bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Energy Switching Method Based on Asymmetric Binary Search Algorithm for SAR ADCs
Authors: Qu Weiyue , Zhao Jinqiang , Zhang Zhaofeng , Mei Niansong
Published: June 2019

An area-efficient and low-energy switching method for the successive approximation register (SAR) analogue-to-digital converters (ADCs) is proposed. Unlike most switching methods, the proposed switching method resolves the first three bits by using asymmetric binary search algorithm. Benefiting from the novel reference voltages – [Formula: see text], [Formula: see text](1/4[Formula: see text]), ground, this proposed switching method achieves 87.5% area reduction and 98.71% energy reduction over the conventional method. Furthermore, it also achieves good linearity.
IMPROVEMENT OF WEAR RESISTANCE OF SHREDDER BLADES USED IN A REFUSE-DERIVED FUEL (RDF) FACILITY BY PLASMA NITRIDING
Authors: AYDIN HAKAN , BOSTANCI FURKAN
Published: June 2019

Refuse-derived fuel (RDF) is a kind of renewable energy source to produce energy for replacement of fossil fuels. Aggressive working conditions in RDF facilities cause the shredder blades to wear out quickly. So, the purpose of this paper was to study the effect of plasma-nitriding process on wear resistance of shredder blades made of AISI D2 tool steel in the service condition of RDF facility. Shredder blades were commercially available from two different suppliers (A and B suppliers). These hardened shredder blades were plasma-nitrided in the mixed nitrogen and hydrogen atmosphere at a volume ratio of 3:1 at 450∘C for 12, 18 and 24[Formula: see text]h at a total pressure of 250 Pa. Characterisation of plasma-nitrided layers on the shredder blades was carried out by means of microstructure and microhardness measurements. Wear tests of plasma-nitrided shredder blades were performed under actual working conditions in the RDF facility. Wear analysis of these shredder blades was conducted using three-dimensional (3D) optical measuring instrument GOM ATOS II. The compositional difference of the shredder blades provided by A and B suppliers played an important role on the nitrided layer. The case depth of A-blades significantly increased with increasing plasma-nitriding time. However, the case depth of B-blades was fairly lower at the same nitriding time and only slightly increased with increasing plasma-nitriding time. Plasma-nitriding process significantly improved the surface hardness of the shredder blades. Maximum surface hardness values were achieved at nitriding time of 18 h for both blades. In this case, this increase in surface hardness values was above 100%. At nitriding time of 24[Formula: see text]h, the maximum surface hardness of A-blades significantly decreased, whereas this decrease in surface hardness of B-blades was the negligible value. The wear test results showed that plasma-nitriding process significatly decreased the wear of shredder blades; 18 h nitriding for A-blades and 24[Formula: see text]h nitriding for B-blades had better wear-reducing ability in the service condition of RDF facility. In these cases, the decreases in the total volume wear loss for A- and B-blades were 53% and 60%, respectively.
ON SPREAD OPTION PRICING USING TWO-DIMENSIONAL FOURIER TRANSFORM
Authors: ALFEUS MESIAS , SCHLÖGL ERIK
Published: June 2019

Spread options are multi-asset options with payoffs dependent on the difference of two underlying financial variables. In most cases, analytically closed form solutions for pricing such payoffs are not available, and the application of numerical pricing methods turns out to be nontrivial. We consider several such nontrivial cases and explore the performance of the highly efficient numerical technique of Hurd & Zhou[(2010) A Fourier transform method for spread option pricing, SIAM J. Financial Math. 1(1), 142–157], comparing this with Monte Carlo simulation and the lower bound approximation formula of Caldana & Fusai[(2013) A general closed-form spread option pricing formula, Journal of Banking & Finance 37, 4893–4906]. We show that the former is in essence an application of the two-dimensional Parseval’s Identity.

As application examples, we price spread options in a model where asset prices are driven by a multivariate normal inverse Gaussian (NIG) process, in a three-factor stochastic volatility model, as well as in examples of models driven by other popular multivariate Lévy processes such as the variance Gamma process, and discuss the price sensitivity with respect to volatility. We also consider examples in the fixed-income market, specifically, on cross-currency interest rate spreads and on LIBOR/OIS spreads.
Stochastic Stability of a Planner Gyropendulum System with Synchronous Motor Driven by Gaussian White Noises
Authors: Li Shenghong , Xu Zurun
Published: June 2019

In this paper, the stochastic moment stability and almost-sure stability of a planner gyropendulum system with synchronous motor under the white noises are investigated. By applying the theory of diffusion process, an eigenvalue problem for the moment Lyapunov exponent is formulated. Then, through a perturbation method and a Fourier cosine series expansion, the second-order expansion of the moment Lyapunov exponent is solved, which is just the leading eigenvalue of an infinite matrix. Finally, the convergence and validity of the procedure are numerically verified, and the effects of system and noise parameters on the moment Lyapunov exponent are discussed. It was found that the increase in both the noise intensity and coefficient of the synchronous motor torque will weaken the stability of the gyropendulum system, and when they reach certain values, the system becomes unstable. In addition, according to the relationship between the moment Lyapunov exponent and maximal Lyapunov exponent, the stable thresholds are also given.
Modeling the dynamics of black holes through balanced equations of motion in the null gauge
Authors: Gallo Emanuel , Moreschi Osvaldo M.
Published: June 2019

We develop further the general framework for modeling the dynamics of the motion of black holes, presented in [E. Gallo and O. M. Moreschi, Modeling the dynamics of black holes through balanced equations of motion, Int. J. Geom. Meth. Mod. Phys. 16(3) (2019) 1950034], by employing a convenient null gauge, in general relativity, for the construction of the balanced equations of motion. This null gauge has the property that the asymptotic structure is intimately related to the interior one; in particular there is a strong connection between the field equations and the balanced equations of motion.

