bluuebunny/crossref_metadata_2025 huggingface dataset:
Span effect on the turbulence nature of flow past a circular cylinder
Authors: Font Garcia Bernat , Weymouth Gabriel D. , Nguyen Vinh-Tan , Tutty Owen R.
Published: September 2019

Turbulent flow evolution and energy cascades are significantly different in two-dimensional (2-D) and three-dimensional (3-D) flows. Studies have investigated these differences in obstacle-free turbulent flows, but solid boundaries have an important impact on the cross-over from 3-D to 2-D turbulence dynamics. In this work, we investigate the span effect on the turbulence nature of flow past a circular cylinder at $Re=10\,000$. It is found that even for highly anisotropic geometries, 3-D small-scale structures detach from the walls. Additionally, the natural large-scale rotation of the Kármán vortices rapidly two-dimensionalise those structures if the span is 50 % of the diameter or less. We show this is linked to the span being shorter than the Mode B instability wavelength. The conflicting 3-D small-scale structures and 2-D Kármán vortices result in 2-D and 3-D turbulence dynamics which can coexist at certain locations of the wake depending on the domain geometric anisotropy.
System approaches to school psychology (or why school psychologists shouldn’t see kids)
Authors: Russell Paul
Published: September 2019

In a world where the only constant is change, schools are faced with the need to adapt creatively to changing societal demands, parental expectations, and children with increasingly diverse needs. Lasting and effective change can only occur with systemic and organisational change, and this essay argues that school-based psychologists are an invaluable, but potentially overlooked, resource in driving and supporting effective, evidence-supported, organisational change in schools. It is suggested that this can occur best when school-based psychologists are able to move away from direct service models that treat individual children to a systemic model that supports whole-school change.
Instruments and methods: hot-water borehole drilling at a high-elevation debris-covered glacier
Authors: Miles Katie E. , Miles Evan S. , Hubbard Bryn , Quincey Duncan J. , Rowan Ann V. , Pallett Mark
Published: September 2019

While hot-water drilling is a well-established technique used to access the subsurface of ice masses, drilling into high-elevation (≳ 4000 m a.s.l.) debris-covered glaciers faces specific challenges. First, restricted transport capacity limits individual equipment items to a volume and mass that can be slung by small helicopters. Second, low atmospheric oxygen and pressure reduces the effectiveness of combustion, limiting a system's ability to pump and heat water. Third, thick supraglacial debris, which is both highly uneven and unstable, inhibits direct access to the ice surface, hinders the manoeuvring of equipment and limits secure sites for equipment placement. Fourth, englacial debris can slow the drilling rate such that continued drilling becomes impracticable and/or boreholes deviate substantially from vertical. Because of these challenges, field-based englacial and subglacial data required to calibrate numerical models of high-elevation debris-covered glaciers are scarce or absent. Here, we summarise our experiences of hot-water drilling over two field seasons (2017–2018) at the debris-covered Khumbu Glacier, Nepal, where we melted 27 boreholes up to 192 m length, at elevations between 4900 and 5200 m a.s.l. We describe the drilling equipment and operation, evaluate the effectiveness of our approach and suggest equipment and methodological adaptations for future use.
Portion size normality and additional within-meal food intake: two crossover laboratory experiments
Authors: Haynes Ashleigh , Hardman Charlotte A. , Halford Jason C. G. , Jebb Susan A. , Robinson Eric
Published: September 2019

Reducing food portion size could reduce energy intake. However, it is unclear at what point consumers respond to reductions by increasing intake of other foods. We predicted that a change in served portion size would only result in significant additional eating within the same meal if the resulting portion size was no longer visually perceived as ‘normal’. Participants in two crossover experiments (Study 1: n 45; Study 2: n 37; adults, 51 % female) were served different-sized lunchtime portions on three occasions that were perceived by a previous sample of participants as ‘large-normal’, ‘small-normal’ and ‘smaller than normal’, respectively. Participants were able to serve themselves additional helpings of the same food (Study 1) or dessert items (Study 2). In Study 1 there was a small but significant increase in additional intake when participants were served the ‘smaller than normal’ compared with the ‘small-normal’ portion (m difference = 161 kJ, P = 0·002, d = 0·35), but there was no significant difference between the ‘small-normal’ and ‘large-normal’ conditions (m difference = 88 kJ, P = 0·08, d = 0·24). A similar pattern was observed in Study 2 (m difference = 149 kJ, P = 0·06, d = 0·18; m difference = 83 kJ, P = 0·26, d = 0·10). However, smaller portion sizes were each associated with a significant reduction in total meal intake. The findings provide preliminary evidence that reductions that result in portions appearing ‘normal’ in size may limit additional eating, but confirmatory research is needed.
Does Luke's Preface Resemble a Greek Decree? Comparing the Epigraphical and Papyrological Evidence of Greek Decrees with Ancient Preface Formulae
Authors: Dawson Zachary K.
Published: September 2019

This article challenges the argument of John Moles that Luke's preface (1.1–4) resembles a Greek decree more than any other type of writing. Although Moles is not the first to recognise the supposed decree-like features in Luke's preface, he goes further by arguing that the preface is intentionally structured like a decree for the author's rhetorical aim. In this article, I demonstrate that Moles’ argument goes too far and that Luke's preface simply displays features conventional to prefaces of historiographical writing – despite common structural patterns of preface writing and decree formulae – and is not layered with additional rhetorical meaning.
The Theological Gospel of Peter?
Authors: Edwards Robert G. T.
Published: September 2019

