bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells
Authors: Mauro-Lizcano Marta , López-Rivas Abelardo 
Published: February 2018

AbstractGlutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth. Herein we demonstrate that TNBC cells are markedly sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon glutamine deprivation. Upregulation of pro-apoptotic TRAIL receptor 2 (TRAIL-R2/DR5) and downregulation of FLICE-inhibitory protein (FLIP) are observed in glutamine-deprived TNBC cells. Activation of the amino-acid-sensing kinase general control nonderepressible 2 (GCN2) upon glutamine deprivation is responsible for TRAIL-R2 upregulation through a signaling pathway involving ATF4 and CHOP transcription factors. In contrast, FLIP downregulation in glutamine-deprived TNBC occurs by a GCN2-independent mechanism. Importantly, silencing FLIP expression by RNA interference results in a marked sensitization of TNBC cells to TRAIL-induced apoptosis. In addition, pharmacological or genetic inhibition of transaminases increases TRAIL-R2 expression and downregulates FLIP levels, sensitizing TNBC cells to TRAIL. Interestingly, treatment with l-asparaginase markedly sensitizes TNBC cells to TRAIL through its glutaminase activity. Overall, our findings suggest that targeting the glutamine addiction phenotype of TNBC can be regarded as a potential antitumoral target in combination with agonists of proapoptotic TRAIL receptors.
Cadherin-26 (CDH26) regulates airway epithelial cell cytoskeletal structure and polarity
Authors: Lachowicz-Scroggins Marrah E. , Gordon Erin D. , Wesolowska-Andersen Agata , Jackson Nathan D. , MacLeod Hannah J. , Sharp Louis Z. , Sun Matthew , Seibold Max A. , Fahy John V. 
Published: February 2018

AbstractPolarization of the airway epithelial cells (AECs) in the airway lumen is critical to the proper function of the mucociliary escalator and maintenance of lung health, but the cellular requirements for polarization of AECs are poorly understood. Using human AECs and cell lines, we demonstrate that cadherin-26 (CDH26) is abundantly expressed in differentiated AECs, localizes to the cell apices near ciliary membranes, and has functional cadherin domains with homotypic binding. We find a unique and non-redundant role for CDH26, previously uncharacterized in AECs, in regulation of cell–cell contact and cell integrity through maintaining cytoskeletal structures. Overexpression of CDH26 in cells with a fibroblastoid phenotype increases contact inhibition and promotes monolayer formation and cortical actin structures. CDH26 expression is also important for localization of planar cell polarity proteins. Knockdown of CDH26 in AECs results in loss of cortical actin and disruption of CRB3 and other proteins associated with apical polarity. Together, our findings uncover previously unrecognized functions for CDH26 in the maintenance of actin cytoskeleton and apicobasal polarity of AECs.
Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration
Authors: Huang Wei , Feng Yuliang , Liang Jialiang , Yu Hao , Wang Cheng , Wang Boyu , Wang Mingyang , Jiang Lin , Meng Wei , Cai Wenfeng , Medvedovic Mario , Chen Jenny , Paul Christian , Davidson W. Sean , Sadayappan Sakthivel , Stambrook Peter J. , Yu Xi-Yong , Wang Yigang 
Published: February 2018

AbstractThe goal of replenishing the cardiomyocyte (CM) population using regenerative therapies following myocardial infarction (MI) is hampered by the limited regeneration capacity of adult CMs, partially due to their withdrawal from the cell cycle. Here, we show that microRNA-128 (miR-128) is upregulated in CMs during the postnatal switch from proliferation to terminal differentiation. In neonatal mice, cardiac-specific overexpression of miR-128 impairs CM proliferation and cardiac function, while miR-128 deletion extends proliferation of postnatal CMs by enhancing expression of the chromatin modifier SUZ12, which suppresses p27 (cyclin-dependent kinase inhibitor) expression and activates the positive cell cycle regulators Cyclin E and CDK2. Furthermore, deletion of miR-128 promotes cell cycle re-entry of adult CMs, thereby reducing the levels of fibrosis, and attenuating cardiac dysfunction in response to MI. These results suggest that miR-128 serves as a critical regulator of endogenous CM proliferation, and might be a novel therapeutic target for heart repair.
Localization of adaptive variants in human genomes using averaged one-dependence estimation
Authors: Sugden Lauren Alpert , Atkinson Elizabeth G. , Fischer Annie P. , Rong Stephen , Henn Brenna M. , Ramachandran Sohini 
Published: February 2018