Our work is very related to what we have called “Robinson–Trautman (RT) geometries” [S. Dain, O. M. Moreschi and R. J. Gleiser, Photon rockets and the Robinson–Trautman geometries, Class. Quantum Grav. 13(5) (1996) 1155–1160] in the past. These geometries are used in the sense of the general framework, we have presented in [E. Gallo and O. M. Moreschi, Modeling the dynamics of black holes through balanced equations of motion, Int. J. Geom. Meth. Mod. Phys. 16(3) (2019) 1950034].

We present the balanced equations of motion in second order of the acceleration. We solve the required components of the field equation at their respective required orders, [Formula: see text] and [Formula: see text], in terms of the gravitational constant.

We indicate how this approach can be extended to higher orders.
Completeness of the known graptoloid palaeontological record
Authors: Foote Michael , Sadler Peter M. , Cooper Roger A. , Crampton James S.
Published: June 2019

Using a high-resolution chronology of graptoloid first and last appearances, we apply mathematical models that allow the simultaneous inference of the probability distribution of species durations and the effective sampling rate relating those durations to the observed stratigraphic ranges. This approach allows the completeness of the documented palaeontological record of graptoloids to be assessed. We estimate that
c.
75% of species in the geographical regions that contribute to the stratigraphic data have been sampled and that, of those species known from more than a single stratigraphic horizon,
c.
85% of their original durations, on average, are represented by their global composite stratigraphic ranges. As expected in light of their biostratigraphic importance, graptoloids have one of the most completely documented records among groups of fossil organisms. We expect that application of the methods used herein will show comparably complete records for other biostratigraphically relevant groups.

Supplementary material:
The R code and data are available at
https://doi.org/10.6084/m9.figshare.c.4547174
Danmaku
Authors: Wu Qunfang , Sang Yisi , Huang Yun
Published: June 2019

Danmaku is a new commentary design for online videos. Unlike traditional forums where comments are displayed asynchronously below a video screen in order of when the comments are posted, danmaku comments are overlaid on the screen and displayed along with the video. This new design creates a pseudo-synchronous effect by displaying asynchronous comments with certain video segments in a synchronous fashion, and the links between danmaku comments and the video segments are defined by users. Danmaku is gaining popularity; however, little is known, compared to the traditional forum design, regarding how effective the new danmaku design is in promoting social interactions among online users. In this work, we collected 38,399 danmaku comments and 16,414 forum comments posted in 2017 on 30 popular videos on Bilibili.com. We compared user participation from different perspectives, e.g., number of comments, sentiment of the comments, language patterns, and ways of knowledge sharing. Our results showed that compared to the traditional linear design, the danmaku design significantly promoted user participation, i.e., there were more users and more comments in danmaku. Additionally, active users posted more positive comments, though they were anonymous; more linguistic memes were used in danmaku, suggesting that it was used to facilitate community-building. In addition to its effectiveness in promoting social interactions, our results also show that danmaku and forum designs play complementary roles in knowledge sharing, where danmaku comments involved more explicit (know-what) knowledge sharing, and forum comments exhibited more tacit (know-how) knowledge sharing. Our findings contribute to the development of social presence theory and have design implications for better social interaction via online videos.
Urdu Named Entity Recognition
Authors: Kanwal Safia , Malik Kamran , Shahzad Khurram , Aslam Faisal , Nawaz Zubair
Published: June 2019

Named Entity Recognition (NER) plays a pivotal role in various natural language processing tasks, such as machine translation and automatic question-answering systems. Recognizing the importance of NER, a plethora of NER techniques for Western and Asian languages have been developed. However, despite having over 490 million Urdu language speakers worldwide, NER resources for Urdu are either non-existent or inadequate. To fill this gap, this article makes four key contributions. First, we have developed the largest Urdu NER corpus, which contains 926,776 tokens and 99,718 carefully annotated NEs. The developed corpus has at least doubled the number of manually tagged NEs as compared to any of the existing Urdu NER corpora. Second, we have generated six new word embeddings using three different techniques, fastText, Word2vec, and Glove, on two corpora of Urdu text. These are the only publicly available embeddings for the Urdu language, besides the recently released Urdu word embeddings by Facebook. Third, we have pioneered in the application of deep learning techniques, NN and RNN, for Urdu named entity recognition. Finally, we have performed 10-folds of 32 different experiments using the combinations of a traditional supervised learning and deep learning techniques, seven types of word embeddings, and two different Urdu NER datasets. Based on the analysis of the results, several valuable insights are provided about the effectiveness of deep learning techniques, the impact of word embeddings, and variations of datasets.
Communicating Citizenship
Authors: Paz Alejandro I.
Published: June 2019

