bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlating Navigation Barriers on Web 2.0 with Accessibility Guidelines
Authors: Pereira Letícia Seixas , Archambault Dominique
Published: June 2018

The constant emergence of new resources and interaction possibilities brought by web 2.0 brings a constant urge of keeping in track how those new elements can affect the interaction of people with disabilities and how far current re-search has managed to address existing problems. This paper presents the results of an empirical study designed to gather navigation barriers affecting blind people when interacting with some widely used web widgets – such as Popup windows, Auto Suggest Lists, etc. The aim is to correlate those barriers with WCAG 2.0 and ARIA guidelines. From this point of view, it is possible to determine which barriers are being covered by current guide-lines and which ones are still on the wild. As conducting users’ evaluations are really costly, the more barriers can be eliminated beforehand, the more useful those sessions can be.
A Public Barrier Tracker to Support the Web Accessibility Directive
Authors: Alarcon Diane , Andreasson Kim , Mucha Justyna , Nietzio Annika , Sawicka Agata , Snaprud Mikael
Published: June 2018

In this paper we propose the Public Barrier Tracker (PBT) – a comprehensive solution that supports both filing and handling of user feedback on web accessibility. We give an overview of some existing approaches for gathering user feedback on accessibility barriers and outline the PBT functionality. The PBT can also offer further support for the implementation of the WAD: The collected data could be useful for monitoring and reporting as well as the enforcement mechanism.
Levumi: A Web-Based Curriculum-Based Measurement to Monitor Learning Progress in Inclusive Classrooms
Authors: Jungjohann Jana , DeVries Jeffrey M. , Gebhardt Markus , Mühling Andreas
Published: June 2018

Our paper introduces and assesses the Levumi platform’s web-based assessment of reading fluency. One challenges of inclusive education is meeting the needs of the learners with special education needs (SEN). Children with SEN and other risk factors face an increased risk of failing in schools and manifesting academic and social problems over the time. Web-based curriculum-based measurement (CBM) can provide an effective tool to track progress of learners and limit such risks. In particular, it can ease the challenges of test administration in inclusive classrooms through automation and providing multiple difficulty levels without the need of different paper-forms. Furthermore, Levumi can help educators track children and thus provide support for learners. Levumi takes advantage of the strengths of web-based CBM to assess reading fluency in primary school students. We confirmed the reading fluency test’s test-retest reliability (n = 334), its ability to measure learning over time in individual learners with SEN (n = 8, across 14 MPs), and its applicability to learners with SEN (n = 300, including n = 46 with SEN). We evaluate Levumi’s overall usefulness in assessing different types of learners, and discuss its contributions to CBM research.
How to Use Plain and Easy-to-Read Language for a Positive User Experience on Websites
Authors: Vollenwyder Beat , Schneider Andrea , Krueger Eva , Brühlmann Florian , Opwis Klaus , Mekler Elisa D.
Published: June 2018

Plain Language and Easy-to-Read Language are two approaches to reduce language complexity, which are also applied in the context of Web Accessibility. While Easy-to-Read Language was specifically designed to meet the needs of people with cognitive and learning disabilities, benefits for users with a variety of abilities have been reported. However, studies have also found unintended side-effects on non-disabled users, such as reduced text liking and intention to revisit a website compared to variants in conventional language. The present study addresses this issue by testing two approaches combining conventional with Easy-to-Read Language against a Plain Language variant, as well as a control group in conventional language. In an online study, 308 non-disabled participants read three texts presented in one of the four language variants. Measurements of performance indicators as well as subjective responses show that Easy-to-Read language may be implemented without unintended side-effects.
Localization Scheme of Assistive Tools for Print-Disabled People to Access STEM Contents
Authors: Yamaguchi Katsuhito , Suzuki Masakazu
Published: June 2018

To facilitate the spread of accessible e-books, especially books in STEM much more in developing countries, an efficient/systematic scheme to localize producing/reading tools should be established. Here, multilingual support in our tool to produce accessible STEM contents and problems in localizing it are discussed. Our new localization scheme and the localization for Vietnamese as a model case are shown.
First Do No Harm: Predicting Surgical Morbidity During Humanitarian Medical Missions
Authors: Berger Jonathan H. , Jiang Zhengran , O’Reilly Eamon B. , Christman Matthew S.
Published: June 2018

Background

Despite good intentions, humanitarian surgical missions are unavoidably linked to some degree of complication. We hypothesized that the American College of Surgeons Surgical Risk Calculator (ACS‐SRC) could estimate the risk of complications of procedures performed during the US Navy’s Pacific Partnership 2015 (PP15) mission.

Methods

Patient information and surgical details recorded during PP15 were entered into the ACS‐SRC. Risks of complications for each procedure were calculated. Receiver operating characteristics and Brier scores were calculated to compare the predicted outcomes to the observed complications.

Results

Of the 174 unique procedures performed during PP15 (representing 465 patients), 99 were found in the ACS‐SRC (representing 256 patients). Risk calculations for PP15 were: 1.5% risk (IQR 0.9, 2.4) of “serious” complications and 2.0% risk (IQR 1.3, 2.8) of “any” complication. ACS‐SRC specific risks were calculated as follows: pneumonia 0.1%, cardiac 0.0%, surgical site infection (SSI) 0.6%, urinary tract infection 0.2%, venous thromboembolism 0.1%, renal failure 0.0%, OR return 0.9%, and death 0.0%. The only specific ACS‐SRC complication observed was “OR return” (0.35%) and SSI (0.35%). The observed PP15 rates for “serious” or “any” complications (ACS‐SRC definition) were 0.70% (2/285) each. Receiver operating characteristics for ACS‐SRC for predicting “serious” or “any” complication were 0.743 (p = 0.118) and 0.654 (p = 0.227), respectively.