The Gospel of Peter (GP), often claimed to be theologically unsophisticated, offers a theological reflection upon the saving work of the Lord in his resurrection. GP receives the synoptic tradition, which itself has no narration of the resurrection (but only narrations of ‘appearances’), and fills in this lacuna. The narration of the resurrection is patterned upon GP's narration of the crucifixion, thereby suggesting that the resurrection and the crucifixion are two coordinated salvific events. GP's reception of the synoptic tradition is thus not only apologetic or polemical, but also theological.
The Syntax of the Correlative οὕτως … ὥστε in John 3.16 in the Light of Parallel Constructions in the Ancient Greek Corpus
Authors: Jensen Aaron Michael
Published: September 2019

While it has recently become a common assumption that the traditional understanding of the grammar of John 3.16 (‘For God so loved the world that …’) is misleading or simply inaccurate, this article demonstrates on the basis of parallel constructions from the ancient Greek corpus that οὕτως … ὥστε, when used with ἀγαπάω, functions as a correlative intensifier–result pair, exactly as it is presented in the traditional understanding.
A Human Rights Approach to Conflict Resolution
Authors: Fuentes-Julio Claudia , Ibrahim Raslan
Published: September 2019

Human rights and conflict resolution have been traditionally perceived as two separate fields, with contradictory principles and conflicting approaches toward achieving peace. This essay aims to understand these two fields in a more integrative way, showing how a human rights perspective can enrich the theory and practice of conflict resolution. It clarifies the main characteristics of a human rights approach to conflict resolution and identifies a set of human rights standards guiding its implementation: a normative legal framework; structural conditions for peace; participation and inclusion; and accountability and redress. The essay also briefly applies a human rights approach to the Colombian peace process and to the Oslo Accords between Israel and the Palestine Liberation Organization. The conclusion addresses one of the main criticisms of this approach and its principal challenges.
Fathering Through Change (FTC) intervention for single fathers: Preventing coercive parenting and child problem behaviors
Authors: DeGarmo David S. , Jones Jeremy A.
Published: September 2019

Dishion and Patterson's work on the unique role of fathers in the coercive family process showed that fathers' coercion explained twice the variance of mothers' in predicting children's antisocial behavior and how treatment and prevention of coercion and promotion of prosocial parenting can mitigate children's problem behaviors. Using these ideas, we employed a sample of 426 divorced or separated fathers randomly assigned to Fathering Through Change (FTC), an interactive online behavioral parent training program or to a waitlist control. Participating fathers had been separated or divorced within the past 24 months with children ages 4 to 12 years. We tested an intent to treat (ITT) mediation hypothesis positing that intervention-induced changes in child problem behaviors would be mediated by changes in fathers' coercive parenting. We also tested complier average causal effects (CACE) models to estimate intervention effects, accounting for compliers and noncompliers in the treatment group and would-be compliers in the controls. Mediation was supported. ITT analyses showed the FTC obtained a small direct effect on father-reported pre–post changes in child adjustment problems (d = .20), a medium effect on pre–post changes in fathers' coercive parenting (d = .61), and a moderate indirect effect to changes in child adjustment (d = .30). Larger effects were observed in CACE analyses.
Why do health technology assessment drug reimbursement recommendations differ between countries? A parallel convergent mixed methods study
Authors: Nicod Elena , Maynou Laia , Visintin Erica , Cairns John
Published: September 2019

Using quantitative and qualitative research designs, respectively, two studies investigated why countries make different health technology assessment (HTA) drug reimbursement recommendations. Building on these, the objective of this study was to (a) develop a conceptual framework integrating the factors explaining these decisions, (b) explore their relationship and (c) assess if they are congruent, complementary or discrepant. A parallel convergent mixed methods design was used. Countries included in both previous studies were selected (England, Sweden, Scotland and France). A conceptual framework that integrated and organised the factors explaining the decisions from the two studies was developed. Relationships between factors were explored and illustrated through case studies. The framework distinguishes macro-level factors from micro-level ones. Only two of the factors common to both studies were congruent, while two others reached discrepant conclusions (stakeholder input and external review of the evidence processes). The remaining factors identified within one or both studies were complementary. Bringing together these findings contributed to generating a more complete picture of why countries make different HTA recommendations. Results were mostly complementary, explaining and enhancing each other. We conclude that differences often result from a combination of factors, with an important component relating to what occurs during the deliberative process.
Development and Psychometric Evaluation of the Questionnaire of	Ethical Leadership (QueL)
Authors: Mitropoulou Eirini M. , Tsaousis Ioannis , Xanthopoulou Despoina , Petrides Konstantinos V.
Published: September 2019

