bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand
Authors: Ali Remah , Brown Wells , Purdy Stephen Connor , Davisson V. Jo , Wendt Michael K. 
Published: September 2018

AbstractInhibition of epidermal growth factor receptor (EGFR) signaling by small molecule kinase inhibitors and monoclonal antibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here, we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling. This change in downstream signaling leads to apoptosis and growth inhibition in response to epidermal growth factor (EGF) in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to the nuclear pool of STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death, without affecting EGFR:ERK1/2 signaling. Pharmacologic blockade of ERK1/2 signaling through the use of the allosteric MEK1/2 inhibitor, trametinib, dramatically biases downstream EGFR signaling toward a STAT1-dominated event, resulting in enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, combined administration of trametinib and EGF also facilitated an apoptotic switch in EGFR-transformed primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental distinction for EGFR function in metastatic BC. Furthermore, the data demonstrate that pharmacological biasing of EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway.
AIMP3 depletion causes genome instability and loss of stemness in mouse embryonic stem cells
Authors: Kim Sun Mi , Jeon Yoon , Kim Doyeun , Jang Hyonchol , Bae June Sung , Park Mi Kyung , Kim Hongtae , Kim Sunghoon , Lee Ho 
Published: September 2018

AbstractAminoacyl-tRNA synthetase-interacting multifunctional protein-3 (AIMP3) is a component of the multi-aminoacyl-tRNA synthetase complex and is involved in diverse cellular processes. Given that AIMP3 deficiency causes early embryonic lethality in mice, AIMP3 is expected to play a critical role in early mouse development. To elucidate a functional role of AIMP3 in early mouse development, we induced AIMP3 depletion in mouse embryonic stem cells (mESCs) derived from blastocysts ofAIMP3f/f; CreERT2mice. In the present study, AIMP3 depletion resulted in loss of self-renewal and ability to differentiate to three germ layers in mESCs. AIMP3 depletion led to accumulation of DNA damage by blocking double-strand break repair, in particular homologous recombination. Through microarray analysis, the p53 signaling pathway was identified as being activated in AIMP3-depleted mESCs. Knockdown of p53 rescued loss of stem cell characteristics by AIMP3 depletion in mESCs. These results imply that AIMP3 depletion in mESCs leads to accumulation of DNA damage and p53 transactivation, resulting in loss of stemness. We propose that AIMP3 is involved in maintenance of genome stability and stemness in mESCs.
GRP75 modulates oncogenic Dbl-driven endocytosis derailed via the CHIP-mediated ubiquitin degradation pathway
Authors: Niu Xiuran , Su Linjia , Qi Shanshan , Gao Zhihui , Zhang Qing , Zhang Sihe 
Published: September 2018

AbstractChaperone-assisted proteasome degradation of oncogenic protein acts as an upstream signal controlling tumorigenesis and progression. The understanding of the co-regulation of chaperone and oncoprotein of endocytosis pathways is extremely limited. In this study, we showed for the first time that proto-Dbl (dbl proto-oncogene product) is co-enriched with mitochondrial chaperone GRP75 in endocytosis vesicles from ovarian cancer cells. onco-Dbl, produced by oncogenic mutation/degradation of proto-Dbl, markedly enhanced cellular macropinocytosis but suppressed clathrin-mediated endocytosis and clathrin-independent endocytosis pathways, presenting a derailed endocytosis phenotype. GRP75 was associated with proto-Dbl inside cells and modulated Dbl-driven endocytosis derailed by a co-regulatory mode. In spite of not being a component of the Hsc70/Hsp90/proto-Dbl complex, the degradation of proto-Dbl was promoted by GRP75 through the CHIP-mediated ubiquitin–proteasome pathway, of which GRP75 acts as a cooperator with CHIP but also acts as a competitor to Hsc70 and Hsp90 in the multiple chaperones-assisted pro-folding/pro-degradation machinery. Knockdown or inhibition of GRP75 attenuated proto-Dbl degradation and reduced the onco-Dbl level, which differentially impaired Rho GTPases activation and therefore shifted the endocytosis-derailed phenotype. Our data uncovered a novel GRP75-Dbl endocytosis regulatory axis and provided an alternative using chaperone inhibitor to shut down the oncoprotein-driven endocytosis derailment mechanism.
RIPK1 is a critical modulator of both tonic and TLR-responsive inflammatory and cell death pathways in human macrophage differentiation
Authors: Buchrieser Julian , Oliva-Martin Maria Jose , Moore Michael D. , Long Joshua C. D. , Cowley Sally A. , Perez-Simón Jose Antonio , James William , Venero Jose Luis 
Published: September 2018

