bluuebunny/crossref_metadata_2025_split huggingface dataset:
Generalized solitary waves in a finite‐difference Korteweg‐de Vries equation
Authors: Joshi N. , Lustri C. J. 
Published: January 2019

AbstractGeneralized solitary waves with exponentially small nondecaying far field oscillations have been studied in a range of singularly perturbed differential equations, including higher order Korteweg‐de Vries (KdV) equations. Many of these studies used exponential asymptotics to compute the behavior of the oscillations, revealing that they appear in the solution as special curves known as Stokes lines are crossed. Recent studies have identified similar behavior in solutions to difference equations. Motivated by these studies, the seventh‐order KdV and a hierarchy of higher order KdV equations are investigated, identifying conditions which produce generalized solitary wave solutions. These results form a foundation for the study of infinite‐order differential equations, which are used as a model for studying lattice equations. Finally, a lattice KdV equation is generated using finite‐difference discretization, in which a lattice generalized solitary wave solution is found.
Meta‐analysis of the prevalence of thermotolerant Campylobacter in food‐producing animals worldwide
Authors: Rossler Eugenia , Signorini Marcelo L. , Romero‐Scharpen Analía , Soto Lorena P. , Berisvil Ayelén , Zimmermann Jorge A. , Fusari Marcia L. , Olivero Carolina , Zbrun María V. , Frizzo Laureano S. 
Published: January 2019

AbstractThe objective of this meta‐analysis was to summarize available information on the prevalence of thermotolerant Campylobacter (TC) in different food‐producing animals worldwide. Databases (i.e., PubMed, ScienceDirect, Scopus) were searched from 1980 to 2017 unrestricted by language. The inclusion criteria were as follows: prevalence or incidence studies, published in peer‐reviewed journals, and they must have reported the total number of animal samples studied and the number of samples that were positive for the presence of TC. When the identification of Campylobacter species was available, this information was included in the analysis. Multilevel random‐effect meta‐analysis models were fitted to estimate mean occurrence rate of TC and to compare them among different factors potentially associated with the outcome. The mean occurrence rate of TC in food‐producing animals was 0.424 (95% CI: 0.394–0.455), and the mean occurrence rate of Campylobacter jejuni and Campylobacter coli were 0.214 and 0.133, respectively. Pigs and poultry showed the highest prevalence of TC; however, there were differences in the prevalence of each Campylobacter species. Campylobacter jejuni was observed in broilers (0.322; 95% CI: 0.273–0.377) and hens (0.395; 95% CI: 0.265–0.542), while C. coli was restricted essentially in pigs (0.553; 95% CI: 0.541–0.650). The prevalence of C. jejuni in intensively bred cattle was higher (0.302; 95% CI: 0.227–0.389) than the prevalence in extensively bred cattle (0.172; 95% CI: 0.119–0.242) while the prevalence of C. coli was similar (0.051; 95% CI: 0.028–0.091 vs. 0.050; 95% CI: 0.027–0.091) in both production systems. Agar with or without blood used for the isolation of TC did not affect the prevalence observed. The method of species identification did not seem to generate differences in the prevalence of Campylobacter species. The prevalence of Campylobacter in primary food production has a strong impact on the entire agri‐food chain. National authorities must monitor the situation with the aim to establish the appropriate risk management measures.
Carotid chemoreflex activity restrains post‐exercise cardiac autonomic control in healthy humans and in patients with pulmonary arterial hypertension
Authors: Paula‐Ribeiro Marcelle , Ribeiro Indyanara C. , Aranda Liliane C. , Silva Talita M. , Costa Camila M. , Ramos Roberta P. , Ota‐Arakaki Jaquelina S. , Cravo Sergio L. , Nery Luiz E. , Stickland Michael K. , Silva Bruno M. 
Published: January 2019

