bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early-Life Growth and Benign Breast Disease
Authors: Goldberg Mandy , Cohn Barbara A , Houghton Lauren C , Flom Julie D , Wei Ying , Cirillo Piera , Michels Karin B , Terry Mary Beth 
Published: May 2019

AbstractUsing prospective data from the Early Determinants of Mammographic Density study (United States, 1959–2008, n = 1121), we examined the associations between maternal body size, birth size, and infant and early childhood growth during 3 time periods (0–4 months, 4–12 months, and 1–4 years) and benign breast disease (BBD) using multivariable logistic regression with generalized estimating equations. A total of 197 women (17.6%) reported receiving a diagnosis of BBD by a physician. Higher body mass index at age 7 years was inversely associated with BBD risk. Rapid weight gain from age 1 year to 4 years, defined as an increase of least 2 major percentiles (e.g., 5th, 10th, 25th, 50th, 75th, and 95th) relative to stable growth, defined as remaining within 2 percentiles, was also inversely associated with BBD (odds ratio (OR) = 0.51, 95% confidence interval (CI): 0.23, 1.15). In contrast, rapid weight gain in infancy was positively associated with BBD relative to stable growth (from 0 to 4 months, OR = 1.65, 95% CI: 1.04, 2.62; from 4 to 12 months, 1.85, 95% CI: 0.89, 3.85), independent of birth weight, which was not associated with BBD. Our results suggest that patterns of early-life weight gain are important to BBD risk. Thus, susceptibility to BBD, like susceptibility to breast cancer, might start in early life.
Egg discrimination is mediated by individual differences in queen olfactory responsiveness and boldness
Authors: Wright Colin M , McEwen Brendan L , Fisher David N , Lichtenstein James L L , Antoun Angelle , Tibbetts Elizabeth A , Pruitt Jonathan N 
Published: May 2019

AbstractNest parasites attempt to shift the cost of rearing young from themselves to others. Despite strong selection to avoid this exploitation, there is considerable variation among-individuals in susceptibility to nest parasites. We evaluated the effects of individual variation in boldness, aggressiveness, and olfactory responsiveness on egg discrimination in wasps: Polistes metricus, which founds nests as singleton individuals, and P. dominula, which founds nests in small coalitions. Aggressiveness and boldness were evaluated using individuals’ response to mechanical disturbance, and olfactory responsiveness was evaluated using individuals’ tendency to respond to a novel rewarding stimulus. Egg discrimination was evaluated by presenting each queen with a variety of foreign eggs: 1) unaltered eggs laid by the resident (negative control group), 2) eggs produced by the resident female that were removed and replaced (procedural control), 3) eggs of foreign conspecifics (conspecific egg), and 4) eggs of a heterospecific congener (heterospecific egg). Females of both species never rejected untampered eggs and rejected procedural controls in only 35% of cases. Both species were twice as likely (70% rejection rate) to reject eggs of foreign conspecifics or heterospecifics. In P. dominula, bolder individuals and those with low olfactory responsiveness were more likely to reject foreign eggs. In P. metricus, boldness was not associated with egg rejection, but individuals with heightened olfactory responsiveness were more likely to reject foreign eggs. Thus, there are contrasting associations between behavioral phenotypes and egg rejection across species. These results are discussed in light of differences in the colony founding behavior of these species.
Inferring signalling dynamics by integrating interventional with observational data
Authors: Cardner Mathias , Meyer-Schaller Nathalie , Christofori Gerhard , Beerenwinkel Niko 
Published: May 2019

Abstract

Motivation
In order to infer a cell signalling network, we generally need interventional data from perturbation experiments. If the perturbation experiments are time-resolved, then signal progression through the network can be inferred. However, such designs are infeasible for large signalling networks, where it is more common to have steady-state perturbation data on the one hand, and a non-interventional time series on the other. Such was the design in a recent experiment investigating the coordination of epithelial–mesenchymal transition (EMT) in murine mammary gland cells. We aimed to infer the underlying signalling network of transcription factors and microRNAs coordinating EMT, as well as the signal progression during EMT.

Results
In the context of nested effects models, we developed a method for integrating perturbation data with a non-interventional time series. We applied the model to RNA sequencing data obtained from an EMT experiment. Part of the network inferred from RNA interference was validated experimentally using luciferase reporter assays. Our model extension is formulated as an integer linear programme, which can be solved efficiently using heuristic algorithms. This extension allowed us to infer the signal progression through the network during an EMT time course, and thereby assess when each regulator is necessary for EMT to advance.

