists whereas the more mature stingrays (exceptH. bennetti) become more specialized in their feeding habits. This shift in feeding strategy reflects the diversity of prey taxa abundantly available to young stingrays on the mudflats, while the larger stingrays adapt to feed on larger prey once they enter deeper waters.
The need for Inuit parents’ perspectives on outdoor risky play
Authors: Bauer Michelle E.E. , Giles Audrey R.
Published: October 2018

Parents’ perspectives on their children’s outdoor risky play behaviours influence their children’s adoption of safety strategies and their children’s approach to risky and dangerous situations (Brussoni & Olsen, 2011). Over the past decade, researchers have explored many Canadian mothers’ and fathers’ perspectives on this topic; however, to date, there has been a lack of research on Indigenous parents’ perspectives, particularly those of Inuit parents. This lack of research means that Inuit families are unaccounted for in research used to create and promote safety policies and practices in Canada. The present research commentary is the first to address the urgent need for research on northern Canadian Inuit parents’ perspectives on outdoor risky play. Specifically, outdoor risky play is defined, and Inuit children’s outdoor play experiences are compared to non-Inuit children’s experiences. Further, Inuit children’s experiences of injury are discussed to further situate the dire need to work with the most vulnerable population in Canada – Inuit – in child injury prevention research.
Knowledge machines
Authors: Smart Paul
Published: October 2018

The World Wide Web has had a notable impact on a variety of epistemically relevant activities, many of which lie at the heart of the discipline of knowledge engineering. Systems like Wikipedia, for example, have altered our views regarding the acquisition of knowledge, while citizen science systems such as Galaxy Zoo have arguably transformed our approach to knowledge discovery. Other Web-based systems have highlighted the ways in which the human social environment can be used to support the development of intelligent systems, either by contributing to the provision of epistemic resources or by helping to shape the profile of machine learning. In the present paper, such systems are referred to asknowledge machines. In addition to providing an overview of the knowledge machine concept, the present paper reviews a number of issues that are associated with the scientific and philosophical study of knowledge machines. These include the potential impact of knowledge machines for the theory and practice of knowledge engineering, the role of social participation in the realization of knowledge-based processes, and the role of standardized, semantically enriched data formats in supporting thead hocassembly of special-purpose knowledge systems and knowledge processing pipelines.
The Gorenstein-projective modules over a monomial algebra
Authors: Chen Xiao-Wu , Shen Dawei , Zhou Guodong
Published: October 2018

We introduce the notion of a perfect path for a monomial algebra. We classify indecomposable non-projective Gorenstein-projective modules over the given monomial algebra via perfect paths. We apply the classification to a quadratic monomial algebra and describe explicitly the stable category of its Gorenstein-projective modules.
Mortality at Music Festivals: An Update for 2016-2017 – Academic and Grey Literature for Case Finding
Authors: Turris Sheila A. , Jones Tracie , Lund Adam
Published: October 2018

In 2016, the authors published a paper on music festival fatalities between the years 1999 and 2014 (n=722). In this Special Report, they provide an update on fatalities reported at music festivals globally for the period 2016-2017 (n=201). Using a search strategy designed to capture grey literature and media reports of music festival fatalities, reports of the overall frequency and cause-of-death breakdown for publicly reported, festival-related deaths are recorded. This update shows an increase in the frequency of festival-related fatality reports during the new period, together with an increase in the number of deaths attributable to terror (n=60) and overdose/poisoning (n=41). Drawing conclusions about the cause of this increase is challenging given the growth in Internet use, online media reports, and number of music festivals occurring annually when compared with the previous reporting period. The authors re-emphasize the need for a uniform reporting standard and reliable epidemiological data for fatalities related to music festivals, mass gatherings, and special events.

