bluuebunny/crossref_metadata_2025 huggingface dataset:
Classification of postoperative behavior disturbances in preschool children: A qualitative study
Authors: Lopez Ursula , Martin Jennifer , van Assche Mitsouko , Fleury Schubert Aline , Fournet Maryll , Quartier Vincent , Habre Walid , Van der Linden Martial
Published: March 2019

Background/Aim

Negative postoperative changes in children are frequent and have been described for decades. However, there is currently no theoretical framework, nor any consensual operational criteria for identifying them. This study aims at characterizing the many dimensions involved in postoperative behavioral disturbances in early childhood, using a qualitative analysis applied for the first time to these symptoms.

Method

Fifty‐seven parents of preschool children (1‐5 years old; 38 boys), who underwent general anesthesia, were interviewed 10 days after surgery. Semi‐structured interviews investigated behavioral disturbances classically described in preschool children. Qualitative analysis of the transcripts allied both deductive and inductive reasoning, and inductive coding was carried out using constant comparison method with dedicated qualitative software.

Results

Parents reported both positive and negative postoperative changes. Negative changes were classified in four main categories: (a) Externalizing and (b) Internalizing problems behaviors, (c) Feeding sleeping disruption and (d) Somatic problems, each comprising different sub‐categories. Importantly within these categories, the symptoms distribution changed in 5 years old children, compared to younger children. Finally, our method allowed defining whether these (negative or positive) changes were significant or not, that is, the importance of postoperative behavioral changes.

Conclusion

The results of this study highlight the heterogeneity of postoperative disturbances in preschool children. These results are of primary importance for the definition and measurement of postoperative behavioral disturbances.
Arc-smooth functions on closed sets
Authors: Rainer Armin
Published: March 2019

By an influential theorem of Boman, a function$f$on an open set$U$in$\mathbb{R}^{d}$is smooth (${\mathcal{C}}^{\infty }$) if and only if it isarc-smooth, that is,$f\,\circ \,c$is smooth for every smooth curve$c:\mathbb{R}\rightarrow U$. In this paper we investigate the validity of this result on closed sets. Our main focus is on sets which are the closure of their interior, so-calledfatsets. We obtain an analogue of Boman’s theorem on fat closed sets with Hölder boundary and on fat closed subanalytic sets with the property that every boundary point has a basis of neighborhoods each of which intersects the interior in a connected set. If$X\subseteq \mathbb{R}^{d}$is any such set and$f:X\rightarrow \mathbb{R}$is arc-smooth, then$f$extends to a smooth function defined on$\mathbb{R}^{d}$. We also get a version of the Bochnak–Siciak theorem on all closed fat subanalytic sets and all closed sets with Hölder boundary: if$f:X\rightarrow \mathbb{R}$is the restriction of a smooth function on$\mathbb{R}^{d}$which is real analytic along all real analytic curves in$X$, then$f$extends to a holomorphic function on a neighborhood of$X$in$\mathbb{C}^{d}$. Similar results hold for non-quasianalytic Denjoy–Carleman classes (of Roumieu type). We will also discuss sharpness and applications of these results.
¿Estar indizados o no? Esa es la cuestión
Authors: Delgado Troncoso Jorge Enrique , Delgado Troncoso Sandra Cecilia
Published: March 2019

Reacciones ante la más reciente evaluación y escalafonamiento de las revistas científicas colombianas. Las odontológicas salieron mal libradas.
Testing of Scintillation Detectors in Quasi-Monoenergetic Neutron Spectra in a Silicon Filtered Neutron Beam at the LVR-15 Research Reactor
Authors: Košťál Michal , Matěj Zdeněk , Mravec Filip , Cvachovec František , Schulc Martin , Juříček Vlastimil , Rypar Vojtěch , Šoltés Jaroslav , Losa Evžen , Viererbl Ladislav
Published: March 2019

With increasing needs of neutron detection in energy and homeland security sectors, there is an aim in the development of new suitable detection materials with possible n/g separation and also satisfactory resolution. This issue is connected with a well-defined neutron field. The neutron standards 252Cf(spontaneous fission) and 235U(nth fission) have smooth spectra; thus, the tests in these fields can be used for testing of neutron gamma pulse shape discrimination (PSD), but cannot reveal possible problems in the deconvolution. New neutron field which is formed from fission spectrum filtered by 1 m thick silicon block was developed in Research Center Rez. Due to the course of the silicon cross section, the well-distinguished neutron peaks occur in filtered neutron spectrum. In this field, various scintillation materials, HIDEX Aqualight, and EJ299-33A were tested.
A Numerical Study of Heat Transfer Enhancement by a Rectangular Cylinder Placed Parallel to the Heated Wall
Authors: Derakhshandeh J. F. , Alam Md. Mahbub
Published: March 2019