Key points
Dysfunction of post‐exercise cardiac autonomic control is associated with increased mortality risk in healthy adults and in patients with cardiorespiratory diseases.
The afferent mechanisms that regulate the post‐exercise cardiac autonomic control remain unclear.
We found that afferent signals from carotid chemoreceptors restrain the post‐exercise cardiac autonomic control in healthy adults and patients with pulmonary arterial hypertension (PAH).
Patients with PAH had higher carotid chemoreflex sensitivity, and the magnitude of carotid chemoreceptor restraint of autonomic control was greater in patients with PAH as compared to healthy adults.
The results demonstrate that the carotid chemoreceptors contribute to the regulation of post‐exercise cardiac autonomic control, and suggest that the carotid chemoreceptors may be a potential target to treat post‐exercise cardiac autonomic dysfunction in patients with PAH.
AbstractDysfunction of post‐exercise cardiac autonomic control predicts mortality, but its underlying mechanisms remain unclear. We tested whether carotid chemoreflex activity restrains post‐exercise cardiac autonomic control in healthy adults (HA), and whether such restraint is greater in patients with pulmonary arterial hypertension (PAH) who may have both altered carotid chemoreflex and altered post‐exercise cardiac autonomic control. Twenty non‐hypoxaemic patients with PAH and 13 age‐ and sex‐matched HA pedalled until 90% of peak work rate observed in a symptom‐limited ramp‐incremental exercise test. Recovery consisted of unloaded pedalling for 5 min followed by seated rest for 6 min. During recovery, subjects randomly inhaled either 100% O2 (hyperoxia) to inhibit the carotid chemoreceptor activity, or 21% O2 (normoxia) as control. Post‐exercise cardiac autonomic control was examined via heart rate (HR) recovery (HRR; HR change after 30, 60, 120 and 300 s of recovery, using linear and non‐linear regressions of HR decay) and HR variability (HRV; time and spectral domain analyses). As expected, the PAH group had higher carotid chemosensitivity and worse post‐exercise HRR and HRV than HA. Hyperoxia increased HRR at 30, 60 and 120 s and absolute spectral power HRV in both groups. Additionally, hyperoxia resulted in an accelerated linear HR decay and increased time domain HRV during active recovery only in the PAH group. In conclusion, the carotid chemoreceptors restrained recovery of cardiac autonomic control from exercise in HA and in patients with PAH, with the restraint greater for some autonomic indexes in patients with PAH.
Protocol for a prospective observational study to develop a frailty index for use in perioperative and critical care
Authors: Darvall Jai N , Braat Sabine , Story David A , Greentree Kate , Bose Tony , Loth Joel , Lim Wen K 
Published: January 2019

IntroductionFrailty is of increasing importance to perioperative and critical care medicine, as the proportion of older patients increases globally. Evidence continues to emerge of the considerable impact frailty has on adverse outcomes from both surgery and critical care, which has led to a proliferation of different frailty measurement tools in recent years. Despite this, there remains a lack of easily implemented, comprehensive frailty assessment tools specific to these complex populations. Development of a frailty index using routinely collected hospital data, able to leverage the automated aspects of an electronic medical record, would aid risk stratification and benefit clinicians and patients alike.Methods and analysisThis is a prospective observational study. 150 intensive care unit (ICU) patients aged ≥50 years and 200 surgical patients aged ≥65 years will be enrolled. The primary objective is to develop a frailty index. Secondary objectives include assessing its ability to predict in-hospital mortality and/or discharge to a new non-home location; the performance of the frailty index in predicting postoperative and ICU complications, as well as health-related quality of life at 6 months; to compare the performance of the frailty index against existing frailty measurement and risk stratification tools; and to assess its modification by patients’ health assets.Ethics and disseminationThis study has been approved by the Melbourne Health Human Research Ethics Committee(20 January 2017, HREC/16/MH/321). Dissemination will be via international and national anaesthetic and critical care conferences, and publication in the peer-reviewed literature.
Study rationale and protocol of the BARICO study: a longitudinal, prospective, observational study to evaluate the effects of weight loss on brain function and structure after bariatric surgery
Authors: Vreeken Debby , Wiesmann Maximilian , Deden Laura N , Arnoldussen Ilse A C , Aarts Esther , Kessels Roy P C , Kleemann Robert , Hazebroek Eric J , Aarts Edo O , Kiliaan Amanda J 
Published: January 2019