TurrisSA, JonesT, LundA. Mortality at music festivals: an update for 2016-2017 – academic and grey literature for case finding. Prehosp Disaster Med. 2018;33(5):553–557.
Is Self-Compassion a Worthwhile Therapeutic Target for ICD-11 Complex PTSD (CPTSD)?
Authors: Karatzias Thanos , Hyland Philip , Bradley Aoife , Fyvie Claire , Logan Katharine , Easton Paula , Thomas Jackie , Philips Sarah , Bisson Jonathan I. , Roberts Neil P. , Cloitre Marylene , Shevlin Mark
Published: October 2018

Background:Two ‘sibling’ disorders have been proposed for the fourthcoming 11th version of theInternational Classification of Diseases(ICD-11): post-traumatic stress disorder (PTSD) and complex PTSD (CPTSD). Examining psychological factors that may be associated with CPTSD, such as self-compassion, is an important first step in its treatment that can inform consideration of which problems are most salient and what interventions are most relevant.Aims:We set out to investigate the association between self-compassion and the two factors of CPTSD: the PTSD factor (re-experiencing, avoidance, sense of threat) and the Disturbances in Self-Organization (DSO) factor (affect dysregulation, negative self-concept and disturbances in relationships). We hypothesized that self-compassion subscales would be negatively associated with both PTSD and DSO symptom clusters.Method:A predominantly female, clinical sample (n= 106) completed self-report scales to measure traumatic life events, ICD-11 CPTSD and self-compassion.Results:Significant negative associations were found between the CPTSD DSO clusters of symptoms and self-compassion subscales, but not for the PTSD ones. Specifically it was also found that self-judgement and common humanity significantly predicted hypoactive affect dysregulation whereas self-judgement and isolation significantly predicted negative self-concept.Conclusions:Our results indicate that self-compassion may be a useful treatment target for ICD-11 CPTSD, particularly for symptoms of negative self-concept and affect dysregulation. Future research is required to investigate the efficacy and acceptability of interventions that have implicit foundations on compassion.
Relative validity of brief-type self-administered diet history questionnaire among very old Japanese aged 80 years or older
Authors: Kobayashi Satomi , Yuan Xiaoyi , Sasaki Satoshi , Osawa Yusuke , Hirata Takumi , Abe Yukiko , Takayama Michiyo , Arai Yasumichi , Masui Yukie , Ishizaki Tatsuro
Published: October 2018

Objective

Dietary questionnaires for assessing dietary intakes among populations of individuals aged 80 years or older (the very old) are very limited. We examined the relative validity of forty-three nutrients and twenty-seven food groups estimated by a brief-type self-administered diet history questionnaire (BDHQ) targeting very old Japanese, using semi-weighed dietary records (DR) as a reference.

Design

Between June and August 2012 and between June 2015 and February 2016, a three-day non-consecutive DR (at two-week intervals) and a BDHQ were completed.

Setting

Tokyo, the capital prefecture of Japan.

Subjects

Eighty very old Japanese (thirty-six men and forty-four women) aged 82–94 years.

Results

The median intakes of 40–70 % of the crude and energy-adjusted nutrients estimated by the BDHQ were significantly different from those estimated by the DR. The median Spearman’s correlation coefficient of nutrient intakes between the BDHQ and the DR was 0·39–0·46. About half (48–56 %) of the food groups were significantly different in terms of the median intakes estimated by the BDHQ and the DR in crude and energy-adjusted values. The median Spearman’s correlation coefficient between the BDHQ and the DR was 0·45–0·48.

Conclusions

Acceptable Spearman’s correlations (≥0·3) were obtained for many dietary intakes among the very old Japanese population. The BDHQ is a good candidate for epidemiological studies among very old Japanese, although, for some nutrients and food groups, the difficulty of estimating accurate median intakes is one of the limitations for the tool. Further efforts to enhance the validity of the BDHQ for very old populations are needed.
Disparity Surface Reconstruction Based on a Stereo Light Microscope and Laser Fringes
Authors: Wang Yuezong
Published: October 2018

Microscopic vision systems based on a stereo light microscope (SLM) are used in microscopic measuring fields. Conventional measuring methods output the disparity surface based on stereo matching methods; however, these methods require that stereo images contain sufficient distinguishing features. Moreover, matching results typically contain many mismatched points. This paper presents a novel method for disparity surface reconstruction by combining an SLM and laser measuring techniques. The surfaces of small objects are scanned by a laser fringe, and a stereo image sequence containing laser stripes is obtained. The central contours of the laser stripes are extracted, and central contours are derived for alignment. A disparity coordinate system is then defined and used to analyze the relationship between the motion direction and reference plane. Next, the method of aligning disparity contours is proposed. The results show that our method can achieve a precision of ±0.5 pixels and that the real and measured shapes described by the disparity surface are consistent based on our method. Our method is confirmed to perform much better than the conventional block-matching method. The disparity surface output obtained by our method can be used to measure the surface profiles of microscopic objects accurately.
EDITORIAL
Authors: HUNTER MARY
Published: October 2018

