bluuebunny/crossref_metadata_2025 huggingface dataset:
Global Environmental Law: Context and Theory, Challenge and Promise
Authors: Kulovesi Kati , Mehling Michael , Morgera Elisa
Published: October 2019

Few issue areas exemplify the centrifugal forces that have prompted the emergence of global law scholarship better than the environment. With its propensity to blur or transcend conventional distinctions between national and international, public and private, and formal and informal, environmental governance offers a consummate case study to test the promise and perils of global law. In this article we situate global environmental law in the broader debate about lawmaking and application beyond the nation state, tracing the evolution and elusive boundaries of this nascent field. Our survey allows us to identify conceptual ambiguities and missed opportunities in the literature on global environmental law, including challenges to its normativity and legitimacy. From there, however, we proceed to outline a twofold opportunity for the global environmental law project: (i) an opportunity to enrich environmental law with more diverse and inclusive practices; and (ii) an opportunity for collaborative self-reflexivity by the scholars and practitioners of environmental law as these not only interpret and apply but, through their work, actively shape the content of the law.
Gender Composition in Contentious Collective Action: “Girl Strikers” in Gilded Age America—Harmful, Helpful, or Both?
Authors: Jacobs Anna W. , Isaac Larry W.
Published: October 2019

The Gilded Age was a tumultuous period for US labor and capital: the labor movement grew in size and intensity, strikes mushroomed, and women’s labor force and strike participation grew in tandem. Yet little is known about how women’s participation influenced strike efficacy. On the one hand, women may have added numerical force, militant energy for gendered solidarity and therefore contributed to strike success. On the other hand, women’s participation may have hindered the cause by delegitimizing it or by producing harmful internal factionalism. In this article, we ask:How did women’s participation in Gilded Age strikes influence strike success?We use a unique data source to test the impact of women’s participation relative to men on the success of every strike that took place in the Northeastern United States from 1881 to 1886. We find that striking gender composition ratios matter and are reflected in a nonlinear pattern: for male-dominated and female-dominated strikes, greater numbers of female strikers reduce the chances of success. However, when gender composition approaches approximate parity, the effect of female strikers enhances strike success. We suggest that in approximate proportional parity range, women were more likely to participate and also be taken more seriously by male co-workers. We supplement quantitative findings with qualitative accounts from specific strikes. Our findings have important implications for diversity in contentious collective action in general and strike success in particular.
New Developments in the PuffinPlot Paleomagnetic Data Analysis Program
Authors: Lurcock P. C. , Florindo F.
Published: October 2019

PuffinPlot is a program for paleomagnetic data analysis and plotting, first released in 2012 and under continuous development since then. It is free, cross‐platform software and provides both a graphical desktop interface for interactive use and an application‐programmer interface for scripting. We present a major new release of the program, describe significant new features added since the first release, and demonstrate their application to real‐world data. New features include automatic magnetic declination realignment, relative paleointensity calculation, virtual geomagnetic pole determination, calculation of inclination‐only statistics, support for reproducible research via the export of self‐contained data bundles, and support for reading a number of popular paleomagnetic file formats. We also discuss the application of unit tests in ensuring PuffinPlot's long‐term reliability and outline directions for future development of the software.
Observations of Asymmetric Lobe Convection for Weak and Strong Tail Activity
Authors: Ohma A. , Østgaard N. , Reistad J. P. , Tenfjord P. , Laundal K. M. , Moretto Jørgensen T. , Haaland S. E. , Krcelic P. , Milan S.
Published: October 2019

In this study we use high‐quality convection data from the Electron Drift Instrument on board Cluster to investigate how near‐Earth tail activity affects the average convection pattern in the magnetotail lobes when the interplanetary magnetic field has a dominating east‐west (By) component. Two different proxies have been used to represent different levels of reconnection in the near‐Earth tail: The value of the AL index and the substorm phases identified by the Substorm Onsets and Phases from Indices of the Electrojet algorithm. We find that the convection changes from a dominantly YGSM direction, but opposite in the two hemispheres, to a flow oriented more toward the plasma sheet, as the north‐south component of the convection increases when reconnection enhances in the near Earth tail. This result is consistent with recent observations of the convection in the ionosphere, which suggest that the nightside convection pattern becomes more north‐south symmetric when tail reconnection increases. This is also supported by simultaneous auroral observations from the two hemispheres, which shows that conjugate auroral features become more symmetric during substorm expansion phase. The reduced asymmetry implies that the asymmetric pressure balance in the lobes is altered during periods with strong reconnection in the near‐Earth tail.
A Study of Automatically Detected Flow Channels in the Polar Cap Ionosphere
Authors: Herlingshaw K. , Baddeley L. J. , Oksavik K. , Lorentzen D. A. , Bland E. C.
Published: October 2019