Availability and implementation
R package at https://github.com/cbg-ethz/timeseriesNEM. The RNA sequencing data and microscopy images can be explored through a Shiny app at https://emt.bsse.ethz.ch.

Supplementary information
Supplementary data are available at Bioinformatics online.
Estimating the strength of expression conservation from high throughput RNA-seq data
Authors: Gu Xun , Ruan Hang , Yang Jingwen 
Published: May 2019

Abstract

Motivation
Evolution of gene across species is usually subject to the stabilizing selection to maintain the optimal expression level. While it is generally accepted that the resulting expression conservation may vary considerably among genes, statistically reliable estimation remains challenging, due to few species included in current comparative RNA-seq data with high number of unknown parameters.

Results
In this paper, we develop a gamma distribution model to describe how the strength of expression conservation (denoted by W) varies among genes. Given the high throughput RNA-seq datasets from multiple species, we then formulate an empirical Bayesian procedure to estimate W for each gene. Our case studies showed that those W-estimates are useful to study the evolutionary pattern of expression conservation.

Availability and implementation
Our method has been implemented in the R-package software, TreeExp, which is publically available at Github develop site https://github.com/hr1912/TreeExp. It involves three functions: estParaGamma, estParaQ and estParaWBayesian. The manual for software TreeExp is available at https://github.com/hr1912/TreeExp/tree/master/vignettes. For any question, one may contact Dr Hang Ruan (Hang.Ruan@uth.tmc.edu).
Stratifying drug treatment of cognitive impairments after traumatic brain injury using neuroimaging
Authors: Jenkins Peter O , De Simoni Sara , Bourke Niall J , Fleminger Jessica , Scott Gregory , Towey David J , Svensson William , Khan Sameer , Patel Maneesh C , Greenwood Richard , Friedland Daniel , Hampshire Adam , Cole James H , Sharp David J 
Published: May 2019

Abstract
Cognitive impairment is common following traumatic brain injury. Dopaminergic drugs can enhance cognition after traumatic brain injury, but individual responses are highly variable. This may be due to variability in dopaminergic damage between patients. We investigate whether measuring dopamine transporter levels using 123I-ioflupane single-photon emission computed tomography (SPECT) predicts response to methylphenidate, a stimulant with dopaminergic effects. Forty patients with moderate-severe traumatic brain injury and cognitive impairments completed a randomized, double-blind, placebo-controlled, crossover study. 123I-ioflupane SPECT, MRI and neuropsychological testing were performed. Patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Subjects received neuropsychological assessment after each block and completed daily home cognitive testing during the trial. The primary outcome measure was change in choice reaction time produced by methylphenidate and its relationship to stratification of patients into groups with normal and low dopamine transporter binding in the caudate. Overall, traumatic brain injury patients showed slow information processing speed. Patients with low caudate dopamine transporter binding showed improvement in response times with methylphenidate compared to placebo [median change = −16 ms; 95% confidence interval (CI): −28 to −3 ms; P = 0.02]. This represents a 27% improvement in the slowing produced by traumatic brain injury. Patients with normal dopamine transporter binding did not improve. Daily home-based choice reaction time results supported this: the low dopamine transporter group improved (median change −19 ms; 95% CI: −23 to −7 ms; P = 0.002) with no change in the normal dopamine transporter group (P = 0.50). The low dopamine transporter group also improved on self-reported and caregiver apathy assessments (P = 0.03 and P = 0.02, respectively). Both groups reported improvements in fatigue (P = 0.03 and P = 0.007). The cognitive effects of methylphenidate after traumatic brain injury were only seen in patients with low caudate dopamine transporter levels. This shows that identifying patients with a hypodopaminergic state after traumatic brain injury can help stratify the choice of cognitive enhancing therapy.
Comparison of Adalimumab Serum Drug Levels When Delivered by Pen Versus Syringe in Patients With Inflammatory Bowel Disease. An International, Multicentre Cohort Analysis
Authors: Little Robert D , Chu Isabel E , van der Zanden Esmerij P , Flanagan Emma , Bell Sally J , Gibson Peter R , Sparrow Miles P , Shelton Edward , Connor Susan J , Roblin Xavier , Ward Mark G 
Published: May 2019

Abstract

Background
Adalimumab is administered via a pre-filled syringe or spring-loaded pen. In a previous study in Crohn’s disease, higher drug levels were observed in syringe users. The aim of this study was to evaluate the impact of delivery device on adalimumab drug levels in patients with Crohn’s disease.