In the world of historically informed performance (HIP) the word ‘authenticity’ is, if not exactly dead, certainly taboo (‘I know that we shouldn't use the A-word’), fenced in with qualifiers (‘Of course we can't be fully authentic’) or softened to clarify that of course HIP performances are aiming for something less than a full realization of the composer's intentions (‘This may be the way Mozart could have heard it’, or ‘This represents some of the practices of the time’). But at least for the most successful practitioners of HIP (epigones may be a different matter), authenticity discourse was always a significant but simplified version of one part of a more complex and even contradictory set of justifications for using old instruments and techniques. Indeed, HIP practitioners regularly invoke chapter and verse from the treatises or other primary sources in the same breath as claiming not to be interested in authenticity per se or not to be engaged in any kind of ‘reconstruction’. This discursive rupture may be more striking with music of the later seventeenth, eighteenth and nineteenth centuries, where the performance-practice sources are more numerous and the scores are more ‘complete’ by modern standards than those of much earlier music, whose performance has always been more frankly imaginative and conjectural.
TWO HUNTERS, A MILKMAID AND THE FRENCH ‘REVOLUTIONARY’ CANON
Authors: DOE JULIA
Published: October 2018

Large-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

Onshore 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

The 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

It 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

The 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

Non-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

The 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

Being 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

Medulloblastoma 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

Human 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

Infection 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

A 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

Artificial 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

There 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

Ceramides 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

Inactivation 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.
Direct protein-lipid interactions shape the conformational landscape of secondary transporters
Authors: Martens Chloe , Shekhar Mrinal , Borysik Antoni J. , Lau Andy M. , Reading Eamonn , Tajkhorshid Emad , Booth Paula J. , Politis Argyris
Published: October 2018

Secondary transporters undergo structural rearrangements to catalyze substrate translocation across the cell membrane – yet how such conformational changes happen within a lipid environment remains poorly understood. Here, we combine hydrogen-deuterium exchange mass spectrometry (HDX-MS) with molecular dynamics (MD) simulations to understand how lipids regulate the conformational dynamics of secondary transporters at the molecular level. Using the homologous transporters XylE, LacY and GlpT from Escherichia coli as model systems, we discover that conserved networks of charged residues act as molecular switches that drive the conformational transition between different states. We reveal that these molecular switches are regulated by interactions with surrounding phospholipids and show that phosphatidylethanolamine interferes with the formation of the conserved networks and favors an inward-facing state. Overall, this work provides insights into the importance of lipids in shaping the conformational landscape of an important class of transporters.
Designed synthesis of stable light-emitting two-dimensional sp2 carbon-conjugated covalent organic frameworks
Authors: Jin Enquan , Li Juan , Geng Keyu , Jiang Qiuhong , Xu Hong , Xu Qing , Jiang Donglin
Published: October 2018

Covalent organic frameworks enable the topological connection of organic chromophores into π lattices, making them attractive for creating light-emitting polymers that are predesignable for both the primary- and high-order structures. However, owing to linkages, covalent organic frameworks are either unstable or poor luminescent, leaving the practical synthesis of stable light-emitting frameworks challenging. Here, we report the designed synthesis of sp2 carbon-conjugated frameworks that combine stability with light-emitting activity. The C=C linkages topologically connect pyrene knots and arylyenevinylene linkers into two-dimensional all sp2 carbon lattices that are designed to be π conjugated along both the x and y directions and develop layer structures, creating exceptionally stable frameworks. The resulting frameworks are capable of tuning band gap and emission by the linkers, are highly luminescent under various conditions and can be exfoliated to produce brilliant nanosheets. These results suggest a platform based on sp2 carbon frameworks for designing robust photofunctional materials.
Retraction Note: Hsa-miR-520d induces hepatoma cells to form normal liver tissues via a stemness-mediated process
Authors: Tsuno Satoshi , Wang Xinhui , Shomori Kohei , Hasegawa Junichi , Miura Norimasa
Published: October 2018

This paper has been retracted.
Personalized Integrated Network Modeling of the Cancer Proteome Atlas
Authors: Ha Min Jin , Banerjee Sayantan , Akbani Rehan , Liang Han , Mills Gordon B. , Do Kim-Anh , Baladandayuthapani Veerabhadran
Published: October 2018