This paper presents a new algorithm for detecting high‐speed flow channels in the polar cap. The algorithm was applied to Super Dual Auroral Radar Network data, specifically to data from the new Longyearbyen radar. This radar is located at 78.2°N, 16.0°E geographical coordinates looking north‐east, and is therefore at an ideal location to measure flow channels in the high‐latitude polar cap. The algorithm detected >500 events over 1 year of observations, and within this paper two case studies are considered in more detail. A flow channel on “old‐open field lines” located on the dawn flank was directly driven under quiet conditions over 13 min. This flow channel contributed to a significant fraction (60%) of the cross polar cap potential and was located on the edge of a polar cap arc. Another case study follows the development of a flow channel on newly opened field lines within the cusp. This flow channel is a spontaneously driven event forming under strong solar wind driving and is intermittently excited over the course of almost an hour. As they provide a high fraction of the cross polar cap potential, these small‐scale structures are vital for understanding the transport of magnetic flux over the polar cap.
Quantification of the Vertical Transport and Escape of Atomic Hydrogen in the Terrestrial Upper Atmosphere
Authors: Joshi P. P. , Phal Y. D. , Waldrop L. S.
Published: October 2019

Measurements of the limiting escape rate of atomic hydrogen (H) atoms at Earth and the relative significance of thermal evaporation and nonthermal escape mechanisms, such as charge exchange and polar wind, have long been lacking. Our recent development of sophisticated radiative transport analysis techniques now enables the reliable interpretation of remotely sensed measurements of optically thick H emission, such as those acquired along the Earth's limb by the Global Ultraviolet Imager (GUVI) onboard the NASA Thermosphere Ionosphere Mesosphere Energetics and Dynamics (TIMED) spacecraft, in terms of physical parameters such as exobase density and, crucially, vertical diffusive flux. In this work, we present results from a systematic investigation of H Lya emission measured by TIMED/GUVI along the Earth's dayside limb from 2002–2007, which we use to derive the vertical H flux and associated density distribution from 250 km out to 1 Earth radius. Our analysis reveals that the vertical flux of thermospheric H is nearly constant over a large range of solar activity and typically exceeds the calculated thermal evaporative flux, suggesting that terrestrial H escape is indeed limited by its vertical diffusion. The excess supply of H atoms to the exobase associated with large observed vertical fluxes requires that nonthermal escape mechanisms be operative for steady‐state continuity balance. We find that such nonthermal processes are a particularly significant component of total H escape during low solar activity, when thermal evaporation is weakest.
Coseismic Slip and Early Afterslip of the M6.0 24 August 2014 South Napa, California, Earthquake
Authors: Pollitz Fred F. , Murray Jessica R. , Minson Sarah E. , Wicks Charles W. , Svarc Jerry L. , Brooks Benjamin A.
Published: October 2019

We employ strong motion seismograms and static offsets from the Global Positioning System, Interferometric Synthetic Aperture Radar, and other measurements in order to derive a coseismic slip and afterslip model of the M6.0 24 August 2014 South Napa earthquake. This earthquake ruptured an ∼13‐km‐long portion of the West Napa fault with predominantly right‐lateral strike slip. In the kinematic seismic slip inversions, we couple the coseismic slip and afterslip distributions by requiring both distributions to involve right‐lateral strike slip with positive amplitude, with the net static slip being the sum of the two. We consider several candidate fault geometries: a first involving two steeply east dipping fault planes that reach Earth's surface at the western surface trace (STW), where most surface rupture was observed, a second involving a steeply west dipping plane that also reaches Earth's surface at the STW, and a third involving a combination of two variably west dipping planes constrained to pass through the locus of postseismic seismicity located ∼1 km west of the STW. The data are best fit using the model of two east dipping fault planes, with coseismic slip up to ∼1.2 m on a dominant shallow asperity about 10 km north of the hypocenter and on deeper asperities on the southern part of the rupture. Afterslip up to 1 m is concentrated along the southern part of the rupture at depths
5 km, consistent with surface observations of afterslip. Seismic moments associated with coseismic slip and afterslip are 1.13×1018 N m (Mw 6.00) and 3.64×1017 N m, respectively.
What Caused Recent Shifts in Tropical Pacific Decadal Sea‐Level Trends?
Authors: Piecuch Christopher G. , Thompson Philip R. , Ponte Rui M. , Merrifield Mark A. , Hamlington Benjamin D.
Published: October 2019

Satellite altimetry reveals substantial decadal variability in sea level ζ across the tropical Pacific during 1993–2015. An ocean state estimate that faithfully reproduces the observations is used to elucidate the origin of these low‐frequency tropical Pacific ζ variations. Analysis of the hydrostatic equation reveals that recent decadal ζ changes in the tropical Pacific are mainly thermosteric in nature, related to changes in upper‐ocean heat content. A forcing experiment performed with the numerical model suggests that anomalous wind stress was an important driver of the relevant heat storage and thermosteric variation. Closed budget diagnostics further clarify that the wind‐stress‐related thermosteric ζ variation resulted from the joint actions of large‐scale ocean advection and local surface heat flux, such that advection controlled the budget over shorter, intraseasonal to interannual time scales, and local surface heat flux became increasingly influential at longer decadal periods. In particular, local surface heat flux was important in contributing to a recent reversal of decadal ζ trends in the tropical Pacific. Contributions from local surface heat flux partly reflect damping latent heat flux tied to wind‐stress‐driven sea‐surface‐temperature variations.
Comparing Ocean Surface Boundary Vertical Mixing Schemes Including Langmuir Turbulence
Authors: Li Qing , Reichl Brandon G. , Fox‐Kemper Baylor , Adcroft Alistair J. , Belcher Stephen E. , Danabasoglu Gokhan , Grant Alan L. M. , Griffies Stephen M. , Hallberg Robert , Hara Tetsu , Harcourt Ramsey R. , Kukulka Tobias , Large William G. , McWilliams James C. , Pearson Brodie , Sullivan Peter P. , Van Roekel Luke , Wang Peng , Zheng Zhihua
Published: October 2019