Citizenship has become a major topic in anthropology and the study of language (including sociolinguistics) since the early 1990s, with scholars in these fields especially examining the status and political claims of immigrants, refugees, indigenous groups, and other subaltern populations. This article argues that models of communication lie at the heart of debates about citizenship and explores two fundamentally communicative processes: first, the mutual recognition of citizens as citizens, and second, the interpellation by state apparatuses of citizens. It first discusses the emergence of the question of citizenship within anthropology and the study of language. It then considers the tension that arises as any recognition of difference confronts the normative model of citizenship already institutionalized in the state apparatus. Finally, this article examines the interlacing of these scholarly trajectories in one of the premier sites where citizens communicate as citizens: the public sphere.
The Most Luminous Supernovae
Authors: Gal-Yam Avishay
Published: June 2019

Over a decade ago, a group of supernova explosions with peak luminosities far exceeding (often by >100 times) those of normal events has been identified. These superluminous supernovae (SLSNe) have been a focus of intensive study. I review the accumulated observations and discuss the implications for the physics of these extreme explosions. ▪ SLSNe can be classified into hydrogen-poor (SLSNe-I) and hydrogen-rich (SLSNe-II) events. ▪ Combining photometric and spectroscopic analysis of samples of nearby SLSNe-I and lower-luminosity events, a threshold of [Formula: see text] mag at peak appears to separate SLSNe-I from the normal population. ▪ SLSN-I light curves can be quite complex, presenting both early bumps and late postpeak undulations. ▪ SLSNe-I spectroscopically evolve from an early hot photospheric phase with a blue continuum and weak absorption lines, through a cool photospheric phase resembling spectra of SNe Ic, and into the late nebular phase. ▪ SLSNe-II are not nearly as well studied, lacking information based on large-sample studies. Proposed models for the SLSN power source are challenged to explain all the observations. SLSNe arise from massive progenitors, with some events associated with very massive stars ([Formula: see text] M[Formula: see text]). Host galaxies of SLSNe in the nearby Universe tend to have low mass and subsolar metallicity. SLSNe are rare, with rates <100 times lower than ordinary supernovae. SLSN cosmology and their use as beacons to study the high-redshift Universe offer exciting prospects.
Star Clusters Across Cosmic Time
Authors: Krumholz Mark R. , McKee Christopher F. , Bland-Hawthorn Joss
Published: June 2019

Star clusters stand at the intersection of much of modern astrophysics: the ISM, gravitational dynamics, stellar evolution, and cosmology. Here, we review observations and theoretical models for the formation, evolution, and eventual disruption of star clusters. Current literature suggests a picture of this life cycle including the following several phases: ▪ Clusters form in hierarchically structured, accreting molecular clouds that convert gas into stars at a low rate per dynamical time until feedback disperses the gas. ▪ The densest parts of the hierarchy resist gas removal long enough to reach high star-formation efficiency, becoming dynamically relaxed and well mixed. These remain bound after gas removal. ▪ In the first ∼100 Myr after gas removal, clusters disperse moderately fast, through a combination of mass loss and tidal shocks by dense molecular structures in the star-forming environment. ▪ After ∼100 Myr, clusters lose mass via two-body relaxation and shocks by giant molecular clouds, processes that preferentially affect low-mass clusters and cause a turnover in the cluster mass function to appear on ∼1–10-Gyr timescales. ▪ Even after dispersal, some clusters remain coherent and thus detectable in chemical or action space for multiple galactic orbits. In the next decade, a new generation of space– and adaptive optics–assisted ground-based telescopes will enable us to test and refine this picture.
The Faintest Dwarf Galaxies
Authors: Simon Joshua D.
Published: June 2019

The lowest luminosity ([Formula: see text] L[Formula: see text]) Milky Way satellite galaxies represent the extreme lower limit of the galaxy luminosity function. These ultra-faint dwarfs are the oldest, most dark matter–dominated, most metal-poor, and least chemically evolved stellar systems known. They therefore provide unique windows into the formation of the first galaxies and the behavior of dark matter on small scales. In this review, we summarize the discovery of ultra-faint dwarfs in the Sloan Digital Sky Survey in 2005 and the subsequent observational and theoretical progress in understanding their nature and origin. We describe their stellar kinematics, chemical abundance patterns, structural properties, stellar populations, orbits, and luminosity function, as well as what can be learned from each type of measurement. We conclude the following: ▪ In most cases, the stellar velocity dispersions of ultra-faint dwarfs are robust against systematic uncertainties such as binary stars and foreground contamination. ▪ The chemical abundance patterns of stars in ultra-faint dwarfs require two sources of r-process elements, one of which can likely be attributed to neutron star mergers. ▪ Even under conservative assumptions, only a small fraction of ultra-faint dwarfs may have suffered significant tidal stripping of their stellar components. ▪ Determining the properties of the faintest dwarfs out to the virial radius of the Milky Way will require very large investments of observing time with future telescopes. Finally, we offer a look forward at the observations that will be possible with future facilities as the push toward a complete census of the Local Group dwarf galaxy population continues.
Redox Chemistry in the Genome: Emergence of the [4Fe4S] Cofactor in Repair and Replication
Authors: Barton Jacqueline K. , Silva Rebekah M.B. , O'Brien Elizabeth
Published: June 2019