Methods
Consecutive Crohn’s disease patients treated with maintenance adalimumab [40 mg fortnightly] were recruited from five centres. The first recorded drug level with matched clinical and biochemical markers of disease activity was compared between pen and syringe users.

Results
Of 218 patients, 64% used pen, with a median faecal calprotectin 110 μg/g and serum C-reactive protein 4 mg/L. In comparison to pen, syringe users had higher albumin [39 vs 42 g/L; p = 0.016], lower Harvey-Bradshaw Index [2 vs 1; p = 0.017], and higher rates of concomitant immunomodulation [54% vs 71%; p = 0.014]. Drug levels were equivalent between pen and syringe users [median 5.3 vs 5.2 μg/ml; p = 0.584], even after controlling for disease activity and immunomodulation. Syringe users at Alfred Health had higher drug levels than pen [6.1 vs 4.5 μg/ml; p = 0.039]; a greater proportion achieved therapeutic levels [75% vs 44%; p = 0.045]. A higher proportion of pen users from Saint-Étienne had therapeutic levels [79% vs 42%; p = 0.027], yet no significant difference in drug levels [7.9 vs 4.5 μg/ml; p = 0.119].

Conclusions
Delivery device does not appear to significantly affect adalimumab drug levels. Given differences between study sites, studies evaluating administration education and technique are warranted.
Optimization with levosimendan improves outcomes after left ventricular assist device implantation
Authors: Kocabeyoglu Sinan Sabit , Kervan Umit , Sert Dogan Emre , Karahan Mehmet , Aygun Emre , Beyazal Osman Fehmi , Unal Ertekin Utku , Akin Yesim , Demirkan Burcu , Pac Mustafa 
Published: May 2019

Abstract

OBJECTIVES
The aim of this study was to examine the haemodynamic effects of preoperative levosimendan infusion in patients who underwent left ventricular assist device implantation and evaluate the prognoses.

METHODS
Between May 2013 and October 2018, 85 adult patients who underwent left ventricular assist device implantation were included; 44 and 41 patients suffered from dilated cardiomyopathy and ischaemic cardiomyopathy, respectively. Patients were divided into 2 groups: group A (58 patients) included those who received levosimendan infusion in addition to other inotropes and group B (27 patients) included those who received inotropic agents other than levosimendan. Levosimendan infusion was started at a dose of 0.1 µg⋅kg−1⋅min−1 for a maximum of 48 h without a bolus. The primary outcome was early right ventricular failure (RVF). The secondary outcomes were in-hospital mortality, need for right ventricular assist device, late RVF and recovery of end-organ functions. The safety end points of levosimendan included hypotension, atrial fibrillation, ventricular tachycardia or fibrillation and resuscitated cardiac arrest.

RESULTS
Patient characteristics were similar in both groups. No significant differences between groups were observed in the rates of early mortality, RVF, need for right ventricular assist device, cardiopulmonary bypass time and intensive care unit stay. Survival rates at 30 days, 1 year and 3 years and freedom from late RVF were similar between the groups. Administration of levosimendan was safe, generally well-tolerated and not interrupted because of side effects.

CONCLUSIONS
Levosimendan therapy was well-tolerated in patients who received permanent left ventricular assist devices. Combined preoperative therapy with inotropes and levosimendan significantly improves end-organ functions.
Cardiac arrhythmias in the emergency settings of acute coronary syndrome and revascularization: an European Heart Rhythm Association (EHRA) consensus document, endorsed by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), and European Acute Cardiovascular Care Association (ACCA)
Authors: Kalarus Zbigniew , Svendsen Jesper Hastrup , Capodanno Davide , Dan Gheorghe-Andrei , De Maria Elia , Gorenek Bulent , Jędrzejczyk-Patej Ewa , Mazurek Michał , Podolecki Tomasz , Sticherling Christian , Tfelt-Hansen Jacob , Traykov Vassil , Lip Gregory Y H , Fauchier Laurent , Boriani Giuseppe , Mansourati Jacques , Blomström-Lundqvist Carina , Mairesse Georges H , Rubboli Andrea , Deneke Thomas , Dagres Nikolaos , Steen Torkel , Ahrens Ingo , Kunadian Vijay , Berti Sergio 
Published: May 2019

