bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impacts of helmet law on the changes in potential years of life lost due to traffic injury: a multiple-province evaluation in Vietnam
Authors: Phung Dung , Nguyen Ha Trong , Chu Cordia , Sadler Ross , Luong Anh Mai , Nguyen Huyen Thi , Pham Tuan Cong , Huang Cunrui 
Published: March 2019

IntroductionThis study aimed to evaluate the impact of the helmet law on the changes in potential years of life lost (PYLL) due to traffic mortality and to examine modification effects of socioeconomic factors on the impacts in Vietnam.MethodsWe applied an interrupted time series design using the Bayesian framework to estimate the impact of the law at the provincial level. Then, we used random effects meta-analysis to estimate the impact of the law at the country level and to examine the modification effects of socioeconomic factors.ResultsThe results indicate that the impacts varied among the provinces. These impacts could be classified by four main groups comprising positive impact, and positive impact without sustainability, possible positive impact, negative or inconsistent impact. For the country-level impact, the results reveal a significantly consistent change in monthly PYLLs at the level of 18 per 100 000 persons, and the post-trend was stable without significant change. The results of meta-regression show that 1 unit increase in the population density (persons/km2), migration rate (%) and income (×1000 dong) are non-significantly associated with increases of PYLLs at 1.3, 27 and 27 per 100 000 person-months, respectively, whereas 1% increase in literacy associated with a decrease of PYLL at 44 per 100 000 person-months.DiscussionFurther studies should be warranted to provide a comprehensive evaluation of the law implementation, including its acceptability, adoption, appropriateness, feasibility, cost-effectiveness and sustainability.
Performance challenges in modular parallel programs
Authors: Acar Umut A. , Aksenov Vitaly , Charguéraud Arthur , Rainey Mike 
Published: March 2019

Over the past decade, many programming languages and systems for parallel-computing have been developed, including Cilk, Fork/Join Java, Habanero Java, Parallel Haskell, Parallel ML, and X10. Although these systems raise the level of abstraction at which parallel code are written, performance continues to require the programmer to perform extensive optimizations and tuning, often by taking various architectural details into account. One such key optimization is granularity control, which requires the programmer to determine when and how parallel tasks should be sequentialized.
In this paper, we briefly describe some of the challenges associated with automatic granularity control when trying to achieve portable performance for parallel programs with arbitrary nesting of parallel constructs. We consider a result from the functional-programming community, whose starting point is to consider an "oracle" that can predict the work of parallel codes, and thereby control granularity. We discuss the challenges in implementing such an oracle and proving that it has the desired theoretical properties under the nested-parallel programming model.
Multi-Omics Profiling Reveals Distinct Microenvironment Characterization and Suggests Immune Escape Mechanisms of Triple-Negative Breast Cancer
Authors: Xiao Yi , Ma Ding , Zhao Shen , Suo Chen , Shi Jinxiu , Xue Meng-Zhu , Ruan Miao , Wang Hai , Zhao Jingjing , Li Qin , Wang Peng , Shi Leming , Yang Wen-Tao , Huang Wei , Hu Xin , Yu Ke-Da , Huang Shenglin , Bertucci François , Jiang Yi-Zhou , Shao Zhi-Ming 
Published: March 2019

Abstract

Purpose:
The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood.

Experimental Design:
Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC.

Results:
The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the “immune-desert” cluster, with low microenvironment cell infiltration; cluster 2, the “innate immune-inactivated” cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the “immune-inflamed” cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathologic sections and externally with The Cancer Genome Atlas and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules.

Conclusions:
Our study represents a step toward personalized immunotherapy for patients with TNBC. Immune checkpoint inhibitors might be effective for “immune-inflamed” cluster, and the transformation of “cold tumors” into “hot tumors” should be considered for “immune-desert” and “innate immune-inactivated” clusters.
Direct CDKN2 Modulation of CDK4 Alters Target Engagement of CDK4 Inhibitor Drugs
Authors: Green Jennifer L. , Okerberg Eric S. , Sejd Josilyn , Palafox Marta , Monserrat Laia , Alemayehu Senait , Wu Jiangyue , Sykes Maria , Aban Arwin , Serra Violeta , Nomanbhoy Tyzoon 
Published: March 2019