Abstract. In this five-study paper, we developed and validated the Questionnaire of ethical Leadership (QueL). We examined the factor structure of QueL using Exploratory and Confirmatory Factor Analysis, along with measurement invariance techniques, using data from more than 1,200 leaders and subordinates working in Greece. Exploratory analysis indicated two latent highly-correlated factors that were labeled “Telos” and “Ethos.” Confirmatory analysis verified a bifactor solution. The bifactor QueL showed configural, metric, and scalar invariance across independent samples of leaders and subordinates. QueL was found to be a reliable measure across time and occupational groups (leaders and subordinates). We found criterion correlations in the expected direction with other ethical leadership scales, related constructs (i.e., integrity, trust, ethical climate), as well as workplace attitudes and behaviors (i.e., burnout, organizational commitment, organizational citizenship behaviors, deviant behaviors), leadership characteristics (transformational and transactional leadership, abusive supervision, personality), and socio-demographics (i.e., educational level and gender). We conclude that the new measure is a valuable tool for measuring workplace ethical leadership.
Psychometric Evaluation of an Episodic Future Thinking Variant of the	Autobiographical Memory Test – Episodic Future Thinking-Test	(EFT-T)
Authors: Hallford David J. , Takano Keisuke , Raes Filip , Austin David W.
Published: September 2019

Abstract. Future-oriented variants of the Autobiographical Memory Test (AMT) are often used to assess the generation of specific episodic future thoughts, however, as yet the underlying factor structure of items in this modified test has not been examined. Therefore, over two studies we examined the factor structure and validity of an episodic future thinking variant of the Autobiographical Memory Test (Episodic Future Thinking-Test; EFT-T). In Study 1, exploratory factor analysis ( N = 466) showed a one-factor structure underlying responses to positive, negative, and concrete noun cue words on the EFT-T. In Study 2, confirmatory factor analysis with a different sample ( N = 304) and using different cue words showed a good fit for a single-factor structure. In both studies, good convergent validity was found with scores on the EFT-T correlating with autobiographical memory specificity scores, with support for divergent factors also. Mixed support was found for associations with measures of mental imagery, and the implications for measurement are discussed. These studies provide the first evidence that the EFT-T unidimensionally assesses specificity in episodic future thinking across two cue word sets.
Systematic Scatterometer Wind Errors Near Coastal Mountains
Authors: Kilpatrick Thomas , Xie Shang‐Ping , Tokinaga Hiroki , Long David , Hutchings Nolan
Published: September 2019

Satellite scatterometers provide the only regular observations of surface wind vectors over vast swaths of the world oceans, including coastal regions, which are of great scientific and societal interest but still present challenges for remote sensing. Here we demonstrate systematic scatterometer wind errors near Hawaii's Big Island: Two counter‐rotating lee vortices, which are clear in the International Comprehensive Ocean‐Atmosphere Data Set ship‐based wind climatology and in aircraft observations, are absent in the Jet Propulsion Laboratory and Remote Sensing Systems scatterometer wind climatologies. We demonstrate similar errors in the representation of transient Catalina Eddy events in the Southern California Bight. These errors likely arise from the nonuniqueness of scatterometer wind observations, that is, an “ambiguity removal” is required during processing to select from multiple wind solutions to the geophysical model function. We discuss strategies to improve the ambiguity selection near coastal mountains, where small‐scale wind reversals are common.
Overcoming Ice and Stereotypes at the Bottom of the World
Authors: Peggau Karina
Published: September 2019

The Byrd Polar and Climate Research Center celebrates the 50th anniversary of the first all-women research team in Antarctica.
Correcting Parker Solar Probe Electron Measurements for Spacecraft Magnetic and Electric Fields
Authors: McGinnis Daniel , Halekas Jasper , Whittlesey Phyllis , Larson Davin , Kasper Justin
Published: September 2019

The spacecraft body of the Parker Solar Probe may interfere with electron measurements in two ways. The first is the presence of several permanent magnets near the Solar Probe Analyzers (SPAN) instruments. The second is the widely varying spacecraft potential. We estimate the effect of these interferences by performing particle tracing simulations on electrons of various energies using a simplified model of the spacecraft potential and measurements of the magnetic fields. From this we can (1) estimate the individual and combined fields of view of the SPAN‐E instruments, (2) identify regions of phase space that may be highly distorted, and (3) simulate measurements of the velocity distribution function. We compute density, temperature, and bulk velocity moments of the measured distribution functions and find that a correction table derived from the particle tracing results can be incorporated in the computation to greatly decrease the errors caused by the spacecraft potential and magnetic fields. Similar tables could be computed for a wide range of spacecraft potentials and applied during the processing of actual SPAN data.
Modernization of Atmospheric Physics Parameterization in Canadian NWP
Authors: McTaggart‐Cowan R. , Vaillancourt P. A. , Zadra A. , Chamberland S. , Charron M. , Corvec S. , Milbrandt J. A. , Paquin‐Ricard D. , Patoine A. , Roch M. , Separovic L. , Yang J.
Published: September 2019

Atmospheric physics is represented in numerical models by parameterizations that use resolved‐scale information to estimate the effects of physical processes on the atmospheric state. Over time, our understanding of these processes improves, new techniques are introduced to represent physics in a numerical model, and increased resolution changes the relative importance of different parameterizations within the system. As a result, the physical parameterization packages of numerical weather prediction (NWP) models undergo regular updates as older schemes are replaced with newer ones that offer an improved, and often more complex, depiction of relevant physical processes. Such changes are typically combined with a rebalancing of the physics suite because of strong interactions between parameterization schemes and the presence of compensating errors in the system. In this study, a major update to the package of physical parameterizations used in Canadian operational NWP is introduced. The primary goals of this effort were to improve the global energy budget and to facilitate an increase in the vertical resolution of operational configurations. Both of these objectives were achieved, along with a significant improvement in guidance quality for global and regional prediction systems.
Early Mesozoic Magmatism Within the Tibetan Plateau: Implications for the Paleo‐Tethyan Tectonic Evolution and Continental Amalgamation
Authors: Li Shan , Chung Sun‐Lin , Hou Zengqian , Chew David , Wang Tao , Wang Baodi , Wang Yanbin
Published: September 2019