AbstractStatistical methods for identifying adaptive mutations from population genetic data face several obstacles: assessing the significance of genomic outliers, integrating correlated measures of selection into one analytic framework, and distinguishing adaptive variants from hitchhiking neutral variants. Here, we introduce SWIF(r), a probabilistic method that detects selective sweeps by learning the distributions of multiple selection statistics under different evolutionary scenarios and calculating the posterior probability of a sweep at each genomic site. SWIF(r) is trained using simulations from a user-specified demographic model and explicitly models the joint distributions of selection statistics, thereby increasing its power to both identify regions undergoing sweeps and localize adaptive mutations. Using array and exome data from 45 ‡Khomani San hunter-gatherers of southern Africa, we identify an enrichment of adaptive signals in genes associated with metabolism and obesity. SWIF(r) provides a transparent probabilistic framework for localizing beneficial mutations that is extensible to a variety of evolutionary scenarios.
Identifying noncoding risk variants using disease-relevant gene regulatory networks
Authors: Gao Long , Uzun Yasin , Gao Peng , He Bing , Ma Xiaoke , Wang Jiahui , Han Shizhong , Tan Kai 
Published: February 2018

AbstractIdentifying noncoding risk variants remains a challenging task. Because noncoding variants exert their effects in the context of a gene regulatory network (GRN), we hypothesize that explicit use of disease-relevant GRNs can significantly improve the inference accuracy of noncoding risk variants. We describe Annotation of Regulatory Variants using Integrated Networks (ARVIN), a general computational framework for predicting causal noncoding variants. It employs a set of novel regulatory network-based features, combined with sequence-based features to infer noncoding risk variants. Using known causal variants in gene promoters and enhancers in a number of diseases, we show ARVIN outperforms state-of-the-art methods that use sequence-based features alone. Additional experimental validation using reporter assay further demonstrates the accuracy of ARVIN. Application of ARVIN to seven autoimmune diseases provides a holistic view of the gene subnetwork perturbed by the combinatorial action of the entire set of risk noncoding mutations.
Physical basis of amyloid fibril polymorphism
Authors: Close William , Neumann Matthias , Schmidt Andreas , Hora Manuel , Annamalai Karthikeyan , Schmidt Matthias , Reif Bernd , Schmidt Volker , Grigorieff Nikolaus , Fändrich Marcus 
Published: February 2018

AbstractPolymorphism is a key feature of amyloid fibril structures but it remains challenging to explain these variations for a particular sample. Here, we report electron cryomicroscopy-based reconstructions from different fibril morphologies formed by a peptide fragment from an amyloidogenic immunoglobulin light chain. The observed fibril morphologies vary in the number and cross-sectional arrangement of a structurally conserved building block. A comparison with the theoretically possible constellations reveals the experimentally observed spectrum of fibril morphologies to be governed by opposing sets of forces that primarily arise from the β-sheet twist, as well as peptide–peptide interactions within the fibril cross-section. Our results provide a framework for rationalizing and predicting the structure and polymorphism of cross-β fibrils, and suggest that a small number of physical parameters control the observed fibril architectures.
Structural determinants of the SINE B2 element embedded in the long non-coding RNA activator of translation AS Uchl1
Authors: Podbevšek Peter , Fasolo Francesca , Bon Carlotta , Cimatti Laura , Reißer Sabine , Carninci Piero , Bussi Giovanni , Zucchelli Silvia , Plavec Janez , Gustincich Stefano 
Published: February 2018

