bluuebunny/crossref_metadata_2025 huggingface dataset:
Policy programme cycles through old and new programmatic groups
Authors: Bandelow Nils C. , Hornung Johanna
Published: August 2020

This article draws on the Programmatic Action Framework (PAF) to tackle the question of how the dominance and decline of a specific policy programme in a policy sector can be explained. It starts from the observation that visionary policy programmes, defined as a set of policy goals and instruments that find their expression in subsequently adopted and interconnected policy reforms, may shape a sector’s policies over several decades. Linking policy programmes to programmatic groups that promote these programmes in search of boosting their careers and authority, the programme’s rising and declining dominance can be explained by the career trajectories of programmatic actors. By displaying empirical evidence for the argument from German health policy, the article shows that proponents of today’s change are opponents of tomorrow’s change since individual careers depend on the dominance of policy programmes.
Crosslinguistic influence and L2 grammar learning: Proposed replications of Ellis and Sagarra (2011) and Tolentino and Tokowicz (2014)
Authors: McManus Kevin
Published: August 2020

Investigations of crosslinguistic effects in second language acquisition (SLA) have contributed rich understandings about the ways in which prior language knowledge and experience can influence additional language learning. Building on this work, one recent line of research has examined the extent to which SLA findings about crosslinguistic influence can be used to improve L2 learning, indicating that explicit instruction tailored to address the nature of the crosslinguistic learning problem can benefit L2 performance. At the same time, however, this line of inquiry is relatively novel and under-researched. The aim of this paper, therefore, is to suggest further research which might advance knowledge and understanding about the ways in which explicit instruction can facilitate second language (L2) learning of crosslinguistically difficult target features. To this end, I lay the ground for a series of close replications designed to understand the role of prior language knowledge and experience in L2 learning: Ellis and Sagarra (2011) and Tolentino and Tokowicz (2014). These studies were selected because they are grounded in empirical SLA research and SLA theory. In addition, the selected studies facilitate replication because they have either (i) made their data collection materials available in digital repositories or (ii) have robustly described their design and provided the stimuli used.
Impact of rarity on Canadian oncology health technology assessment and funding
Authors: Keech James , Dai Wei Fang , Trudeau Maureen , Mercer Rebecca E. , Naipaul Rohini , Wright Frances C. , Ferguson Sarah E. , Darling Gail , Gavura Scott , Eisen Andrea , Kouroukis C. Tom , Beca Jaclyn , Chan Kelvin K.W.
Published: August 2020

Objectives

The pan-Canadian Oncology Drug Review (pCODR) evaluates new cancer drugs for public funding recommendations. While pCODR's deliberative framework evaluates overall clinical benefit and includes considerations for exceptional circumstances, rarity of indication is not explicitly addressed. Given the high unmet need that typically accompanies these indications, we explored the impact of rarity on oncology HTA recommendations and funding decisions.

Methods

We examined pCODR submissions with final recommendations from 2012 to 2017. Incidence rates were calculated using pCODR recommendation reports and statistics from the Canadian Cancer Society. Indications were classified as rare if the incidence rate was lower than 1/100,000 diagnoses, a definition referenced by the Canadian Agency for Drugs and Technologies in Health. Each pCODR final report was examined for the funding recommendation/justification, level of supporting evidence (presence of a randomized control trial [RCT]), and time to funding (if applicable).

Results

Of the ninety-six pCODR reviews examined, 16.6 percent were classified as rare indications per above criteria. While the frequency of positive funding recommendations were similar between rare and nonrare indication (78.6 vs. 75 percent), rare indications were less likely to be presented with evidence from RCT (50 vs. 90 percent). The average time to funding did not differ significantly across provinces.

Conclusion

Rare indications appear to be associated with weaker clinical evidence. There appears to be no association between rarity, positive funding recommendations, and time to funding. Further work will evaluate factors associated with positive recommendations and the real-world utilization of funded treatments for rare indications.
LARGE SAMPLE PROPERTIES OF BAYESIAN ESTIMATION OF SPATIAL ECONOMETRIC MODELS
Authors: Han Xiaoyi , Lee Lung-Fei , Xu Xingbai
Published: August 2020

This paper studies asymptotic properties of a posterior probability density and Bayesian estimators of spatial econometric models in the classical statistical framework. We focus on the high-order spatial autoregressive model with spatial autoregressive disturbance terms, due to a computational advantage of Bayesian estimation. We also study the asymptotic properties of Bayesian estimation of the spatial autoregressive Tobit model, as an example of nonlinear spatial models. Simulation studies show that even when the sample size is small or moderate, the posterior distribution of parameters is well approximated by a normal distribution, and Bayesian estimators have satisfactory performance, as classical large sample theory predicts.
A tale of three cities: urban and cultural resilience and heritage between the Late Bronze Age and Early Iron Age in the eastern Mediterranean
Authors: Middleton Guy D.
Published: August 2020

The turbulent years aroundc. 1200 BC in the eastern Mediterranean are known as a period of the collapse of states and empires. Yet by zooming in on three important royal cities, Tiryns, Hattusa and Carchemish, we can question this collapse narrative whilst at the same time exploring the now popular concept of resilience, in this case urban and cultural resilience. First these ancient cities are presented as interactive and meaningful spaces in which architecture and art were used to shape people's experience of them and the world in which they lived, before their urban fabric and functions are examined in turn. It will become clear that they had radically different fates throughc. 1200 BC. Some of the difficulties in applying ideas from resilience thinking and how it might or might not be useful as an approach in studying these and other examples are then discussed.
Hilfebedarf und Hilfesysteme für Kinder und Familien
Authors: Petermann Ulrike
Published: August 2020