Conclusions

Although the ACS‐SRC over‐predicted risk compared to observed outcomes, it may offer a good starting point for humanitarian surgery risk calculation. Observed outcomes may be limited by loss‐to‐follow‐up bias. Emphasis should be placed on establishing patient follow‐up as part of humanitarian surgical mission planning and execution.
Application of Lean principles and software solutions for maintenance records in continuing airworthiness management organisations
Authors: Shakir H. M. , Iqbal B.
Published: June 2018

This paper discusses how the processes of Continuing Airworthiness Management Organisations can be made more efficient by applying Lean principles and digital solutions, to obtain costs savings and improved compliance standards. Lean management is the process of eliminating waste by maximising value through balancing workloads and cutting out inefficient processes. Though Lean was initially applied to manufacturing production lines, an opportunity exists to apply the principles of Lean in airworthiness management. One such aspect of airworthiness management is the processing of records which is an essential part of safety and compliance. Software solutions designed with Lean philosophy and focus on airworthiness management processes can provide benefits in managing the flow of records and extracting actionable information from them for cost reduction and improving safety. Further value can be extracted by applying additional software solutions that will lay a strong foundation for machine learning and predictive analytics – taking aircraft maintenance from a reactive model towards a proactive model.
An exploratory study of Clinical and Translational Science Award community-engaged research training programs
Authors: Ziegahn Linda , Nevarez Lucinda , Hurd Thelma , Evans Jill , Joosten Yvonne , Dumbauld Jill , Eder Milton “Mickey”
Published: June 2018

Background

The Clinical and Translational Science Award (CTSA) institutions are increasing development of training programs in community-engaged research (CEnR) to support translational science.

Methods

This study sampled posters at CTSA national meetings to identify CEnR training approaches, topics, and outcomes.

Results

Qualitative analysis of 30 posters revealed training topics and outcomes focused primarily on CEnR capacity building, overcoming barriers, systems change, and sustainability.

Conclusion

Further research should focus on development and results of CTSA CEnR training program metrics.
Vitamin D supplementation and inflammatory and metabolic biomarkers in patients with knee osteoarthritis: post hoc analysis of a randomised controlled trial
Authors: Zheng Shuang , Wang Bing , Han Weiyu , Zhu Zhaohua , Wang Xia , Jin Xingzhong , Antony Benny , Cicuttini Flavia , Wluka Anita , Winzenberg Tania , Aitken Dawn , Blizzard Leigh , Jones Graeme , Ding Changhai
Published: June 2018

The aim of this study was to determine whether vitamin D supplementation and maintaining vitamin D sufficiency are associated with changes in inflammatory and metabolic biomarkers in patients with knee osteoarthritis (OA) and vitamin D deficiency. A total of 413 participants with symptomatic knee OA and vitamin D deficiency were enrolled in a randomised, placebo-controlled trial and received 1·25 mg vitamin D3 or placebo monthly for 24 months across two sites. In this post hoc analysis, 200 participants from one site (ninety-four from the placebo group and 106 from the vitamin D group; mean age 63·1 (sd 7·3) years, 53·3 % women) were randomly selected for measurement of serum levels of inflammatory and metabolic biomarkers at baseline and 24 months using immunoassays. In addition, participants were classified into two groups according to serum 25-hydroxyvitamin D (25(OH)D) levels at months 3 and 24: (1) not consistently sufficient (25(OH)D≤50 nmol/l at either month 3 or 24, n 61), and (2) consistently sufficient (25(OH)D>50 nmol/l at both months 3 and 24, n 139). Compared with placebo, vitamin D supplementation had no significant effect on change in serum high-sensitive C-reactive protein, IL-6, IL-8, IL-10, leptin, adiponectin, resistin, adipsin and apelin. Being consistently vitamin D sufficient over 2 years was also not associated with changes in these biomarkers compared with not being consistently sufficient. Vitamin D supplementation and maintaining vitamin D sufficiency did not alter serum levels of inflammatory and metabolic biomarkers over 2 years in knee OA patients who were vitamin D insufficient, suggesting that they may not affect systemic inflammation in knee OA patients.
Effect of liquid ubiquinol supplementation on glucose, lipids and antioxidant capacity in type 2 diabetes patients: a double-blind, randomised, placebo-controlled trial
Authors: Yen Chi-Hua , Chu Ying-Ju , Lee Bor-Jen , Lin Yi-Chin , Lin Ping-Ting
Published: June 2018