The flow around a rectangular cylinder mounted in the vicinity of a hot wall is numerically studied at a Reynolds number of 200. While the cylinder chord-to-height ratio C/W is varied from 2 to 10, the gap distance G from the wall to the cylinder is changed from 0.25 to 6.25. The focus of this study is given on the dependence of G/W and C/W on the heat transfer from the wall and associated physics. The variation in the Strouhal number is presented as a function of C/W. It is observed that the effect of G/W on the vortex dynamics and heat transfer is much more than that of C/W. Based on the dependence of the vortex dynamics and heat transfer on G/W, we have identified four distinct flows: no vortex street flow (G/W < 0.75), single-row vortex street flow (0.75 ≤ G/W ≤ 1.25), inverted two-row vortex street flow (1.25 < G/W ≤ 2.5), and two-row vortex street flow (G/W > 2.5). At the single-row vortex street flow, the two opposite-sign vortices appearing in a jetlike flow carry heat from the wall to the wake and then to the freestream. The maximum heat transfer is achieved at the single-row vortex street flow and 8% increase occurs at C/W = 2, G/W = 0.75–1.25.
Vapor-printed polymer electrodes for long-term, on-demand health monitoring
Authors: Kim Jae Joon , Allison Linden K. , Andrew Trisha L.
Published: March 2019

Vapor printing electrodes on seedlings allows on-demand health monitoring of growing plants using bioimpedance spectroscopy.
Therapeutic Approaches Targeting the Assembly and Function of Chaperone-Usher Pili
Authors: Psonis John J. , Thanassi David G.
Published: March 2019

The chaperone-usher (CU) pathway is a conserved secretion system dedicated to the assembly of a superfamily of virulence-associated surface structures by a wide range of Gram-negative bacteria. Pilus biogenesis by the CU pathway requires two specialized assembly components: a dedicated periplasmic chaperone and an integral outer membrane assembly and secretion platform termed the usher. The CU pathway assembles a variety of surface fibers, ranging from thin, flexible filaments to rigid, rod-like organelles. Pili typically act as adhesins and function as virulence factors that mediate contact with host cells and colonization of host tissues. Pilus-mediated adhesion is critical for early stages of infection, allowing bacteria to establish a foothold within the host. Pili are also involved in modulation of host cell signaling pathways, bacterial invasion into host cells, and biofilm formation. Pili are critical for initiating and sustaining infection and thus represent attractive targets for the development of antivirulence therapeutics. Such therapeutics offer a promising alternative to broad-spectrum antibiotics and provide a means to combat antibiotic resistance and treat infection while preserving the beneficial microbiota. A number of strategies have been taken to develop antipilus therapeutics, including vaccines against pilus proteins, competitive inhibitors of pilus-mediated adhesion, and small molecules that disrupt pilus biogenesis. Here we provide an overview of the function and assembly of CU pili and describe current efforts aimed at interfering with these critical virulence structures.
Long-term medical and psychosocial outcomes in congenital diaphragmatic hernia survivors
Authors: Tan Jason K , Banton Georgia , Minutillo Corrado , Hall Graham L , Wilson Andrew , Murray Conor , Nathan Elizabeth A , Verheggen Maureen , Ramsay James , Samnakay Naeem , Dickinson Jan
Published: March 2019

Objective

Survival rates for congenital diaphragmatic hernia (CDH) are increasing. The long-term outcomes of CDH survivors were compared with a healthy control group to assess the morbidity for guidance of antenatal counselling and long-term follow-up programmes.

Participants and design

Participants born with CDH in Western Australia 1993–2008 were eligible with matched controls from the general population. Participants had comprehensive lung function tests, echocardiogram, low-dose chest CT scan and completed a Strengths and Difficulties Questionnaire (SDQ) and quality of life (QOL) questionnaire.

Results

34 matched case–control pairs were recruited. Demographic data between groups were similar. Cases were smaller at follow-up (weight Z-score of −0.2vs0.3; p=0.03; height Z-score of −0.3vs0.6; p=0.01). Cases had lower mean Z-scores for forced expiratory volume in 1 s (FEV1) (−1.49 vs −0.01; p=0.004), FEV1/forced vital capacity (−1.92 vs −1.2; p=0.009) and forced expiratory flow at 25-75% (FEF25-75) (−1.18vs0.23; p=0.007). Cases had significantly worse respiratory mechanics using forced oscillation technique. Subpleural triangles architectural distortion, linear opacities and scoliosis on chest CT were significantly higher in cases. Prosthetic patch requirement was associated with worse lung mechanics and peak cough flow. Cases had significantly higher rates of gastro-oesophageal reflux disease (GORD) and GORD medication usage. Developmental delay was significantly higher in cases. More cases had a total difficulties score in the high to very high range (25% vs 0%, p=0.03) on the SDQ and reported lower objective QOL scores (70.2 vs 79.8, p=0.02).

Conclusion

Survivors of CDH may have significant adverse long-term medical and psychosocial issues that would be better recognised and managed in a multidisciplinary clinic.
Lonicera japonica Attenuates Carbon Tetrachloride-Induced Liver Fibrosis in Mice: Molecular Mechanisms of Action
Authors: Miao Hui , Zhang Yi , Huang Zhenlin , Lu Bin , Ji Lili
Published: March 2019