Zusammenfassung. Für Kinder und Jugendliche mit psychischen und Verhaltensstörungen sowie Entwicklungsstörungen existiert in Deutschland ein differenziertes Angebot an Hilfen. Dieses reicht von der Pädiatrie, über die Kinder-/Jugendpsychiatrie, die ambulante Psychotherapie bis zur Kinder- und Jugendhilfe und zu schulischen Fördermaßnahmen. Die Effizienz dieser Hilfesysteme hängt auch von deren Vernetzung und interdisziplinären Kooperation ab. Die Lösung von Schnittstellenproblemen steigert Therapieerfolge und verbessert die Langzeiteffekte.
Analyses of High‐Iron Sedimentary Bedrock and Diagenetic Features Observed With ChemCam at Vera Rubin Ridge, Gale Crater, Mars: Calibration and Characterization
Authors: David G. , Cousin A. , Forni O. , Meslin P.‐Y. , Dehouck E. , Mangold N. , L'Haridon J. , Rapin W. , Gasnault O. , Johnson J. R. , Ollila A. M. , Newell A. R. , Salvatore M. , Gabriel T. S. J. , Wiens R. C. , Maurice S.
Published: August 2020

Curiosity investigated a topographic rise named Vera Rubin Ridge (VRR) in Gale Crater, for which a distinct hematite‐like signature was observed from orbit. However, the Chemistry and Camera (ChemCam) and Alpha Particle x‐ray Spectrometer (APXS) instruments on board the rover did not record any significant iron enrichment in the bulk of the ridge compared to previous terrains. For this study, we have reverified ChemCam iron calibration at moderate abundances and developed more accurate calibrations at high‐iron abundances using iron‐oxide mixtures in a basaltic matrix in order to complete the ChemCam calibration database. The high‐iron calibration was first applied to the analysis of dark‐toned diagenetic features encountered at several locations on VRR, which showed that their chemical compositions are close to pure anhydrous iron oxides. Then, we tracked iron abundances in the VRR bedrock and demonstrated that although there is no overall iron enrichment in the bulk of the ridge (21.2 ± 1.8‐wt.% FeOT) compared to underlying terrains, the iron content is more variable in its upper section with areas of enhanced iron abundances in the bedrock (up to 26.6 ± 0.85‐wt.% FeOT). Since the observed variability in iron abundances does not conform to the stratigraphy, the involvement of diagenetic fluid circulation was likely. An in‐depth chemical study of these Fe‐rich rocks reveals that spatial gradients in redox potential (Eh) may have driven iron mobility and reactions that precipitated and accumulated iron oxides. We hypothesize that slightly reducing fluids were probably involved in transporting ferrous iron. Mobile Fe2+ could have precipitated as iron oxides in more oxidizing conditions.
Abrupt Climate and Weather Changes Across Time Scales
Authors: Lohmann Gerrit , Butzin Martin , Eissner Nina , Shi Xiaoxu , Stepanek Christian
Published: August 2020

The past provides evidence of abrupt climate shifts and changes in the frequency of climate and weather extremes. We explore the nonlinear response to orbital forcing and then consider climate millennial variability down to daily weather events. Orbital changes are translated into regional responses in temperature, where the precessional response is related to nonlinearities and seasonal biases in the system. We question regularities found in climate events by analyzing the distribution of interevent waiting times. Periodicities of about 900 and 1,150 yr are found in ice cores besides the prominent 1,500 yr cycle. However, the variability remains indistinguishable from a random process, suggesting that centennial‐to‐millennial variability is stochastic in nature. New numerical techniques are developed allowing for a high resolution in the dynamically relevant regions like coasts, major upwelling regions, and high latitudes. Using this model, we find a strong sensitivity of the Atlantic meridional overturning circulation depending on where the deglacial meltwater is injected into. Meltwater into the Mississippi and near Labrador hardly affect the large‐scale ocean circulation, whereas subpolar hosing mimicking icebergs yields a quasi shutdown. The same multiscale approach is applied to radiocarbon simulations enabling a dynamical interpretation of marine sediment cores. Finally, abrupt climate events also have counterparts in the recent climate records, revealing a close link between climate variability, the statistics of North Atlantic weather patterns, and extreme events.
Engaging Communities in Geoscience with STEM Learning Ecosystems
Authors: Manning Cheryl
Published: August 2020

Geo-STEM learning ecosystems can empower community-based solutions and broaden participation in the geosciences by connecting diverse participants who contribute unique skill sets and ways of knowing.
Atmospheric Dynamics Patterns in Southern Central Asia Since 800 ka Revealed by Loess‐Paleosol Sequences in Tajikistan
Authors: Lu Hao , Jia Jia , Yin Qiuzhen , Xia Dunsheng , Gao Fuyuan , Liu Hao , Fan Yijiao , Li Zaijun , Wang Xin , Berger André , Oimuhammadzoda Ilhomjon , Gadoev Mustafo
Published: August 2020