Ubiquinone is a lipid antioxidant, and a novel liquid ubiquinol (a hydro-soluble, reduced form of coenzyme Q10) supplement was recently developed. The purpose of this study was to examine the levels of glucose, lipids and antioxidant capacity of type 2 diabetes patients after liquid ubiquinol supplementation. This study was designed as a randomised, double-blind, placebo-controlled trial. In all, fifty participants were randomly assigned to a placebo (n 25) or liquid ubiquinol (100 mg/d, n 25) group, and the intervention lasted for 12 weeks. Plasma coenzyme Q10, glucose homoeostasis parameters, lipid profiles, oxidative stress and antioxidative enzyme activities were measured during the study. After 12 weeks of supplementation, glyco Hb (HbA1c) value was significantly decreased in the liquid ubiquinol group (P=0·03), and subjects in the liquid ubiquinol group had significantly lower anti-glycaemic medication effect scores (MES) compared with those in the placebo group (P=0·03). The catalase (P<0·01) and glutathione peroxidase (P=0·03) activities were increased significantly after supplementation. Plasma coenzyme Q10 was correlated with the insulin level (P=0·05), homoeostatic model assessment-insulin resistance (P=0·07), quantitative insulin sensitivity check index (P=0·03) and the anti-hyperglycaemic agents’ MES (P=0·03) after supplementation. Lipid profiles did not change after supplementation; however, the subjects in the placebo group had a significantly lower level of HDL-cholesterol after 12 weeks of intervention. In conclusion, oral intake of 100 mg/d liquid ubiquinol might benefit type 2 diabetes patients by increasing antioxidant enzyme activity levels, reducing HbA1c levels and maintaining HDL-cholesterol levels.
Expression of the candidate fat taste receptors in human fungiform papillae and the association with fat taste function
Authors: Liu Dongli , Costanzo Andrew , Evans Margaret D. M. , Archer Nicholas S. , Nowson Caryl , Duesing Konsta , Keast Russell
Published: June 2018

Significant experimental evidence supports fat as a taste modality; however, the associated peripheral mechanisms are not well established. Several candidate taste receptors have been identified, but their expression pattern and potential functions in human fungiform papillae remain unknown. The aim of this study is to identify the fat taste candidate receptors and ion channels that were expressed in human fungiform taste buds and their association with oral sensory of fatty acids. For the expression analysis, quantitative RT-PCR (qRT-PCR) from RNA extracted from human fungiform papillae samples was used to determine the expression of candidate fatty acid receptors and ion channels. Western blotting analysis was used to confirm the presence of the proteins in fungiform papillae. Immunohistochemistry analysis was used to localise the expressed receptors or ion channels in the taste buds of fungiform papillae. The correlation study was analysed between the expression level of the expressed fat taste receptors or ion channels indicated by qRT-PCR and fat taste threshold, liking of fatty food and fat intake. As a result, qRT-PCR and western blotting indicated that mRNA and protein of CD36, FFAR4, FFAR2, GPR84 and delayed rectifying K+channels are expressed in human fungiform taste buds. The expression level ofCD36was associated with the liking difference score (R−0·567,β=−0·04,P=0·04) between high-fat and low-fat food andFFAR2was associated with total fat intake (ρ=−0·535,β=−0·01,P=0·003) and saturated fat intake (ρ=−0·641,β=−0·02,P=0·008).
Voluntary fortification is ineffective to maintain the vitamin B12and folate status of older Irish adults: evidence from the Irish Longitudinal Study on Ageing (TILDA)
Authors: Laird Eamon J. , O’Halloran Aisling M. , Carey Daniel , O’Connor Deirdre , Kenny Rose A. , Molloy Anne M.
Published: June 2018

Mandatory fortification of staple grains with folic acid and/or vitamin B12(B12) is under debate in many countries including Ireland, which has a liberal, but voluntary, fortification policy. Older adults can be at risk of both deficiency and high folate status, although little is known on the actual prevalence and the major predictors. Population prevalence estimates from older adults (n5290 ≥50 years) from the Irish Longitudinal Study on Ageing (TILDA) (Wave 1) are presented here. Measures included plasma total vitamin B12and folate, whereas predictors included detailed demographic, socio-economic, geographic, seasonal and health/lifestyle data. The prevalence of deficient or low B12status (<185 pmol/l) was 12 %, whereas the prevalence of deficient/low folate status was 15 %. High folate status (>45 nmol/l) was observed in 8·9 %, whereas high B12status was observed in 3·1 % (>601 pmol/l). The largest positive predictor of B12concentration was self-reported B12injection and/or supplement use (coefficient 51·5 pmol/; 95 % CI 9·4, 93·6;P=0·016) followed by sex and geographic location. The largest negative predictor was metformin use (−33·6; 95 % CI −51·9, −15·4;P<0·0001). The largest positive predictor of folate concentration was folic acid supplement use (6·0; 95 % CI 3·0, 9·0 nmol/l;P<0·001) followed by being female and statin medications. The largest negative predictor was geographic location (−5·7; 95 % CI −6·7, −4·6;P<0·0001) followed by seasonality and smoking. B-vitamin status in older adults is affected by health and lifestyle, medication, sampling period and geographic location. We observed a high prevalence of low B12and folate status, indicating that the current policy of voluntary fortification is ineffective for older adults.
ON DEGENERATE SIGMA-FUNCTIONS IN GENUS 2
Authors: BERNATSKA JULIA , LEYKIN DMITRY
Published: June 2018

We obtain explicit expressions for genus 2 degenerate sigma-function in terms of genus 1 sigma-function and elementary functions as solutions of a system of linear partial differential equations satisfied by the sigma-function. By way of application, we derive a solution for a class of generalized Jacobi inversion problems on elliptic curves, a family of Schrödinger-type operators on a line with common spectrum consisting of a point and two segments, explicit construction of a field of three-periodic meromorphic functions. Generators of rank 3 lattice in ℂ2are given explicitly.
The EC/EU between the Art of Forgetting and the Palimpsest of Empire
Authors: Pasture Patrick
Published: June 2018