Many DNA-processing enzymes have been shown to contain a [4Fe4S] cluster, a common redox cofactor in biology. Using DNA electrochemistry, we find that binding of the DNA polyanion promotes a negative shift in [4Fe4S] cluster potential, which corresponds thermodynamically to a ∼500-fold increase in DNA-binding affinity for the oxidized [4Fe4S]3+cluster versus the reduced [4Fe4S]2+cluster. This redox switch can be activated from a distance using DNA charge transport (DNA CT) chemistry. DNA-processing proteins containing the [4Fe4S] cluster are enumerated, with possible roles for the redox switch highlighted. A model is described where repair proteins may signal one another using DNA-mediated charge transport as a first step in their search for lesions. The redox switch in eukaryotic DNA primases appears to regulate polymerase handoff, and in DNA polymerase δ, the redox switch provides a means to modulate replication in response to oxidative stress. We thus describe redox signaling interactions of DNA-processing [4Fe4S] enzymes, as well as the most interesting potential players to consider in delineating new DNA-mediated redox signaling networks.
Lysosomal Glycosphingolipid Storage Diseases
Authors: Breiden Bernadette , Sandhoff Konrad
Published: June 2019

Glycosphingolipids are cell-type-specific components of the outer leaflet of mammalian plasma membranes. Gangliosides, sialic acid–containing glycosphingolipids, are especially enriched on neuronal surfaces. As amphi-philic molecules, they comprise a hydrophilic oligosaccharide chain attached to a hydrophobic membrane anchor, ceramide. Whereas glycosphingolipid formation is catalyzed by membrane-bound enzymes along the secretory pathway, degradation takes place at the surface of intralysosomal vesicles of late endosomes and lysosomes catalyzed in a stepwise fashion by soluble hydrolases and assisted by small lipid-binding glycoproteins. Inherited defects of lysosomal hydrolases or lipid-binding proteins cause the accumulation of undegradable material in lysosomal storage diseases (GM1 and GM2 gangliosidosis; Fabry, Gaucher, and Krabbe diseases; and metachromatic leukodystrophy). The catabolic processes are strongly modified by the lipid composition of the substrate-carrying membranes, and the pathological accumulation of primary storage compounds can trigger an accumulation of secondary storage compounds (e.g., small glycosphingolipids and cholesterol in Niemann-Pick disease).
Ocean Wave Interactions with Sea Ice: A Reappraisal
Authors: Squire Vernon A.
Published: June 2019

A spectacular resurgence of interest in the topic of ocean wave/sea ice interactions has unfolded over the last two decades, fueled primarily by the deleterious ramifications of global climate change on the polar seas. The Arctic is particularly affected, with a widespread reduction of the extent, thickness, and compactness of its sea ice during the summer, creating an ice cover that is analogous to that in the Southern Ocean surrounding Antarctica. With the additional fetches over which waves can form and mature within more open ice fields, there has also been a documented global uptrend of winds and wave height, which is most severe at high latitudes. Bigger ocean waves affect the way sea ice forms, contribute to how the ice edge moves, penetrate farther into the sea ice, have more destructive power to break up the ice and to change the distribution of floe sizes because the ice is weaker, and assist in lateral melting. These feedbacks collectively identify a parametrization currently absent from Earth system models, as well as shortcomings in wave forecasts arising from limited understanding of the impact of sea ice on ocean waves.
The North Atlantic Ecosystem, from Plankton to Whales
Authors: Pershing Andrew J. , Stamieszkin Karen
Published: June 2019

Compared with terrestrial ecosystems, marine ecosystems have a higher proportion of heterotrophic biomass. Building from this observation, we define the North Atlantic biome as the region where the large, lipid-rich copepod Calanus finmarchicus is the dominant mesozooplankton species. This species is superbly adapted to take advantage of the intense pulse of productivity associated with the North Atlantic spring bloom. Most of the characteristic North Atlantic species, including cod, herring, and right whales, rely on C. finmarchicus either directly or indirectly. The notion of a biome rests inherently on an assumption of stability, yet conditions in the North Atlantic are anything but stable. Humans have reduced the abundance of many fish and whales (though some recovery is underway). Humans are also introducing physical and chemical trends associated with global climate change. Thus, the future of the North Atlantic depends on the biome's newest species, Homo sapiens.
Combining Molecular Observations and Microbial Ecosystem Modeling: A Practical Guide
Authors: Hellweger Ferdi L.
Published: June 2019

Advances in technologies for molecular observation are leading to novel types of data, including gene, transcript, protein, and metabolite levels, which are fundamentally different from the types traditionally compared with microbial ecosystem models, such as biomass (e.g., chlorophyll a) and nutrient concentrations. A grand challenge is to use these data to improve predictive models and use models to explain observed patterns. This article presents a framework that aligns observations and models along the dimension of abstraction or biological organization—from raw sequences to ecosystem patterns for observations, and from sequence simulators to ecological theory for models. It then reviews 16 studies that compared model results with molecular observations. Molecular data can and are being combined with microbial ecosystem models, but to keep up with and take advantage of the full scope of observations, models need to become more mechanistically detailed and complex, which is a technical and cultural challenge for the ecological modeling community.
Economics of Aquaculture Policy and Regulation
Authors: Anderson James L. , Asche Frank , Garlock Taryn
Published: June 2019