The atmospheric mechanisms responsible for the loess grain‐size variations in central Asia are less clear, and an increasing number of studies have found that the coarse‐grained component is likely supplied by the surface circulation rather than by the westerlies (westerlies circulation). In this study, we attempt to determine the atmospheric dynamics patterns in the Afghan‐Tajik Basin during the past 800 kyr, based on the coarse grain‐size fraction of loess, combined with a study of modern dust transport processes. We suggest that the coarse grain‐size fraction can be used to indicate the intensity of near‐surface winds, while on glacial‐interglacial time scales, the variations of loess grain size in Tajikistan are dominated by Northern Hemisphere ice volume via its effect on the strength of the Siberian High. In addition, we suggest that atmospheric greenhouse gases concentration affected the loess grain size during interglacials via their influence on the temperature of southern high latitudes.
Modeling Marsh‐Forest Boundary Transgression in Response to Storms and Sea‐Level Rise
Authors: Carr J. , Guntenspergen G. , Kirwan M.
Published: August 2020

The lateral extent and vertical stability of salt marshes experiencing rising sea levels depend on interacting drivers and feedbacks with potential for nonlinear behaviors. A two‐dimensional transect model was developed to examine changes in marsh and upland forest lateral extent and to explore controls on marsh inland transgression. Model behavior demonstrates limited and abrupt forest retreat with long‐term upland boundary migration rates controlled by slope, sea‐level rise (SLR), high water events, and biotic‐abiotic interactions. For low to moderate upland slopes the landward marsh edge is controlled by the interaction of these inundation events and forest recovery resulting in punctuated transgressive events. As SLR rates increase, the importance of the timing and frequency of water‐level deviations diminishes, and migration rates revert back to a slope‐SLR‐dominated process.
Quantification of the Atmospheric Relativistic Electron Precipitation on 17 January 2013
Authors: Shekhar S. , Millan R. M. , Woodger L. A. , Qin M.
Published: August 2020

On 17 January 2013, relativistic electron precipitation (REP) was observed on Balloon Array for Radiation Belt Relativistic Electron Losses (BARREL) payloads, National Oceanic and Atmospheric Administration Polar orbiting Operational Environmental Satellites (NOAA POES), and European Space Agency (ESA) MetOp between 2:44 to 15:04 h UT, scattered across dusk to early morning magnetic local time (MLT) sectors. The observations could be grouped into multiple observations of seven REP events spatially separated by more than 2 h in MLT and at least 1 h in UT. Almost all the events were localized in L shell with dL < 0.5 and MLT with dMLT < 3. A net loss of ∼5% of the relativistic electrons from the radiation belts is estimated between 2:44 to 15:04 h UT (∼13.5 h). A majority of atmospheric REP (nearly 75% through six REP events) was observed before the onset of a minor storm around 14:00 UT; the rest (25% through one REP event) was observed during the commencement of the storm which was followed by a major dropout of MeV electrons from the radiation belts during the main phase. However, no atmospheric precipitation was observed during the main phase, indicating that the dropouts may not have been caused by particle loss into the atmosphere.
Rheological Weakening of Olivine + Orthopyroxene Aggregates Due to Phase Mixing: Effects of Orthopyroxene Volume Fraction
Authors: Tasaka Miki , Zimmerman Mark E. , Kohlstedt David L.
Published: August 2020

To understand the effects of secondary minerals on changes in the mechanical properties of upper mantle rocks due to phase mixing, we conducted high‐strain torsion experiments on aggregates of iron‐rich olivine + orthopyroxene (opx) with opx volume fractions of fopx = 0.15, 0.26, and 0.35. For samples with larger amounts of opx, fopx = 0.26 and 0.35, the value of the stress exponent decreases with increasing strain from n ≈ 3 for γ ≲ 5 to n ≈ 2 for 5 ≲ γ ≲ 25, indicating that the deformation mechanism changes as strain increases. In contrast, for samples with fopx = 0.15, the stress exponent is constant at n ≈ 3.3 for 1 ≲ γ ≲ 25, suggesting that no change in deformation mechanism occurs with increasing strain for samples with smaller amounts of opx. The microstructures of samples with larger amounts of opx provide insight into the change in deformation mechanism derived from the mechanical data. Elongated grains align subparallel to the shear direction for samples of all three compositions deformed to lower strains. However, strain weakening with grain size reduction and the formation of a thoroughly mixed, fine‐grained texture only develops in samples with fopx = 0.26 and 0.35 deformed to higher strains of γ ≳ 16. These mechanical and associated microstructural properties imply that rheological weakening due to phase mixing only occurs in the samples with larger fopx, which is an important constraint for understanding strain localization in the upper mantle of Earth.
Temperature‐Dependent Optical Properties of Liquid Water From 240 to 298 K
Authors: Rowe P. M. , Fergoda M. , Neshyba S.
Published: August 2020

Clouds play a key role in Earth's radiative balance. Radiative transfer through liquid clouds depends on the optical properties of liquid water. Although these optical properties are known to be temperature dependent, radiative transfer simulations typically use properties based on measurements made at 298 K, even for supercooled liquid clouds at temperatures as low as 240 K. Here we report temperature‐dependent complex refractive indices (CRIs) of liquid water at 240, 253, 263, and 273 K from 1 to 15,000 cm−1 (0.7 to 10,000 μm). Imaginary parts of the CRI (k) are inferred from values reported in the literature for temperatures of 238 to 298 K and the real parts are obtained via Kramers‐Kronig transformation. Mie theory is used to calculate single scattering albedos and Legendre moments from the CRI, producing a set of optical constants suitable for radiative transfer calculations through supercooled liquid cloud at temperatures as low as 240 K. Ignoring the temperature dependence of complex refractive indices of liquid water is thereby found to result in biased‐high supercooled liquid‐cloud fluxes from 250 to 580 cm−1 and biased‐low fluxes from 710 to 940 cm−1.
LncRNA DANCR and miR-320a suppressed osteogenic differentiation in osteoporosis by directly inhibiting the Wnt/β-catenin signaling pathway
Authors: Wang Cheng-Gong , Hu Yi-He , Su Shi-Long , Zhong Da
Published: August 2020

