bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH
Authors: Hernandez Gabriella V. , Smith Victoria A. , Melnyk Megan , Burd Matthew A. , Sprayberry Kimberly A. , Edwards Mark S. , Peterson Daniel G. , Bennet Darin C. , Fanter Rob K. , Columbus Daniel A. , Steibel Juan P. , Glanz Hunter , Immoos Chad , Rice Margaret S. , Santiago-Rodriguez Tasha M. , Blank Jason , VanderKelen Jennifer J. , Kitts Christopher L. , Piccolo Brian D. , La Frano Michael R. , Burrin Douglas G. , Maj Magdalena , Manjarin Rodrigo 
Published: January 2020

To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a “Western-style diet” [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine- N-oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver.NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine- N-oxide in the liver.
Preservación digital
Authors: Claudio Escobar Arriagada  
Published: January 2020

La preservación digital es un conjunto de tareas, técnicas, métodos y tecnologías que buscan garantizar el acceso a la información en formato digital. Este artículo presenta una aproximación a los conceptos clave relacionados con la preservación digital, los beneficios de su implementación, los principales aspectos tecnológicos asociados, los desafíos y una mirada a la situación actual de la preservación digital en Chile.
Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia–Related Head and Neck Cancer
Authors: Montanuy Helena , Martínez-Barriocanal Águeda , Antonio Casado José , Rovirosa Llorenç , Ramírez Maria José , Nieto Rocío , Carrascoso-Rubio Carlos , Riera Pau , González Alan , Lerma Enrique , Lasa Adriana , Carreras-Puigvert Jordi , Helleday Thomas , Bueren Juan A. , Arango Diego , Minguillón Jordi , Surrallés Jordi 
Published: January 2020

AbstractPurpose:Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia.Experimental Design:We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety.Results:Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non–small cell lung cancer (NSCLC), displayed nontumor/tumor IC50 ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient–derived HNSCCs. Finally, in vivo toxicity studies in Fanca-deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters.Conclusions:Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.
Aortic Stiffness and Infarct Healing in Survivors of Acute ST‐Segment–Elevation Myocardial Infarction
Authors: Reindl Martin , Tiller Christina , Holzknecht Magdalena , Lechner Ivan , Hein Nicolas , Pamminger Mathias , Henninger Benjamin , Mayr Agnes , Feistritzer Hans‐Josef , Klug Gert , Bauer Axel , Metzler Bernhard , Reinstadler Sebastian J. 
Published: January 2020

Background

In survivors of acute
ST
‐segment–elevation myocardial infarction (
STEMI
), increased aortic stiffness is associated with worse clinical outcome; however, the underlying pathomechanisms are incompletely understood. We aimed to investigate associations between aortic stiffness and infarct healing using comprehensive cardiac magnetic resonance imaging in patients with acute
STEMI
.

Methods and Results

This was a prospective observational study including 103 consecutive
STEMI
patients treated with primary percutaneous coronary intervention. Pulse wave velocity (
PWV
), the reference standard for aortic stiffness assessment, was determined by a validated phase‐contrast cardiac magnetic resonance imaging protocol within the first week after
STEMI
. Infarct healing, defined as relative infarct size reduction from baseline to 4 months post‐
STEMI
, was determined using late gadolinium‐enhanced cardiac magnetic resonance. Median infarct size significantly decreased from 17% of left ventricular mass (interquartile range 9% to 28%) at baseline to 12% (6% to 17%) at 4‐month follow‐up (
P
<0.001). Relative infarct size reduction was 36% (interquartile range 15% to 52%). Patients with a reduction >36% were younger (
P
=0.01) and had lower baseline NT‐proBNP (N‐terminal pro–B‐type natriuretic peptide) concentrations (
P
=0.047) and aortic
PWV
values (
P
=0.003). In a continuous (odds ratio 0.64 [95% CI, 0.49–0.84];
P
=0.001) as well as categorical (
PWV
<7 m/s; odds ratio 4.80 [95% CI, 1.89–12.20];
P
=0.001) multivariable logistic regression model, the relation between aortic
PWV
and relative infarct size reduction remained significant after adjustment for baseline infarct size, age, NT‐proBNP, and C‐reactive protein.