Since the Blue Revolution began in the late 1960s, global aquaculture production has grown rapidly. Aquaculture now accounts for over half of the world's fish for direct human consumption and is expected to approach two-thirds by 2030. With aquaculture's growth, a number of high-profile concerns have arisen, including pollution, feeding practices, disease management and antibiotic use, habitat use, non-native species, food safety, fraud, animal welfare, impacts on traditional wild fisheries, access to water and space, market competition, and genetics. Managing these concerns requires thoughtful and well-designed policies and regulations. This manuscript reviews the contributions natural resource economics has made to evaluating aquaculture policy and regulation. Despite their valuable contributions, however, economists have been largely underrepresented in the debate. The primary influencers of aquaculture policies and regulations have been traditional fisheries managers, environmental groups, and natural scientists. We identify many important areas that should be more thoroughly addressed by economists.
Light: Toward a Transdisciplinary Science of Appearance and Atmosphere
Authors: Pont Sylvia C.
Published: June 2019

To understand the processes behind seeing light, we need to integrate knowledge about the incoming optical structure, its perception, and how light interacts with material, shape, and space—objectively and subjectively. To that end, we need a novel approach to the science of light, namely, a transdisciplinary science of appearance, integrating optical, perceptual, and design knowledge and methods. In this article, I review existing literature as a basis for such a synthesis, which should discuss light in its full complexity, including its spatial properties and interactions with materials, shape, and space. I propose to investigate this by representing the endless variety of light, materials, shapes, and space as canonical modes and their combinations.
Impact of diet on the persistence of early vascular remodeling and stiffening induced by intrauterine growth restriction and a maternal high-fat diet
Authors: Miller Thomas A. , Dodson R. Blair , Mankouski Anastasiya , Powers Kyle N. , Yang Yueqin , Yu Baifeng , Zinkhan Erin K.
Published: June 2019

Intrauterine growth restriction (IUGR) and maternal high-fat diet (HFD) independently predispose offspring to hypertension. In a rat model, IUGR more so than maternal HFD increases arterial stiffness with vascular remodeling as early as postnatal day (PND) 21. The trajectory of such early vascular changes remains unknown. We hypothesized that IUGR would increase blood pressure (BP), arterial stiffness, and markers of ongoing detrimental vascular remodeling in adult rats exposed to a maternal HFD regardless of weaning diet. Adult female rats were fed either a regular diet (RD) or an HFD before mating through lactation. IUGR was induced by uterine artery ligation. Offspring were weaned to either a RD or HFD through PND 60. For both control and IUGR rats, this design resulted in the following three diet groups: offspring from RD dams weaned to a RD and offspring from HFD dams weaned to a RD or to an HFD (IHH). In both males and females, only IHH increased systolic BP, but IUGR and HFD both alone and in combination increased arterial stiffness. Aortas contained fewer but thicker elastin bands in IHH rats and IUGR offspring from dams fed an HFD and weaned to a regular diet. IHH increased aortic lysl oxidase protein. In summary, the PND 21 rat mediators of vascular remodeling from IUGR and maternal HFD normalize by PND 60 while changes in elastin and arterial stiffness persist. We speculate that the longer-term risk of hypertension from dietary mediators is augmented by underlying IUGR-induced structural changes to the extracellular matrix.

NEW & NOTEWORTHY We report that a combined insult of intrauterine growth restriction and maternal high-fat diet increases the risk of early cardiovascular pathology both independently and in conjunction with a continued high-fat diet in offspring.
V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer
Authors: Gao Yijun , Maria Ann , Na Na , da Cruz Paula Arnaud , Gorelick Alexander N. , Hechtman Jaclyn F. , Carson Julianne , Lefkowitz Robert A. , Weigelt Britta , Taylor Barry S. , Zhao HuiYong , Reis-Filho Jorge S. , de Stanchina Elisa , Rosen Neal , Yao Zhan , Yaeger Rona
Published: June 2019

We report the emergence of the novel MEK1V211D gatekeeper mutation in a patient with BRAFK601E colon cancer treated with the allosteric MEK inhibitor binimetinib and the anti-EGFR antibody panitumumab. The MEK1V211D mutation concurrently occurs in the same cell with BRAFK601E and leads to RAF-independent activity but remains regulated by RAF. The V211D mutation causes resistance to binimetinib by both increasing the catalytic activity of MEK1 and reducing its affinity for the drug. Moreover, the mutant exhibits reduced sensitivity to all the allosteric MEK inhibitors tested. Thus, this mutation serves as a general resistance mutation for current MEK inhibitors; however, it is sensitive to a newly reported ATP-competitive MEK inhibitor, which therefore could be used to overcome drug resistance.

Significance:

We report a resistance mechanism to allosteric MEK inhibitors in the clinic. A MEK1V211D mutation developed in a patient with BRAFK601E colon cancer on MEK and EGFR inhibitors. This mutant increases the catalytic activity of MEK1 and reduces its affinity for binimetinib, but remains sensitive to ATP-competitive MEK inhibitors.