AbstractThe interaction of a drug with its target is critical to achieve drug efficacy. In cases where cellular environment influences target engagement, differences between individuals and cell types present a challenge for a priori prediction of drug efficacy. As such, characterization of environments conducive to achieving the desired pharmacologic outcome is warranted. We recently reported that the clinical CDK4/6 inhibitor palbociclib displays cell type–specific target engagement: Palbociclib engaged CDK4 in cells biologically sensitive to the drug, but not in biologically insensitive cells. Here, we report a molecular explanation for this phenomenon. Palbociclib target engagement is determined by the interaction of CDK4 with CDKN2A, a physiologically relevant protein inhibitor of CDK4. Because both the drug and CDKN2A prevent CDK4 kinase activity, discrimination between these modes of inhibition is not possible by traditional kinase assays. Here, we describe a chemo-proteomics approach that demonstrates high CDK4 target engagement by palbociclib in cells without functional CDKN2A and attenuated target engagement when CDKN2A (or related CDKN2/INK4 family proteins) is abundant. Analysis of biological sensitivity in engineered isogenic cells with low or absent CDKN2A and of a panel of previously characterized cell lines indicates that high levels of CDKN2A predict insensitivity to palbociclib, whereas low levels do not correlate with sensitivity. Therefore, high CDKN2A may provide a useful biomarker to exclude patients from CDK4/6 inhibitor therapy. This work exemplifies modulation of kinase target engagement by endogenous proteinaceous regulators and highlights the importance of cellular context in predicting inhibitor efficacy.
Stratified Flows over and around Long Dynamically Tall Mountain Ridges
Authors: Jagannathan Arjun , Winters Kraig , Armi Laurence 
Published: March 2019

AbstractUniformly stratified flows approaching long and dynamically tall ridges develop two distinct flow components over disparate time scales. The fluid upstream and below a “blocking level” is stagnant in the limit of an infinite ridge and flows around the sides when the ridge extent is finite. The streamwise half-width of the obstacle at the blocking level arises as a natural inner length scale for the flow, while the excursion time over this half-width is an associated short time scale for the streamwise flow evolution. Over a longer time scale, low-level horizontal flow splitting leads to the establishment of an upstream layerwise potential flow beneath the blocking level. We demonstrate through numerical experiments that for sufficiently long ridges, crest control and streamwise asymmetry are seen on both the short and long time scales. On the short time scale, upstream blocking is established quickly and the flow is well described as a purely infinite-ridge overflow. Over the long time scale associated with flow splitting, low-level flow escapes around the sides, but the overflow continues to be hydraulically controlled and streamwise asymmetric in the neighborhood of the crest. We quantify this late-time overflow by estimating its volumetric transport and then briefly demonstrate how this approach can be extended to predict the overflow across nonuniform ridge shapes.
Recent Surface Air Temperature Change over Mainland China Based on an Urbanization-Bias Adjusted Dataset
Authors: Wen Kangmin , Ren Guoyu , Li Jiao , Zhang Aiying , Ren Yuyu , Sun Xiubao , Zhou Yaqing 
Published: March 2019

AbstractA dataset from 763 national Reference Climate and Basic Meteorological Stations (RCBMS) was used to analyze surface air temperature (SAT) change in mainland China. The monthly historical observational records had been adjusted for urbanization bias existing in the data series of size-varied urban stations, after they were corrected for data inhomogeneities mainly caused by relocation and instrumentation. The standard procedures for creating area-averaged temperature time series and for calculating linear trend were used. Analyses were made for annual and seasonal mean temperature. Annual mean SAT in mainland China as a whole rose by 1.24°C for the last 55 years, with a warming rate of 0.23°C decade−1. This was close to the warming of 1.09°C observed in global mean land SAT over the period 1951–2010. Compared to the SAT before correction, after-corrected data showed that the urbanization bias had caused an overestimate of the annual warming rate of more than 19.6% during 1961–2015. The winter, autumn, spring, and summer mean warming rates were 0.28°, 0.23°, 0.23°, and 0.15°C decade−1, respectively. The spatial patterns of the annual and seasonal mean SAT trends also exhibited an obvious difference from those of the previous analyses. The largest contrast was a weak warming area appearing in central parts of mainland China, which included a small part of southwestern North China, the northwestern Yangtze River, and the eastern part of Southwest China. The annual mean warming trends in Northeast and North China obviously decreased compared to the previous analyses, which caused a relatively more significant cooling in Northeast China after 1998 under the background of global warming slowdown.
First Effort at Constructing a High-Density Photosynthetically Active Radiation Dataset during 1961–2014 in China
Authors: Qin Wenmin , Wang Lunche , Zhang Ming , Niu Zigeng , Luo Ming , Lin Aiwen , Hu Bo 
Published: March 2019