Six recent Langmuir turbulence parameterization schemes and five traditional schemes are implemented in a common single‐column modeling framework and consistently compared. These schemes are tested in scenarios versus matched large eddy simulations, across the globe with realistic forcing (JRA55‐do, WAVEWATCH‐III simulated waves) and initial conditions (Argo), and under realistic conditions as observed at ocean moorings. Traditional non‐Langmuir schemes systematically underpredict large eddy simulation vertical mixing under weak convective forcing, while Langmuir schemes vary in accuracy. Under global, realistic forcing Langmuir schemes produce 6% (−1% to 14% for 90% confidence) or 5.2 m (−0.2 m to 17.4 m for 90% confidence) deeper monthly mean mixed layer depths than their non‐Langmuir counterparts, with the greatest differences in extratropical regions, especially the Southern Ocean in austral summer. Discrepancies among Langmuir schemes are large (15% in mixed layer depth standard deviation over the mean): largest under wave‐driven turbulence with stabilizing buoyancy forcing, next largest under strongly wave‐driven conditions with weak buoyancy forcing, and agreeing during strong convective forcing. Non‐Langmuir schemes disagree with each other to a lesser extent, with a similar ordering. Langmuir discrepancies obscure a cross‐scheme estimate of the Langmuir effect magnitude under realistic forcing, highlighting limited understanding and numerical deficiencies. Maps of the regions and seasons where the greatest discrepancies occur are provided to guide further studies and observations.
Mesospheric Wind Estimation With the Jicamarca MST Radar Using Spectral Mainlobe Identification
Authors: Lee Kiwook , Kudeki Erhan , Reyes Pablo M. , Lehmacher Gerald A. , Milla Marco
Published: October 2019

MST (mesosphere, stratosphere, troposphere) radar observations at Jicamarca use four antenna beams, one vertical, others tilted to the east, west, and south, to detect the scattered pulse returns from mesospheric heights (∼55–85 km). Doppler shifts of scattered returns, estimated by fitting the observed signal spectra by generalized Gaussian‐shaped models, are used to estimate mesospheric wind vectors. At some heights two spectral peaks are seen in which case a dual‐peaked model is fitted the spectrum. Dual peaks are more common for returns from the east and west tilted beams with stronger sidelobes. When sidelobe‐caused peaks are dominant and are mistaken for mainlobe peaks, wind errors occur since the estimation algorithm uses the pointing angle of the mainbeam. To avoid such errors we implemented a clustering‐based machine learning procedure to identify and use only the mainbeam components of dual‐peaked spectra. Wind estimates made before and after the procedure will be presented to assess the improvements achieved by this new method to be used routinely in Jicamarca mesospheric wind measurements and applied to past MST data.
The subgingival microbiome associated with periodontitis in type 2 diabetes mellitus
Authors: Shi Baochen , Lux Renate , Klokkevold Perry , Chang Michaela , Barnard Emma , Haake Susan , Li Huiying
Published: October 2019

Type 2 diabetes mellitus (T2DM) is a systemic disease, predisposing patients to other inflammatory conditions including periodontitis. The subgingival microbiome, a key player in periodontitis pathogenesis, is not well characterized in T2DM population. To better understand whether the subgingival microbiome is different between T2DM and systemically healthy, nondiabetic (ND) subjects, we performed a longitudinal analysis of the subgingival microbiome in T2DM patients (n = 15) compared with ND subjects (n = 16). Using metagenomic shotgun sequencing, we investigated the microbiome in the healthy periodontal state, periodontitis state, and resolved state after treatment. We found that in the periodontitis state, the shift in the subgingival microbiome from the healthy state was less prominent in T2DM compared with ND subjects, yet the clinical signs of disease were similar for both. Furthermore, we revealed highly correlated presence of pathogenic species in relative abundance not only in the periodontitis state, but also in the healthy state in T2DM, suggesting an elevated risk of progression to periodontitis in this cohort. We further investigated the functional potentials of the subgingival microbiome and identified a set of microbial marker genes associated with the clinical states. These genes were significantly enriched in 21 pathways, some of which are associated with periodontitis and some potentially link T2DM and periodontitis. This study identified the longitudinal changes of the subgingival microbiome associated with periodontitis in T2DM and suggests that T2DM patients are more susceptible to shifts in the subgingival microbiome toward dysbiosis, potentially due to impaired host metabolic and immune regulation.
Treatment patterns and survival in HER2-positive early breast cancer: a whole-of-population Australian cohort study (2007–2016)
Authors: Tang Monica , Schaffer Andrea , Kiely Belinda E. , Daniels Benjamin , Simes Robert J. , Lee Chee K. , Pearson Sallie-Anne
Published: November 2019

Background

Randomised clinical trials (RCTs) demonstrate that trastuzumab improves survival in patients with human epidermal growth factor 2-positive early breast cancer (HER2 + EBC), but real-world patients and clinical practice often differ from RCTs. We examine real-world treatment patterns and outcomes associated with trastuzumab for HER2 + EBC.