The history of European integration is usually presented as both a peace project and an economic endeavour. What is largely ignored is that it also had a colonial dimension. This article first recalls this largely forgotten history, asking why and how it could be erased from memory. It then explores ways in which the EU and its predecessors constituted a new postcolonial identity and how colonial legacies somehow reappear in policies and representations.
Multilink for bilingual language production
Authors: IVANOVA IVA , KLEINMAN DANIEL
Published: June 2018

A major benefit of computational models is their ability to demonstrate which theoretical assumptions are truly necessary to explain a pattern of data. Dijkstra, Wahl, Buytenhuijs, van Halem, Al-jibouri, de Korte, and Rekké (in press) have impressively shown with Multilink that it is possible to account for a range of findings from bilingual lexical decision, word naming, and forward and backward translation tasks with an integrated lexicon, without lateral connections between translation equivalents, and without inhibition. In this commentary, we consider the applicability of the current model to other multilingual language production tasks, and note where the model's assumptions might need revision as its scope is expanded.
Solar‐Induced Fluorescence Detects Interannual Variation in Gross Primary Production of Coniferous Forests in the Western United States
Authors: Zuromski Lauren M. , Bowling David R. , Köhler Philipp , Frankenberg Christian , Goulden Michael L. , Blanken Peter D. , Lin John C.
Published: June 2018

Quantifying gross primary production (GPP), the largest flux of the terrestrial carbon cycle, remains difficult at the landscape scale. Evergreen needleleaf (coniferous) forests in the western United States constitute an important carbon reservoir whose annual GPP varies from year‐to‐year due to drought, mortality, and other ecosystem disturbances. Evergreen forest productivity is challenging to determine via traditional remote sensing indices (i.e., NDVI and EVI), because detecting environmental stress conditions is difficult. We investigated the utility of solar‐induced chlorophyll fluorescence (SIF) to detect year‐to‐year variation in GPP in four coniferous forests varying in species composition in the western United States (Sierra Nevada, Cascade, and Rocky Mountains). We show that annually averaged, satellite‐based observations of SIF (retrieved from GOME‐2) were significantly correlated with annual GPP observed at eddy covariance towers over several years. Further, SIF responded quantitatively to drought‐induced mortality, suggesting that SIF may be capable of detecting ecosystem disturbance in coniferous forests.
Self‐Consistent Modeling of Electron Precipitation and Responses in the Ionosphere: Application to Low‐Altitude Energization During Substorms
Authors: Yu Yiqun , Jordanova Vania K. , McGranaghan Ryan M. , Solomon Stanley C.
Published: June 2018

We report a new modeling capability that self‐consistently couples physics‐based magnetospheric electron precipitation with its impact on the ionosphere. Specifically, the ring current model RAM‐SCBE is two‐way coupled to an ionospheric electron transport model GLOW (GLobal airglOW), representing a significant improvement over previous models, in which the ionosphere is either treated as a 2‐D spherical boundary of the magnetosphere or is driven by empirical precipitation models that are incapable of capturing small‐scale, transient variations. The new model enables us to study the impact of substorm‐associated, spectrum‐resolved electron precipitation on the 3‐D ionosphere. We found that after each substorm injection, a high‐energy tail of precipitation is produced in the dawn sector outside the plasmapause, by energetic electrons (10 < E < 100 keV) scattered by whistler‐mode chorus waves. Consequently, an ionospheric sublayer characterized by enhanced Pedersen conductivity arises at unusually low altitude (∼85 km), with its latitudinal width of ∼5–10° in the auroral zone. The sublayer structure appears intermittently, in correlation with recurrent substorm injections. It propagates eastward from the nightside to the dayside in the same drift direction of source electrons injected from the plasma sheet, resulting in global impact within the ionosphere. This study demonstrates the model's capability of revealing complex cross‐scale interactions in the geospace environment.
How Uneven Are Changes to Impact‐Relevant Climate Hazards in a 1.5 °C World and Beyond?
Authors: Harrington Luke J. , Frame Dave , King Andrew D. , Otto Friederike E. L.
Published: June 2018

In the last decade, climate mitigation policy has galvanized around staying below specified thresholds of global mean temperature, with an understanding that exceeding these thresholds may result in dangerous interference of the climate system. United Nations Framework Convention on Climate Change texts have developed thresholds in which the aim is to limit warming to well below 2 °C of warming above preindustrial levels, with an additional aspirational target of 1.5 °C. However, denoting a specific threshold of global mean temperatures as a target for avoiding damaging climate impacts implicitly obscures potentially significant regional variations in the magnitude of these projected impacts. This study introduces a simple framework to quantify the magnitude of this heterogeneity in changing climate hazards at 1.5 °C of warming, using case studies of emergent increases in temperature and rainfall extremes. For example, we find that up to double the amount of global warming (3.0 °C) is needed before people in high‐income countries experience the same relative changes in extreme heat that low‐income nations should anticipate after only 1.5 °C of warming. By mapping how much warming is needed in one location to match the impacts of a fixed temperature threshold in another location, this “temperature of equivalence” index is a flexible and easy‐to‐understand communication tool, with the potential to inform where targeted support for adaptation projects should be prioritized in a warming world.
Regional Trends in Weather Systems Help Explain Antarctic Sea Ice Trends
Authors: Schemm Sebastian
Published: June 2018