AbstractIn this study, we took advantage of human-induced pluripotent stem cells (hiPSC) and CRISPR/Cas9 technology to investigate the potential roles of RIPK1 in regulating hematopoiesis and macrophage differentiation, proinflammatory activation, and cell death pathways. Knock-out of RIPK1 in hiPSCs demonstrated that this protein is not required for erythro-myeloid differentiation. Using a well-established macrophage differentiation protocol, knock-out of RIPK1 did not block the differentiation of iPSC-derived macrophages, which displayed a similar phenotype to WT hiPSC-derived macrophages. However, knock-out of RIPK1 leads to a TNFα-dependent apoptotic death of differentiated hiPSC-derived macrophages (iPS-MΦ) and progressive loss of iPS-MΦ production irrespective of external pro-inflammatory stimuli. Live video analysis demonstrated that TLR3/4 activation of RIPK1 KO hiPSC-derived macrophages triggered TRIF and RIPK3-dependent necroptosis irrespective of caspase-8 activation. In contrast, TLR3/4 activation of WT macrophages-induced necroptosis only when caspases were inhibited, confirming the modulating effect of RIPK1 on RIPK3-mediated necroptosis through the FADD, Caspase-8 pathway. Activation of these inflammatory pathways required RIPK3 kinase activity while RIPK1 was dispensable. However, loss of RIPK1 sensitizes macrophages to activate RIPK3 in response to inflammatory stimuli, thereby exacerbating a potentially pathological inflammatory response. Taken together, these results reveal that RIPK1 has an important role in regulating the potent inflammatory pathways in authentic human macrophages that are poised to respond to external stimuli. Consequently, RIPK1 activity might be a valid target in the development of novel therapies for chronic inflammatory diseases.
TFAW: Wavelet-based signal reconstruction to reduce photometric noise in time-domain surveys
Authors: del Ser D. , Fors O. , Núñez J. 
Published: September 2018

Context. There have been many efforts to correct systematic effects in astronomical light curves to improve the detection and characterization of planetary transits and astrophysical variability. Algorithms such as the trend filtering algorithm (TFA) use simultaneously-observed stars to measure and remove systematic effects, and binning is used to reduce high-frequency random noise.
Aims. We present TFAW, a wavelet-based modified version of TFA. First, TFAW aims to increase the periodic signal detection and second, to return a detrended and denoised signal without modifying its intrinsic characteristics.
Methods. We modified TFA’s frequency analysis step adding a stationary wavelet transform filter to perform an initial noise and outlier removal and increase the detection of variable signals. A wavelet-based filter was added to TFA’s signal reconstruction to perform an adaptive characterization of the noise- and trend-free signal and the underlying noise contribution at each iteration while preserving astrophysical signals. We carried out tests over simulated sinusoidal and transit-like signals to assess the effectiveness of the method and applied TFAW to real light curves from TFRM. We also studied TFAW’s application to simulated multiperiodic signals.
Results. TFAW improves the signal detection rate by increasing the signal detection efficiency (SDE) up to a factor ∼2.5× for low S/R light curves. For simulated transits, the transit detection rate improves by a factor ∼2 − 5× in the low-S/R regime compared to TFA. TFAW signal approximation performs up to a factor ∼2× better than bin averaging for planetary transits. The standard deviations of simulated and real TFAW light curves are ∼40% better compared to TFA. TFAW yields better MCMC posterior distributions and returns lower uncertainties, less biased transit parameters and narrower (by approximately ten times) credibility intervals for simulated transits. TFAW is also able to improve the characterization of multiperiodic signals. We present a newly-discovered variable star from TFRM.
Hybrid Off-pump Second-Stage Aortic Arch Repair after Type A Dissection
Authors: Lescan Mario , Andic Mateja , Krüger Tobias , Ivosevic Vedran , Schlensak Christian 
Published: September 2018