This article is highlighted in the In This Issue feature, p. 1143
Incidence of Rhegmatogenous Retinal Detachment in Europe – A Systematic Review and Meta-Analysis
Authors: Li Jeany Q. , Welchowski Thomas , Schmid Matthias , Holz Frank G. , Finger Robert P.
Published: June 2019

Purpose: To examine the prevalence and incidence of rhegmatogenous retinal detachment (RRD) in Europe. Methods: A systematic review of the prevalence and incidence of RRD in Europe according to the meta-analyses of observational studies in epidemiology (MOOSE) guidelines was performed using the databases PubMed, Embase, and Web of Science followed by a meta-analysis of incidence data. Results: 658 studies were identified, 76 full-text articles were assessed, and 5 studies were eligible for meta-analysis. Random-effects pooled mean annual incidence of RRD in Europe was 13.3 cases per 100,000 inhabitants (95% CI: 11.3–15.6) based on the examination of 95,765 individuals from the 5 incidence studies. No European studies reporting prevalence of retinal detachment were identified. Conclusion: Published articles on the prevalence and incidence of RRD in Europe are limited. Further epidemiological research is needed for adequate healthcare planning.
Oncologic Outcomes of Adjuvant versus Salvage Radiotherapy after Prostatectomy
Authors: Seddik Sofiane , Silva Marlon , Dugué Audrey-Emmanuel , Ait Said Khelifa , Joly Florence , Tillou Xavier
Published: June 2019

Introduction: The benefit of adjuvant radiotherapy (AR) or salvage radiotherapy (SR) after prostatectomy is still unclear. We wanted to compare both types of radiotherapy after prostatectomy in terms of oncological and functional results. Methods: We included 173 patients treated at a single center between January 2005 and December 2008. All patients were treated with the same radiotherapy protocol (3D conformal radiotherapy accelerator 6 mV, 66 GY). AR was defined as radiotherapy initiated in a patient with a PSA level <0.2 ng/mL after prostatectomy otherwise it was defined as SR. No patients received neoadjuvant therapy prior to prostatectomy (whether hormone therapy or chemotherapy). Patients in the SR group had a PSA level ≥0.2 ng/mL during the treatment in accordance with the Phoenix criteria. The lymph nodes were irradiated if the patient had no lymph node dissection and if the risk of nodal involvement was >10%. Both groups were compared in terms of biological progression-free, metastasis-free, and overall survival (OS) using log-rank tests. Moreover, acute and late urinary and gastrointestinal toxicity were also compared. Results: One hundred and fifty-seven patients underwent an open retropubic prostatectomy whereas 16 underwent a laparoscopy (6 subperitoneal and 10 transperitoneal). Eighty-six patients had AR with a median time of 6.7 months after surgery and 87 had SR with a median time of 21.4 months after surgery. Median follow-up was 6.7 years. Metastasis-free survival (MFS) was better in the AR than in the SR group (p = 0.01, 6-year MFS 95 and 89%, respectively). OS was also better in the AR than in the SR group (p = 0.02, 6-year OS 100 vs. 95%, respectively). AR was associated with better survival with no biochemical recurrence (85 vs. 63%, p < 0.00001). There was no significant difference between groups for acute or late urinary or gastrointestinal toxicity. Conclusion: Our study suggests that patients treated by AR have better results in terms of OS, disease-specific survival, survival without metastatic recurrence, and survival without biochemical recurrence compared with SR. Toxicity was comparable between both groups.
No Treatment Required for Asymptomatic Vaginal Mesh Exposure
Authors: Illiano Ester , Giannitsas Konstantinos , Li Marzi Vincenzo , Natale Franca , Mancini Vito , Costantini Elisabetta
Published: June 2019

Introduction: There is no specific recommendation for the management of asymptomatic vaginal mesh erosions post antiincontinence or prolapse surgery, but revision or excision may represent overtreatment. We hypothesize that asymptomatic vaginal exposures remain asymptomatic during follow-up and do not require any intervention. Methods: We evaluated a “no treatment” approach by prospectively following-up women with asymptomatic vaginal exposures after antiincontinence and pelvic organ prolapse surgery. After a 1-month course of vaginal oestrogen, they underwent the “wait and see” protocol. It consisted of no treatment. Women were followed-up every 3 months, for the first year and then every 6 months with history, clinical examination with measurement of size of the exposure, and the evaluation of possible infection signs or vaginal discharge. Results: Forty women were followed-up for a median of 33.52 months (range 8–48 months). All exposures were ≤1 cm (mean 6.5 ± 1.5 mm, range 4–10 mm), patients were asymptomatic and without pain. During the observation period, the size of the exposure did not change and all women remained asymptomatic. Discussion/Conclusion: No treatment seems to be required for asymptomatic and small vaginal mesh exposures after prolapse or incontinence surgery.
Utility of the Cardiovascular Physical Examination and Impact of Spironolactone in Heart Failure With Preserved Ejection Fraction
Authors: Selvaraj Senthil , Claggett Brian , Shah Sanjiv J. , Anand Inder S. , Rouleau Jean L. , Desai Akshay S. , Lewis Eldrin F. , Vaduganathan Muthiah , Wang Stephen Y. , Pitt Bertram , Sweitzer Nancy K. , Pfeffer Marc A. , Solomon Scott D.
Published: June 2019

Background:

The prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known.