In contrast to Arctic sea ice extent, Antarctic sea ice extent has increased since 1979. On a regional scale, however, the trends exhibit high spatial variability and are even of the opposite sign. This study examines connections between sea ice extent and the frequencies of extratropical cyclones and blocks. Consideration is given to regions that exhibit long‐term sea ice trends during spring and autumn. Significant connections exist in almost all examined regions. Typically, the region of maximum correlation is shifted upstream or downstream of the sea ice target region, which indicates that the 10‐m wind associated with the examined weather systems is the chief thermodynamic and dynamic agent underlying sea ice variability. Along the ice edge of the Weddell and Ross Seas, the correlation between springtime sea ice extent and cyclone frequencies displays a wave number 3 pattern. Eastward of the Ross Sea, along the transition into the Amundsen Sea, spring sea ice extent is connected to cyclone and blocking frequencies during spring and the preceding autumn. Westward of the Ross Sea, autumn sea ice extent is strongly connected to blocking frequencies during the preceding spring. For the Bellingshausen Sea, an inverse relationship exists between autumn cyclone frequencies and autumn sea ice extent. Significant cyclone and blocking trends that are consistent with long‐term sea ice trends exist in most examined regions. These findings point toward identifying regional trends in extratropical cyclone and blocking frequencies as a useful step toward a better understanding of couplings between Southern Hemisphere climate and regional trends in sea ice extent.
Correction: Author Correction: Thermogenesis-triggered seed dispersal in dwarf mistletoe
Authors: deBruyn Rolena A. J. , Paetkau Mark , Ross Kelly A. , Godfrey David V. , Church John S. , Friedman Cynthia Ross
Published: June 2018

Nature Communications 6: Article number: 6262 (2015); Published: 9 February 2015, Updated: 25 June 2018 John S. Church, who provided access to the FLIR E60 infrared camera and provided guidance in its use, was inadvertently omitted from the author list in the originally published version of this Article.
Correction: Publisher Correction: Abrupt cooling over the North Atlantic in modern climate models
Authors: Sgubin Giovanni , Swingedouw Didier , Drijfhout Sybren , Mary Yannick , Bennabi Amine
Published: June 2018

Nature Communications 8: Article number: 14375 (2017); Published online: 15 February 2017, Updated: 25 June 2018 The original HTML version of this Article omitted the article number; it should have been ‘14375’. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication.
Correction: Publisher Correction: Demonstration of qubit operations below a rigorous fault tolerance threshold with gate set tomography
Authors: Blume-Kohout Robin , Gamble John King , Nielsen Erik , Rudinger Kenneth , Mizrahi Jonathan , Fortier Kevin , Maunz Peter
Published: June 2018

Nature Communications 8: Article number: 14485 (2017); Published: 15 February 2017; Updated: 25 June 2018 The original HTML version of this Article omitted the article number; it should have been ‘14485’. This has now been corrected in the HTML version of the Article. The PDF version was correct from the time of publication.
Context-dependent AMPK activation distinctly regulates TAp73 stability and transcriptional activity
Authors: Li Dan , Dulloo Iqbal , Sabapathy Kanaga
Published: June 2018

TAp73, the homologue of the tumour suppressor p53, has dual roles in tumourigenesis: both as a tumour suppressor and as a promoter of tumour growth. We have recently shown that hypoxia, a condition prevalent in tumours, results in the stabilisation of TAp73 through a mechanism involving HIF-1α-mediated repression of the E3 ligase Siah1. Elevated TAp73 in turn regulates the angiogenic transcriptional programme, exemplified by vegf-A activation, thereby promoting angiogenesis and tumour growth. To further understand hypoxia-mediated TAp73 regulation, we have focused on the Adenosine monophosphate (AMP)-dependent protein kinase (AMPK) signalling pathway induced by hypoxia. We show that hypoxia-mediated AMPK activation is required for efficient TAp73 stabilisation, through multiple means by using AMPK-deficient cells or inhibiting its activity and expression. Conversely, direct AMPK activation using its activator AICAR is also sufficient to induce TAp73 stabilisation but this is independent of putative AMPK phosphorylation sites on TAp73, HIF-1α activation, and transcriptional repression of Siah1. Furthermore, while vegf-A up-regulation upon hypoxia requires AMPK, direct activation of AMPK by AICAR does not activate vegf-A. Consistently, supernatant from cells exposed to hypoxia, but not AICAR, was able to induce tube formation in HUVECs. These data therefore highlight that the processes of TAp73 stabilisation and transcriptional activation of angiogenic target genes by AMPK activation can be decoupled. Collectively, these results suggest that the context of AMPK activation determines the effect on TAp73, and proposes a model in which hypoxia-induced TAp73 stabilisation occurs by parallel pathways converging to mediate its transactivation potential.
Macroevolution of gastric Helicobacter species unveils interspecies admixture and time of divergence
Authors: Smet Annemieke , Yahara Koji , Rossi Mirko , Tay Alfred , Backert Steffen , Armin Ensser , Fox James G , Flahou Bram , Ducatelle Richard , Haesebrouck Freddy , Corander Jukka
Published: June 2018