Background Ascending aorta or hemi-arch repair are common in the acute phase of type A dissection. Postdissection aneurysms can develop with antegrade perfusion of the false lumen in the dissected aortic arch and require reoperation.
Methods From 2012 to 2018, we reoperated nine patients with postdissection aneurysms using a hybrid technique without cardiopulmonary bypass. The patients had a EuroSCORE II of 13% and a logistic EuroSCORE I of 45% and were not candidates for frozen elephant trunk surgery. The median interval since the acute ascending repair was 184 (92; 528) days. All patients were treated by median resternotomy, ascending to carotid bypass on a partially clamped ascending graft, and transfemoral endovascular repair with a Relay NBS (nonbare stent) or conformable Gore C-TAG stent graft.
Results Technical success was achieved in all cases. Mean follow-up was 405 (220; 672) days. There was no disabling stroke, endoleak, paraplegia, in-hospital, or late mortality. In all patients, the false lumen was completely thrombosed at the aortic arch level with a median aneurysm shrinkage of 13 mm in the distal arch. There was no bird beak or stent graft migration. Distal stent-induced new entry was observed in one case. Reinterventions were not necessary due to diameter stability.
Conclusion Complete debranching with transfemoral thoracic endovascular aneurysm repair showed encouraging results in patients with relevant comorbidities. The used stent grafts performed well in the mid-term follow-up period with no endoleaks or migration.
The challenges of behavioural insights for effective policy design
Authors: Kuehnhanss Colin R 
Published: September 2018

AbstractBehavioural insights are becoming increasingly popular with policy practitioners. Findings and methods originally provided by cognitive psychology and later behavioural economics have found use in the formulation of public policies. Their most popularised application has emerged under the auspices of libertarian paternalism in the form of ‘nudging’. Its proponents claim to provide a new instrument to facilitate the formulation of effective and evidence-based policy, taking people’s actual behaviour into account from the outset, while preserving their liberty to choose. This article reviews the origins of libertarian paternalism and the behavioural insights it builds on and takes a critical look at the foundations nudging relies on as a policy tool. It also discusses the ongoing efforts to build policy capacity to integrate behavioural insights and experimental methods in the creation of public policy. Behavioural insights offer a powerful tool to reshape and design new evidence-based policy. However, designers ought to be aware of the underlying assumptions on individual behaviour, the broadness of the mandate the nudging approach claims and the challenges they pose for design effectiveness.
Plasma Biomarkers to Detect Prevalent or Predict Progressive Tuberculosis Associated With Human Immunodeficiency Virus–1
Authors: Lesosky Maia , Rangaka Molebogeng X , Pienaar Cara , Coussens Anna K , Goliath Rene , Mathee Shaheed , Mwansa-Kambafwile Judith , Maartens Gary , Wilkinson Robert J , Wilkinson Katalin Andrea 
Published: September 2018

AbstractBackgroundThe risk of individuals infected with human immunodeficiency virus (HIV)-1 developing tuberculosis (TB) is high, while both prognostic and diagnostic tools remain insensitive. The potential for plasma biomarkers to predict which HIV-1–infected individuals are likely to progress to active disease is unknown.MethodsThirteen analytes were measured from QuantiFERON Gold in-tube (QFT) plasma samples in 421 HIV-1–infected persons recruited within the screening and enrollment phases of a randomized, controlled trial of isoniazid preventive therapy. Blood for QFT was obtained pre-randomization. Individuals were classified into prevalent TB, incident TB, and control groups. Comparisons between groups, supervised learning methods, and weighted correlation network analyses were applied utilizing the unstimulated and background-corrected plasma analyte concentrations.ResultsUnstimulated samples showed higher analyte concentrations in the prevalent and incident TB groups compared to the control group. The largest differences were seen for C-X-C motif chemokine 10 (CXCL10), interleukin-2 (IL-2), IL-1α, transforming growth factor-α (TGF-α). A predictive model analysis using unstimulated analytes discriminated best between the control and prevalent TB groups (area under the curve [AUC] = 0.9), reasonably well between the incident and prevalent TB groups (AUC &gt; 0.8), and poorly between the control and incident TB groups. Unstimulated IL-2 and IFN-γ were ranked at or near the top for all comparisons, except the comparison between the control vs incident TB groups. Models using background-adjusted values performed poorly.ConclusionsSingle plasma biomarkers are unlikely to distinguish between disease states in HIV-1 co-infected individuals, and combinations of biomarkers are required. The ability to detect prevalent TB is potentially important, as no blood test hitherto has been suggested as having the utility to detect prevalent TB amongst HIV-1 co-infected persons.
The nature of heterodox economics revisited
Authors: Slade-Caffarel Yannick 
Published: September 2018