Methods and Results:

We studied participants from the Americas with available physical examination (jugular venous distention, rales, and edema) at baseline in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). The association of the number of signs of congestion with the primary outcome (cardiovascular death or heart failure hospitalization), its individual components, and all-cause mortality was assessed using time-updated, multivariable-adjusted Cox regression analyses. We evaluated whether spironolactone improved congestion at 4 months and whether improvement in congestion was related to quality of life as assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores and to outcomes. Among 1644 participants, 22%, 54%, 20%, and 4% had 0, 1, 2, and 3 signs of congestion, respectively, at baseline. After multivariable adjustment, each additional increase in sign of congestion was associated with a 30% to 60% increased risk of each outcome (
P
<0.001). Spironolactone reduced the total number of signs of congestion by −0.10 (
P
=0.005) signs, jugular venous distention (odds ratio, 0.60;
P
=0.01), and edema (odds ratio, 0.74;
P
=0.006) at 4 months compared with placebo. Each reduction in sign of congestion was independently associated with a 4.0 (95% CI, 2.4–5.6) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score. When assessed simultaneously, time-updated, but not baseline congestion, predicted outcomes.

Conclusions:

In heart failure with preserved ejection fraction, the physical exam provides independent prognostic value for adverse outcomes. Spironolactone improved congestion compared with placebo. Reducing congestion was independently associated with improved quality of life and outcomes and is a modifiable risk factor.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00094302.
Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin in Cardiac Tissue Repair and the Development of Diastolic Dysfunction
Authors: Hara Akitoshi , Kobayashi Hiroki , Asai Naoya , Saito Shigeyoshi , Higuchi Takahiro , Kato Katsuhiro , Okumura Takahiro , Bando Yasuko K. , Takefuji Mikito , Mizutani Yasuyuki , Miyai Yuki , Saito Shoji , Maruyama Shoichi , Maeda Keiko , Ouchi Noriyuki , Nagasaka Arata , Miyata Takaki , Mii Shinji , Kioka Noriyuki , Worthley Daniel L. , Murohara Toyoaki , Takahashi Masahide , Enomoto Atsushi
Published: June 2019

Rationale:

Myofibroblasts have roles in tissue repair following damage associated with ischemia, aging, and inflammation and also promote fibrosis and tissue stiffening, causing organ dysfunction. One source of myofibroblasts is mesenchymal stromal/stem cells that exist as resident fibroblasts in multiple tissues. We previously identified meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue), a glycosylphosphatidylinositol-anchored membrane protein, as a specific marker of mesenchymal stromal/stem cells and a regulator of their undifferentiated state. The roles of meflin in the development of heart disease, however, have not been investigated.

Objective:

We examined the expression of meflin in the heart and its involvement in cardiac repair after ischemia, fibrosis, and the development of heart failure.

Methods and Results:

We found that meflin has an inhibitory role in myofibroblast differentiation of cultured mesenchymal stromal/stem cells. Meflin expression was downregulated by stimulation with TGF (transforming growth factor)-β, substrate stiffness, hypoxia, and aging. Histological analysis revealed that meflin-positive fibroblastic cells and their lineage cells proliferated in the hearts after acute myocardial infarction and pressure-overload heart failure mouse models. Analysis of meflin knockout mice revealed that meflin is essential for the increase in the number of cells that highly express type I collagen in the heart walls after myocardial infarction induction. When subjected to pressure overload by transverse aortic constriction, meflin knockout mice developed marked cardiac interstitial fibrosis with defective compensation mechanisms. Analysis with atomic force microscopy and hemodynamic catheterization revealed that meflin knockout mice developed stiff failing hearts with diastolic dysfunction. Mechanistically, we found that meflin interacts with bone morphogenetic protein 7, an antifibrotic cytokine that counteracts the action of TGF-β and augments its intracellular signaling.

Conclusions:

These data suggested that meflin is involved in cardiac tissue repair after injury and has an inhibitory role in myofibroblast differentiation of cardiac fibroblastic cells and the development of cardiac fibrosis.
Single-Cell Transcriptomics Reveals Chemotaxis-Mediated Intraorgan Crosstalk During Cardiogenesis
Authors: Xiong Haiqing , Luo Yingjie , Yue Yanzhu , Zhang Jiejie , Ai Shanshan , Li Xin , Wang Xuelian , Zhang Yun-Long , Wei Yusheng , Li Hui-Hua , Hu Xinli , Li Cheng , He Aibin
Published: June 2019

Rationale:

We hypothesized that the differentiation processes of cardiac progenitor cell (CP) from first and second heart fields (FHF and SHF) may undergo the unique instructive gene regulatory networks or signaling pathways, and the precise SHF progression is contingent on the FHF signaling developmental cues.

Objective:

We investigated how the intraorgan communications control sequential building of discrete anatomic regions of the heart at single-cell resolution.