Numerous early Mesozoic magmatic rocks within the Tibetan Plateau ultimately have a geodynamic controll caused by the Paleo‐Tethyan tectonic evolution and the assembly of Pangea. Based on their temporal variation and the timing of closure (235 ± 10 Ma) of the Paleo‐Tethys Ocean, they can be broadly divided into two groups by zircon U‐Pb geochronology: an Early to Middle Triassic (252–235 Ma) group and a Late Triassic to Early Jurassic (ca. 235–190 Ma) group. Early magmatic rocks are mainly found in the middle northern Tibetan Plateau, whereas late magmatic rocks are more widespread in the whole Tibetan Plateau. Nd and Hf isotope mapping suggests that the eastern segment of the Qiangtang is underlain by old (late Archean to early Paleoproterozoic) basement, while Southern Lhasa is underlain by juvenile lower crust, which yields Neoproterozoic to early Paleozoic model ages. Early Mesozoic tectonomagmatism was likely caused by episodic southward opening of multi‐Tethys oceans, punctuated by episodes of subduction and collision. The Middle to Late Permian tectonomagmatic history of Paleo‐Tethys was dominated by continental arc‐related systems. During the Early to Middle Triassic, the tectonomagmatic history was associated with the ongoing closure of the Paleo‐Tethys Ocean and a tectonic transition from subduction to collision. Late Triassic tectonomagmatism formed in a post‐collisional setting following the closure of the Paleo‐Tethys Ocean and the ultimate assembly of Pangea. Early Mesozoic magmatism within the Tibetan Plateau thus provides crucial information on the history of oceanic‐continental evolution and helps constrain the tectonic transition from subduction/accretion through to collision/postcollision for East Paleo‐Tethys.
Exhuming the Top End of North America: Episodic Evolution of the Eurekan Belt and Its Potential Relationships to North Atlantic Plate Tectonics and Arctic Climate Change
Authors: Vamvaka Agni , Pross Jörg , Monien Patrick , Piepjohn Karsten , Estrada Solveig , Lisker Frank , Spiegel Cornelia
Published: September 2019

We present the first low‐temperature thermochronology data from northernmost Ellesmere Island (Canadian Arctic), along with palynological data from Paleogene sediments. Our study area is part of the >2,500‐km‐long Eurekan deformation belt that formed across the High Arctic during the Eocene. The aim of this study is to investigate the exhumation of the Eurekan belt and potential relationships with the opening of the North Atlantic, as well as with environmental changes of the Arctic. Our data show that the Canadian Arctic margin was characterized by stretching and basin formation during the Paleocene. Sediment deposition occurred in a coastal swamp environment under a warm and humid climate that lasted into the early Eocene. Exhumation of northern Ellesmere Island was episodic and was presumably controlled by strike‐slip movements along the De Geer Fracture Zone between Svalbard and Greenland. Enhanced exhumation of northern Ellesmere Island occurred ~66–60 Ma, ~55–48 Ma, 44–38 Ma, and 34–26 Ma. These exhumation periods largely correlate with changes of spreading rates and movement directions of the Norwegian‐Greenland Sea. Main topographic growth along the Eurekan belt was temporally coincident with deposition of ice‐rafted debris off eastern Greenland. We suggest that Eurekan topography growth was an important trigger for glacier formation in Greenland. The cessation of rapid exhumation at ~26 Ma can be explained by continental separation between Greenland and Svalbard, which decoupled northern Ellesmere Island from strike‐slip movements along the De Geer Fracture Zone, eventually leading to the opening of the Fram Strait.
Local delivery of arsenic trioxide nanoparticles for hepatocellular carcinoma treatment
Authors: Hu Jian , Dong Yi , Ding Li , Dong Yang , Wu Zhihua , Wang Wenping , Shen Ming , Duan Yourong
Published: September 2019

Hepatocellular carcinoma (HCC) is a malignancy with a poor prognosis. Surgery combined with chemotherapy has been recommended as a curative regimen for HCC. Nevertheless, the anticancer mechanisms of chemicals in hepatocellular carcinoma remain unclear. Pyroptosis is a type of programmed necrosis, and its mechanism in hepatocellular carcinoma is poorly understood. The efficacy and mechanism of arsenic trioxide nanoparticles in the treatment of HCC were explored in this research. Arsenic trioxide alone and arsenic trioxide nanoparticles were conveniently administered to mice intratumorally using a needle. Compared with As2O3, As2O3nanoparticles (As2O3-NPs) showed better inhibition, promoted greater LDH release, and induced cell morphology indicative of pyroptosis in vitro. Compared with the free drug, As2O3-NPs increased GSDME-N expression and decreased Dnmt3a, Dnmt3b, and Dnmt1 expression in Huh7 cells. In vivo, As2O3-NPs induced a significant decrease in the expression of Dnmt3a, Dnmt3b and Dnmt1, but significantly upregulated the expression of GSDME-N (gasdermin E (GSDME) was originally found to be related to deafness; recently, it has been defined as a gasdermin family member associated with pyroptosis). As2O3-NPs inhibited tumor growth more strongly than As2O3or control, a finding likely attributed to the downregulation of PCNA and DNMT-related proteins and the upregulation of GSDME-N.
The Dutch Y-chromosomal landscape
Authors: Altena Eveline , Smeding Risha , van der Gaag Kristiaan J. , Larmuseau Maarten H. D. , Decorte Ronny , Lao Oscar , Kayser Manfred , Kraaijenbrink Thirsa , de Knijff Peter
Published: September 2019