IntroductionWeight loss after bariatric surgery (BS) is often associated with improved cognition and structural brain recovery. However, improved cognition after BS is not always exhibited by patients, in fact, in some cases there is even a decline in cognition. Long-term consequences of BS weight loss, in terms of obesity and related diseases, can be hard to determine due to studies having short follow-up periods and small sample sizes.The aim of the BARICO study (BAriatric surgeryRijnstate and Radboudumc neuroImaging andCognition inObesity) is to determine the long-term effect of weight loss after BS on brain function and structure, using sensitive neuropsychological tests and (functional) MRI ((f)MRI). Secondary study endpoints are associated with changes in metabolic and inflammation status of adipose tissue, liver and gut, in relation to brain structure and function. Also, the possible correlation between weight loss, gut microbiota composition change and neuropsychological outcomes will be investigated.Methods and analysisData from 150 Dutch BS patients (ages between 35 and 55, men and women) will be collected at various time points between 2 months before and up to 10 years after surgery. Neuropsychological tests, questionnaires, blood, faeces and tissue samples will be collected before, during and after surgery to measure changes in cognition, microbiota, metabolic activity and inflammation over time. A subgroup of 75 participants will undergo (f)MRI in relation to executive functioning (determined by the Stroop task), grey and white matter volumes and cerebral blood flow. Regression analyses will be used to explore associations between weight loss and outcome measures.Ethics and disseminationThis study has been approved by the medical review ethics committee CMO Region Arnhem and Nijmegen (NL63493.091.17). Research findings will be published in peer-reviewed journals and at conferences.Trial registration numberNTR7288.
Dietary cholesterol and apolipoprotein A-I are trafficked in endosomes and lysosomes in the live zebrafish intestine
Authors: Otis Jessica P. , Shen Meng-Chieh , Caldwell Blake A. , Reyes Gaido Oscar E. , Farber Steven A. 
Published: January 2019

Difficulty in imaging the vertebrate intestine in vivo has hindered our ability to model nutrient and protein trafficking from both the lumenal and basolateral aspects of enterocytes. Our goal was to use live confocal imaging to increase understanding of intestinal trafficking of dietary cholesterol and apolipoprotein A-I (APOA-I), the main structural component of high-density lipoproteins. We developed a novel assay to visualize live dietary cholesterol trafficking in the zebrafish intestine by feeding TopFluor-cholesterol (TF-cholesterol), a fluorescent cholesterol analog, in a lipid-rich, chicken egg yolk feed. Quantitative microscopy of transgenic zebrafish expressing fluorescently tagged protein markers of early, recycling, and late endosomes/lysosomes provided the first evidence, to our knowledge, of cholesterol transport in the intestinal endosomal-lysosomal trafficking system. To study APOA-I dynamics, transgenic zebrafish expressing an APOA-I fluorescent fusion protein (APOA-I-mCherry) from tissue-specific promoters were created. These zebrafish demonstrated that APOA-I-mCherry derived from the intestine accumulated in the liver and vice versa. Additionally, intracellular APOA-I-mCherry localized to endosomes and lysosomes in the intestine and liver. Moreover, live imaging demonstrated that APOA-I-mCherry colocalized with dietary TF-cholesterol in enterocytes, and this colocalization increased with feeding time. This study provides a new set of tools for the study of cellular lipid biology and elucidates a key role for endosomal-lysosomal trafficking of intestinal cholesterol and APOA-I.NEW & NOTEWORTHY A fluorescent cholesterol analog was fed to live, translucent larval zebrafish to visualize intracellular cholesterol and apolipoprotein A-I (APOA-I) trafficking. With this model intestinal endosomal-lysosomal cholesterol trafficking was observed for the first time. A new APOA-I fusion protein (APOA-I-mCherry) expressed from tissue-specific promoters was secreted into the circulation and revealed that liver-derived APOA-I-mCherry accumulates in the intestine and vice versa. Intestinal, intracellular APOA-I-mCherry was observed in endosomes and lysosomes and colocalized with dietary cholesterol.
Fractal dimension and directional analysis of elastic and collagen fiber arrangement in unsectioned arterial tissues affected by atherosclerosis and aging
Authors: Mostaço-Guidolin Leila B. , Smith Michael S. D. , Hewko Mark , Schattka Bernie , Sowa Michael G. , Major Arkady , Ko Alex C.-T. 
Published: January 2019