Methods and Results:

By single-cell transcriptomic analysis of Nkx2-5 (NK2 homeobox 5) and Isl1 (ISL LIM homeobox 1) lineages at embryonic day 7.75, embryonic day 8.25, embryonic day 8.75, and embryonic day 9.25, we present a panoramic view of distinct CP differentiation hierarchies. Computational identifications of FHF- and SHF-CP descendants revealed that SHF differentiation toward cardiomyocytes underwent numerous step-like transitions, whereas earlier FHF progressed toward cardiomyocytes in a wave-like manner. Importantly, single-cell pairing analysis demonstrated that SHF-CPs were attracted to and expanded FHF-populated heart tube region through interlineage communications mediated by the chemotactic guidance (MIF [macrophage migration inhibitory factor]-CXCR2 [C-X-C motif chemokine receptor 2]). This finding was verified by pharmacological blockade of this chemotaxis in embryos manifesting limited SHF cell migration and contribution to the growth of the outflow tract and right ventricle but undetectable effects on the left ventricle or heart tube initiation. Genetic loss-of-function assay of Cxcr2 showed that the expression domain of CXCR4 was expanded predominantly at SHF. Furthermore, double knockout of Cxcr2/Cxcr4 exhibited defective SHF development, corroborating the redundant function. Mechanistically, NKX2-5 directly bound the Cxcr2 and Cxcr4 genomic loci and activated their transcription in SHF.

Conclusions:

Collectively, we propose a model in which the chemotaxis-mediated intraorgan crosstalk spatiotemporally guides the successive process of positioning SHF-CP and promoting primary heart expansion and patterning upon FHF-derived heart tube initiation.
S100a8/a9 Signaling Causes Mitochondrial Dysfunction and Cardiomyocyte Death in Response to Ischemic/Reperfusion Injury
Authors: Li Yulin , Chen Boya , Yang Xinying , Zhang Congcong , Jiao Yao , Li Ping , Liu Yan , Li Zhenya , Qiao Bokang , Bond Lau Wayne , Ma Xin-liang , Du Jie
Published: June 2019

Background:

Myocardial ischemia-reperfusion (MI/R) injury is a significant clinical problem without effective therapy. Unbiased omics approaches may reveal key MI/R mediators to initiate MI/R injury.

Methods:

We used a dynamic transcriptome analysis of mouse heart exposed to various MI/R periods to identify S100a8/a9 as an early mediator. Using loss/gain-of-function approaches to understand the role of S100a8/a9 in MI/R injury, we explored the mechanisms through transcriptome and functional experiment. Dynamic serum S100a8/a9 levels were measured in patients with acute myocardial infarction before and after percutaneous coronary intervention. Patients were prospectively followed for the occurrence of major adverse cardiovascular events.

Results:

S100a8/a9 was identified as the most significantly upregulated gene during the early reperfusion stage. Knockout of S100a9 markedly decreased cardiomyocyte death and improved heart function, whereas hematopoietic overexpression of S100a9 exacerbated MI/R injury. Transcriptome/functional studies revealed that S100a8/a9 caused mitochondrial respiratory dysfunction in cardiomyocytes. Mechanistically, S100a8/a9 downregulated NDUF gene expression with subsequent mitochondrial complex I inhibition via Toll-like receptor 4/Erk–mediated Pparg coactivator 1 alpha/nuclear respiratory factor 1 signaling suppression. Administration of S100a9 neutralizing antibody significantly reduced MI/R injury and improved cardiac function. Finally, we demonstrated that serum S100a8/a9 levels were significantly increased 1 day after percutaneous coronary intervention in patients with acute myocardial infarction, and elevated S100a8/a9 levels were associated with the incidence of major adverse cardiovascular events.

Conclusions:

Our study identified S100a8/a9 as a master regulator causing cardiomyocyte death in the early stage of MI/R injury via the suppression of mitochondrial function. Targeting S100a8/a9-intiated signaling may represent a novel therapeutic intervention against MI/R injury.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03752515
Do Cerebral Small Vessel Disease and Multiple Sclerosis Share Common Mechanisms of White Matter Injury?
Authors: Brown Robin B. , Traylor Matthew , Burgess Stephen , Sawcer Stephen , Markus Hugh S.
Published: June 2019

Background and Purpose—

The role of inflammation in ischemic white matter disease is increasingly recognized, and further understanding of the pathophysiology might inform future treatment strategies. Multiple sclerosis (MS) is a chronic autoimmune condition in which inflammation plays a central role that also affects the white matter. We hypothesized that white matter injury might share common mechanisms and used statistical genetics techniques to assess whether having genetically elevated white matter hyperintensity (WMH) volume was associated with increased MS risk.

Methods—

We investigated the genetic association in 2 cohorts with magnetic resonance imaging-quantified ischemic white matter lesion volume (WMH in stroke; n=2797 and UK Biobank; n=8353) and 14 802 cases of MS and 26 703 controls from the International Multiple Sclerosis Genetics Consortium. We further performed individual-level polygenic risk score calculations for MS and measures of structural white matter disease in UK Biobank. Finally, we looked for evidence of overlapping risk across the whole genome.

Results—

There was no association of genetic variants influencing MS with WMH volume using summary statistics in the WMH in stroke cohort (relative risk score =1.014; 95% CI, 0.936–1.110) or in the UK Biobank cohort (relative risk score =1.030; 95% CI, 0.932–1.117). Conversely, assessing the contribution of single nucleotide polymorphisms significantly associated with WMH on the risk of MS there was no significant association (relative risk score =0.930; 95% CI, 0.736–1.191). There were no significant associations between polygenic risk scores calculations; these results were robust to the selection of single nucleotide polymorphisms at a range of significance thresholds. Whole genome analysis did not reveal any overlap of risk between the traits.

Conclusions—

Our results do not provide evidence to suggest a shared mechanism of white matter damage in ischemia and MS. We propose that inflammation acts in distinct pathways because of the differing nature of the primary insult.