AbstractPhotosynthetically active radiation (PAR) is a key factor for vegetation growth and climate change. Different types of PAR models, including four physically based models and eight artificial intelligence (AI) models, were proposed for predicting daily PAR. Multiyear daily meteorological parameters observed at 29 Chinese Ecosystem Research Network (CERN) stations and 2474 Chinese Meteorological Administration (CMA) stations across China were used for testing, validating, and comparing the above models. The optimized back propagation (BP) neural network based on the mind evolutionary algorithm (MEA-BP) was the model with highest accuracy and strongest robustness. The correlation coefficient R, mean absolute bias error (MAE), and RMSE for MEA-BP were 0.986, 0.302 MJ m−2 day−1 and 0.393 MJ m−2 day−1, respectively. Then, a high-density PAR dataset was constructed for the first time using the MEA-BP model at 2474 CMA stations of China. A quality control process and homogenization test (using RHtestsV4) for the PAR dataset were further conducted. This high-density PAR dataset would benefit many climate and ecological studies.
High-throughput quantification of carboxymethyl lysine in serum and plasma using high-resolution accurate mass Orbitrap mass spectrometry
Authors: Rankin Naomi J , Burgess Karl , Weidt Stefan , Wannamethee Goya , Sattar Naveed , Welsh Paul 
Published: March 2019

Background Carboxymethyl lysine is an advanced glycation end product of interest as a potential biomarker of cardiovascular and other diseases. Available methods involve ELISA, with potential interference, or isotope dilution mass spectrometry (IDMS), with low-throughput sample preparation. Methods A high-throughput sample preparation method based on 96-well plates was developed. Protein-bound carboxymethyl lysine and lysine were quantified by IDMS using reversed phase chromatography coupled to a high-resolution accurate mass Orbitrap Exactive mass spectrometer. The carboxymethyl lysine concentration (normalized to lysine concentration) was measured in 1714 plasma samples from the British Regional Heart Study (BRHS). Results For carboxymethyl lysine, the lower limit of quantification (LLOQ) was estimated at 0.16 μM and the assay was linear between 0.25 and 10 μM. For lysine, the LLOQ was estimated at 3.79 mM, and the assay was linear between 2.5 and 100 mM. The intra-assay coefficient of variation was 17.2% for carboxymethyl lysine, 9.3% for lysine and 10.5% for normalized carboxymethyl lysine. The inter-assay coefficient of variation was 18.1% for carboxymethyl lysine, 14.8 for lysine and 16.2% for normalized carboxymethyl lysine. The median and inter-quartile range of all study samples in each batch were monitored. A mean carboxymethyl lysine concentration of 2.7 μM (IQR 2.0–3.2 μM, range 0.2–17.4 μM) and a mean normalized carboxymethyl lysine concentration of 69 μM/M lysine (IQR 54–76 μM/M, range 19–453 μM/M) were measured in the BRHS. Conclusion This high-throughput sample preparation method makes it possible to analyse large cohorts required to determine the potential of carboxymethyl lysine as a biomarker.
Context and the mechanisms in intersectoral school-based health promotion interventions: A critical interpretative synthesis
Authors: Bergeron Dave A , Talbot Lise R , Gaboury Isabelle 
Published: March 2019