Methods

We identified all Australians dispensed trastuzumab for HER2 + EBC between 1/1/2007 and 30/6/2016. We estimated the proportion of patients completing 12 months of treatment (defined as ≥350 days of exposure within 540 days of initiation). We estimated overall survival (OS) and recurrence-free survival (RFS) by using trastuzumab dispensing for metastatic breast cancer as a surrogate for recurrence.

Results

Our study included 14,644 patients. Among patients with ≥540 days of follow-up (n = 11,903), 67.4% completed 12 months of trastuzumab. OS rates at 5 and 9 years were 92.7 and 87.9%, and RFS rates at 5 and 9 years were 86.8 and 81.4%, respectively. Patients who completed 12 months of trastuzumab had a 9-year OS rate of 90.2% compared with 86.2% among patients receiving <12 months of therapy (adjusted HR 0.71, 95% CI 0.62–0.81).

Conclusions

Real-world HER2 + EBC patients are less likely to complete 12 months of trastuzumab than some clinical trial counterparts but have survival outcomes comparable to those reported in landmark RCTs.
Phase separation of Polo-like kinase 4 by autoactivation and clustering drives centriole biogenesis
Authors: Park Jung-Eun , Zhang Liang , Bang Jeong Kyu , Andresson Thorkell , DiMaio Frank , Lee Kyung S.
Published: October 2019

Tight control of centriole duplication is critical for normal chromosome segregation and the maintenance of genomic stability. Polo-like kinase 4 (Plk4) is a key regulator of centriole biogenesis. How Plk4 dynamically promotes its symmetry-breaking relocalization and achieves its procentriole-assembly state remains unknown. Here we show that Plk4 is a unique kinase that utilizes its autophosphorylated noncatalytic cryptic polo-box (CPB) to phase separate and generate a nanoscale spherical condensate. Analyses of the crystal structure of a phospho-mimicking, condensation-proficient CPB mutant reveal that a disordered loop at the CPB PB2-tip region is critically required for Plk4 to generate condensates and induce procentriole assembly. CPB phosphorylation also promotes Plk4’s dissociation from the Cep152 tether while binding to downstream STIL, thus allowing Plk4 condensate to serve as an assembling body for centriole biogenesis. This study uncovers the mechanism underlying Plk4 activation and may offer strategies for anti-Plk4 intervention against genomic instability and cancer.
Clathrin light chain A drives selective myosin VI recruitment to clathrin-coated pits under membrane tension
Authors: Biancospino Matteo , Buel Gwen R. , Niño Carlos A. , Maspero Elena , Scotto di Perrotolo Rossella , Raimondi Andrea , Redlingshöfer Lisa , Weber Janine , Brodsky Frances M. , Walters Kylie J. , Polo Simona
Published: October 2019

Clathrin light chains (CLCa and CLCb) are major constituents of clathrin-coated vesicles. Unique functions for these evolutionary conserved paralogs remain elusive, and their role in clathrin-mediated endocytosis in mammalian cells is debated. Here, we find and structurally characterize a direct and selective interaction between CLCa and the long isoform of the actin motor protein myosin VI, which is expressed exclusively in highly polarized tissues. Using genetically-reconstituted Caco-2 cysts as proxy for polarized epithelia, we provide evidence for coordinated action of myosin VI and CLCa at the apical surface where these proteins are essential for fission of clathrin-coated pits. We further find that myosin VI and Huntingtin-interacting protein 1-related protein (Hip1R) are mutually exclusive interactors with CLCa, and suggest a model for the sequential function of myosin VI and Hip1R in actin-mediated clathrin-coated vesicle budding.
De novo synthesized Min proteins drive oscillatory liposome deformation and regulate FtsA-FtsZ cytoskeletal patterns
Authors: Godino Elisa , López Jonás Noguera , Foschepoth David , Cleij Céline , Doerr Anne , Castellà Clara Ferrer , Danelon Christophe
Published: October 2019

The Min biochemical network regulates bacterial cell division and is a prototypical example of self-organizing molecular systems. Cell-free assays relying on purified proteins have shown that MinE and MinD self-organize into surface waves and oscillatory patterns. In the context of developing a synthetic cell from elementary biological modules, harnessing Min oscillations might allow us to implement higher-order cellular functions. To convey hereditary information, the Min system must be encoded in a DNA molecule that can be copied, transcribed, and translated. Here, the MinD and MinE proteins are synthesized de novo from their genes inside liposomes. Dynamic protein patterns and accompanying liposome shape deformation are observed. When integrated with the cytoskeletal proteins FtsA and FtsZ, the synthetic Min system is able to dynamically regulate FtsZ patterns. By enabling genetic control over Min protein self-organization and membrane remodeling, our methodology offers unique opportunities towards directed evolution of bacterial division processes in vitro.
Active generation of nanoholes in DNA origami scaffolds for programmed catalysis in nanocavities
Authors: Wang Jianbang , Yue Liang , Li Ziyuan , Zhang Junji , Tian He , Willner Itamar
Published: October 2019