Since the discovery of the human pathogen Helicobacter pylori, various other Helicobacter species have been identified in the stomach of domesticated and wild mammals. To better understand the evolutionary history of these ecologically similar but genetically distinct species, we analyzed 108 gastric Helicobacter genomes and included 54 enterohepatic Helicobacter genomes for comparison purposes. An admixture analysis supported the presence of an ecological barrier, preventing the genetic exchange between the gastric and enterohepatic Helicobacter species, and unraveled many gene flow events within and across species residing in the stomach. As pets can be colonized by multiple gastric Helicobacter species, the genetic exchange between the canine and feline strains was evident, with H. heilmannii and H. bizzozeronii showing the highest interspecies recombination. An admixture between H. pylori (in particular, the ancestral African strains), H. acinonychis from wild felines and H. cetorum from marine mammals was also identified. Because these latter species do not share the same host, this phenomenon is most likely a remaining signal of shared ancestry. A reconstruction of the time of divergence of the gastric Helicobacter spp. revealed that the domestic animal-related Helicobacter species evolved in parallel with H. pylori and its two closest relatives (H. acinonychis and H. cetorum), rather than together.
NLRP3 inflammasome is expressed and regulated in human islets
Authors: Lebreton Fanny , Berishvili Ekaterine , Parnaud Géraldine , Rouget Caroline , Bosco Domenico , Berney Thierry , Lavallard Vanessa
Published: June 2018

NRLP3 inflammasome is a protein complex involved in the maturation of IL1β. In the onset of type 1 diabetes as well as in islet transplantation, IL-1β is one of the cytokines involved in the recruitment of immune cells in islets and eventually in islet destruction. Whether IL-1β is produced by islet cells is still under debate and NLRP3 inflammasome-dependent IL-1β production has not been yet determined in human islets. The aim of this study was to determine the expression and the regulation of the NRLP3 inflammasome in human islets. Human islets were stimulated with LPS and successively with ATP (LPS + ATP) in the presence or absence of the inflammasome inhibitor glyburide. Islets were also incubated in hypoxic or normoxic conditions for 24 h in the presence or absence of glyburide. Then, IL1B and NLRP3 expression was studied by real time PCR, protein expression by western blot, protein localization by immunofluorescence and protein secretion by ELISA. LPS + ATP increased gene expression of NRLP3 and IL1B. Glyburide partially prevented this effect. IL-1β protein was localized in β and non-β cells. Moreover, LPS + ATP increased IL-1β protein expression and production, which were prevented by glyburide. Hypoxia increased gene expression of NRLP3 and IL1B and induced IL-1β and caspase-1 production. Finally, hypoxia-induced cell death which was not prevented by inhibition of NLRP3 inflammasome. NRLP3 inflammasome is expressed and plays a role in IL-1β production by human islets. By contrast, NRLP3 inflammasome activation is not involved in islet cell death induced by hypoxia.
Author Correction: Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin
Authors: DeWaal Dannielle , Nogueira Veronique , Terry Alexander R. , Patra Krushna C. , Jeon Sang-Min , Guzman Grace , Au Jennifer , Long Christopher P. , Antoniewicz Maciek R. , Hay Nissim
Published: June 2018

In the originally published version of this Article, the colours of the bars in Fig. 4b were inadvertently switched during the production process, such that ‘HK2-Dox’ and ‘HK2+Dox’ were depicted in red and ‘Nt-Dox’ and ‘Nt+Dox’ were depicted in blue. These errors have now been corrected in both the PDF and HTML versions of the Article.
Osteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin
Authors: Stegen Steve , Stockmans Ingrid , Moermans Karen , Thienpont Bernard , Maxwell Patrick H. , Carmeliet Peter , Carmeliet Geert
Published: June 2018

Preservation of bone mass is crucial for healthy ageing and largely depends on adequate responses of matrix-embedded osteocytes. These cells control bone formation and resorption concurrently by secreting the WNT/β-catenin antagonist sclerostin (SOST). Osteocytes reside within a low oxygen microenvironment, but whether and how oxygen sensing regulates their function remains elusive. Here, we show that conditional deletion of the oxygen sensor prolyl hydroxylase (PHD) 2 in osteocytes results in a high bone mass phenotype, which is caused by increased bone formation and decreased resorption. Mechanistically, enhanced HIF-1α signalling increases Sirtuin 1-dependent deacetylation of the Sost promoter, resulting in decreased sclerostin expression and enhanced WNT/β-catenin signalling. Additionally, genetic ablation of PHD2 in osteocytes blunts osteoporotic bone loss induced by oestrogen deficiency or mechanical unloading. Thus, oxygen sensing by PHD2 in osteocytes negatively regulates bone mass through epigenetic regulation of sclerostin and targeting PHD2 elicits an osteo-anabolic response in osteoporotic models.
Early-warning signals for Dansgaard-Oeschger events in a high-resolution ice core record
Authors: Boers Niklas
Published: June 2018

The Dansgaard–Oeschger (DO) events, as observed in oxygen isotope ratios from the North Greenland Ice Core Project (NGRIP) record, are an outstanding example of past abrupt climate transitions. Their physical cause remains debated, and previous research indicated that they are not preceded by classical early-warning signals (EWS). Subsequent research hypothesized that the DO events are caused by bifurcations of physical mechanisms operating at decadal timescales, and proposed to search for EWS in the high-frequency fluctuation levels. Here, a time series with 5-year resolution is obtained from the raw NGRIP record, and significant numbers of EWS in terms of variance and autocorrelation increases are revealed in the decadal-scale variability. Wavelet analysis indicates that the EWS are most pronounced in the 10–50-year periodicity band, confirming the above hypothesis. The DO events are hence neither directly noise-induced nor purely externally forced, which provides valuable constraints regarding potential physical causes.
Taxonomic and functional diversity change is scale dependent
Authors: Jarzyna Marta A. , Jetz Walter
Published: June 2018