Introduction: School-based health promotion interventions (SHPI) have been introduced extensively over the last decades, but their implementation and evaluation still present challenges. Among these, the complexity of the environments in which SHPI are implemented, and intersectoral collaboration to promote more sustainable change, must be better addressed within evaluation processes. Objectives: The objectives of this study were to (1) identify pertinent scientific literature on the implementation processes for intersectoral SHPI and (2) develop a programme theory that maps potential elements of context and underlying mechanisms that may influence intersectoral SHPI. Method: A critical interpretative synthesis was performed of elements of context and underlying situational and transformational mechanisms. These were identified based on the scientific literature published between 1997 and 2017 addressing intersectoral SHPI. Results: Six potential elements of context, seven potential situational mechanisms and seven potential transformational mechanisms that can explain SHPI outcomes were identified from 28 articles. The results were integrated into a framework to pinpoint elements that facilitate or impede intersectoral SHPI implementation. Conclusion: The results of this synthesis support a more comprehensive approach to evaluating SHPI, and improved consideration of intersectoral collaboration and the complexity associated with this type of intervention.
Adjunctive tianeptine treatment for bipolar disorder: A 24-week randomized, placebo-controlled, maintenance trial
Authors: Kauer-Sant’Anna Márcia , Frey Benicio N , Fijtman Adam , Loredo-Souza Ana C , Dargél Aroldo A , Pfaffenseller Bianca , Wollenhaupt-Aguiar Bianca , Gazalle Fernando K , Colpo Gabriela D , Passos Ives C , Bücker Joana , Walz Júlio C , Jansen Karen , Mendes Ceresér Keila M , Bürke Bridi Kelen P , dos Santos Sória Lisiane , Kunz Maurício , Pinho Michele , Kapczinski Natália S , Goi Pedro D , Magalhães Pedro VS , Reckziegel Ramiro , Burque Renan K , de Azevedo Cardoso Taiane , Kapczinski Flávio 
Published: March 2019

Objective: The purpose of this study was to assess the efficacy and tolerability of tianeptine as an adjunctive maintenance treatment for bipolar depression. Methods: This is a multicenter double-blind randomized placebo-controlled maintenance trial of adjunctive tianeptine 37.5 mg/day. Participants ( n=161) had a Montgomery-Asberg Depression Rating Scale ⩾12 at entry. After eight weeks of open-label tianeptine treatment, those who responded to tianeptine ( n=69) were randomized to adjunctive tianeptine ( n=36) or placebo ( n=33) in addition to usual treatment. Kaplan-Meier estimates and the Mantel-Cox log-rank test were used to evaluate differences in time to intervention for a mood episode between the tianeptine and placebo groups. We also assessed overall functioning, biological rhythms, quality of life, rates of manic switch and serum brain-derived neurotrophic factor levels. Results: There were no differences between adjunctive tianeptine or placebo regarding time to intervention or depression scores in the 24-week double-blind controlled phase. Patients in the tianeptine group showed better performance in the letter-number sequencing subtest from the Wechsler Adult Intelligence Scale at the endpoint ( p=0.014). Tianeptine was well tolerated and not associated with higher risk for manic switch compared to placebo. Conclusion: Tianeptine was not more effective than placebo in the maintenance treatment of bipolar depression. There is preliminary evidence suggesting a pro-cognitive effect of tianeptine in working memory compared to placebo.
Reduced phosphodiesterase-2 activity in the amygdala results in anxiolytic-like effects on behavior in mice
Authors: Chen Ling , Cui Suying , Yu Haiyang , Li Gaowen , Liu Na , Wu Qiang , Zhang Han-Ting , O’Donnell James M , Wang Gang , Xu Ying 
Published: March 2019