AbstractThis paper revisits the conception of heterodox economics advanced by Tony Lawson in 2006 and critically assesses its reception. I consider the bearing of later contributions—most importantly, his 2013 paper ‘What is this “school” called neoclassical economics’—in which Lawson further develops his analysis of heterodox economics. The goal is to provide additional clarity to the discussion.
Women Missionaries and Colonial Silences in Kenya’s Female ‘Circumcision’ Controversy, 1906–1930
Authors: Anderson David M 
Published: September 2018

Abstract
For the people of Kenya, recent global debates on the emotional and medical harm caused by female genital mutilation (FGM), allied to arguments about the human rights of the women subjected to such acts, have a significant historical resonance. In the 1920s, Christian missionaries in central Kenya mounted a concerted campaign to prohibit ‘female circumcision’ among their flourishing African congregations. This provoked a backlash, with thousands of Kikuyu Christians deserting the missions to found their own independent churches and schools in the early 1930s. These events, commonly referred to as the ‘female circumcision controversy’, mark a turning point in Kenya’s colonial history. Taking as its starting-point the murder in 1930 of a female missionary with the African Inland Mission, the article explores the actions and attitudes of white women missionaries, revealing a subtle and complex picture of missionary views of African society and the process of Christian conversion, arguing that, as the circumcision crisis developed during 1929, these women stood at the centre of the gathering storm, their experience emblematic of the emotional, cultural and political challenges in the circumcision debate. This account adds an important new dimension to our understanding of gender in Kenya’s circumcision debate, but it also reveals why colonial silence has surrounded the event at the very centre of the crisis: the murder of Hulda Stumpf.
Older Black Adults’ Satisfaction and Anxiety Levels After Completing Alternative Versus Traditional Cognitive Batteries
Authors: Gamaldo Alyssa A , Tan Shyuan Ching , Sardina Angie L , Henzi Carolyn , Guest Rosalyn , Ross Lesley A , Willingham Kurtis , Zonderman Alan B , Andel Ross A 
Published: September 2018

Abstract

Objective
The objective of this study was to examine satisfaction, test anxiety, and performance using computer-based cognitive batteries versus a paper-and-pencil neuropsychological battery among older Blacks.

Method
Self-identified Black adults (n = 87, age range: 55–86; mean education = 14) completed two computer-based tests (CogState and Joggle) and a paper-and-pencil neuropsychological battery. After each battery, participants reported their testing anxiety and satisfaction using the batteries. Descriptive, correlational, and regression analyses compared satisfaction, anxiety, and performance across the batteries.

Results
Majority of the participants reported more satisfaction with the computer-based (Joggle: 66%; CogState: 77%) than the neuropsychological (52%) battery. Participants also reported less testing anxiety after completing the computer-based batteries than the neuropsychological battery, F(2, 172) = 22.96, p &lt; .001. Older adults’ familiarity and comfort level with the computer were not associated with their performance on the computer-based tests (p &gt; .05). Although testing anxiety was not associated with performance across the batteries, age and education quality were uniquely associated with performance on the CogState and neuropsychological batteries.