Structural proteins like collagen and elastin are major constituents of the extracellular matrix (ECM). ECM degradation and remodeling in diseases significantly impact the microorganization of these structural proteins. Therefore, tracking the changes of collagen and elastin fiber morphological features within ECM impacted by disease progression could provide valuable insight into pathological processes such as tissue fibrosis and atherosclerosis. Benefiting from its intrinsic high-resolution imaging power and superior biochemical specificity, nonlinear optical microscopy (NLOM) is capable of providing information critical to the understanding of ECM remodeling. In this study, alterations of structural fibrillar proteins such as collagen and elastin in arteries excised from atherosclerotic rabbits were assessed by the combination of NLOM images and textural analysis methods such as fractal dimension (FD) and directional analysis (DA). FD and DA were tested for their performance in tracking the changes of extracellular elastin and fibrillar collagen remodeling resulting from atherosclerosis progression/aging. Although other methods of image analysis to study the organization of elastin and collagen structures have been reported, the simplified calculations of FD and DA presented in this work prove that they are viable strategies for extracting and analyzing fiber-related morphology from disease-impacted tissues. Furthermore, this study also demonstrates the potential utility of FD and DA in studying ECM remodeling caused by other pathological processes such as respiratory diseases, several skin conditions, or even cancer. NEW & NOTEWORTHY Textural analyses such as fractal dimension (FD) and directional analysis (DA) are straightforward and computationally viable strategies to extract fiber-related morphological data from optical images. Therefore, objective, quantitative, and automated characterization of protein fiber morphology in extracellular matrix can be realized by using these methods in combination with digital imaging techniques such as nonlinear optical microscopy (NLOM), a highly effective visualization tool for fibrillar collagen and elastic network. Combining FD and DA with NLOM is an innovative approach to track alterations of structural fibrillar proteins. The results illustrated in this study not only prove the effectiveness of FD and DA methods in extracellular protein characterization but also demonstrate their potential value in clinical and basic biomedical research where protein microstructure characterization is critical.
Enhancer Domains in Gastrointestinal Stromal Tumor Regulate KIT Expression and Are Targetable by BET Bromodomain Inhibition
Authors: Hemming Matthew L. , Lawlor Matthew A. , Andersen Jessica L. , Hagan Timothy , Chipashvili Otari , Scott Thomas G. , Raut Chandrajit P. , Sicinska Ewa , Armstrong Scott A. , Demetri George D. , Bradner James E. 
Published: January 2019

Abstract

Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, resulting in high expression levels of the oncogene required for tumor growth. Although kinase inhibition is an effective therapy for many patients with GIST, disease progression from kinase-resistant mutations is common and no other effective classes of systemic therapy exist. In this study, we identify regulatory regions of the KIT enhancer essential for KIT gene expression and GIST cell viability. Given the dependence of GIST upon enhancer-driven expression of RTKs, we hypothesized that the enhancer domains could be therapeutically targeted by a BET bromodomain inhibitor (BBI). Treatment of GIST cells with BBIs led to cell-cycle arrest, apoptosis, and cell death, with unique sensitivity in GIST cells arising from attenuation of the KIT enhancer domain and reduced KIT gene expression. BBI treatment in KIT-dependent GIST cells produced genome-wide changes in the H3K27ac enhancer landscape and gene expression program, which was also seen with direct KIT inhibition using a tyrosine kinase inhibitor (TKI). Combination treatment with BBI and TKI led to superior cytotoxic effects in vitro and in vivo, with BBI preventing tumor growth in TKI-resistant xenografts. Resistance to select BBI in GIST was attributable to drug efflux pumps. These results define a therapeutic vulnerability and clinical strategy for targeting oncogenic kinase dependency in GIST.

Significance:
Expression and activity of mutant KIT is essential for driving the majority of GIST neoplasms, which can be therapeutically targeted using BET bromodomain inhibitors.
Distinct Molecular Profiles and Immunotherapy Treatment Outcomes of V600E and V600K BRAF-Mutant Melanoma
Authors: Pires da Silva Inês , Wang Kevin Y.X. , Wilmott James S. , Holst Jeff , Carlino Matteo S. , Park John J. , Quek Camelia , Wongchenko Matthew , Yan Yibing , Mann Graham , Johnson Douglas B. , McQuade Jennifer L. , Rai Rajat , Kefford Richard F. , Rizos Helen , Scolyer Richard A. , Yang Jean Y.H. , Long Georgina V. , Menzies Alexander M. 
Published: January 2019

Abstract

Purpose:
BRAF V600E and V600K melanomas have distinct clinicopathologic features, and V600K appear to be less responsive to BRAFi±MEKi. We investigated mechanisms for this and explored whether genotype affects response to immunotherapy.