Previous studies indicated existing, albeit limited, genetic-geographic population substructure in the Dutch population based on genome-wide data and a lack of this for mitochondrial SNP based data. Despite the aforementioned studies, Y-chromosomal SNP data from the Netherlands remain scarce and do not cover the territory of the Netherlands well enough to allow a reliable investigation of genetic-geographic population substructure. Here we provide the first substantial dataset of detailed spatial Y-chromosomal haplogroup information in 2085 males collected across the Netherlands and supplemented with previously published data from northern Belgium. We found Y-chromosomal evidence for genetic–geographic population substructure, and several Y-haplogroups demonstrating significant clinal frequency distributions in different directions. By means of prediction surface maps we could visualize (complex) distribution patterns of individual Y-haplogroups in detail. These results highlight the value of a micro-geographic approach and are of great use for forensic and epidemiological investigations and our understanding of the Dutch population history. Moreover, the previously noted absence of genetic-geographic population substructure in the Netherlands based on mitochondrial DNA in contrast to our Y-chromosome results, hints at different population histories for women and men in the Netherlands.
Cellular responses to beating hydrogels to investigate mechanotransduction
Authors: Chandorkar Yashoda , Castro Nava Arturo , Schweizerhof Sjören , Van Dongen Marcel , Haraszti Tamás , Köhler Jens , Zhang Hang , Windoffer Reinhard , Mourran Ahmed , Möller Martin , De Laporte Laura
Published: September 2019

Cells feel the forces exerted on them by the surrounding extracellular matrix (ECM) environment and respond to them. While many cell fate processes are dictated by these forces, which are highly synchronized in space and time, abnormal force transduction is implicated in the progression of many diseases (muscular dystrophy, cancer). However, material platforms that enable transient, cyclic forces in vitro to recreate an in vivo-like scenario remain a challenge. Here, we report a hydrogel system that rapidly beats (actuates) with spatio-temporal control using a near infra-red light trigger. Small, user-defined mechanical forces (~nN) are exerted on cells growing on the hydrogel surface at frequencies up to 10 Hz, revealing insights into the effect of actuation on cell migration and the kinetics of reversible nuclear translocation of the mechanosensor protein myocardin related transcription factor A, depending on the actuation amplitude, duration and frequency.
Next-generation unnatural monosaccharides reveal that ESRRB O-GlcNAcylation regulates pluripotency of mouse embryonic stem cells
Authors: Hao Yi , Fan Xinqi , Shi Yujie , Zhang Che , Sun De-en , Qin Ke , Qin Wei , Zhou Wen , Chen Xing
Published: September 2019

Unnatural monosaccharides such as azidosugars that can be metabolically incorporated into cellular glycans are currently used as a major tool for glycan imaging and glycoproteomic profiling. As a common practice to enhance membrane permeability and cellular uptake, the unnatural sugars are per-O-acetylated, which, however, can induce a long-overlooked side reaction, non-enzymatic S-glycosylation. Herein, we develop 1,3-di-esterified N-azidoacetylgalactosamine (GalNAz) as next-generation chemical reporters for metabolic glycan labeling. Both 1,3-di-O-acetylated GalNAz (1,3-Ac2GalNAz) and 1,3-di-O-propionylated GalNAz (1,3-Pr2GalNAz) exhibit high efficiency for labeling protein O-GlcNAcylation with no artificial S-glycosylation. Applying 1,3-Pr2GalNAz in mouse embryonic stem cells (mESCs), we identify ESRRB, a critical transcription factor for pluripotency, as an O-GlcNAcylated protein. We show that ESRRB O-GlcNAcylation is important for mESC self-renewal and pluripotency. Mechanistically, ESRRB is O-GlcNAcylated by O-GlcNAc transferase at serine 25, which stabilizes ESRRB, promotes its transcription activity and facilitates its interactions with two master pluripotency regulators, OCT4 and NANOG.
Mitigation of off-target toxicity in CRISPR-Cas9 screens for essential non-coding elements
Authors: Tycko Josh , Wainberg Michael , Marinov Georgi K. , Ursu Oana , Hess Gaelen T. , Ego Braeden K. , Aradhana  , Li Amy , Truong Alisa , Trevino Alexandro E. , Spees Kaitlyn , Yao David , Kaplow Irene M. , Greenside Peyton G. , Morgens David W. , Phanstiel Douglas H. , Snyder Michael P. , Bintu Lacramioara , Greenleaf William J. , Kundaje Anshul , Bassik Michael C.
Published: September 2019