Our study aimed to determine how lncRNA DANCR, miR-320a, and CTNNB1 interact with each other and regulate osteogenic differentiation in osteoporosis. qRT-PCR and western blotting were performed to determine the expression of DANCR, miR-320a, CTNNB1, and the osteoporosis- or Wnt/β-catenin pathway-related markers T-cell factor 1 (TCF-1), runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), osteocalcin (OCN), and osteopontin (OPN). Interactions between CTNNB1, DANCR, and miR-320a were predicted by bioinformatics approaches and validated using a luciferase assay. Osteoblastic phenotypes were evaluated by ALP staining, ALP activity assay and Alizarin Red staining. The bilateral ovariectomy method was used to establish an in vivo osteoporosis model. Bone morphological changes were examined using hematoxylin and eosin (H&E) and Alcian Blue staining. The expression levels of DANCR and miR-320a in BMSCs derived from osteoporosis patients were upregulated, whereas CTNNB1 expression was downregulated compared with that in healthy controls. Importantly, we demonstrated that miR-320a and DANCR acted independently from each other and both inhibited CTNNB1 expression, whereas the inhibitory effect was additive when miR-320a and DANCR were cooverexpressed. Moreover, we found that DANCR overexpression largely abrogated the effect of the miR-320a inhibitor on CTNNB1 expression and the Wnt/β-catenin signaling pathway in BMSCs during osteogenic differentiation. We further confirmed the results above in BMSCs derived from an osteoporosis animal model. Taken together, our findings revealed that DANCR and miR-320a regulated the Wnt/β-catenin signaling pathway during osteogenic differentiation in osteoporosis through CTNNB1 inhibition. Our results highlight the potential value of DANCR and miR-320a as promising therapeutic targets for osteoporosis treatment.
Diffraction-limited imaging with monolayer 2D material-based ultrathin flat lenses
Authors: Lin Han , Xu Zai-Quan , Cao Guiyuan , Zhang Yupeng , Zhou Jiadong , Wang Ziyu , Wan Zhichen , Liu Zheng , Loh Kian Ping , Qiu Cheng-Wei , Bao Qiaoliang , Jia Baohua
Published: August 2020

Ultrathin flat optics allow control of light at the subwavelength scale that is unmatched by traditional refractive optics. To approach the atomically thin limit, the use of 2D materials is an attractive possibility due to their high refractive indices. However, achievement of diffraction-limited focusing and imaging is challenged by their thickness-limited spatial resolution and focusing efficiency. Here we report a universal method to transform 2D monolayers into ultrathin flat lenses. Femtosecond laser direct writing was applied to generate local scattering media inside a monolayer, which overcomes the longstanding challenge of obtaining sufficient phase or amplitude modulation in atomically thin 2D materials. We achieved highly efficient 3D focusing with subwavelength resolution and diffraction-limited imaging. The high focusing performance even allows diffraction-limited imaging at different focal positions with varying magnifications. Our work paves the way for downscaling of optical devices using 2D materials and reports an unprecedented approach for fabricating ultrathin imaging devices.
Computational causal discovery for post-traumatic stress in police officers
Authors: Saxe Glenn N. , Ma Sisi , Morales Leah J. , Galatzer-Levy Isaac R. , Aliferis Constantin , Marmar Charles R.
Published: August 2020

This article reports on a study aimed to elucidate the complex etiology of post-traumatic stress (PTS) in a longitudinal cohort of police officers, by applying rigorous computational causal discovery (CCD) methods with observational data. An existing observational data set was used, which comprised a sample of 207 police officers who were recruited upon entry to police academy training. Participants were evaluated on a comprehensive set of clinical, self-report, genetic, neuroendocrine and physiological measures at baseline during academy training and then were re-evaluated at 12 months after training was completed. A data-processing pipeline—the Protocol for Computational Causal Discovery in Psychiatry (PCCDP)—was applied to this data set to determine a causal model for PTS severity. A causal model of 146 variables and 345 bivariate relations was discovered. This model revealed 5 direct causes and 83 causal pathways (of four steps or less) to PTS at 12 months of police service. Direct causes included single-nucleotide polymorphisms (SNPs) for the Histidine Decarboxylase (HDC) and Mineralocorticoid Receptor (MR) genes, acoustic startle in the context of low perceived threat during training, peritraumatic distress to incident exposure during first year of service, and general symptom severity during training at 1 year of service. The application of CCD methods can determine variables and pathways related to the complex etiology of PTS in a cohort of police officers. This knowledge may inform new approaches to treatment and prevention of critical incident related PTS.
An in vitro assessment of the physical properties of manually- mixed and encapsulated glass-ionomer cements
Authors: Al-Taee Lamis , Deb Sanjukta , Banerjee Avijit
Published: August 2020

Objectives

The last decade has seen a variety of modifications of glass-ionomer cements (GICs), such as inclusion of bioactive glass particles and dispensing systems. Hence, the aim was to systematically evaluate effect of mixing modes and presence of reactive glass additives on the physical properties of several GICs.