Experimental Design:
Pretreatment formalin-fixed paraffin-embedded tumors from patients treated with BRAFi±MEKi underwent gene expression profiling and DNA sequencing. Molecular results were validated using The Cancer Genome Atlas (TCGA) data. An independent cohort of V600E/K patients treated with anti–PD-1 immunotherapy was examined.

Results:
Baseline tissue and clinical outcome with BRAFi±MEKi were studied in 93 patients (78 V600E, 15 V600K). V600K patients had numerically less tumor regression (median, −31% vs. −52%, P = 0.154) and shorter progression-free survival (PFS; median, 5.7 vs. 7.1 months, P = 0.15) compared with V600E. V600K melanomas had lower expression of the ERK pathway feedback regulator dual-specificity phosphatase 6, confirmed with TCGA data (116 V600E, 17 V600K). Pathway analysis showed V600K had lower expression of ERK and higher expression of PI3K-AKT genes than V600E. Higher mutational load was observed in V600K, with a higher proportion of mutations in PIK3R1 and tumor-suppressor genes. In patients treated with anti–PD-1, V600K (n = 19) had superior outcomes than V600E (n = 84), including response rate (53% vs. 29%, P = 0.059), PFS (median, 19 vs. 2.7 months, P = 0.049), and overall survival (20.4 vs. 11.7 months, P = 0.081).

Conclusions:
BRAF V600K melanomas appear to benefit less from BRAFi±MEKi than V600E, potentially due to less reliance on ERK pathway activation and greater use of alternative pathways. In contrast, these melanomas have higher mutational load and respond better to immunotherapy.
Spermine on Endothelial Extracellular Vesicles Mediates Smoking-Induced Pulmonary Hypertension Partially Through Calcium-Sensing Receptor
Authors: Zhu Liping , Xiao Rui , Zhang Xiuyun , Lang Yuheng , Liu Fangbo , Yu Zhe , Zhang Jiwei , Su Yuan , Lu Yankai , Wang Tao , Luo Shengquan , Wang Jian , Liu Ming-Lin , Dupuis Jocelyn , Jing Zhi-Cheng , Li Tong , Xiong Weining , Hu Qinghua 
Published: January 2019

Objective—
This study aims to determine whether and how the enriched metabolites of endothelial extracellular vesicles (eEVs) are critical for cigarette smoke-induced direct injury of endothelial cells and the development of pulmonary hypertension, rarely explored in contrast to long-investigated mechanisms secondary to chronic hypoxemia.

Approach and Results—

Metabonomic screen of eEVs from cigarette-smoking human subjects reveals prominent elevation of spermine—a polyamine metabolite with potent agonist activity for the extracellular CaSR (calcium-sensing receptor). CaSR inhibition with the negative allosteric modulator Calhex231 or CaSR knockdown attenuates cigarette smoke-induced pulmonary hypertension in rats without emphysematous changes in lungs or chronic hypoxemia. Cigarette smoke exposure increases the generation of spermine-positive eEVs and their spermine content. Immunocytochemical staining and immunogold electron microscopy recognize the spermine enrichment not only within the cytosol but also on the outer surface of eEV membrane. The repression of spermine synthesis, the inhibitory analog of spermine, N
1
-dansyl-spermine, Calhex231, or CaSR knockdown profoundly suppresses eEV exposure-mobilized cytosolic calcium signaling, pulmonary artery constriction, and smooth muscle cell proliferation. Confocal imaging of immunohistochemical staining demonstrates the migration of spermine-positive eEVs from endothelium into smooth muscle cells in pulmonary arteries of cigarette smoke-exposed rats. The repression of spermine synthesis or CaSR knockout results in attenuated development of pulmonary hypertension induced by an intravascular administration of eEVs.

Conclusions—
Cigarette smoke enhances eEV generation with spermine enrichment at their outer surface and cytosol, which activates CaSR and subsequently causes smooth muscle cell constriction and proliferation, therefore, directly leading to the development of pulmonary hypertension.