Liver fibrosis is a worldwide clinical issue that generally causes hepatic cirrhosis. Lonicerae Japonicae Flos (dried flower buds of Lonicera japonica Thunb) is a traditional heat-clearing and detoxifying herbal medicine in China. This study aims to observe the protection of the water extract of Lonicerae Japonicae Flos (FL) from carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Liver fibrosis was induced in mice by intraperitoneal injection of 2[Formula: see text]ml/kg CCl4 twice a week for 4 weeks. FL’s attenuation of CCl4-induced liver fibrosis in mice was evidenced by the results of Masson’s trichrome and Sirius red staining, liver hydroxyproline content and serum amount of collagen IV. FL reduced hepatic stellate cells (HSCs) activation and reversed the epithelial-mesenchymal transition (EMT) process in mice treated with CCl4. FL also alleviated liver oxidative stress injury and enhanced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant signaling pathway in mice treated with CCl4. Additionally, the main phenolic acids in FL including chlorogenic acid (CGA) and caffeic acid (CA) both reduced HSCs activation in vitro. In summary, FL attenuates CCl4-induced liver fibrosis in mice by inhibiting HSCs activation, reversing EMT and reducing liver oxidative stress injury via inducing Nrf2 activation. CGA may be the main active compound contributing to the antifibrotic activity of FL.
MACROECONOMIC DETERMINANTS OF FIRM PERFORMANCE: EVIDENCE FROM TURKEY
Authors: DORUK ÖMER TUĞSAL
Published: March 2019

The relationship between macroeconomic factors and firm performance is important, especially for growth and development in developing countries. In this paper, a firm-level dataset is used for estimating the role of macroeconomic factors on firm performance in the period 2006–2017 for the Turkish manufacturing sector by using GMM model. Four macroeconomic factors are considered for estimating their roles on firm performance; openness, financial depth, real exchange rate, and economic growth rate. The obtained findings show that the macroeconomic conditions have a significant effect on firm performance in the manufacturing sector in Turkey.
THE EFFECT OF REVENUE SHARES ON LOCAL GOVERNMENT SPENDING: EVIDENCE FROM PHILIPPINE PROVINCES
Authors: CANARE TRISTAN
Published: March 2019

Intergovernmental fiscal transfer (IFT) is one of the several sources of funds of sub-national governments. There are two general types of IFT — conditional and unconditional. In many developing economies including the Philippines, the usual existing IFT is a form of unconditional fiscal transfer called revenue shares. In the Philippines, this revenue-sharing scheme is called the internal revenue allotment (IRA). Empirical literature says that unconditional IFTs are the type of fiscal transfers with the least effect on local government spending. The literature posits that the reason for this is that local governments use these transfers to substitute for own-sourced revenues such as local taxes. This explanation was formalized through a framework presented in this paper. Using panel data from Philippine provinces for the years 2001 to 2015, this paper attempted to determine the effect of revenue shares, in the form of IRA, on local government expenditures. Using different econometric methodologies, this paper arrived at several conclusions. First, IRA has a strong positive effect on total local government spending with a marginal effect slightly greater than one — much higher than what comparable studies found using data from other countries. Secondly, the effect of IRA on local government expenditures is even stronger for provinces with relatively greater ability to generate its own funds. Next, IRA and other externally sourced revenues have much stronger marginal effects on local government spending than do own-sourced revenues. Finally, IRA has widely varying effects on different components of local government expenditures.
Solitons: Conservation laws and dressing methods
Authors: Doikou Anastasia , Findlay Iain
Published: March 2019

We review some of the fundamental notions associated with the theory of solitons. More precisely, we focus on the issue of conservation laws via the existence of the Lax pair and also on methods that provide solutions to partial or ordinary differential equations that are associated to discrete or continuous integrable systems. The Riccati equation associated to a given continuous integrable system is also solved and hence suitable conserved quantities are derived. The notion of the Darboux–Bäcklund transformation is introduced and employed in order to obtain soliton solutions for specific examples of integrable equations. The Zakharov–Shabat dressing scheme and the Gelfand–Levitan–Marchenko equation are also introduced. Via this method, generic solutions are produced and integrable hierarchies are explicitly derived. Various discrete and continuous integrable models are employed as examples such as the Toda chain, the discrete nonlinear Schrödinger model, the Korteweg–de Vries and nonlinear Schrödinger equations as well as the sine-Gordon and Liouville models.
New physics in inclusive semileptonic B decays including nonperturbative corrections
Authors: Kamali Saeed
Published: March 2019

In this work, we study the effects of New Physics (NP) operators on the inclusive [Formula: see text] decay including power [Formula: see text] corrections in the NP operators. In analogy with [Formula: see text] observables, we study the observable [Formula: see text]. We present some numerical results for [Formula: see text] and compare the results for this observable with and without power corrections in the NP contributions.
New exact solutions for the Wick-type stochastic nonlinear Schrödinger equation in nonlinear optics
Authors: Singh S. , Ray S. Saha
Published: March 2019

The exact solutions of Wick-type stochastic nonlinear Schrödinger equation (NLSE) using extended auxiliary equation method (EAEM) has been obtained in this paper. Hermite transform has been used for transforming the stochastic NLSE into deterministic PDE. Also, the stochastic solutions in the white noise space have been obtained by applying inverse Hermite transform on the deterministic set of solutions.
Mapping the Global Knowledge Domain for Building Information Models
Authors: Zhang Wei , Zhao Liang
Published: March 2019