Conclusions

Aortic
PWV
independently predicted infarct size reduction as assessed by cardiac magnetic resonance, revealing a novel pathophysiological link between aortic stiffness and adverse infarct healing during the early phase after
STEMI
treated with contemporary primary percutaneous coronary intervention.
Ischemic Stroke and Bleeding
Authors: Stanton Robert J. , Eckman Mark H. , Woo Daniel , Moomaw Charles J. , Haverbusch Mary , Flaherty Matthew L. , Kleindorfer Dawn O. 
Published: January 2020

Background and Purpose—

Patients with intracerebral hemorrhage (ICH) and atrial fibrillation (AF) are at risk for ischemic events. While risk calculators (CHA
2
DS
2
-VASc and HAS-BLED) have been validated to assess risk for ischemic stroke and major bleeding in AF patients, decisions about anticoagulation must consider the net clinical benefit of anticoagulation. Furthermore, stroke and bleeding risk are highly correlated, making decisions more difficult.

Methods—

We examined patients in the GERFHS III study (Genetic and Environmental Risk Factors for Hemorrhagic Stroke)—a population-based retrospective study of spontaneous ICH patients without a structural or traumatic cause in the Greater Cincinnati/Northern Kentucky region between July 2008 and December 2012. CHA
2
DS
2
-VASc and HAS-B(L)ED (minus L because labile international normalized ratio was unavailable) scores were calculated for ICH patients with AF. Using a Markov state transition model, we estimated net clinical benefit of anticoagulation relative to no treatment in quality-adjusted life years (QALYs). We defined minimal clinically relevant benefit as 0.1 QALYs.

Results—
Among 1186 cases of spontaneous ICH, 95 cases had AF and met our survival criteria. Within 1 year, 8 of 95 (8%) would be expected to have a major bleeding event on anticoagulation, and 5 of 95 (5%) of patients would be expected to have an ischemic stroke off anticoagulation. Sixty-eight of 95 (71%) patients would have higher risk for major bleeding than for ischemic stroke. Anticoagulation with directly acting anticoagulants would result in no clinically significant gain or loss in 73%. Roughly 12% would gain >0.1 QALYs, and 15% would lose >0.1 QALYs. Among patients receiving aspirin, most have no significant net clinical benefit or loss. Overall, anticoagulation of the entire cohort would result in an aggregate loss of 0.92 QALYs.

Conclusions—
Our analysis suggests that universal anticoagulation after ICH would be associated with a net loss of QALY. Additional factors should be considered before anticoagulating patients with AF after ICH.

Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00930280.
Genome-Wide Polygenic Score and the Risk of Ischemic Stroke in a Prospective Cohort
Authors: Hachiya Tsuyoshi , Hata Jun , Hirakawa Yoichiro , Yoshida Daigo , Furuta Yoshihiko , Kitazono Takanari , Shimizu Atsushi , Ninomiya Toshiharu 
Published: January 2020

Background and Purpose—
Environmental and genetic factors contribute to the development of ischemic stroke (IS). We recently developed a genome-wide polygenic risk score (PRS) for IS using case-control datasets from 4 large-scale observational studies conducted in Japan. Our objective in the present study was to confirm the association between the PRS and the risk of IS with data from an independent prospective cohort recruited from the general Japanese population.

Methods—
A total of 3038 subjects aged ≥40 years were followed up for 10 years (2002–2012). The genome-wide PRS was calculated using genotype data from >350 000 single-nucleotide polymorphisms. The PRS levels were divided into quintiles. High and low genetic risk groups were defined as top 60% and bottom 40% of PRS, respectively. The hazard ratio (HR) for the development of IS was estimated using a Cox proportional hazards model.

Results—

During the follow-up period, 91 cases developed first-ever IS. The age- and sex-adjusted HR for IS increased with higher PRS levels (
P
for trend, 0.03). Subjects with the highest quintile level of PRS had a 2.44-fold (95% CI, 1.16–5.12) greater risk for IS than those with the lowest quintile level after adjusting for age and sex. A similar association was observed after adjusting for environmental risk factors (
P
for trend, 0.03). As compared with low genetic risk group, the age- and sex-adjusted HR in high genetic risk group was 1.63 (95% CI, 1.04–2.55), which was comparable to the HR of hypertension (HR, 1.41), diabetes mellitus (HR, 1.72), and smoking (HR, 1.54). The age- and sex-adjusted HR increased with the number of environmental risk factors in both high and low genetic risk groups without significant interaction.