AbstractDespite major therapeutic advances over the last decades, complex supraventricular and ventricular arrhythmias (VAs), particularly in the emergency setting or during revascularization for acute myocardial infarction (AMI), remain an important clinical problem. Although the incidence of VAs has declined in the hospital phase of acute coronary syndromes (ACS), mainly due to prompt revascularization and optimal medical therapy, still up to 6% patients with ACS develop ventricular tachycardia and/or ventricular fibrillation within the first hours of ACS symptoms. Despite sustained VAs being perceived predictors of worse in-hospital outcomes, specific associations between the type of VAs, arrhythmia timing, applied treatment strategies and long-term prognosis in AMI are vague. Atrial fibrillation (AF) is the most common supraventricular tachyarrhythmia that may be asymptomatic and/or may be associated with rapid haemodynamic deterioration requiring immediate treatment. It is estimated that over 20% AMI patients may have a history of AF, whereas the new-onset arrhythmia may occur in 5% patients with ST elevation myocardial infarction. Importantly, patients who were treated with primary percutaneous coronary intervention for AMI and developed AF have higher rates of adverse events and mortality compared with subjects free of arrhythmia. The scope of this position document is to cover the clinical implications and pharmacological/non-pharmacological management of arrhythmias in emergency presentations and during revascularization. Current evidence for clinical relevance of specific types of VAs complicating AMI in relation to arrhythmia timing has been discussed.
Cas3-stimulated runaway replication of modified ColE1 plasmids in Escherichia coli is temperature dependent
Authors: Radovčić Marin , Čulo Anja , Ivančić-Baće Ivana 
Published: May 2019

ABSTRACT
The clustered regularly interspersed short palindromic repeats (CRISPR)-Cas system constitutes an adaptive immunity system of prokaryotes against mobile genetic elements using a CRISPR RNA (crRNA)-mediated interference mechanism. In Type I CRISPR-Cas systems, crRNA guided by a Cascade complex recognises the matching target DNA and promotes an R-loop formation, RNA-DNA hybrid. The helicase-nuclease Cas3 protein is then recruited to the Cascade/R-loop complex where it nicks and degrades DNA. The Cas3 activity in CRISPR-Cas immunity is reduced in Δhns cells at 37°C for unknown reasons. Cas3 can also influence regulation of plasmid replication and promote uncontrolled (‘runaway’) replication of ColE1 plasmids independently of other CRISPR-Cas components, requiring only its helicase activity. In this work we wanted to test whether Cas3-stimulated uncontrolled plasmid replication is affected by the temperature in Δhns and/or ΔhtpG mutants. We found that Cas3-stimulated uncontrolled plasmid replication occurs only at 37°C, irrespective of the genotype of the analysed mutants, and dependent on Cas3 helicase function. We also found that plasmid replication was strongly reduced by the hns mutation at 30°C and that Cas3 could interfere with T4 phage replication at both incubation temperatures.
Prevalence, Incidence, and Risk Factors for Overall, Physical, and Cognitive Independence Among Those From Exceptionally Long-Lived Families: The Long Life Family Study
Authors: Santanasto Adam J , Marron Megan M , Boudreau Robert M , Feitosa Mary F , Wojczynski Mary K , Arbeev Konstantin G , Thyagarajan Bharat , Schupf Nicole , Stallard Eric , Sebastiani Paola , Cosentino Stephanie , Christensen Kaare , Newman Anne B 
Published: May 2019

Abstract

Background
The Long Life Family Study (LLFS) enrolled families exhibiting exceptional longevity. The goal of this article was to determine the prevalence and predictors of remaining independent after 7 years in the oldest generation.

Methods
We examined 7-year change in physical (free of activities of daily living difficulty), cognitive (Mini-Mental State Examination score ≥ 24), and overall independence (physically/cognitively independent) in adults aged 90.3 ± 6.3 from LLFS’s oldest generation. Potential predictors (n = 28) of remaining independent included demographics, diseases, biomarkers, anthropometrics, and physical and cognitive performance tasks and were determined using generalized estimating equations (α: p &lt; .05). This was a discovery/exploratory analysis, so no multiple testing correction was employed and the results require independent replication.