This paper presents the method and findings of a visual knowledge domain map used to explore the development and evolution of Building information modeling (BIM) technology. Metadata taken from 806 literature records is used to visualize the state of BIM research. The records were published between 1998 and 2017, and Citespace software is employed to visualize key data about the research contained on the Web of Science platform, including nationality of research institutions, research themes, co-citations of periodicals, authorship, literature sources, and the development of the discipline over time. The distribution of power in this field is also examined by interrogating the BIM knowledge base, identifying research hotspots to provide a reference for assessing the current state-of-the-art.
3D Micro-Structural Modeling of Vibration Characteristics of Smart Particle-Reinforced Metal-Matrix Composite Beams
Authors: Ekici Recep , Abaci Vahdet Mesut , Reddy J. N.
Published: March 2019

In this study, the effects of micro-structural parameters such as particle volume fraction, size and random distribution of Al 6061/SiC particulate metal-matrix composite (MMC) beams on free vibration response and the active vibration control are investigated. For this purpose, numerical particle-reinforced MMC (PRMMC) beam specimens were modeled with 3D finite elements, and the cubic-shaped reinforcing SiC particles were randomly distributed in Al 6061 metal matrix similar to an actual micro-structure. The particle size and especially volume fraction play an important role on the natural frequencies of the smart PRMMCs although they have no effect on the mode shapes. The random particle distribution has minor effect on the natural frequencies of the smart PRMMCs. With the increase of the feedback control gain, both the vibration amplitude and the suppression time are reduced reasonably. Increasing the particle volume fraction induces an important reduction in the damping time and the vibration amplitude for both the controlled and uncontrolled damped vibrations. Finally, increasing the particle size decreases the vibration suppression capacity and increases the vibration amplitude and time slightly. Random particle distribution had no obvious effect on the uncontrolled and controlled vibrations.
A Compact Higher-Order Scheme for Two-Dimensional Unsteady Convection–Diffusion Equations
Authors: Kim Yon-Chol
Published: March 2019

In this paper, we study a compact higher-order scheme for the two-dimensional unsteady convection–diffusion problems using the nearly analytic discrete method (NADM), especially, focusing on the convection dominated-diffusion problems. The numerical scheme is constructed and the stability analysis is implemented. We find the order of accuracy of scheme is [Formula: see text], where [Formula: see text] is the size of time steps and [Formula: see text] the size of spacial steps, especially, making clear the relation between [Formula: see text] and [Formula: see text] is according to the different values of diffusion parameter [Formula: see text] through von Neumann stability analysis. The obtained numerical results for several benchmark problems show that our method makes progress in the numerical study of NADM for convection–diffusion equation and is to be effective and helpful particularly in computations for the convection dominated-diffusion equations and, furthermore, valuable in the numerical treatment of many real-world problems such as MHD natural convection flow.
A Model for an Anisotropic Flexoelectric Material with Cubic Symmetry
Authors: El Dhaba A. R.
Published: March 2019

In this study, the responsive-behavior of an anisotropic, elastic, flexoelectric material with cubic internal structure to mechanical loads is formulated and examined. The elastic deformation and spontaneous polarization patterns of these materials, as well as the mechanical properties, are described. The first strain gradient theory is employed to describe flexoelectric phenomenon in dielectric materials. The equations governing the elastostatic equilibrium of flexoelectric materials under infinitesimal strain gradient regimes are derived depending on the elegant variational formulation introduced by Topuin [1956] and Mindlin [1972]. Explicit analytical expressions of the displacement and spontaneous polarization for the plane strain problem of the rectangular domain subjected to external forces are derived using the so-called semi-inverse method. The magnesium oxide MgO (magnesia) is used as an example of dielectric materials with cubic internal structure since it is widely used in thin-film substrate and fabrication of microwave devices. The results revealed that flexoelectric materials exhibit spontaneous polarization due to the elastic extensibility and elastic compressibility.
Climate Change Actions and Just Transition
Authors: ZHANG Ying , WANG Mou
Published: March 2019

This paper elaborates the progress of the studies and negotiations on a just transition of the workforce and the creation of decent and quality jobs, in the context of implementing response measures under the United Nations Framework Convention on Climate Change (UNFCCC). Just transition in essence deals with the employment issues, thus the impact of climate change policies on employment should be understood in the first place. Low-carbon development refers to a development path to low-carbon economic growth by phasing out fossil fuels, with the objective of achieving sustainable development while fighting climate change. Adjustments in the industry structure and energy structure will not only have an impact on the employment scale and structure but also generate new demand for job skills. In order to achieve just transition in implementing climate policies, China should promote targeted research, create more low-carbon jobs by increasing green investment, and pay special attention to people who lose their jobs due to the implementation of climate policies and keep them from falling into poverty.
Blastocoel Fluid Biopsy
Authors: Gianaroli Luca , Albanese Cristina , Tabanelli Carla , Crippa Andor , Magli Maria Cristina
Published: March 2019

The identification of viable embryos for transfer is one of the main challenges in reproductive medicine. As chromosomal abnormalities are the major cause of implantation failure, preimplantation genetic testing of aneuploidy plays an important role in embryo selection. To make this approach more efficient, the possibility to retrieve informative DNA through a moderately invasive technique compared to the traditional forms of biopsy is appealing. Blastocoelic fluid is a valuable source of DNA. Its presence, as detected by whole genomic amplification, and the following analysis by comprehensive chromosome screening could add important information on the blastocyst ploidy condition and developmental potential.
SOD
Authors: Brocanelli Marco , Wang Xiaorui
Published: March 2019

A major concern for today’s smartphones is their much faster battery drain than traditional feature phones, despite their greater battery capacities. The difference is mainly contributed by those more powerful but also much more power-consuming smartphone components, such as the multi-core application processor and the high-definition (HD) display. While the application processor must be active when any smart apps are being used, it is also unnecessarily waken up, even during idle periods, to perform operations related to basic phone functions (i.e., incoming calls and text messages). In addition, the power-hungry HD display is also used unnecessarily for such basic functions.