Pooled CRISPR-Cas9 screens are a powerful method for functionally characterizing regulatory elements in the non-coding genome, but off-target effects in these experiments have not been systematically evaluated. Here, we investigate Cas9, dCas9, and CRISPRi/a off-target activity in screens for essential regulatory elements. The sgRNAs with the largest effects in genome-scale screens for essential CTCF loop anchors in K562 cells were not single guide RNAs (sgRNAs) that disrupted gene expression near the on-target CTCF anchor. Rather, these sgRNAs had high off-target activity that, while only weakly correlated with absolute off-target site number, could be predicted by the recently developed GuideScan specificity score. Screens conducted in parallel with CRISPRi/a, which do not induce double-stranded DNA breaks, revealed that a distinct set of off-targets also cause strong confounding fitness effects with these epigenome-editing tools. Promisingly, filtering of CRISPRi libraries using GuideScan specificity scores removed these confounded sgRNAs and enabled identification of essential regulatory elements.
Forecasting the magnitude of the largest expected earthquake
Authors: Shcherbakov Robert , Zhuang Jiancang , Zöller Gert , Ogata Yosihiko
Published: September 2019

The majority of earthquakes occur unexpectedly and can trigger subsequent sequences of events that can culminate in more powerful earthquakes. This self-exciting nature of seismicity generates complex clustering of earthquakes in space and time. Therefore, the problem of constraining the magnitude of the largest expected earthquake during a future time interval is of critical importance in mitigating earthquake hazard. We address this problem by developing a methodology to compute the probabilities for such extreme earthquakes to be above certain magnitudes. We combine the Bayesian methods with the extreme value theory and assume that the occurrence of earthquakes can be described by the Epidemic Type Aftershock Sequence process. We analyze in detail the application of this methodology to the 2016 Kumamoto, Japan, earthquake sequence. We are able to estimate retrospectively the probabilities of having large subsequent earthquakes during several stages of the evolution of this sequence.
A lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites
Authors: Suarez Catherine , Lentini Gaëlle , Ramaswamy Raghavendran , Maynadier Marjorie , Aquilini Eleonora , Berry-Sterkers Laurence , Cipriano Michael , Chen Allan L. , Bradley Peter , Striepen Boris , Boulanger Martin J. , Lebrun Maryse
Published: September 2019

Members of the Apicomplexa phylum, including Plasmodium and Toxoplasma, have two types of secretory organelles (micronemes and rhoptries) whose sequential release is essential for invasion and the intracellular lifestyle of these eukaryotes. During invasion, rhoptries inject an array of invasion and virulence factors into the cytoplasm of the host cell, but the molecular mechanism mediating rhoptry exocytosis is unknown. Here we identify a set of parasite specific proteins, termed rhoptry apical surface proteins (RASP) that cap the extremity of the rhoptry. Depletion of RASP2 results in loss of rhoptry secretion and completely blocks parasite invasion and therefore parasite proliferation in both Toxoplasma and Plasmodium. Recombinant RASP2 binds charged lipids and likely contributes to assembling the machinery that docks/primes the rhoptry to the plasma membrane prior to fusion. This study provides important mechanistic insight into a parasite specific exocytic pathway, essential for the establishment of infection.
Emergent honeycomb network of topological excitations in correlated charge density wave
Authors: Park Jae Whan , Cho Gil Young , Lee Jinwon , Yeom Han Woong
Published: September 2019

When two periodic potentials compete in materials, one may adopt the other, which straightforwardly generates topological defects. Of particular interest are domain walls in charge-, dipole-, and spin-ordered systems, which govern macroscopic properties and important functionality. However, detailed atomic and electronic structures of domain walls have often been uncertain and the microscopic mechanism of their functionality has been elusive. Here, we clarify the complete atomic and electronic structures of the domain wall network, a honeycomb network connected by Z3 vortices, in the nearly commensurate Mott charge-density wave (CDW) phase of 1T-TaS2. Scanning tunneling microscopy resolves characteristic charge orders within domain walls and their vortices. Density functional theory calculations disclose their unique atomic relaxations and the metallic in-gap states confined tightly therein. A generic theory is constructed, which connects this emergent honeycomb network of conducting electrons to the enhanced superconductivity.
A streamlined and predominantly diploid genome in the tiny marine green alga Chloropicon primus
Authors: Lemieux Claude , Turmel Monique , Otis Christian , Pombert Jean-François
Published: September 2019

Tiny marine green algae issued from two deep branches of the Chlorophyta, the Mamiellophyceae and Chloropicophyceae, dominate different regions of the oceans and play key roles in planktonic communities. Considering that the Mamiellophyceae is the sole lineage of prasinophyte algae that has been intensively investigated, the extent to which these two algal groups differ in their metabolic capacities and cellular processes is currently unknown. To address this gap of knowledge, we investigate here the nuclear genome sequence of a member of the Chloropicophyceae, Chloropicon primus. Among the main biological insights that emerge from this 17.4 Mb genome, we find an unexpected diploid structure for most chromosomes and a propionate detoxification pathway in green algae. Our results support the notion that separate events of genome minimization, which entailed differential losses of genes/pathways, have occurred in the Chloropicophyceae and Mamiellophyceae, suggesting different strategies of adaptation to oceanic environments.
CRISPR-Cas9-based mutagenesis frequently provokes on-target mRNA misregulation
Authors: Tuladhar Rubina , Yeu Yunku , Tyler Piazza John , Tan Zhen , Rene Clemenceau Jean , Wu Xiaofeng , Barrett Quinn , Herbert Jeremiah , Mathews David H. , Kim James , Hyun Hwang Tae , Lum Lawrence
Published: September 2019