Background: Phosphodiesterase-2 (PDE2) is a cyclic nucleotide phosphodiesterase and is highly expressed in the amygdala, which suggests its important role in anxiety-like behavior. Aims: The present study examined whether reduced PDE2A expression in the central nucleus of the amygdala (CeA) produces anxiolytic-like effects in mice. Methods: PDE2A knockdown in amygdaloid (AR5) cells or the CeA was established using a lentiviral vector-based siRNA system. The anxiety-like behaviors were detected by the elevated plus maze (EPM) and hole-board tests in mice. The related proteins involved in cAMP/cGMP-dependent signaling, such as specific marker VASPser239, CREBser133 and BDNF were detected by immunoblot analysis. Results: PDE2A inhibition in AR-5 cells resulted in increases in cAMP/cGMP-related pVASPser239 and pCREBser133. Behavioral tests showed that PDE2A knockdown in the CeA induced anxiolytic-like effects as evidenced by the increases in percentages of open-arm entries and time spent in the open arms in the EPM test, and the increases in head dips and time spent in head dipping in the hole-board test. However, these anxiolytic-like effects were antagonized by pre-treatment of soluble guanylyl cyclase inhibitor ODQ or adenylate cyclase inhibitor SQ. Furthermore, PDE2A knockdown significantly increased pVASPSer239, pCREBSer133 and decreased BDNF expression in the amygdala. Pre-intra-CeA of ODQ or SQ reversed or partially prevented the eﬀects of PDE2A knockdown on these proteins. Conclusions: The results suggest that PDE2A plays a crucial role in the regulation of anxiety by the cGMP/cAMP-dependent pVASP-pCREB-BDNF signaling pathway.
Machine-readable Yin–Yang imbalance: traditional Chinese medicine syndrome computer modeling based on three-dimensional noninvasive cardiac electrophysiology imaging
Authors: Cen Wei , Hoppe Ralph , Sun Aiwu , Ding Hongyan , Gu Ning 
Published: March 2019

Objectives The principal diagnostic methods of traditional Chinese medicine (TCM) are inspection, auscultation and olfaction, inquiry, and pulse-taking. Treatment by syndrome differentiation is likely to be subjective. This study was designed to provide a basic theory for TCM diagnosis and establish an objective means of evaluating the correctness of syndrome differentiation. Methods We herein provide the basic theory of TCM syndrome computer modeling based on a noninvasive cardiac electrophysiology imaging technique. Noninvasive cardiac electrophysiology imaging records the heart’s electrical activity from hundreds of electrodes on the patient’s torso surface and therefore provides much more information than 12-lead electrocardiography. Through mathematical reconstruction algorithm calculations, the reconstructed heart model is a machine-readable description of the underlying mathematical physics model that reveals the detailed three-dimensional (3D) electrophysiological activity of the heart. Results From part of the simulation results, the imaged 3D cardiac electrical source provides dynamic information regarding the heart’s electrical activity at any given location within the 3D myocardium. Conclusions This noninvasive cardiac electrophysiology imaging method is suitable for translating TCM syndromes into a computable format of the underlying mathematical physics model to offer TCM diagnosis evidence-based standards for ensuring correct evaluation and rigorous, scientific data for demonstrating its efficacy.
Modified Chuanhu anti-gout mixture, a traditional Chinese medicine, protects against potassium oxonate-induced hyperuricemia and renal dysfunction in mice
Authors: You Wenjun , Wang Jie , Zou Yaowu , Che Kui , Hou Xu , Fei Honghua , Wang Yangang 
Published: March 2019

Objective Acute gout is a painful, inflammatory arthritis that features a rapidly escalating inflammatory response resulting from the formation of monosodium urate crystals in the affected joint space. Previously, we found that Chuanhu anti-gout mixture (CAGM) had similar effects as colchicine against gout in the clinic. Subsequently, to improve its effectiveness and efficacy, we modified the original formulation of CAGM. The current study evaluated the effectiveness of the modified formulation in mice. Methods Potassium oxonate (PO) was used to establish a mouse model of hyperuricemia. Plasma levels of uric acid and creatine were determined using the respective test kits. Hepatic xanthine oxidase (XOD) expression was examined by enzyme-linked immunosorbent assay. To explore the underlying mechanism, renal urate transporter 1 (URAT1) mRNA levels were evaluated by quantitative real-time PCR. Allopurinol and benzbromarone were used as reference drugs. Results The original CAGM and its modified high-dose formulation significantly reduced serum uric acid and creatine levels in hyperuricemic mice. In addition, the CAGM-treated groups displayed lower mRNA levels of hepatic XOD and renal URAT1. Conclusions CAGM and its modified formulation significantly ameliorated PO-induced hyperuricemia in mice, which might be partially attributable to reductions of hepatic XOD and renal URAT1 levels.