In this article, we investigate how to increase the battery life of smartphones by minimizing the use of application processor and HD display for operations related to basic functions. We find that the application processor is often waken up by a process running on it, called the Radio Interface Layer Daemon (RILD), which interfaces the user and apps to the GSM/LTE cellular network. In particular, we demonstrate that a great amount of energy could be saved if RILD is stopped, such that the application processor can sleep more often. Based on this key finding, we design a Smart On Demand (SOD) configuration that reduces the smartphone energy consumption by running RILD operations on a secondary low-power microcontroller and by using a secondary low-power display to interface the user with basic functions. As a result, basic phone functions can be handled at much lower energy costs and the power-consuming components, i.e., application processor and HD display, are waken up only when one needs to use any smart apps, in an on-demand manner. We have built a hardware prototype of SOD and evaluated it with real user traces. Our results show that SOD can increase its battery life by up to 2.5 more days.
Improving Data-Analytics Performance Via Autonomic Control of Concurrency and Resource Units
Authors: Lee Gil Jae , Fortes José A. B.
Published: March 2019

Many big-data processing jobs use data-analytics frameworks such as Apache Hadoop (currently also known as YARN). Such frameworks have tunable configuration parameters set by experienced system administrators and/or job developers. However, tuning parameters manually can be hard and time-consuming because it requires domain-specific knowledge and understanding of complex inter-dependencies among parameters. Most of the frameworks seek efficient resource management by assigning resource units to jobs, the maximum number of units allowed in a system being part of the static configuration of the system. This static resource management has limited effectiveness in coping with job diversity and workload dynamics, even in the case of a single job. The work reported in this article seeks to improve performance (e.g., multiple-jobs makespan and job completion time) without modification of either the framework or the applications and avoiding problems of previous self-tuning approaches based on performance models or resource usage. These problems include (1) the need for time-consuming training, typically offline and (2) unsuitability for multi-jobs/tenant environments. This article proposes a hierarchical self-tuning approach using (1) a fuzzy-logic controller to dynamically adjust the maximum number of concurrent jobs and (2) additional controllers (one for each cluster node) to adjust the maximum number of resource units assigned to jobs on each node. The fuzzy-logic controller uses fuzzy rules based on a concave-downward relationship between aggregate CPU usage and the number of concurrent jobs. The other controllers use a heuristic algorithm to adjust the number of resource units on the basis of both CPU and disk IO usage by jobs. To manage the maximum number of available resource units in each node, the controllers also take resource usage by other processes (e.g., system processes) into account. A prototype of our approach was implemented for Apache Hadoop on a cluster running at CloudLab. The proposed approach was demonstrated and evaluated with workloads composed of jobs with similar resource usage patterns as well as other realistic mixed-pattern workloads synthesized by SWIM, a statistical workload injector for MapReduce. The evaluation shows that the proposed approach yields up to a 48% reduction of the jobs makespan that results from using Hadoop-default settings.
Hemodynamic characterization of a transgenic rat strain stably expressing the calcium sensor protein GCaMP2
Authors: Oláh Attila , Ruppert Mihály , Orbán Tamás István , Apáti Ágota , Sarkadi Balázs , Merkely Béla , Radovits Tamás
Published: March 2019

A novel transgenic rat strain has recently been generated that stably expresses the genetically engineered calcium sensor protein GCaMP2 in different cell types, including cardiomyocytes, to investigate calcium homeostasis. To investigate whether the expression of the GCaMP2 protein itself affects cardiac function, in the present work we aimed at characterizing in vivo hemodynamics in the GCaMP2 transgenic rat strain. GCaMP2 transgenic rats and age-matched Sprague-Dawley control animals were investigated. In vivo hemodynamic characterization was performed by left ventricular (LV) pressure-volume analysis. Postmortem heart weight data showed cardiac hypertrophy in the GCaMP2 group (heart-weight-to-tibial-length ratio: 0.26 ± 0.01 GCaMP2 vs. 0.23 ± 0.01 g/cm Co, P < 0.05). We detected elevated mean arterial pressure and increased total peripheral resistance in transgenic rats. GCaMP2 transgenesis was associated with prolonged contraction and relaxation. LV systolic function was not altered in transgenic rats, as indicated by conventional parameters and load-independent, sensitive indices. We found a marked deterioration of LV active relaxation in GCaMP2 animals (τ: 16.8 ± 0.7 GCaMP2 vs. 12.2 ± 0.3 ms Co, P < 0.001). Our data indicated myocardial hypertrophy, arterial hypertension, and impaired LV active relaxation along with unchanged systolic performance in the heart of transgenic rats expressing the GCaMP2 fluorescent calcium sensor protein. Special caution should be taken when using transgenic models in cardiovascular studies.