AbstractPervasive transcription of mammalian genomes leads to a previously underestimated level of complexity in gene regulatory networks. Recently, we have identified a new functional class of natural and synthetic antisense long non-coding RNAs (lncRNA) that increases translation of partially overlapping sense mRNAs. These molecules were named SINEUPs, as they require an embedded inverted SINE B2 element for their UP-regulation of translation. Mouse AS Uchl1 is the representative member of natural SINEUPs. It was originally discovered for its role in increasing translation of Uchl1 mRNA, a gene associated with neurodegenerative diseases. Here we present the secondary structure of the SINE B2 Transposable Element (TE) embedded in AS Uchl1. We find that specific structural regions, containing a short hairpin, are required for the ability of AS Uchl1 RNA to increase translation of its target mRNA. We also provide a high-resolution structure of the relevant hairpin, based on NMR observables. Our results highlight the importance of structural determinants in embedded TEs for their activity as functional domains in lncRNAs.
Step-wise evolution of complex chemical defenses in millipedes: a phylogenomic approach
Authors: Rodriguez Juanita , Jones Tappey H. , Sierwald Petra , Marek Paul E. , Shear William A. , Brewer Michael S. , Kocot Kevin M. , Bond Jason E. 
Published: February 2018

AbstractWith fossil representatives from the Silurian capable of respiring atmospheric oxygen, millipedes are among the oldest terrestrial animals, and likely the first to acquire diverse and complex chemical defenses against predators. Exploring the origin of complex adaptive traits is critical for understanding the evolution of Earth’s biological complexity, and chemical defense evolution serves as an ideal study system. The classic explanation for the evolution of complexity is by gradual increase from simple to complex, passing through intermediate “stepping stone” states. Here we present the first phylogenetic-based study of the evolution of complex chemical defenses in millipedes by generating the largest genomic-based phylogenetic dataset ever assembled for the group. Our phylogenomic results demonstrate that chemical complexity shows a clear pattern of escalation through time. New pathways are added in a stepwise pattern, leading to greater chemical complexity, independently in a number of derived lineages. This complexity gradually increased through time, leading to the advent of three distantly related chemically complex evolutionary lineages, each uniquely characteristic of each of the respective millipede groups.
Altered immunity in crowded Mythimna separata is mediated by octopamine and dopamine
Authors: Kong Hailong , Dong Chuanlei , Tian Zhen , Mao Nian , Wang Cheng , Cheng Yunxia , Zhang Lei , Jiang Xingfu , Luo Lizhi 
Published: February 2018

AbstractSimilar to pathogenic infection, high population density alters insects’ prophylactic immunity. Density-dependent prophylaxis has been reported in many polyphenic insects, but the regulatory mechanism underlying this phenomenon remains unclear. The biogenic monoamines are known to play critical roles in mediating insect immune responses. In the current study, the immune capacity and the levels of three biogenic monoamines were investigated in the polyphenic larvae of Mythimna separata, reared at the densities of 1, 2, 5, 10, and 30 larvae per 650-mL jar. Concomitant with the increased phenoloxidase (PO) activity and total haemocyte count in the larvae at high densities (5, 10, 30 larvae/jar), the octopamine level was also increased. In contrast, the dopamine level was decreased, and the 5-hydroxytryptamine level was not significantly affected. Injection of octopamine induced significant increases in the total haemocyte count and PO activity. Conversely, epinastine, a specific antagonist of octopamine, decreased the total haemocyte count and PO activity. Another octopamine antagonist, phentolamine, inhibited the activity of PO and lysozymes. In addition, injection of dopamine induced a significant increase in PO activity and decreased the total haemocyte count and lysozyme activity. These results suggested that both octopamine and dopamine mediate the increases in total haemocyte count and PO activity in the crowded larvae.
Cardiovascular and renal protective role of angiotensin blockade in hypertension with advanced CKD: a subgroup analysis of ATTEMPT-CVD randomized trial
Authors: Kim-Mitsuyama Shokei , Soejima Hirofumi , Yasuda Osamu , Node Koichi , Jinnouchi Hideaki , Yamamoto Eiichiro , Sekigami Taiji , Ogawa Hisao , Matsui Kunihiko 
Published: February 2018