Conclusions—
A high genome-wide PRS was a significant risk factor for IS independent of environmental risk factors in a general Japanese population. This finding suggests that PRS may be useful to identify individuals at a high risk of IS.
Twenty-First-Century Climate Change Hot Spots in the Light of a Weakening Sun
Authors: Spiegl Tobias , Langematz Ulrike 
Published: January 2020

AbstractSatellite measurements over the last three decades show a gradual decrease in solar output, which can be indicative as a precursor to a modern grand solar minimum (GSM). Using a chemistry–climate model, this study investigates the potential of two GSM scenarios with different magnitude to counteract the climate change by projected anthropogenic greenhouse gas (GHG) emissions through the twenty-first century. To identify regions showing enhanced vulnerability to climate change (hot spots) and to estimate their response to a possible modern GSM, a multidimensional metric is applied that accounts for—in addition to changes in mean quantities—seasonal changes in the variability and occurrence of extreme events. We find that a future GSM in the middle of the twenty-first century would temporarily mitigate the global mean impact of anthropogenic climate change by 10%–23% depending on the GSM scenario. A future GSM would, however, not be able to stop anthropogenic global warming. For the GHG-only scenario, our hot-spot analysis suggests that the midlatitudes show a response to rising GHGs below global average, while in the tropics, climate change hot spots with more frequent extreme hot seasons will develop during the twenty-first century. A GSM would reduce the climate change warming in all regions. The GHG-induced warming in Arctic winter would be dampened in a GSM due to the impact of reduced solar irradiance on Arctic sea ice. However, even an extreme GSM could only mitigate a fraction of the tropical hot-spot pattern (up to 24%) in the long term.
A Subjective and Objective Evaluation of Model Forecasts of Sumatra Squall Events
Authors: Sun Xiangming , Huang Xiang-Yu , Gordon Chris , Mittermaier Marion , Beckett Rebecca , Cheong Wee Kiong , Barker Dale , North Rachel , Semple Allison 
Published: January 2020

Abstract
Sumatra squalls are important rain-bearing weather systems that affect Singapore and southern Peninsular Malaysia. The performance of forecasts for 63 past squall events is evaluated using a subjective evaluation by forecasters and an objective evaluation based on the fractions skill score (FSS). The purpose of this study is to investigate whether an objective procedure can reproduce the main results of the subjective evaluation. A convection permitting version of the Met Office (UKMO) Unified Model (UM), configured for a limited domain in the southern region of the South China Sea, is used with two driving global deterministic models: the UM and the European Centre for Medium-Range Weather Forecasts (ECMWF) model. Subjective and objective evaluation scoring methods for the two limited-area forecasts of the UM are compared, and it is shown that the objective procedure can reasonably emulate the scores produced by the forecasters in the context of parameters that are of direct relevance to the forecast process. This indicates that automated objective verification methods may be a reasonable alternative to resource intensive subjective evaluations for some cases. The robustness of the objective results is investigated using 7 months of data, and issues of statistical significance are considered.
Static, Dynamic, and Cognitive Fit of Exosystems for the Human Operator
Authors: Stirling Leia , Kelty-Stephen Damian , Fineman Richard , Jones Monica L. H. , Daniel Park Byoung-Keon , Reed Matthew P. , Parham Joseph , Choi Hyeg Joo 
Published: January 2020

Objective To define static, dynamic, and cognitive fit and their interactions as they pertain to exosystems and to document open research needs in using these fit characteristics to inform exosystem design. Background Initial exosystem sizing and fit evaluations are currently based on scalar anthropometric dimensions and subjective assessments. As fit depends on ongoing interactions related to task setting and user, attempts to tailor equipment have limitations when optimizing for this limited fit definition. Method A targeted literature review was conducted to inform a conceptual framework defining three characteristics of exosystem fit: static, dynamic, and cognitive. Details are provided on the importance of differentiating fit characteristics for developing exosystems. Results Static fit considers alignment between human and equipment and requires understanding anthropometric characteristics of target users and geometric equipment features. Dynamic fit assesses how the human and equipment move and interact with each other, with a focus on the relative alignment between the two systems. Cognitive fit considers the stages of human-information processing, including somatosensation, executive function, and motor selection. Human cognitive capabilities should remain available to process task- and stimulus-related information in the presence of an exosystem. Dynamic and cognitive fit are operationalized in a task-specific manner, while static fit can be considered for predefined postures. Conclusion A deeper understanding of how an exosystem fits an individual is needed to ensure good human–system performance. Development of methods for evaluating different fit characteristics is necessary. Application Methods are presented to inform exosystem evaluation across physical and cognitive characteristics.
Interactions between institutional logics and cultural dynamics in the public–private integration process
Authors: Thelisson Anne-Sophie , Meier Olivier 
Published: January 2020