Personalized (patient-specific) approaches have recently emerged with a precision medicine paradigm that acknowledges the fact that molecular pathway structures and activity might be considerably different within and across tumors. The functional cancer genome and proteome provide rich sources of information to identify patient-specific variations in signaling pathways and activities within and across tumors; however, current analytic methods lack the ability to exploit the diverse and multi-layered architecture of these complex biological networks. We assessed pan-cancer pathway activities for >7700 patients across 32 tumor types from The Cancer Proteome Atlas by developing a personalized cancer-specific integrated network estimation (PRECISE) model. PRECISE is a general Bayesian framework for integrating existing interaction databases, data-driven de novo causal structures, and upstream molecular profiling data to estimate cancer-specific integrated networks, infer patient-specific networks and elicit interpretable pathway-level signatures. PRECISE-based pathway signatures, can delineate pan-cancer commonalities and differences in proteomic network biology within and across tumors, demonstrates robust tumor stratification that is both biologically and clinically informative and superior prognostic power compared to existing approaches. Towards establishing the translational relevance of the functional proteome in research and clinical settings, we provide an online, publicly available, comprehensive database and visualization repository of our findings (https://mjha.shinyapps.io/PRECISE/).
Illustrating the effect of viscoelastic additives on cavitation and turbulence with X-ray imaging
Authors: Karathanassis I. K. , Trickett K. , Koukouvinis P. , Wang J. , Barbour R. , Gavaises M.
Published: October 2018

The effect of viscoelastic additives on the topology and dynamics of the two-phase flow arising within an axisymmetric orifice with a flow path constriction along its main axis has been investigated employing high-flux synchrotron radiation. X-ray Phase Contrast Imaging (XPCI) has been conducted to visualise the cavitating flow of different types of diesel fuel within the orifice. An additised blend containing Quaternary Ammonium Salt (QAS) additives with a concentration of 500 ppm has been comparatively examined against a pure (base) diesel compound. A high-flux, 12 keV X-ray beam has been utilised to obtain time resolved radiographs depicting the vapour extent within the orifice from two views (side and top) with reference to its main axis. Different test cases have been examined for both fuel types and for a range of flow conditions characterised by Reynolds number of 35500 and cavitation numbers (CN) lying in the range 3.0–7.7. It has been established that the behaviour of viscoelastic micelles in the regions of shear flow is not consistent depending on the cavitation regimes encountered. Namely, viscoelastic effects enhance vortical (string) cavitation, whereas hinder cloud cavitation. Furthermore, the use of additised fuel has been demonstrated to suppress the level of turbulence within the orifice.
Stable and discriminating features are predictive of cancer presence and Gleason grade in radical prostatectomy specimens: a multi-site study
Authors: Leo Patrick , Elliott Robin , Shih Natalie N. C. , Gupta Sanjay , Feldman Michael , Madabhushi Anant
Published: October 2018

Site variation in fixation, staining, and scanning can confound automated tissue based image classifiers for disease characterization. In this study we incorporated stability into four feature selection methods for identifying the most robust and discriminating features for two prostate histopathology classification tasks. We evaluated 242 morphology features from N = 212 prostatectomy specimens from four sites for automated cancer detection and grading. We quantified instability as the rate of significant cross-site feature differences. We mapped feature stability and discriminability using 188 non-cancerous and 210 cancerous regions via 3-fold cross validation, then held one site out, creating independent training and testing sets. In training, one feature set was selected only for discriminability, another for discriminability and stability. We trained a classifier with each feature set, testing on the hold out site. Experiments were repeated with 117 Gleason grade 3 and 112 grade 4 regions. Stability was calculated across non-cancerous regions. Gland shape features yielded the best stability and area under the receiver operating curve (AUC) trade-off while co-occurrence texture features were generally unstable. Our stability-informed method produced a cancer detection AUC of 0.98 ± 0.05 and increased average Gleason grading AUC by 4.38%. Color normalization of the images tended to exacerbate feature instability.
Transplantation of a bone marrow mesenchymal stem cell line increases neuronal progenitor cell migration in a cerebral ischemia animal model
Authors: Shiota Yuri , Nagai Atsushi , Sheikh Abdullah Md. , Mitaki Shingo , Mishima Seiji , Yano Shozo , Haque Md. Ahsanul , Kobayashi Shotai , Yamaguchi Shuhei
Published: October 2018