DNA origami tiles provide nanostructures for the spatial and temporal control of functional loads on the scaffolds. Here we introduce the active generation of nanoholes in the origami scaffolds using DNAzymes or light as triggers and present the programmed and switchable catalysis in the resulting nanocavities. We engineer “window” domains locked into the origami scaffolds by substrates of the Zn2+-ion- or Pb2+-ion-dependent DNAzymes. Using Zn2+ ions and/or Pb2+ ions, the programmed unlocking of the “window” domains is demonstrated. The tailored functionalization of the origami scaffolds allows the programmed operation of catalytic processes in the confined nanocavities. Also, the “window” domain is integrated into the origami scaffold using photoisomerizable azobenzene-modified locks. The cyclic photoisomerization of the locks between the cis and trans states leads to a reversible opening and closure of the nanoholes and to the cyclic light-induced switching of catalytic processes in the nanocavities.
Transcriptomics and proteomics reveal two waves of translational repression during the maturation of malaria parasite sporozoites
Authors: Lindner Scott E. , Swearingen Kristian E. , Shears Melanie J. , Walker Michael P. , Vrana Erin N. , Hart Kevin J. , Minns Allen M. , Sinnis Photini , Moritz Robert L. , Kappe Stefan H. I.
Published: October 2019

Plasmodium sporozoites are transmitted from infected mosquitoes to mammals, and must navigate the host skin and vasculature to infect the liver. This journey requires distinct proteomes. Here, we report the dynamic transcriptomes and proteomes of both oocyst sporozoites and salivary gland sporozoites in both rodent-infectious Plasmodium yoelii parasites and human-infectious Plasmodium falciparum parasites. The data robustly define mRNAs and proteins that are upregulated in oocyst sporozoites (UOS) or upregulated in infectious sporozoites (UIS) within the salivary glands, including many that are essential for sporozoite functions in the vector and host. Moreover, we find that malaria parasites use two overlapping, extensive, and independent programs of translational repression across sporozoite maturation to temporally regulate protein expression. Together with gene-specific validation experiments, these data indicate that two waves of translational repression are implemented and relieved at different times during sporozoite maturation, migration and infection, thus promoting their successful development and vector-to-host transition.
The Signaling Pathways Project, an integrated ‘omics knowledgebase for mammalian cellular signaling pathways
Authors: Ochsner Scott A. , Abraham David , Martin Kirt , Ding Wei , McOwiti Apollo , Kankanamge Wasula , Wang Zichen , Andreano Kaitlyn , Hamilton Ross A. , Chen Yue , Hamilton Angelica , Gantner Marin L. , Dehart Michael , Qu Shijing , Hilsenbeck Susan G. , Becnel Lauren B. , Bridges Dave , Ma’ayan Avi , Huss Janice M. , Stossi Fabio , Foulds Charles E. , Kralli Anastasia , McDonnell Donald P. , McKenna Neil J.
Published: October 2019

Mining of integrated public transcriptomic and ChIP-Seq (cistromic) datasets can illuminate functions of mammalian cellular signaling pathways not yet explored in the research literature. Here, we designed a web knowledgebase, the Signaling Pathways Project (SPP), which incorporates community classifications of signaling pathway nodes (receptors, enzymes, transcription factors and co-nodes) and their cognate bioactive small molecules. We then mapped over 10,000 public transcriptomic or cistromic experiments to their pathway node or biosample of study. To enable prediction of pathway node-gene target transcriptional regulatory relationships through SPP, we generated consensus ‘omics signatures, or consensomes, which ranked genes based on measures of their significant differential expression or promoter occupancy across transcriptomic or cistromic experiments mapped to a specific node family. Consensomes were validated using alignment with canonical literature knowledge, gene target-level integration of transcriptomic and cistromic data points, and in bench experiments confirming previously uncharacterized node-gene target regulatory relationships. To expose the SPP knowledgebase to researchers, a web browser interface was designed that accommodates numerous routine data mining strategies. SPP is freely accessible athttps://www.signalingpathways.org.
The AgeGuess database, an open online resource on chronological and perceived ages of people aged 5–100
Authors: Jones Julia A. Barthold , Nash Ulrik W. , Vieillefont Julien , Christensen Kaare , Misevic Dusan , Steiner Ulrich K.
Published: October 2019