Materials and methods

The physical properties of eight commercial restorative GICs; Fuji IX GP Extra (C&H), KetacTM Fill Plus Applicap (C&H), Fuji II LC (C&H), Glass Carbomer Cement and Equia® Forte Fil, capsulated versus manually mixed were assessed. 256 cylindrical specimens were prepared for compressive strength and microhardness, whilst 128 disc-shaped specimens were prepared for biaxial flexural strength tests. Fluid uptake and fluoride release were assessed. Data were analysed using one-way ANOVA and Games-Howell post-hoc tests (alpha = 0.05).

Results

Both encapsulated GIC/RMGICs exhibited significantly improved mechanical properties in comparison to manually mixed equivalents, which in turn showed higher fluid uptake and early fluoride release (p < 0.05). The glass carbomer cement exhibited improved mechanical properties post ageing and evidence of mineral deposits were apparent in the microstructure.

Conclusions

The mixing mode and inclusion of reactive glass additives in cements had a statistically significant effect on physical properties of the selected GICs-RMGICs.
The genetic architecture of human brainstem structures and their involvement in common brain disorders
Authors: Elvsåshagen Torbjørn , Bahrami Shahram , van der Meer Dennis , Agartz Ingrid , Alnæs Dag , Barch Deanna M. , Baur-Streubel Ramona , Bertolino Alessandro , Beyer Mona K. , Blasi Giuseppe , Borgwardt Stefan , Boye Birgitte , Buitelaar Jan , Bøen Erlend , Celius Elisabeth Gulowsen , Cervenka Simon , Conzelmann Annette , Coynel David , Di Carlo Pasquale , Djurovic Srdjan , Eisenacher Sarah , Espeseth Thomas , Fatouros-Bergman Helena , Flyckt Lena , Franke Barbara , Frei Oleksandr , Gelao Barbara , Harbo Hanne Flinstad , Hartman Catharina A. , Håberg Asta , Heslenfeld Dirk , Hoekstra Pieter J. , Høgestøl Einar A. , Jonassen Rune , Jönsson Erik G. ,   Karolinska Schizophrenia Project (KaSP) consortium, Farde L. , Flyckt L. , Engberg G. , Erhardt S S. , Fatouros-Bergman H. , Cervenka S. , Schwieler L. , Piehl F. , Agartz I. , Collste K. , Victorsson P. , Malmqvist A. , Hedberg M. , Orhan F. , Sellgren C. M. , Kirsch Peter , Kłoszewska Iwona , Lagerberg Trine Vik , Landrø Nils Inge , Le Hellard Stephanie , Lesch Klaus-Peter , Maglanoc Luigi A. , Malt Ulrik F. , Mecocci Patrizia , Melle Ingrid , Meyer-Lindenberg Andreas , Moberget Torgeir , Nordvik Jan Egil , Nyberg Lars , Connell Kevin S. O’ , Oosterlaan Jaap , Papalino Marco , Papassotiropoulos Andreas , Pauli Paul , Pergola Giulio , Persson Karin , de Quervain Dominique , Reif Andreas , Rokicki Jaroslav , van Rooij Daan , Shadrin Alexey A. , Schmidt André , Schwarz Emanuel , Selbæk Geir , Soininen Hilkka , Sowa Piotr , Steen Vidar M. , Tsolaki Magda , Vellas Bruno , Wang Lei , Westman Eric , Ziegler Georg C. , Zink Mathias , Andreassen Ole A. , Westlye Lars T. , Kaufmann Tobias
Published: August 2020

Brainstem regions support vital bodily functions, yet their genetic architectures and involvement in common brain disorders remain understudied. Here, using imaging-genetics data from a discovery sample of 27,034 individuals, we identify 45 brainstem-associated genetic loci, including the first linked to midbrain, pons, and medulla oblongata volumes, and map them to 305 genes. In a replication sample of 7432 participants most of the loci show the same effect direction and are significant at a nominal threshold. We detect genetic overlap between brainstem volumes and eight psychiatric and neurological disorders. In additional clinical data from 5062 individuals with common brain disorders and 11,257 healthy controls, we observe differential volume alterations in schizophrenia, bipolar disorder, multiple sclerosis, mild cognitive impairment, dementia, and Parkinson’s disease, supporting the relevance of brainstem regions and their genetic architectures in common brain disorders.
Efficient variance components analysis across millions of genomes
Authors: Pazokitoroudi Ali , Wu Yue , Burch Kathryn S. , Hou Kangcheng , Zhou Aaron , Pasaniuc Bogdan , Sankararaman Sriram
Published: August 2020

While variance components analysis has emerged as a powerful tool in complex trait genetics, existing methods for fitting variance components do not scale well to large-scale datasets of genetic variation. Here, we present a method for variance components analysis that is accurate and efficient: capable of estimating one hundred variance components on a million individuals genotyped at a million SNPs in a few hours. We illustrate the utility of our method in estimating and partitioning variation in a trait explained by genotyped SNPs (SNP-heritability). Analyzing 22 traits with genotypes from 300,000 individuals across about 8 million common and low frequency SNPs, we observe that per-allele squared effect size increases with decreasing minor allele frequency (MAF) and linkage disequilibrium (LD) consistent with the action of negative selection. Partitioning heritability across 28 functional annotations, we observe enrichment of heritability in FANTOM5 enhancers in asthma, eczema, thyroid and autoimmune disorders.
Analysis of erythrocyte signalling pathways during Plasmodium falciparum infection identifies targets for host-directed antimalarial intervention
Authors: Adderley Jack D. , John von Freyend Simona , Jackson Sarah A. , Bird Megan J. , Burns Amy L. , Anar Burcu , Metcalf Tom , Semblat Jean-Philippe , Billker Oliver , Wilson Danny W. , Doerig Christian
Published: August 2020