The introduction of insertion-deletions (INDELs) by non-homologous end-joining (NHEJ) pathway underlies the mechanistic basis of CRISPR-Cas9-directed genome editing. Selective gene ablation using CRISPR-Cas9 is achieved by installation of a premature termination codon (PTC) from a frameshift-inducing INDEL that elicits nonsense-mediated decay (NMD) of the mutant mRNA. Here, by examining the mRNA and protein products of CRISPR targeted genes in a cell line panel with presumed gene knockouts, we detect the production of foreign mRNAs or proteins in ~50% of the cell lines. We demonstrate that these aberrant protein products stem from the introduction of INDELs that promote internal ribosomal entry, convert pseudo-mRNAs (alternatively spliced mRNAs with a PTC) into protein encoding molecules, or induce exon skipping by disruption of exon splicing enhancers (ESEs). Our results reveal challenges to manipulating gene expression outcomes using INDEL-based mutagenesis and strategies useful in mitigating their impact on intended genome-editing outcomes.
An ultrahigh resolution pressure sensor based on percolative metal nanoparticle arrays
Authors: Chen Minrui , Luo Weifeng , Xu Zhongqi , Zhang Xueping , Xie Bo , Wang Guanghou , Han Min
Published: September 2019

Tunneling conductance among nanoparticle arrays is extremely sensitive to the spacing of nanoparticles and might be applied to fabricate ultra-sensitive sensors. Such sensors are of paramount significance for various application, such as automotive systems and consumer electronics. Here, we represent a sensitive pressure sensor which is composed of a piezoresistive strain transducer fabricated from closely spaced nanoparticle films deposited on a flexible membrane. Benefited from this unique quantum transport mechanism, the thermal noise of the sensor decreases significantly, providing the opportunity for our devices to serve as high-performance pressure sensors with an ultrahigh resolution as fine as about 0.5 Pa and a high sensitivity of 0.13 kPa−1. Moreover, our sensor with such an unprecedented response capability can be operated as a barometric altimeter with an altitude resolution of about 1 m. The outstanding behaviors of our devices make nanoparticle arrays for use as actuation materials for pressure measurement.
A termination-insensitive and robust electron gas at the heterointerface of two complex oxides
Authors: Zhang Meng , Du Kai , Ren Tianshuang , Tian He , Zhang Ze , Hwang Harold Y. , Xie Yanwu
Published: September 2019

The single-crystal SrTiO3 (001) has two different surface terminations, TiO2 and SrO. One most remarkable observation in previous studies is that only the heterointerfaces with TiO2-terminated SrTiO3, which usually combines with polar oxides such as LaAlO3, host an electron gas. Here we show that a robust electron gas can be generated between a non-polar oxide, CaHfO3, and SrTiO3 (001) with either termination. Unlike the well-known electron gas of LaAlO3/SrTiO3, the present one of CaHfO3/SrTiO3 essentially has no critical thickness of CaHfO3, can survive a long-time oxygen annealing at high temperature, and its transport properties are stable under exposure to water and other polar solvents. By electrostatic gating through CaHfO3, field-effect devices are demonstrated using CaHfO3/SrTiO3 heterointerfaces with both terminations. These results show that the electron gas reported in the present study is unique and promising for applications in oxide electronics.
Multifunctional nanoagents for ultrasensitive imaging and photoactive killing of Gram-negative and Gram-positive bacteria
Authors: Tang Jiali , Chu Binbin , Wang Jinhua , Song Bin , Su Yuanyuan , Wang Houyu , He Yao
Published: September 2019

Simultaneous imaging and treatment of infections remains a major challenge, with most current approaches being effective against only one specific group of bacteria or not being useful for diagnosis. Here we develop multifunctional nanoagents that can potentially be used for imaging and treatment of infections caused by diverse bacterial pathogens. The nanoagents are made of fluorescent silicon nanoparticles (SiNPs) functionalized with a glucose polymer (e.g., poly[4-O-(α-D-glucopyranosyl)-D-glucopyranose]) and loaded with chlorin e6 (Ce6). They are rapidly internalized into Gram-negative and Gram-positive bacteria by a mechanism dependent on an ATP-binding cassette (ABC) transporter pathway. The nanoagents can be used for imaging bacteria by tracking the green fluorescence of SiNPs and the red fluorescence of Ce6, allowing in vivo detection of as few as 105 colony-forming units. The nanoagents exhibit in vivo photodynamic antibacterial efficiencies of 98% against Staphylococcus aureus and 96% against Pseudomonas aeruginosa under 660 nm irradiation.
Long valley lifetime of dark excitons in single-layer WSe2
Authors: Tang Yanhao , Mak Kin Fai , Shan Jie
Published: September 2019

Single-layer transition metal dichalcogenides provide a promising material system to explore the electron’s valley degree of freedom as a quantum information carrier. The valley degree of freedom can be directly accessed by means of optical excitation. However, rapid valley relaxation of optically excited electron-hole pairs (excitons) through the exchange interaction has been a major roadblock. Theoretically such valley relaxation is suppressed in dark excitons, suggesting a potential route for long valley lifetimes. Here we develop a waveguide-based method to detect time-resolved and energy-resolved dark exciton emission in single-layer WSe2, which involves spin-forbidden optical transitions with an out-of-plane dipole moment. The valley degree of freedom of dark excitons is accessed through the valley-dependent Zeeman effect under an out-of-plane magnetic field. We find a short valley lifetime for the dark neutral exciton, likely due to the short-range electron-hole exchange, but long valley lifetimes exceeding several nanoseconds for the dark charged excitons.
Author Correction: A data set of inland lake catchment boundaries for the Qiangtang Plateau
Authors: Yan Denghua , Li Meng , Bi Wuxia , Weng Baisha , Qin Tianling , Wang Jianwei , Do Pierre
Published: September 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Flow-driven micro-scale pH variability affects the physiology of corals and coralline algae under ocean acidification
Authors: Comeau S. , Cornwall C. E. , Pupier C. A. , DeCarlo T. M. , Alessi C. , Trehern R. , McCulloch M. T.
Published: September 2019