In many developed countries, human life expectancy has doubled over the last 180 years. Underlying this higher life expectancy is a change in how we age. Biomarkers of ageing are used to quantify changes in the aging process and to determine biological age. Perceived age is such a biomarker that correlates with biological age. Here we present a unique database rich with possibilities to study the human ageing process. Using perceived age enables us to collect large amounts of data on biological age through a citizen science project, where people upload facial pictures and guess the ages of other people at www.ageguess.org. The data on perceived age we present here span birth cohorts from the years 1877 to 2012. The database currently contains around 220,000 perceived age guesses. Almost 4500 citizen scientists from over 120 countries of origin have uploaded ~4700 facial photographs. Beyond studying the ageing process, the data present a wealth of possibilities to study how humans guess ages and who is better at guessing ages.
Molecular harvesting with electroporation for tissue profiling
Authors: Golberg Alexander , Sheviryov Julia , Solomon Oz , Anavy Leon , Yakhini Zohar
Published: October 2019

Recent developments in personalized medicine are based on molecular measurement steps that guide personally adjusted medical decisions. A central approach to molecular profiling consists of measuring DNA, RNA, and/or proteins in tissue samples, most notably in and around tumors. This measurement yields molecular biomarkers that are potentially predictive of response and of tumor type. Current methods in cancer therapy mostly use tissue biopsy as the starting point of molecular profiling. Tissue biopsies involve a physical resection of a small tissue sample, leading to localized tissue injury, bleeding, inflammation and stress, as well as to an increased risk of metastasis. Here we developed a technology for harvesting biomolecules from tissues using electroporation. We show that tissue electroporation, achieved using a combination of high-voltage short pulses, 50 pulses 500 V cm−1, 30 µs, 1 Hz, with low-voltage long pulses 50 pulses 50 V cm−1, 10 ms, delivered at 1 Hz, allows for tissue-specific extraction of RNA and proteins. We specifically tested RNA and protein extraction from excised kidney and liver samples and from excised HepG2 tumors in mice. Further in vivo development of extraction methods based on electroporation can drive novel approaches to the molecular profiling of tumors and of tumor environment and to related diagnosis practices.
Habitat degradation and predators have independent trait-mediated effects on prey
Authors: McCormick Mark I. , Fakan Eric P. , Palacios Maria M.
Published: October 2019

Coral reefs are degrading globally leading to a catastrophic loss of biodiversity. While shifts in the species composition of communities have been well documented associated with habitat change, the mechanisms that underlie change are often poorly understood. Our study experimentally examines the effects of coral degradation on the trait-mediated effects of predators on the morphology, behaviour and performance of a juvenile coral reef fish. Juvenile damselfish were exposed to predators or controls (omnivore or nothing) in seawater that had flowed over either live or dead-degraded coral over a 45d period. No interaction between water source and predator exposure was found. However, fish exposed to degraded water had larger false eyespots relative to the size of their true eyes, and were more active, both of which may lead to a survival advantage. Non-consumptive effects of predators on prey occurred regardless of water source and included longer and deeper bodies, large false eyespots that may distract predator strikes away from the vulnerable head region, and shorter latencies in their response to a simulated predator strike. Research underscores that phenotypic plasticity may assist fishes in coping with habitat degradation and promote greater resilience to habitat change than may otherwise be predicted.
Holistic Monte-Carlo optical modelling of biological imaging
Authors: Carles Guillem , Zammit Paul , Harvey Andrew R.
Published: November 2019

The invention and advancement of biological microscopy depends critically on an ability to accurately simulate imaging of complex biological structures embedded within complex scattering media. Unfortunately no technique exists for rigorous simulation of the complete imaging process, including the source, instrument, sample and detector. Monte-Carlo modelling is the gold standard for the modelling of light propagation in tissue, but is somewhat laborious to implement and does not incorporate the rejection of scattered light by the microscope. On the other hand microscopes may be rigorously and rapidly modelled using commercial ray-tracing software, but excluding the interaction with the biological sample. We report a hybrid Monte-Carlo optical ray-tracing technique for modelling of complete imaging systems of arbitrary complexity. We make the software available to enable user-friendly and rigorous virtual prototyping of biological microscopy of arbitrary complexity involving light scattering, fluorescence, polarised light propagation, diffraction and coherence. Examples are presented for the modelling and optimisation of representative imaging of neural cells using light-sheet and micro-endoscopic fluorescence microscopy and imaging of retinal vasculature using confocal and non-confocal scanning-laser ophthalmoscopes.
Genetic variation affects binge feeding behavior in female inbred mouse strains
Authors: Newmyer Brandon A. , Whindleton Ciarra M. , Srinivasa Nandan , Jones Marieke K. , Scott Michael M.
Published: October 2019

Identifying genetic variants that regulate binge eating (BE) is critical for understanding the factors that control this behavior and for the development of pharmacological treatment strategies. Although several studies have revealed specific genes capable of affecting BE behavior, less is known about how genetic variation modulates BE. Thus, through a paradigm that promoted binge-like food intake through intermittent access to high calorie diet (HCD), we quantified food-intake in four inbred mouse strains: C57Bl/6J (B6), NOD/LtJ (NOD), 129S1/SvlmJ (S1), and A/J (AJ). We report that genetic variation likely influences the chronic regulation of food intake and the binge-like consumption of a palatable HCD. AJ mice consumed more of both standard chow and HCD than the other three strains tested when both diets were available ad libitum, while S1 mice consumed significantly less HCD than other strains during intermittent HCD access. Behavioral differences were also associated with differential changes in c-Fos immunohistochemistry in brain regions traditionally associated with appetite regulation. Our results identify 129S1/SvlmJ as a strain that exhibits low levels of binge feeding behavior and suggests that this strain could be useful in the investigation of the influence of genetic variation in the control of binge food intake.
Association between newborn screening analytes and hypoxic ischemic encephalopathy
Authors: Wilson Lindsay A. , Fell Deshayne B. , Hawken Steven , Wong Coralie A. , Murphy Malia S. Q. , Little Julian , Potter Beth K. , Walker Mark , Lacaze-Masmonteil Thierry , Juul Sandra , Chakraborty Pranesh , Wilson Kumanan
Published: October 2019