NEW & NOTEWORTHY Genetically encoded Ca2+-sensors, like GCaMP2, are important tools to reveal molecular mechanisms for Ca2+-sensing. We provided left ventricular hemodynamic characterization of GCaMP2 transgenic rats and found increased afterload, cardiac hypertrophy, and prolonged left ventricular relaxation, along with unaltered systolic function and contractility. Special caution should be taken when using this rodent model in cardiovascular pharmacological and toxicological studies.
Salt-sensitive transcriptome of isolated kidney distal tubule cells
Authors: Swanson Elizabeth A. , Nelson Jonathan W. , Jeng Sophia , Erspamer Kayla J. , Yang Chao-Ling , McWeeney Shannon , Ellison David H.
Published: March 2019

In the distal kidney tubule, the steroid hormone aldosterone regulates sodium reabsorption via the epithelial sodium channel (ENaC). Most studies seeking to identify ENaC-regulating aldosterone-induced proteins have used transcriptional profiling of cultured cells. To identify salt-sensitive transcripts in an in vivo model, we used low-NaCl or high-NaCl diet to stimulate or suppress endogenous aldosterone, in combination with magnetic- and fluorescence-activated cell sorting to isolate distal tubule cells from mouse kidney for transcriptional profiling. Of the differentially expressed transcripts, 162 were more abundant in distal tubule cells isolated from mice fed low-NaCl diet, and 161 were more abundant in distal tubule cells isolated from mice fed high-NaCl diet. Enrichment analysis of Gene Ontology biological process terms identified multiple statistically overrepresented pathways among the differentially expressed transcripts that were more abundant in distal tubule cells isolated from mice fed low-NaCl diet, including ion transmembrane transport, regulation of growth, and negative regulation of apoptosis. Analysis of Gene Ontology molecular function terms identified differentially expressed transcription factors, transmembrane transporters, kinases, and G protein-coupled receptors. Finally, comparison with a recently published study of gene expression changes in distal tubule cells in response to administration of aldosterone identified 18 differentially expressed genes in common between the two experiments. When expression of these genes was measured in cortical collecting ducts microdissected from mice fed low-NaCl or high-NaCl diet, eight were differentially expressed. These genes are likely to be regulated directly by aldosterone and may provide insight into aldosterone signaling to ENaC in the distal tubule.
Regulation of miRNA Biogenesis and Histone Modification by K63-Polyubiquitinated DDX17 Controls Cancer Stem-like Features
Authors: Kao Shih-Han , Cheng Wei-Chung , Wang Yi-Ting , Wu Han-Tsang , Yeh Han-Yu , Chen Yu-Ju , Tsai Ming-Hsui , Wu Kou-Juey
Published: March 2019

Markers of cancer stemness predispose patients to tumor aggressiveness, drug and immunotherapy resistance, relapse, and metastasis. DDX17 is a cofactor of the Drosha–DGCR8 complex in miRNA biogenesis and transcriptional coactivator and has been associated with cancer stem-like properties. However, the precise mechanism by which DDX17 controls cancer stem-like features remains elusive. Here, we show that the E3 ligase HectH9 mediated K63-polyubiquitination of DDX17 under hypoxia to control stem-like properties and tumor-initiating capabilities. Polyubiquitinated DDX17 disassociated from the Drosha–DGCR8 complex, leading to decreased biogenesis of anti-stemness miRNAs. Increased association of polyubiquitinated DDX17 with p300-YAP resulted in histone 3 lysine 56 (H3K56) acetylation proximal to stemness-related genes and their subsequent transcriptional activation. High expression of HectH9 and six stemness-related genes (BMI1, SOX2, OCT4, NANOG, NOTCH1, and NOTCH2) predicted poor survival in patients with head and neck squamous cell carcinoma and lung adenocarcinoma. Our findings demonstrate that concerted regulation of miRNA biogenesis and histone modifications through posttranslational modification of DDX17 underlies many cancer stem-like features. Inhibition of DDX17 ubiquitination may serve as a new therapeutic venue for cancer treatment.

Significance:

Hypoxia-induced polyubiquitination of DDX17 controls its dissociation from the pri-miRNA–Drosha–DCGR8 complex to reduce anti-stemness miRNA biogenesis and association with YAP and p300 to enhance transcription of stemness-related genes.
Pan-TAM Tyrosine Kinase Inhibitor BMS-777607 Enhances Anti–PD-1 mAb Efficacy in a Murine Model of Triple-Negative Breast Cancer
Authors: Kasikara Canan , Davra Viralkumar , Calianese David , Geng Ke , Spires Thomas E. , Quigley Michael , Wichroski Michael , Sriram Ganapathy , Suarez-Lopez Lucia , Yaffe Michael B. , Kotenko Sergei V. , De Lorenzo Mariana S. , Birge Raymond B.
Published: March 2019