AbstractThe ATTEMPT-CVD study was prospective randomized active-controlled trial and the main findings had been reported. According to baseline GFR and albuminuria categories, we divided the patients of the ATTEMPT-CVD study into 2 subgroups: (Group 1) the patients with at least one of eGFR of <45 ml/min per 1.73 m2 and UACR of ≥300 mg/g creatinine, defined as G3b and/or A3; (Group 2) the patients except for Group 1, defined as the other patients. In patients with G3b and/or A3, the incidence of cardiovascular events was significantly less in ARB group than in non-ARB group (11 vs 22, respectively) (HR = 0.465: 95%CI = 0.224–0.965; P = 0.040). UACR was significantly less in ARB group than in non-ARB group during follow-up period in patients with G3b and/or A3 (P = 0.0003), while eGFR, plasma BNP levels, and blood pressure were comparable between ARB and non-ARB groups. Allocation to ARB therapy was a significant independent prognostic factor for cardiovascular events in patients with G3b and/or A3 (P = 0.0268). On the other hand, in the other patients, the occurrence of cardiovascular events was comparable between ARB and non-ARB groups. In patients with advanced CKD, ARB-based therapy may confer greater benefit in prevention of cardiovascular events than non-ARB therapy.
Rational Construction of Uniform CoNi-Based Core-Shell Microspheres with Tunable Electromagnetic Wave Absorption Properties
Authors: Chen Na , Jiang Jian-Tang , Xu Cheng-Yan , Yan Shao-Jiu , Zhen Liang 
Published: February 2018

AbstractCore-shell particles with integration of ferromagnetic core and dielectric shell are attracting extensive attention for promising microwave absorption applications. In this work, CoNi microspheres with conical bulges were synthesized by a simple and scalable liquid-phase reduction method. Subsequent coating of dielectric materials was conducted to acquire core-shell structured CoNi@TiO2 composite particles, in which the thickness of TiO2 is about 40 nm. The coating of TiO2 enables the absorption band of CoNi to effectively shift from Ku to S band, and endows CoNi@TiO2 microspheres with outstanding electromagnetic wave absorption performance along with a maximum reflection loss of 76.6 dB at 3.3 GHz, much better than that of bare CoNi microspheres (54.4 dB at 17.8 GHz). The enhanced EMA performance is attributed to the unique core-shell structures, which can induce dipole polarization and interfacial polarization, and tune the dielectric properties to achieve good impedance matching. Impressively, TiO2 coating endows the composites with better microwave absorption capability than CoNi@SiO2 microspheres. Compared with SiO2, TiO2 dielectric shells could protect CoNi microspheres from merger and agglomeration during annealed. These results indicate that CoNi@TiO2 core-shell microspheres can serve as high-performance absorbers for electromagnetic wave absorbing application.
A Microvascularized Tumor-mimetic Platform for Assessing Anti-cancer Drug Efficacy
Authors: Pradhan Shantanu , Smith Ashley M. , Garson Charles J. , Hassani Iman , Seeto Wen J. , Pant Kapil , Arnold Robert D. , Prabhakarpandian Balabhaskar , Lipke Elizabeth A. 
Published: February 2018

AbstractAssessment of anti-cancer drug efficacy in in vitro three-dimensional (3D) bioengineered cancer models provides important contextual and relevant information towards pre-clinical translation of potential drug candidates. However, currently established models fail to sufficiently recapitulate complex tumor heterogeneity. Here we present a chip-based tumor-mimetic platform incorporating a 3D in vitro breast cancer model with a tumor-mimetic microvascular network, replicating the pathophysiological architecture of native vascularized breast tumors. The microfluidic platform facilitated formation of mature, lumenized and flow-aligned endothelium under physiological flow recapitulating both high and low perfused tumor regions. Metastatic and non-metastatic breast cancer cells were maintained in long-term 3D co-culture with stromal fibroblasts in a poly(ethylene glycol)-fibrinogen hydrogel matrix within adjoining tissue chambers. The interstitial space between the chambers and endothelium contained pores to mimic the “leaky” vasculature found in vivo and facilitate cancer cell-endothelial cell communication. Microvascular pattern-dependent flow variations induced concentration gradients within the 3D tumor mass, leading to morphological tumor heterogeneity. Anti-cancer drugs displayed cell type- and flow pattern-dependent effects on cancer cell viability, viable tumor area and associated endothelial cytotoxicity. Overall, the developed microfluidic tumor-mimetic platform facilitates investigation of cancer-stromal-endothelial interactions and highlights the role of a fluidic, tumor-mimetic vascular network on anti-cancer drug delivery and efficacy for improved translation towards pre-clinical studies.
Adherence to antiretroviral therapy and factors affecting low medication adherence among incident HIV-infected individuals during 2009–2016: A nationwide study
Authors: Kim Jungmee , Lee Eunyoung , Park Byung-Joo , Bang Ji Hwan , Lee Jin Yong 
Published: February 2018