Estimates of recent biodiversity change remain inconsistent, debated, and infrequently assessed for their functional implications. Here, we report that spatial scale and type of biodiversity measurement influence evidence of temporal biodiversity change. We show a pervasive scale dependence of temporal trends in taxonomic (TD) and functional (FD) diversity for an ~50-year record of avian assemblages from North American Breeding Bird Survey and a record of global extinctions. Average TD and FD increased at all but the global scale. Change in TD exceeded change in FD toward large scales, signaling functional resilience. Assemblage temporal dissimilarity and turnover (replacement of species or functions) declined, while nestedness (tendency of assemblages to be subsets of one another) increased with scale. Patterns of FD change varied strongly among diet and foraging guilds. We suggest that monitoring, policy, and conservation require a scale-explicit framework to account for the pervasive effect that scale has on perceived biodiversity change.
Understanding crystallization pathways leading to manganese oxide polymorph formation
Authors: Chen Bor-Rong , Sun Wenhao , Kitchaev Daniil A. , Mangum John S. , Thampy Vivek , Garten Lauren M. , Ginley David S. , Gorman Brian P. , Stone Kevin H. , Ceder Gerbrand , Toney Michael F. , Schelhas Laura T.
Published: June 2018

Hydrothermal synthesis is challenging in metal oxide systems with diverse polymorphism, as reaction products are often sensitive to subtle variations in synthesis parameters. This sensitivity is rooted in the non-equilibrium nature of low-temperature crystallization, where competition between different metastable phases can lead to complex multistage crystallization pathways. Here, we propose an ab initio framework to predict how particle size and solution composition influence polymorph stability during nucleation and growth. We validate this framework using in situ X-ray scattering, by monitoring how the hydrothermal synthesis of MnO2 proceeds through different crystallization pathways under varying solution potassium ion concentrations ([K+] = 0, 0.2, and 0.33 M). We find that our computed size-dependent phase diagrams qualitatively capture which metastable polymorphs appear, the order of their appearance, and their relative lifetimes. Our combined computational and experimental approach offers a rational and systematic paradigm for the aqueous synthesis of target metal oxides.
Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity
Authors: He Hongbin , Jiang Hua , Chen Yun , Ye Jin , Wang Aoli , Wang Chao , Liu Qingsong , Liang Gaolin , Deng Xianming , Jiang Wei , Zhou Rongbin
Published: June 2018

Oridonin (Ori) is the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens and has anti-inflammatory activity, but the target of Ori remains unknown. NLRP3 is a central component of NLRP3 inflammasome and has been involved in a wide variety of chronic inflammation-driven human diseases. Here, we show that Ori is a specific and covalent inhibitor for NLRP3 inflammasome. Ori forms a covalent bond with the cysteine 279 of NLRP3 in NACHT domain to block the interaction between NLRP3 and NEK7, thereby inhibiting NLRP3 inflammasome assembly and activation. Importantly, Ori has both preventive or therapeutic effects on mouse models of peritonitis, gouty arthritis and type 2 diabetes, via inhibition of NLRP3 activation. Our results thus identify NLRP3 as the direct target of Ori for mediating Ori’s anti-inflammatory activity. Ori could serve as a lead for developing new therapeutics against NLRP3-driven diseases.
Auditory cortical activity drives feedback-dependent vocal control in marmosets
Authors: Eliades Steven J. , Tsunada Joji
Published: June 2018

Vocal communication is a sensory-motor process requiring auditory self-monitoring to correct errors and to ensure accurate vocal production. When presented with altered speech feedback, humans rapidly change their speech to compensate. Although previous evidence has demonstrated suppression of auditory cortex during both speech and animal vocalization, the specific role of auditory cortex in such feedback-dependent control is unknown. Here we show the relationship between neural activity in the auditory cortex and feedback-dependent vocal control in marmoset monkeys. We demonstrate that marmosets, like humans, exhibit feedback control of vocal acoustics. We further show that feedback-sensitive activity of auditory cortex neurons predict such compensatory vocal changes. Finally, we demonstrate that electrical microstimulation of auditory cortex rapidly evokes similar changes in vocal production. These results are evidence for a causal role of auditory cortex in vocal self-monitoring and feedback-dependent control, and have implications for understanding human speech motor control.
Clustering huge protein sequence sets in linear time
Authors: Steinegger Martin , Söding Johannes
Published: June 2018

Metagenomic datasets contain billions of protein sequences that could greatly enhance large-scale functional annotation and structure prediction. Utilizing this enormous resource would require reducing its redundancy by similarity clustering. However, clustering hundreds of millions of sequences is impractical using current algorithms because their runtimes scale as the input set sizeNtimes the number of clustersK, which is typically of similar order asN, resulting in runtimes that increase almost quadratically withN. We developed Linclust, the first clustering algorithm whose runtime scales asN, independent ofK. It can also cluster datasets several times larger than the available main memory. We cluster 1.6 billion metagenomic sequence fragments in 10 h on a single server to 50% sequence identity, >1000 times faster than has been possible before. Linclust will help to unlock the great wealth contained in metagenomic and genomic sequence databases.
A moisture function of soil heterotrophic respiration that incorporates microscale processes
Authors: Yan Zhifeng , Bond-Lamberty Ben , Todd-Brown Katherine E. , Bailey Vanessa L. , Li SiLiang , Liu CongQiang , Liu Chongxuan
Published: June 2018