Intracellular pathogens mobilize host signaling pathways of their host cell to promote their own survival. Evidence is emerging that signal transduction elements are activated in a-nucleated erythrocytes in response to infection with malaria parasites, but the extent of this phenomenon remains unknown. Here, we fill this knowledge gap through a comprehensive and dynamic assessment of host erythrocyte signaling during infection with Plasmodium falciparum. We used arrays of 878 antibodies directed against human signaling proteins to interrogate the activation status of host erythrocyte phospho-signaling pathways at three blood stages of parasite asexual development. This analysis reveals a dynamic modulation of many host signalling proteins across parasite development. Here we focus on the hepatocyte growth factor receptor (c-MET) and the MAP kinase pathway component B-Raf, providing a proof of concept that human signaling kinases identified as activated by malaria infection represent attractive targets for antimalarial intervention.
Corrosion mechanism of an equimolar AlCoCrFeNi high-entropy alloy additively manufactured by electron beam melting
Authors: Yamanaka Kenta , Shiratori Hiroshi , Mori Manami , Omura Kazuyo , Fujieda Tadashi , Kuwabara Kosuke , Chiba Akihiko
Published: August 2020

High-entropy alloys (HEAs) have emerged as a class of structural alloys with various attractive properties, and their application in additive manufacturing, which enables unprecedented thermal history and geometrical complexity, is promising for realising advanced materials. This study investigates the corrosion behaviour and passive film characteristics of an equimolar AlCoCrFeNi HEA additively manufactured by electron beam melting (EBM). Potentiodynamic polarisation in a 3.5 wt% NaCl solution revealed that the bottom part of the EBM specimen shows better corrosion performance than a conventionally prepared cast specimen in terms of both corrosion and passivation current density, while a continuous increase in the current density without any apparent passivity was observed during the anodic polarisation of the top part. The electrochemical impedance spectroscopic study indicated significant differences in the passive film characteristics between the specimens, and revealed an enhanced charge-transfer resistance and the formation of a more protective passive film of the bottom part. The elemental redistribution, in particular, the enrichment of Cr in the B2 phase during the post-melt high-temperature exposure of the alloy during EBM, was responsible for the improved stability of the passive film, retarding the selective dissolution of the B2 phase in the bottom part. These findings indicate that the microstructural evolution caused by ‘in situ annealing’ during the EBM process significantly influences the corrosion behaviour of the HEA.
The clinical and urodynamic outcomes of single-incision mesh surgery using the Uphold system for the treatment of pelvic organ prolapse
Authors: Wu Pei-Chi , Wu Chin-Hu , Liu Yiyin , Loo Zixi , Lin Kun-Ling , Long Cheng-Yu
Published: August 2020

This retrospective cohort study aims to assess the clinical and urodynamic outcomes of single-incision mesh surgery with the Uphold system. The medical records of 140 women with anterior and/or apical compartment prolapse stage 2 or greater who underwent Uphold mesh surgeries were reviewed. The clinical evaluation included a pelvic examination, a urodynamic study (UDS), and a personal interview to evaluate lower urinary tract symptoms (LUTS). After a follow-up time of 12–30 months, the anatomical reduction rates were 100% and 96.4% for the apical and anterior compartments, respectively, and these rates were similar across women with or without hysterectomy. All of the LUTS and several UDS parameters improved significantly. The continence rate in women with stress urinary incontinence (SUI) was improved if they also underwent a mid-urethral sling (MUS) operation. However, the continence rate did not differ between women with and without occult urodynamic stress incontinence who did not undergo a concomitant MUS operation. The rate of vaginal mesh extrusion was 2.8%, and this complication rarely occurred beyond the learning curve. In conclusion, the anatomic correction of the Uphold system was satisfactory with a low rate of mesh extrusion. Women with SUI would benefit from a concomitant MUS operation.
Vanishing fine structure splitting in highly asymmetric InAs/InP quantum dots without wetting layer
Authors: Zieliński Michał
Published: August 2020

Contrary to simplified theoretical models, atomistic calculations presented here reveal that sufficiently large in-plane shape elongation of quantum dots can not only decrease, but even reverse the splitting of the two lowest optically active excitonic states. Such a surprising cancellation of bright-exciton splitting occurs for shape-anisotropic nanostructures with realistic elongation ratios, yet without a wetting layer, which plays here a vital role. However, this non-trivial effect due to shape-elongation is strongly diminished by alloy randomness resulting from intermixing of InAs quantum-dot material with the surrounding InP matrix. Alloying randomizes, and to some degree flattens the shape dependence of fine-structure splitting giving a practical justification for the application of simplified theories. Finally, we find that the dark-exciton spectra are rather weakly affected by alloying and are dominated by the effects of lateral elongation.
A Markov chain model of particle deposition in the lung
Authors: Sonnenberg Adam H. , Herrmann Jacob , Grinstaff Mark W. , Suki Béla
Published: August 2020