Hypoxic ischemic encephalopathy (HIE) is a major cause of neonatal mortality and morbidity. Our study sought to examine whether patterns of newborn screening analytes differed between infants with and without neonatal HIE in order to identify opportunities for potential use of these analytes for diagnosis in routine clinical practice. We linked a population-based newborn screening registry with health databases to identify cases of HIE among term infants (≥37 weeks’ gestation) in Ontario from 2010–2015. Correlations between HIE and screening analytes were examined using multivariable logistic regression models containing clinical factors and individual screening analytes (acyl-carnitines, amino acids, fetal-to-adult hemoglobin ratio, endocrine markers, and enzymes). Among 731,841 term infants, 3,010 were diagnosed with HIE during the neonatal period. Multivariable models indicated that clinical variables alone or in combination with hemoglobin values were not associated with HIE diagnosis. Although the model was improved after adding acyl-carnitines and amino acids, the ability of the model to identify infants with HIE was moderate. Our findings indicate that analytes associated with catabolic stress were altered in infants with HIE; however, future research is required to determine whether amino acid and acyl-carnitine profiles could hold clinical utility in the early diagnosis or clinical management of HIE. In particular, further research should examine whether cord blood analyses can be used to identify HIE within a clinically useful timeframe or to guide treatment and predict long-term health outcomes.
IL-7/IL-7R gene variants impact circulating IL-7/IL-7R homeostasis and ART-associated immune recovery status
Authors: Ceausu Andra , Rodríguez-Gallego Esther , Peraire Joaquim , López-Dupla Miguel , Domingo Pere , Viladés Consuelo , Vidal-Gonzalez Judit , Peraire Maria , Perpiñán Carles , Pacheco Yolanda María , Veloso Sergi , Alba Verónica , Vargas Montserrat , Castellano Alfonso J. , Ruiz-Mateos Ezequiel , Mallolas Josep , Vidal Francesc , Rull Anna
Published: October 2019

A relationship between polymorphisms in genes encoding interleukin 7 (IL-7) and its cellular receptor (IL-7R) and antiretroviral therapy (ART)-associated immune recovery in HIV subjects has been previously reported. However, details of this relationship remain unclear, and the association of these polymorphisms with circulating IL-7/IL-7R levels is scarce. Here, we explored whether IL-7/IL-7R axis was associated with quantitative CD4+ T-cell recovery in HIV-infected subjects. IL-7/IL-7R polymorphisms were assessed by genotyping, and multiple inheritance models were used to estimate both, their association with low pre-ART CD4+ T-cell counts and incomplete immune recovery status after 48 weeks of suppressive ART. Integrated data from genetic variants association and soluble plasma IL-7/IL-7R quantification suggest that IL-7/IL-7R genotype expression could alter the homeostatic balance between soluble and membrane-bound receptors. The haplotype analyses indicates that allele combinations impacts pre-ART circulating CD4+ T-cell counts, immune recovery status and the absolute increment of CD4+ T-cell counts. The knowledge about how IL-7/IL-7R axis is related to quantitative CD4+ T-cell recovery and immune recovery status after initiating ART could be useful regarding T-cell reservoirs investigations in HIV subjects.
Genome-scale CRISPR screens are efficient in non-homologous end-joining deficient cells
Authors: Ferreira da Silva Joana , Salic Sejla , Wiedner Marc , Datlinger Paul , Essletzbichler Patrick , Hanzl Alexander , Superti-Furga Giulio , Bock Christoph , Winter Georg , Loizou Joanna I.
Published: October 2019

The mutagenic repair of Cas9 generated breaks is thought to predominantly rely on non-homologous end-joining (NHEJ), leading to insertions and deletions within DNA that culminate in gene knock-out (KO). In this study, by taking focused as well as genome-wide approaches, we show that this pathway is dispensable for the repair of such lesions. Genetic ablation of NHEJ is fully compensated for by alternative end joining (alt-EJ), in a POLQ-dependent manner, resulting in a distinct repair signature with larger deletions that may be exploited for large-scale genome editing. Moreover, we show that cells deficient for both NHEJ and alt-EJ were still able to repair CRISPR-mediated DNA double-strand breaks, highlighting how little is yet known about the mechanisms of CRISPR-based genome editing.
Air entrapment resembling necrotising fasciitis as a frequent incident following total hip arthroplasty
Authors: Smolle Maria A. , Hörlesberger Nina , Musser Ewald , Maier Michael , Reinbacher Patrick , Friesenbichler Jörg , Leithner Andreas , Maurer-Ertl Werner
Published: October 2019