Tyro3, Axl, and Mertk (TAM) represent a family of homologous tyrosine kinase receptors known for their functional role in phosphatidylserine (PS)-dependent clearance of apoptotic cells and also for their immune modulatory functions in the resolution of inflammation. Previous studies in our laboratory have shown that Gas6/PS-mediated activation of TAM receptors on tumor cells leads to subsequent upregulation of PD-L1, defining a putative PS→TAM receptor→PD-L1 inhibitory signaling axis in the cancer microenvironment that may promote tolerance. In this study, we tested combinations of TAM inhibitors and PD-1 mAbs in a syngeneic orthotopic E0771 murine triple-negative breast cancer model, whereby tumor-bearing mice were treated with pan-TAM kinase inhibitor (BMS-777607) or anti–PD-1 alone or in combination. Tyro3, Axl, and Mertk were differentially expressed on multiple cell subtypes in the tumor microenvironment. Although monotherapeutic administration of either pan-TAM kinase inhibitor (BMS-777607) or anti–PD-1 mAb therapy showed partial antitumor activity, combined treatment of BMS-777607 with anti–PD-1 significantly decreased tumor growth and incidence of lung metastasis. Moreover, combined treatment with BMS-777607 and anti–PD-1 showed increased infiltration of immune stimulatory T cells versus either monotherapy treatment alone. RNA NanoString profiling showed enhanced infiltration of antitumor effector T cells and a skewed immunogenic immune profile. Proinflammatory cytokines increased with combinational treatment. Together, these studies indicate that pan-TAM inhibitor BMS-777607 cooperates with anti–PD-1 in a syngeneic mouse model for triple-negative breast cancer and highlights the clinical potential for this combined therapy.

Significance:

These findings show that pan-inhibition of TAM receptors in combination with anti–PD-1 may have clinical value as cancer therapeutics to promote an inflammatory tumor microenvironment and improve host antitumor immunity.
MRI Imaging of the Hemodynamic Vasculature of Neuroblastoma Predicts Response to Antiangiogenic Treatment
Authors: Zormpas-Petridis Konstantinos , Jerome Neil P. , Blackledge Matthew D. , Carceller Fernando , Poon Evon , Clarke Matthew , McErlean Ciara M. , Barone Giuseppe , Koers Alexander , Vaidya Sucheta J. , Marshall Lynley V. , Pearson Andrew D.J. , Moreno Lucas , Anderson John , Sebire Neil , McHugh Kieran , Koh Dow-Mu , Yuan Yinyin , Chesler Louis , Robinson Simon P. , Jamin Yann
Published: March 2019

Childhood neuroblastoma is a hypervascular tumor of neural origin, for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe an MRI-pathologic cross-correlative approach using intrinsic susceptibility (IS) and susceptibility contrast (SC) MRI to noninvasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib. We showed that the transverse MRI relaxation rate R2* (second−1) and fractional blood volume (fBV, %) were sensitive imaging biomarkers of hemorrhage and vascular density, respectively, and were also predictive biomarkers of response to cediranib. Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic. This study reinforces the potential role of functional MRI in delivering precision medicine to children with neuroblastoma.

Significance:

This study shows that functional MRI predicts response to vascular-targeted therapy in a genetically engineered murine model of neuroblastoma.
Drak, Drak, Goose: A New Signaling Axis in Glioblastoma
Authors: Lathia Justin D.
Published: March 2019

While many molecular alterations in glioblastoma (GBM), the most common primary malignant brain tumor, have been defined, the intricate signaling networks associated with these alterations that represent actionable therapeutic targets are less well established. Chen and colleagues leverage a Drosophila GBM model to identify a conserved signaling axis downstream of the EGFR and PI3K that involves the death-associated protein kinase (Drak), a cytoplasmic serine/threonine kinase orthologous to the human kinase STK17A. Functional studies revealed that targeting this signaling axis attenuated mitosis and cytokinesis, providing a new pathway for therapeutic development in GBM.

See related article by Chen et al., p. 1085
Circulating Inflammation Markers and Risk of Gastric and Esophageal Cancers: A Case–Cohort Study Within the Japan Public Health Center–Based Prospective Study
Authors: Camargo M. Constanza , Song Minkyo , Shimazu Taichi , Charvat Hadrien , Yamaji Taiki , Sawada Norie , Kemp Troy J. , Pfeiffer Ruth M. , Hildesheim Allan , Pinto Ligia A. , Tsugane Shoichiro , Rabkin Charles S.
Published: March 2019

Background:

Circulating inflammation proteins may be important mediators or markers of carcinogenic mechanisms. There have been few studies with limited numbers of analytes in patients with upper gastrointestinal (GI) tract tumors. We therefore evaluated risk associations of gastric and esophageal cancers with prediagnostic levels of a wide range of these molecules.

Methods:

We performed a case–cohort analysis within the Japan Public Health Center–Based Prospective Study Cohort II, including incident cases of gastric (n = 446) and esophageal (n = 68) cancers and a random subcohort (n = 774). A total of 64 biomarkers were measured in baseline plasma using Luminex bead-based assays. The median time between blood collection and diagnosis was 8.1 years for gastric cancer and 9.4 years for esophageal cancer. HRs for association with each marker were adjusted for potential confounders using Cox regression.

Results:

In separate models, sEGFR and TSLP were nominally associated with gastric cancer risk, and CRP, CXCL11/ITAC, and CCL15/MIP1D were associated with esophageal cancer. However, no association satisfied statistical significance after FDR correction. Associations did not differ by time from blood collection to cancer (<5 vs. ≥5 years).

Conclusions:

Our study failed to identify associations of circulating inflammation markers with risk of upper GI tract tumors.