This article underlines the specificities of public–private mergers by presenting the interactions between the institutional logics at stake and the cultural dynamics during the integration process of a public–private merger. The article presents a longitudinal case study of a public–private merger of two listed French companies over two years. Our study completes and enriches Schultz’s model by showing its dynamic nature and highlighting the crucial role of the state as a trigger for the interactions between institutional logics and cultural dynamics. Points for practitioners By highlighting the interactions between cultural dynamics and institutional logics, we trace how cultural dynamics influence the decision-making process and how institutional logics influence integration by becoming dominant. We demonstrate how the state influences the interactions between these forces during the integration process.
Central nervous system variations and abnormalities in anhidrotic ectodermal dysplasia (AED): neuroimaging findings
Authors: Dusak Abdurrahim , Hafizoglu Demet , Kilic Sara Sebnem , Yazıcı Zeynep 
Published: January 2020

Background Anhidrotic ectodermal dysplasia (AED) is a rare, mostly X-linked recessive genodermatosis, characterized by congenital defects of ectodermal derivative structures as the central nervous system (CNS) is primarily ectodermal in origin. Purpose To evaluate CNS variations and abnormalities in AED. Material and Methods A retrospective analysis was made of the neurological and neuroimaging findings of 17 children (12 boys, 5 girls; median age = 8 years; age range = 2–14 years) diagnosed with AED in our pediatric clinics during 2008–2016. The pattern of CNS variation and abnormalities were evaluated by comparing of these findings with an age- and gender-matched healthy control group with no family history. Results Of the 17 AED cases identified on the basis of neuroimaging findings, 6 (35.3%) were seen to be normal. Associated CNS variation and abnormalities including cavum septum pellucidum (35.3%), callosal dysgenesis (11.8%), prominent Virchow–Robin spaces (64.7%), cortical sulcal dilation (41.1%), mega cisterna magna (35.3%), focal cortical dysplasia (11.8%), and delayed myelination (58.8%) were observed in 11 (64.7%) children with AED. Conclusion AED suggests a spectrum of CNS variation and abnormalities, presenting with neurological and neuroimaging findings, demonstrated in the embryonic surface- and neuro-ectoderm derived structures. The results of this study suggest that CNS variation and abnormalities might be associated with AED.
Aquaporin-2 expression in the kidney and urine is elevated in rats with monocrotaline-induced pulmonary heart disease
Authors: Ouyang Shao , Chen Wei , Zeng Gaofeng , Lei Changcheng 
Published: January 2020

Objective Little is known about how renal aquaporin-2 (AQP2) expression is affected by right heart failure caused by pulmonary heart disease (PHD). Therefore, we examined the expression of AQP2 in a rat model of PHD induced by monocrotaline (MCT). Methods After 4 weeks of treatment, urine and blood samples were collected from sham-treated and MCT-treated rats. Plasma arginine vasopressin (AVP) levels were measured by radioimmunoassay, and kidney Aqp2 mRNA expression was detected by reverse transcription (RT)-PCR. Kidney AQP2 protein expression was quantified by immunohistochemistry and western blotting assays. The concentration of urine AQP2 was determined by indirect enzyme-linked immunosorbent assay. Results We successfully established an animal model of MCT-induced PHD in rats. MCT-treated rats had significantly higher mRNA and protein levels of AQP2 in their kidney tissue. Following MCT treatment, rats also had markedly increased concentrations of both urine AQP2 and plasma AVP. Conclusions AQP2 expression was significantly increased in the kidney tissues and urine of rats with PHD induced by MCT. Our findings suggest that the evaluation of AQP2 expression contributes to an early diagnosis of PHD, and may also be an important reference to improve PHD therapeutics.