Conclusions
Computer-based cognitive batteries appear to be less intimidating than the commonly used paper-and-pencil neuropsychological tests for Black adults. Thus, these cognitive batteries may be useful tools for monitoring older Blacks’ cognitive status.
Socioeconomic Status and Biological Risks for Health and Illness Across the Life Course
Authors: Yang Yang Claire , Schorpp Kristen , Boen Courtney , Johnson Moira , Harris Kathleen Mullan 
Published: September 2018

Abstract

Objectives
We assess the temporal properties and biosocial mechanisms underlying the associations between early-life socioeconomic status (SES) and later health. Using a life-course design spanning adolescence to older adulthood, we assess how early life and various dimensions of adult SES are associated with immune and metabolic function in different life stages and examine possible bio-behavioral and psychosocial mechanisms underlying these associations.

Method
Data for this study come from 3 national studies that collectively cover multiple stages of the life course (Add Health, MIDUS, and HRS). We estimated generalized linear models to examine the prospective associations between early-life SES, adult SES, and biomarkers of chronic inflammation and metabolic disorder assessed at follow-up. We further conducted formal tests of mediation to assess the role of adult SES in linking early SES to biological functions.

Results
We found that early-life SES exerted consistent protective effects for metabolic disorder across the life span, but waned with time for CRP. The protective effect of respondent education remained persistent for CRP but declined with age for metabolic disorder. Adult income and assets primarily protected respondents against physiological dysregulation in middle and old ages, but not in early adulthood.

Discussion
These findings are the first to elucidate the life-course patterns of SES that matter for underlying physiological functioning during the aging process to produce social gradients in health.
Ageism Amplifies Cost and Prevalence of Health Conditions
Authors: Levy Becca R , Slade Martin D , Chang E-Shien , Kannoth Sneha , Wang Shi-Yi 
Published: September 2018

Abstract

Background and Objectives
The persistent status of ageism as one of the least acknowledged forms of prejudice may be due in part to an absence of quantifying its costs in economic terms. In this study, we calculated the costs of ageism on health conditions for all persons aged 60 years or older in the United States during 1 year.

Research Design and Materials
The ageism predictors were discrimination aimed at older persons, negative age stereotypes, and negative self-perceptions of aging. Health care costs of ageism were computed by combining analyses of the impact of the predictors with comprehensive health care spending data in 1 year for the eight most-expensive health conditions, among all Americans aged 60 years or older. As a secondary analysis, we computed the number of these health conditions experienced due to ageism.

Results
It was found that the 1-year cost of ageism was $63 billion, or one of every seven dollars spent on the 8 health conditions (15.4%), after adjusting for age and sex as well as removing overlapping costs from the three predictors. Also according to our model, ageism resulted in 17.04 million cases of these health conditions.

Discussion and Implications
This is the first study to identify the economic cost that ageism imposes on health. The findings suggest that a reduction of ageism would not only have a monetary benefit for society, but also have a health benefit for older persons.
Comparison of marine and terrestrial ecosystems: suggestions of an evolutionary perspective influenced by environmental variation
Authors: Steele John H , Brink Kenneth H , Scott Beth E 
Published: September 2018

AbstractThe transition of plants and animals from sea to land required adaptation to a very different physical and chemical environment. In this paper, we focus on the consequences of the differences between the magnitude of the variability of ocean and atmospheric dynamics, with the ocean environment (in particular temperature and currents) being two to three orders of magnitude less variable than that on land. We suggest that greater insights on possible responses of marine vs. terrestrial systems to rapid climate change can be gained by considering that terrestrial vertebrates, invertebrates and plants have evolved from marine organisms that, pre-Cambrian, had early life history developmental stages as planktonic larvae. Marine larvae were/are adapted to the predictable and minimal range of temperature changes and regularities in ocean currents, as most organisms utilize the energy in these currents as an “auxiliary” source for predictable gamete and larvae dispersal. Post-Cambrian, on land, no such simple strategy was available; instead, most terrestrial organisms have evolved reproductive strategies and behaviours to eliminate, or at least minimize, the consequences of much larger atmospheric variability. Adapting our future use of these systems sensibly will require greater understanding of how the two regimes respond to rapid climate change.