In combination with pain and elevated inflammatory parameters that are frequently observed following elective total hip arthroplasty (THA), air entrapment on radiographic images could be indicative of necrotising fasciitis. The aim of the present study was to analyse presence/extent of air entrapment following THA, and to correlate radiological with clinical findings. One-hundred patients undergoing short-stem elective THA (ANA NOVA Alpha Proxy-system) were prospectively included. Patients received pre- and postoperative x-rays (day 1 + discharge) of the affected hip, together with a CT-scan of the lower extremity (discharge). C-reactive-protein-(CRP), leukocyte, haemoglobin-, creatinine-, glucose-, sodium-levels – and based on these the LRINEC score– as well as pain-scores (numeral-rating-scale, NRS) at postoperative days 1, 3 and 5 were documented. Air entrapment was visible in 98% of x-rays taken postoperatively and in 93% of CT-scans at discharge. Leukocyte-levels significantly decreased from postoperative day 1 to 5. CRP-levels had a peak at the 3rd postoperative day (p < 0.001). On discharge-x-rays of patients with low body-mass-indexes, air entrapment was significantly more often visible (p = 0.040). Neither implant-related nor laboratory parameters, LRINEC- or NRS-scores significantly correlated with presence/extent of air entrapment (p > 0.05). Considering the high rate of air entrapment following elective THA postoperatively and at discharge, suspicion of an infection with gas-producing bacteria may only be raised in case of persistent inflammatory parameters, deteriorating general condition and signs of local infection.
Biofilm-stimulated epithelium modulates the inflammatory responses in co-cultured immune cells
Authors: Brown Jason L. , Johnston William , Delaney Chris , Rajendran Ranjith , Butcher John , Khan Shaz , Bradshaw David , Ramage Gordon , Culshaw Shauna
Published: October 2019

The gingival epithelium is a physical and immunological barrier to the microbiota of the oral cavity, which interact through soluble mediators with the immune cells that patrol the tissue at the gingival epithelium. We sought to develop a three-dimensional gingivae-biofilm interface model using a commercially available gingival epithelium to study the tissue inflammatory response to oral biofilms associated with “health”, “gingivitis” and “periodontitis”. These biofilms were developed by sequential addition of microorganisms to mimic the formation of supra- and sub-gingival plaque in vivo. Secondly, to mimic the interactions between gingival epithelium and immune cells in vivo, we integrated peripheral blood mononuclear cells and CD14+ monocytes into our three-dimensional model and were able to assess the inflammatory response in the immune cells cultured with and without gingival epithelium. We describe a differential inflammatory response in immune cells cultured with epithelial tissue, and more so following incubation with epithelium stimulated by “gingivitis-associated” biofilm. These results suggest that gingival epithelium-derived soluble mediators may control the inflammatory status of immune cells in vitro, and therefore targeting of the epithelial response may offer novel therapies. This multi-cellular interface model, both of microbial and host origin, offers a robust in vitro platform to investigate host-pathogens at the epithelial surface.
Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs
Authors: Nakai Sho , Yamada Shutaro , Outani Hidetatsu , Nakai Takaaki , Yasuda Naohiro , Mae Hirokazu , Imura Yoshinori , Wakamatsu Toru , Tamiya Hironari , Tanaka Takaaki , Hamada Kenichiro , Tani Akiyoshi , Myoui Akira , Araki Nobuhito , Ueda Takafumi , Yoshikawa Hideki , Takenaka Satoshi , Naka Norifumi
Published: November 2019

Approximately 60–70% of EWSR1-negative small blue round cell sarcomas harbour a rearrangement of CIC, most commonly CIC-DUX4. CIC-DUX4 sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX4 fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX4 pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo. Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.
Covalently modified carboxyl side chains on cell surface leads to a novel method toward topology analysis of transmembrane proteins
Authors: Müller Anna , Langó Tamás , Turiák Lilla , Ács András , Várady György , Kucsma Nóra , Drahos László , Tusnády Gábor E.
Published: October 2019

The research on transmembrane proteins (TMPs) is quite widespread due to their biological importance. Unfortunately, only a little amount of structural data is available of TMPs. Since technical difficulties arise during their high-resolution structure determination, bioinformatics and other experimental approaches are widely used to characterize their low-resolution structure, namely topology. Experimental and computational methods alone are still limited to determine TMP topology, but their combination becomes significant for the production of reliable structural data. By applying amino acid specific membrane-impermeable labelling agents, it is possible to identify the accessible surface of TMPs. Depending on the residue-specific modifications, new extracellular topology data is gathered, allowing the identification of more extracellular segments for TMPs. A new method has been developed for the experimental analysis of TMPs: covalent modification of the carboxyl groups on the accessible cell surface, followed by the isolation and digestion of these proteins. The labelled peptide fragments and their exact modification sites are identified by nanoLC-MS/MS. The determined peptides are mapped to the primary sequences of TMPs and the labelled sites are utilised as extracellular constraints in topology predictions that contribute to the refined low-resolution structure data of these proteins.