Results
At baseline (n = 1442), 67.3%, 83.8%, and 79.7% were overall, physically, and cognitively independent, respectively. After 7 years, 66% died, 7.5% were lost to follow-up, and the prevalence of overall independence decreased to 59.1% in survivors (−8.2%, 95% confidence interval: −14.1%, 2.2%). Of those with baseline independence, 156/226 (69.0%) remained independent. Predictors of remaining physically independent included younger age, better Short Physical Performance Battery score and lung function, smaller waist circumference, and lower soluble receptor for advanced glycation end-product levels (p &lt; .05). Predictors of remaining cognitively independent included no cancer history, better Digit Symbol Substitution Test performance, and higher body weight (p &lt; .05).

Conclusions
The prevalence of independence decreased by only 8.2% after 7 years, demonstrating the close correspondence between disability and mortality. Further, despite a mean baseline age of 90 years, a large proportion of survivors remained independent, suggesting this exceptional subgroup may harbor protective mechanisms.
NMR-based insight into galectin-3 binding to endothelial cell adhesion molecule CD146: Evidence for noncanonical interactions with the lectin’s CRD β-sandwich F-face
Authors: Zhang Zhongyu , Miller Michelle C , Xu Xuejiao , Song Chengcheng , Zhang Fan , Zheng Yi , Zhou Yifa , Tai Guihua , Mayo Kevin H 
Published: May 2019

AbstractGalectin-3 (Gal-3) binds to cell adhesion glycoprotein CD146 to promote cytokine secretion and mediate endothelial cell migration. Here, we used Nuclear Magnetic Resonance (NMR) 15N-Heteronuclear Single Quantum Coherence (HSQC) spectroscopy to investigate binding between 15N-labeled Gal-3 and the extracellular domain (eFL) of purified CD146 (five Ig-like ectodomains D1–D5) and a shorter, D5-deleted version of CD146 (D1–D4). Binding of Gal-3 and its carbohydrate recognition domain (CRD) to CD146 D1–D4 is greatly reduced vis-à-vis CD146 eFL, supporting the proposal of a larger number of glycosylation sites on D5. Even though the canonical sugar-binding β-sheet S-face (β-strands 1, 10, 3, 4, 5, 6) of the Gal-3 β-sandwich is involved in interactions with CD146 (e.g. N-linked glycosylation sites), equivalent HSQC spectral perturbations at residues on the opposing Gal-3 F-face β-sheet (β-strands 11, 2, 7, 8, 9) indicate involvement of the Gal-3 F-face in binding CD146. This is supported by the observation that addition of lactose, while significantly attenuating Gal-3 binding (primarily with the S-face) to CD146 eFL, does not abolish it. Bio-Layer Interferometry studies with Gal-3 F-face mutants yield KD values to demonstrate a significant decrease (L203A) or increase (V204A, L218A, T243A) in net binding to CD146 eFL compared to wild type Gal-3. However, HSQC lactose titrations show no highly significant effects on sugar binding to the Gal-3 CRD S-face. Overall, our findings indicate that Gal-3 binding to CD146 is more involved than simple interactions with β-galactoside epitopes on the cell receptor, and that there is a direct role for the lectin’s CRD F-face in the CD146 binding process.
Computational Modeling of Anthocyanin Pathway Evolution: Biases, Hotspots, and Trade-offs
Authors: Wheeler L C , Smith S D 
Published: May 2019

AbstractThe alteration of metabolic pathways is a common mechanism underlying the evolution of new phenotypes. Flower color is a striking example of the importance of metabolic evolution in a complex phenotype, wherein shifts in the activity of the underlying pathway lead to a wide range of pigments. Although experimental work has identified common classes of mutations responsible for transitions among colors, we lack a unifying model that relates pathway function and activity to the evolution of distinct pigment phenotypes. One challenge in creating such a model is the branching structure of pigment pathways, which may lead to evolutionary trade-offs due to competition for shared substrates. In order to predict the effects of shifts in enzyme function and activity on pigment production, we created a simple kinetic model of a major plant pigmentation pathway: the anthocyanin pathway. This model describes the production of the three classes of blue, purple, and red anthocyanin pigments, and accordingly, includes multiple branches and substrate competition. We first studied the general behavior of this model using a naïve set of parameters. We then stochastically evolved the pathway toward a defined optimum and analyzed the patterns of fixed mutations. This approach allowed us to quantify the probability density of trajectories through pathway state space and identify the types and number of changes. Finally, we examined whether our simulated results qualitatively align with experimental observations, i.e., the predominance of mutations which change color by altering the function of branching genes in the pathway. These analyses provide a theoretical framework that can be used to predict the consequences of new mutations in terms of both pigment phenotypes and pleiotropic effects.