Impact:

To date, this is the largest assessment of inflammation-related proteins with gastric and esophageal cancer risks. However, the evaluated molecules may not fully represent the complex inflammation processes preceding malignant transformation. Further investigation of other markers in prospective studies is warranted, as demonstration of associations may have important implications for prevention and treatment of these cancers.
Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion–Driven Cancer
Authors: Slotkin Emily K. , Diolaiti Daniel , Shukla Neerav N. , Dela Cruz Filemon S. , Clark Jennifer J. , Gundem Gunes , Yellapantula Venkata D. , Levine Max F. , You Daoqi , Ma Peilin , Pachhal Sagarika , Ibanez Sanchez Glorymar , Benayed Ryma , Jungbluth Achim A. , Smyth Lillian M. , Mauguen Audrey , Gushterova Irena , Ding Hongxu , Spraggon Lee , Darnell Robert , Califano Andrea , Ladanyi Marc , Papaemmanuil Elli , Kung Andrew L. , Hyman David M. , Roberts Stephen S.
Published: March 2019

Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the AKT genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the LAMTOR1 and AKT1 genes. Through expanded use access, she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib. Treatment resulted in dramatic tumor regression, demonstrating through patient-driven discovery that the fusion resulted in activation of AKT1, was an oncogenic driver, and could be therapeutically targeted with clinical benefit. Post-clinical validation using patient-derived model systems corroborated these findings, confirmed a membrane-bound and constitutively active fusion protein, and identified potential mechanisms of resistance to single-agent treatment with ipatasertib.

Significance:

This study describes the patient-driven discovery of the first AKT1 fusion–driven cancer and its treatment with the AKT inhibitor ipatasertib. Patient-derived in vitro and in vivo model systems are used to confirm the LAMTOR1–AKT1 fusion as a tumorigenic driver and identify potential mechanisms of resistance to AKT inhibition.

This article is highlighted in the In This Issue feature, p. 565
A Systematic Ultrasound Evaluation of the Diameter of Deep Veins in the Newborn: Results and Implications for Clinical Practice
Authors: Barone Giovanni , D’Andrea Vito , Vento Giovanni , Pittiruti Mauro
Published: March 2019

Background: In adults and children, current guidelines recommend measuring the diameter of the vein before the insertion of central catheters, in order to match vein diameter with catheter caliber and thus reduce the risk of venous thrombosis. In the neonatal intensive care unit, central catheters are often used but the vein diameter is usually not considered. Method: We assessed the diameter of the most relevant deep veins in 100 newborns, using a strict protocol of ultrasound evaluation. Results: Mean gestational age of studied infants was 32 weeks and mean weight was 1,690 g. The mean diameter of the brachiocephalic vein was consistently ≥3 mm, with no significant difference between the right and the left side. The femoral vein diameter, on the other hand, was considerably smaller than 3 mm for infants with a weight < 2,000 g. Interobserver repeatability was found to be very high. Conclusion: Preprocedural ultrasound scan of veins is feasible and easy, also in newborns, and it should be recommended for optimizing central venous catheterization.
Regional Variation in
RBM20
Causes a Highly Penetrant Arrhythmogenic Cardiomyopathy
Authors: Parikh Victoria N. , Caleshu Colleen , Reuter Chloe , Lazzeroni Laura C. , Ingles Jodie , Garcia John , McCaleb Kristen , Adesiyun Tolulope , Sedaghat-Hamedani Farbod , Kumar Saurabh , Graw Sharon , Gigli Marta , Stolfo Davide , Dal Ferro Matteo , Ing Alexander Y. , Nussbaum Robert , Funke Birgit , Wheeler Matthew T. , Hershberger Ray E. , Cook Stuart , Steinmetz Lars M. , Lakdawala Neal K. , Taylor Matthew R.G. , Mestroni Luisa , Merlo Marco , Sinagra Gianfranco , Semsarian Christopher , Meder Benjamin , Judge Daniel P. , Ashley Euan
Published: March 2019

Background

Variants in the cardiomyocyte-specific RNA splicing factor
RBM20
have been linked to familial cardiomyopathy, but the causative genetic architecture and clinical consequences of this disease are incompletely defined.

Methods and Results

To define the genetic architecture of
RBM20
cardiomyopathy, we first established a database of
RBM20
variants associated with cardiomyopathy and compared these to variants observed in the general population with respect to their location in the
RBM20
coding transcript. We identified 2 regions significantly enriched for cardiomyopathy-associated variants in exons 9 and 11. We then assembled a registry of 74 patients with
RBM20
variants from 8 institutions across the world (44 index cases and 30 from cascade testing). This
RBM20
patient registry revealed highly prevalent family history of sudden cardiac death (51%) and cardiomyopathy (72%) among index cases and a high prevalence of composite arrhythmias (including atrial fibrillation, nonsustained ventricular tachycardia, implantable cardiac defibrillator discharge, and sudden cardiac arrest, 43%). Patients harboring variants in cardiomyopathy-enriched regions identified by our variant database analysis were enriched for these findings. Further, these characteristics were more prevalent in the
RBM20
registry than in large cohorts of patients with dilated cardiomyopathy and
TTNtv
cardiomyopathy and not significantly different from a cohort of patients with
LMNA
-associated cardiomyopathy.

Conclusions

Our data establish
RBM20
cardiomyopathy as a highly penetrant and arrhythmogenic cardiomyopathy. These findings underline the importance of arrhythmia surveillance and family screening in this disease and represent the first step in defining the genetic architecture of
RBM20
disease causality on a population level.