Natural variability in pH in the diffusive boundary layer (DBL), the discrete layer of seawater between bulk seawater and the outer surface of organisms, could be an important factor determining the response of corals and coralline algae to ocean acidification (OA). Here, two corals with different morphologies and one coralline alga were maintained under two different regimes of flow velocities, pH, and light intensities in a 12 flumes experimental system for a period of 27 weeks. We used a combination of geochemical proxies, physiological and micro-probe measurements to assess how these treatments affected the conditions in the DBL and the response of organisms to OA. Overall, low flow velocity did not ameliorate the negative effect of low pH and therefore did not provide a refugia from OA. Flow velocity had species-specific effects with positive effects on calcification for two species. pH in the calcifying fluid (pHcf) was reduced by low flow in both corals at low light only. pHcf was significantly impacted by pH in the DBL for the two species capable of significantly modifying pH in the DBL. The dissolved inorganic carbon in the calcifying fluid (DICcf) was highest under low pH for the corals and low flow for the coralline, while the saturation state in the calcifying fluid and its proxy (FWHM) were generally not affected by the treatments. This study therefore demonstrates that the effects of OA will manifest most severely in a combination of lower light and lower flow habitats for sub-tropical coralline algae. These effects will also be greatest in lower flow habitats for some corals. Together with existing literature, these findings reinforce that the effects of OA are highly context dependent, and will differ greatly between habitats, and depending on species composition.
Anti-oxidative function of follicular fluid HDL and outcomes of modified natural cycle-IVF
Authors: Nagy Ruxandra A. , van Montfoort Aafke P. A. , Groen Henk , Homminga Irene , Andrei Daniela , Mistry Rima H. , Anderson Josephine L. C. , Hoek Annemieke , Tietge Uwe J. F.
Published: September 2019

High density lipoproteins (HDL) are the main cholesterol carriers in follicular fluid (FF), the natural environment of oocyte development. Additionally, HDL have critical biological functions such as anti-oxidative capacity, which have not been studied in reproduction. Therefore, this study aimed to investigate whether the anti-oxidative function of FF-HDL is associated with fertility outcomes. From 253 women undergoing modified natural cycle (MNC)- IVF at a single academic centre FF and plasma were collected (n = 375 cycles). Anti-oxidative function of FF was mainly attributable to HDL (n = 8; 83%). FF-HDL had a higher anti-oxidative function than plasma HDL (n = 19, P < 0.001) coinciding with increased vitamin E and sphingosine 1 phosphate content (P = 0.028 each). Proteomic analysis indicated no significant differences in major anti-oxidative proteins such as paraoxonase 1, apolipoprotein (apo) A-I or apoA-IV between FF-HDL and matched plasma-HDL (n = 5), while apoC-III, apoE and apoC-II were relatively lower in FF-HDL. Finally, FF-HDL anti-oxidative function was related to a decrease in the odds of the oocyte undergoing normal fertilization, an association that persisted after adjustment for confounders (odds ratio 0.97 (0.93–1), P = 0.041). In conclusion, FF-HDL has considerable anti-oxidative properties that might be relevant for embryo quality.
Proliferation Tumour Marker Network (PTM-NET) for the identification of tumour region in Ki67 stained breast cancer whole slide images
Authors: Joseph Jesuchristopher , Roudier Martine P. , Narayanan Priya Lakshmi , Augulis Renaldas , Ros Vidalba Rocher , Pritchard Alison , Gerrard Joe , Laurinavicius Arvydas , Harrington Elizabeth A. , Barrett J. Carl , Howat William J.
Published: September 2019

Uncontrolled proliferation is a hallmark of cancer and can be assessed by labelling breast tissue using immunohistochemistry for Ki67, a protein associated with cell proliferation. Accurate measurement of Ki67-positive tumour nuclei is of critical importance, but requires annotation of the tumour regions by a pathologist. This manual annotation process is highly subjective, time-consuming and subject to inter- and intra-annotator experience. To address this challenge, we have developed Proliferation Tumour Marker Network (PTM-NET), a deep learning model that objectively annotates the tumour regions in Ki67-labelled breast cancer digital pathology images using a convolution neural network. Our custom designed deep learning model was trained on 45 immunohistochemical Ki67-labelled whole slide images to classify tumour and non-tumour regions and was validated on 45 whole slide images from two different sources that were stained using different protocols. Our results show a Dice coefficient of 0.74, positive predictive value of 70% and negative predictive value of 88.3% against the manual ground truth annotation for the combined dataset. There were minimal differences between the images from different sources and the model was further tested in oestrogen receptor and progesterone receptor-labelled images. Finally, using an extension of the model, we could identify possible hotspot regions of high proliferation within the tumour. In the future, this approach could be useful in identifying tumour regions in biopsy samples and tissue microarray images.