Particle deposition in the lung during inhalation is of interest to a wide range of biomedical sciences due to the noninvasive therapeutic route to deliver drugs to the lung and other organs via the blood stream. Before reaching the alveoli, particles must transverse the bifurcating network of airways. Computational fluid mechanical studies are often used to estimate high-fidelity flow patterns through the large conducting airways, but there is a need for reduced-dimensional modeling that enables rapid parameter optimization while accommodating the complete airway network. Here, we introduce a Markov chain model with each state corresponding to an airway segment in which a particle may be located. The local flows and transition probabilities of the Markov chain, verified against computational fluid dynamics simulations, indicate that the independent effects of three fundamental forces (gravity, fluid drag, diffusion) provide a sufficient approximation of overall particle behavior. The model enables fast computation of how different inhalation strategies, called flow policies, determine total particle escape rates and local particle deposition. In a 3-dimensional airway tree model, the optimal flow policy minimizing the risk of deposition at each generation, compared to other inlet flow waveforms, predicted significantly higher probability of escape defined as the fraction of particles exiting the tree. The model also predicts a small influence of body orientation with respect to a gravitational field on total escape probability, but a significant effect of airway narrowing on regional deposition. In summary, this model provides insight into inhalation strategies for targeted drug delivery.
Background choice and immobility as context dependent tadpole responses to perceived predation risk
Authors: Eterovick Paula Cabral , Kloh Jéssica Stephanie , Figueredo Cleber Cunha , Viana Pedro Igor Macário , Goulart Marcella , Milan David Travassos , Fonseca Melissa Bravo , Martins Ítalo Moreira , Pinheiro Luan Tavares , Quintão Rúbia Praxedes , Melo Thais Kelly Fagundes , Magalhães Rodolfo Assis , Campos Caio Motta , Ferreira Vanessa Cristina Monteiro , de Oliveira Ana Laura , Vences Miguel
Published: August 2020

The association of immobility and camouflage is widespread as a defensive mechanism in prey from varied taxa. However, many experiments assessing the reaction of prey to predator cues are conducted under artificial laboratory conditions. In a previous experiment we observed the tadpoles of Ololygon machadoi (Hylidae) to respond to predator visual and/or chemical cues by choosing backgrounds that improve their disruptive properties, but detected no associated reduction of movement. Here we experimentally demonstrate this response in the species' natural habitat, on backgrounds where the tadpoles are likely to achieve their best camouflage. We also tested whether previous experiences could influence both background choice and immobility in O. machadoi tadpoles. These novel experimental results suggest that a defensive behavior—i.e., reduction of movement—in these tadpoles is more strongly expressed under the natural conditions where they evolved, compared to laboratory conditions where prey and predator were brought into closer contact. Besides, previous experiences are likely to play an important role in expressed defensive responses.
Seasonal variation in tap water δ2H and δ18O isotopes reveals two tap water worlds
Authors: de Wet Ruan F. , West Adam G. , Harris Chris
Published: August 2020

Stable isotope ratios of hydrogen and oxygen (δ2H and δ18O) in tap water provide important insights into the way that people interact with and manage the hydrological cycle. Understanding how these interactions vary through space and time allows for the management of these resources to be improved, and for isotope data to be useful in other disciplines. The seasonal variation of δ2H and δ18O in tap water within South Africa was assessed to identify municipalities that are supplied by seasonally invariant sources that have long residence periods, such as groundwater, and those supplied by sources that vary seasonally in a manner consistent with evapoconcentration, such as surface water—the proposed two tap water “worlds”. Doing so allows for the cost-effective spatial interpolation of δ2H and δ18O values that likely reflect that of groundwater, removing the residual error introduced by other sources that are dependent on discrete, isolated factors that cannot be spatially generalised. Applying the proposed disaggregation may also allow for the efficient identification of municipalities that are dependent on highly variable or depleted surface water resources, which are more likely to be vulnerable to climate and demographic changes.
Enhanced electrochemical performance of lithia/Li2RuO3 cathode by adding tris(trimethylsilyl)borate as electrolyte additive
Authors: Lee Byeong Gwan , Park Yong Joon
Published: August 2020

In this study, we used tris(trimethylsilyl)borate (TMSB) as an electrolyte additive and analysed its effect on the electrochemical performance of lithia-based (Lithia/Li2RuO3) cathodes. Our investigation revealed that the addition of TMSB modified the interfacial reactions between a lithia-based cathode and an electrolyte composed of the carbonate solvents and the LiPF6salt. The decomposition of the LiPF6salt and the formation of Li2CO3and -CO2was successfully reduced through the use of TMSB as an electrolyte additive. It is inferred that the protective layer derived from the TMSB suppressed the undesirable side reaction associated with the electrolyte and superoxides (O-or O0.5-) formed in the cathode structure during the charging process. This led to the reduction of superoxide loss through side reactions, which contributed to the increased available capacity of the Lithia/Li2RuO3cathode with the addition of TMSB. The suppression of undesirable side reactions also decreased the thickness of the interfacial layer, reducing the impedance value of the cells and stabilising the cyclic performance of the lithia-based cathode. This confirmed that the addition of TMSB was an effective approach for the improvement of the electrochemical performance of cells containing lithia-based cathodes.
Metformin reduces saturated fatty acid-induced lipid accumulation and inflammatory response by restoration of autophagic flux in endothelial cells
Authors: Kim Hae-Suk , Ren Guang , Kim Teayoun , Bhatnagar Sushant , Yang Qinglin , Bahk Young Yil , Kim Jeong-a
Published: August 2020