Soil heterotrophic respiration (HR) is an important source of soil-to-atmosphere CO2 flux, but its response to changes in soil water content (θ) is poorly understood. Earth system models commonly use empirical moisture functions to describe the HR–θ relationship, introducing significant uncertainty in predicting CO2 flux from soils. Generalized, mechanistic models that address this uncertainty are thus urgently needed. Here we derive, test, and calibrate a novel moisture function, fm, that encapsulates primary physicochemical and biological processes controlling soil HR. We validated fm using simulation results and published experimental data, and established the quantitative relationships between parameters of fm and measurable soil properties, which enables fm to predict the HR–θ relationships for different soils across spatial scales. The fm function predicted comparable HR–θ relationships with laboratory and field measurements, and may reduce the uncertainty in predicting the response of soil organic carbon stocks to climate change compared with the empirical moisture functions currently used in Earth system models.
Vapor sublimation and deposition to build porous particles and composites
Authors: Tung Hsing-Ying , Guan Zhen-Yu , Liu Ting-Yu , Chen Hsien-Yeh
Published: June 2018

The vapor deposition of polymers on regular stationary substrates is widely known to form uniform thin films. Here we report porous polymer particles with sizes controllable down to the nanometer scale can be produced using a fabrication process based on chemical vapor deposition (CVD) on a dynamic substrate, i.e., sublimating ice particles. The results indicate that the vapor deposition of a polymer is directed by the sublimation process; instead of forming a thin film polymer, the deposited polymers replicated the size and shape of the ice particle. Defined size and porosity of the polymer particles are controllable with respect to varying the processing time. Extendable applications are shown to install multiple functional sites on the particles in one step and to localize metals/oxides forming composite particles. In addition, one fabrication cycle requires approximately 60 min to complete, and potential scaling up the production of the porous particles is manageable.
Publisher Correction: Orbital angular momentum analysis for giant spin splitting in solids and nanostructures
Authors: Oh Sehoon , Choi Hyoung Joon
Published: June 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
The relationship of early recurrence of atrial fibrillation and the 3-month integrity of the ablation lesion set
Authors: Mujović Nebojša , Marinković Milan , Marković Nebojša , Vučićević Vera , Lip Gregory Y. H. , Bunch T. Jared , Potpara Tatjana S.
Published: June 2018

Early recurrence of atrial fibrillation (ERAF) after catheter-ablation (CA) can be a transient phenomenon due to inflammation, or a harbinger of late AF recurrence due to CA lesion (re)conduction. We studied the relationship between ERAF and the 3-month CA lesions integrity. Forty one consecutive AF patients who underwent a pulmonary vein isolation (PVI), roof line (RL) and mitral isthmus line (MIL) CA were enrolled. At 3 months all patients underwent invasive assessment of the lesion set integrity irrespective of ERAF. The PVI, RL and MIL ablation was successful in 100.0%, 95.1% and 82.9% patients, respectively. At the 3-month remapping, a gap in PVI-lesion(s), RL or MIL was identified in 61.0%, 31.7% and 36.6% patients, respectively. Patients with (n = 17, 41.5%) compared to those without ERAF (n = 24) had a significantly higher rate of any PV-reconnection (88.2% vs. 41.7%), the right PV(s)-reconnection (82.5% vs. 29.2%) and the RL gap (52.9% vs. 16.7%), as well as a higher number of reconnected right PVI-segments, all p < 0.05. On multivariate analysis, only the number of reconnected right PVI-segments was associated with ERAF (OR 4.26, p = 0.004). The ERAF following PVI + RL + MIL ablation was significantly related to 3-month PV-reconnections and the presence of RL gaps.
Mapping of brain tissue hematocrit in glioma and acute stroke using a dual autoradiography approach
Authors: Broisat A. , Lemasson B. , Ahmadi M. , Collomb N. , Bacot S. , Soubies A. , Fagret D. , Rémy C. , Ghezzi C. , Barbier E. L.
Published: June 2018

Hematocrit (Hct) determines the ability of blood to carry oxygen. While changes in systemic Hct are known to impact stroke or tumor control, changes in local (tissue) Hct (tHct) induced by these diseases have however received little attention. In this study, we evaluate tHct in acute stroke and in glioma models using a new approach to map tHct across the brain, a dual isotope autoradiography, based on injections of 125I-labeled albumin and 99mTc-lalbeled red blood cells in the same animal. For validation purpose, tHct was mapped in the rat brain (i) under physiological conditions, (ii) following erythropoietin injection, and (iii) following hemodilution. Then, tHct was then mapped in stroke (middle cerebral artery occlusion) and tumor models (9LGS and C6). The mean tHct values observed in healthy brains (tHct = 29 ± 1.3%), were modified as expected by erythropoietin (tHct = 36.7 ± 2.6%) and hemodilution (tHct = 24.2 ± 2.4%). Using the proposed method, we observed a local reduction, spatially heterogeneous, in tHct following acute stroke (tHct = 19.5 ± 2.5%) and in both glioma models (9LGS: tHct = 18.5 ± 2.3%, C6: tHct = 16.1 ± 1.2%). This reduction and this heterogeneity in tHct observed in stroke and glioma raises methodological issues in perfusion imaging techniques where tHct is generally overlooked and could impact therapeutic strategies.