Mesenchymal stem cell (MSC) transplantation is demonstrated to improve functional and pathological recovery in cerebral ischemia. To understand the underlying mechanism, we transplanted a MSC line (B10) in a rat middle cerebral artery occlusion (MCAO) model and checked the proliferation and migration of neuronal progenitor cells (NPCs). B10 transplantation increased NPCs in the subventricular zone and their migration towards the lesion area at an earlier time. Fourteen days after MCAO, some NPCs were differentiated to neurons and astrocytes. Although B10 transplantation increased total number of both astrocytes and neurons, it only increased the differentiation of NPC to astrocyte. The mRNA of polysialylation enzyme ST8SiaIV and a chemokine SDF-1 were persistently increased in B10-transplanted groups. SDF-1-positive cell number was increased in the core and penumbra area, which was expressed in macrophage/microglia and transplanted B10 cells at 3 days after MCAO. Furthermore, SDF-1 mRNA expression in cell culture was high in B10 compared to a microglia (HMO) or a neuronal (A1) cell line. B10 culture supernatant increased in vitro A1 cell migration, which was significantly inhibited by siRNA-mediated SDF-1 silencing in B10. Thus, our results suggested that MSC transplantation increased endogenous NPC migration in cerebral ischemic condition by increasing chemokine and polysialylation enzyme expression, which could be helpful for the restorative management of cerebral ischemia.
Probing the origin of matching functional jaws: roles of Dlx5/6 in cranial neural crest cells
Authors: Shimizu Miki , Narboux-Nême Nicolas , Gitton Yorick , de Lombares Camille , Fontaine Anastasia , Alfama Gladys , Kitazawa Taro , Kawamura Yumiko , Heude Eglantine , Marshall Lindsey , Higashiyama Hiroki , Wada Youichiro , Kurihara Yukiko , Kurihara Hiroki , Levi Giovanni
Published: October 2018

Gnathostome jaws derive from the first pharyngeal arch (PA1), a complex structure constituted by Neural Crest Cells (NCCs), mesodermal, ectodermal and endodermal cells. Here, to determine the regionalized morphogenetic impact of Dlx5/6 expression, we specifically target their inactivation or overexpression to NCCs. NCC-specific Dlx5/6 inactivation (NCC∆Dlx5/6) generates severely hypomorphic lower jaws that present typical maxillary traits. Therefore, differently from Dlx5/6 null-embryos, the upper and the lower jaws of NCC∆Dlx5/6 mice present a different size. Reciprocally, forced Dlx5 expression in maxillary NCCs provokes the appearance of distinct mandibular characters in the upper jaw. We conclude that: (1) Dlx5/6 activation in NCCs invariably determines lower jaw identity; (2) the morphogenetic processes that generate functional matching jaws depend on the harmonization of Dlx5/6 expression in NCCs and in distinct ectodermal territories. The co-evolution of synergistic opposing jaws requires the coordination of distinct regulatory pathways involving the same transcription factors in distant embryonic territories.
Evolutionary changes in growth, regrowth and carbohydrate storage in an invasive plant
Authors: Lin Tiantian , Klinkhamer Peter G. L. , Vrieling Klaas
Published: October 2018

We hypothesized that due to the absence of specialist herbivores in introduced ranges, invasive plants have evolved decreased allocation to carbohydrate storage for regrowth ability and as a consequence allocate more to growth. In this study, we compared plant growth, carbohydrate storage and regrowth ability of invasive and native Jacobaea vulgaris in response to complete shoot defoliation. We used invasive J. vulgaris genotypes from three geographically and climactically distinct regions and compared these with native genotypes from Europe. We found that invasive genotypes initially grew larger while native genotypes regrew larger after defoliation. Before defoliation, the carbohydrate storage in roots of invasive genotypes was 38% lower than native genotypes. Biomass after regrowth increased with root carbohydrate storage while it decreased with structural root mass, showing that it is crucial to study root storage and structural components separately in order to investigate plant regrowth. All studied traits of invasive populations from the three geographically and climatologically distinct regions changed in the same expected direction suggesting that the shifts in herbivore guild were causal to the observed change in growth and regrowth ability rather than environmental factors.