Autophagy, an integral part of the waste recycling process, plays an important role in cellular physiology and pathophysiology. Impaired autophagic flux causes ectopic lipid deposition, which is defined as the accumulation of lipids in non-adipose tissue. Ectopic lipid accumulation is observed in patients with cardiometabolic syndrome, including obesity, diabetes, insulin resistance, and cardiovascular complications. Metformin is the first line of treatment for type 2 diabetes, and one of the underlying mechanisms for the anti-diabetic effect of metformin is mediated by the stimulation of AMP-activated protein kinase (AMPK). Because the activation of AMPK is crucial for the initiation of autophagy, we hypothesize that metformin reduces the accumulation of lipid droplets by increasing autophagic flux in vascular endothelial cells. Incubation of vascular endothelial cells with saturated fatty acid (SFA) increased the accumulation of lipid droplets and impaired autophagic flux. We observed that the accumulation of lipid droplets was reduced, and the autophagic flux was enhanced by treatment with metformin. The knock-down of AMPKα by using siRNA blunted the effect of metformin. Furthermore, treatment with SFA or inhibition of autophagy increased leukocyte adhesion, whereas treatment with metformin decreased the SFA-induced leukocyte adhesion. The results suggest a novel mechanism by which metformin protects vascular endothelium from SFA-induced ectopic lipid accumulation and pro-inflammatory responses. In conclusion, improving autophagic flux may be a therapeutic strategy to protect endothelial function from dyslipidemia and diabetic complications.
Effect of hardening and sealing on color of chemically colored stainless steel
Authors: Ji Keming , Ju Hongbin , Xun Jiayao , Su Yuan , Zhang Kan , Liu Ping , Xue Yongqiang
Published: August 2020

A light reflection device combined with visible light spectrophotometer was used to measure the reflectance–wavelength curves of colored stainless steel after coloring, hardening and sealing. After these processes, the coordinate in CIE 1931 color coordinate system and brightness of samples were confirmed by chromatometry method, and the effects of hardening and sealing processes on color were determined. In hardening process, the thickness of coloring film increases significantly, the peaks of reflectance–wavelength curves move to the long-wave region, the hue of samples changes clockwise in CIE 1931 coordinate diagram, and the trend of saturation in hardening process is consistent with the saturation of the sample having larger potential difference. In sealing process, the thickness of film increases slightly, the peaks of reflectance–wavelength curves move to the long-wave region, the reflectivity and brightness of samples increase, the hue of samples moves clockwise in CIE 1931 coordinate diagram, and the saturation of some samples decreases.
Short and long-term evaluation of the impact of proton minibeam radiation therapy on motor, emotional and cognitive functions
Authors: Lamirault Charlotte , Doyère Valérie , Juchaux Marjorie , Pouzoulet Frederic , Labiod Dalila , Dendale Remi , Patriarca Annalisa , Nauraye Catherine , Le Dudal Marine , Jouvion Grégory , Hardy David , Massioui Nicole El , Prezado Yolanda
Published: August 2020

Radiotherapy (RT) is one of the most frequently used methods for cancer treatment. Despite remarkable advancements in RT techniquesthe treatment of radioresistant tumours (i.e. high-grade gliomas) is not yet satisfactory. Finding novel approaches less damaging for normal tissues is of utmost importance. This would make it possible to increase the dose applied to tumours, resulting in an improvement in the cure rate. Along this line, proton minibeam radiation therapy (pMBRT) is a novel strategy that allows the spatial modulation of the dose, leading to minimal damage to brain structures compared to a high dose (25 Gy in one fraction) of standard proton therapy (PT). The aim of the present study was to evaluate whether pMBRT also preserves important cerebral functions. Comprehensive longitudinal behavioural studies were performed in irradiated (peak dose of 57 Gy in one fraction) and control rats to evaluate the impact of pMBRT on motor function (motor coordination, muscular tonus, and locomotor activity), emotional function (anxiety, fear, motivation, and impulsivity), and cognitive function (learning, memory, temporal processing, and decision making). The evaluations, which were conducted over a period of 10 months, showed no significant motor or emotional dysfunction in pMBRT-irradiated rats compared with control animals. Concerning cognitive functions, similar performance was observed between the groups, although some slight learning delays might be present in some of the tests in the long term after irradiation. This study shows the minimal impact of pMBRT on the normal brain at the functional level.
The proteomic analysis of breast cell line exosomes reveals disease patterns and potential biomarkers
Authors: Risha Yousef , Minic Zoran , Ghobadloo Shahrokh M. , Berezovski Maxim V.
Published: August 2020

Cancer cells release small extracellular vesicles, exosomes, that have been shown to contribute to various aspects of cancer development and progression. Differential analysis of exosomal proteomes from cancerous and non-tumorigenic breast cell lines can provide valuable information related to breast cancer progression and metastasis. Moreover, such a comparison can be explored to find potentially new protein biomarkers for early disease detection. In this study, exosomal proteomes of MDA-MB-231, a metastatic breast cancer cell line, and MCF-10A, a non-cancerous epithelial breast cell line, were identified by nano-liquid chromatography coupled to tandem mass spectrometry. We also tested three exosomes isolation methods (ExoQuick, Ultracentrifugation (UC), and Ultrafiltration–Ultracentrifugation) and detergents (n-dodecyl β-d-maltoside, Triton X-100, and Digitonin) for solubilization of exosomal proteins and enhanced detection by mass spectrometry. A total of 1,107 exosomal proteins were identified in both cell lines, 726 of which were unique to the MDA-MB-231 breast cancer cell line. Among them, 87 proteins were predicted to be relevant to breast cancer and 16 proteins to cancer metastasis. Three exosomal membrane/surface proteins, glucose transporter 1 (GLUT-1), glypican 1 (GPC-1), and disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), were identified as potential breast cancer biomarkers and validated with Western blotting and high-resolution flow cytometry. We demonstrated that exosomes are a rich source of breast cancer-related proteins and surface biomarkers that may be used for disease diagnosis and prognosis.