AbstractFor ideal clinical benefit, human immunodeficiency virus (HIV)-infected individuals should receive continuous medication. This is the first nationwide antiretroviral therapy (ART) adherence study in Asia, where medication monitoring at national level is systemically available. We estimated the ART adherence of incident HIV-infected individuals and investigated factors affecting low medication adherence using the national health insurance (NHI) claims data from 2007 to 2016. Medication possession ratio (MPR) was used to measure medication adherence and risk factors were identified by multivariable logistic regression analysis. Of the 8,501 newly diagnosed HIV-infected individuals during 2009–2016 with at least one ART prescription, 70.4% of HIV patients had adequate adherence to ART defined as MPR ≥95%. Requiring prophylactic antibiotics, female gender, age of 0–19 and same or over 50 s compared to 30–39, and having a history of malignancy, lower socioeconomic status, not visiting tertiary hospital, and being diagnosed in the earlier years were risk factors for lower adherence (Odds ratio 1.7, 1.6, 1.6, 1.4, 1.6, 2.1, 1.2, and 1.6 to 3.8 respectively). Health authority should take into consideration of these modifiable and unmodifiable barriers to establish sustainable monitoring system at national level and to improve adherence.
A novel flatworm-specific gene implicated in reproduction in Macrostomum lignano
Authors: Grudniewska Magda , Mouton Stijn , Grelling Margriet , Wolters Anouk H. G. , Kuipers Jeroen , Giepmans Ben N. G. , Berezikov Eugene 
Published: February 2018

AbstractFree-living flatworms, such as the planarian Schmidtea mediterranea, are extensively used as model organisms to study stem cells and regeneration. The majority of flatworm studies so far focused on broadly conserved genes. However, investigating what makes these animals different is equally informative for understanding its biology and might have biomedical value. We re-analyzed the neoblast and germline transcriptional signatures of the flatworm M. lignano using an improved transcriptome assembly and show that germline-enriched genes have a high fraction of flatworm-specific genes. We further identified the Mlig-sperm1 gene as a member of a novel gene family conserved only in free-living flatworms and essential for producing healthy spermatozoa. In addition, we established a whole-animal electron microscopy atlas (nanotomy) to visualize the ultrastructure of the testes in wild type worms, but also as a reference platform for different ultrastructural studies in M. lignano. This work demonstrates that investigation of flatworm-specific genes is crucial for understanding flatworm biology and establishes a basis for such future research in M. lignano.
Scleraxis is a transcriptional activator that regulates the expression of Tenomodulin, a marker of mature tenocytes and ligamentocytes
Authors: Shukunami Chisa , Takimoto Aki , Nishizaki Yuriko , Yoshimoto Yuki , Tanaka Seima , Miura Shigenori , Watanabe Hitomi , Sakuma Tetsushi , Yamamoto Takashi , Kondoh Gen , Hiraki Yuji 
Published: February 2018

AbstractTenomodulin (Tnmd) is a type II transmembrane glycoprotein predominantly expressed in tendons and ligaments. We found that scleraxis (Scx), a member of the Twist-family of basic helix-loop-helix transcription factors, is a transcriptional activator of Tnmd expression in tenocytes. During embryonic development, Scx expression preceded that of Tnmd. Tnmd expression was nearly absent in tendons and ligaments of Scx-deficient mice generated by transcription activator-like effector nucleases-mediated gene disruption. Tnmd mRNA levels were dramatically decreased during serial passages of rat tenocytes. Scx silencing by small interfering RNA significantly suppressed endogenous Tnmd mRNA levels in tenocytes. Mouse Tnmd contains five E-box sites in the ~1-kb 5′-flanking region. A 174-base pair genomic fragment containing a TATA box drives transcription in tenocytes. Enhancer activity was increased in the upstream region (−1030 to −295) of Tnmd in tenocytes, but not in NIH3T3 and C3H10T1/2 cells. Preferential binding of both Scx and Twist1 as a heterodimer with E12 or E47 to CAGATG or CATCTG and transactivation of the 5′-flanking region were confirmed by electrophoresis mobility shift and dual luciferase assays, respectively. Scx directly transactivates Tnmd via these E-boxes to positively regulate tenocyte differentiation and maturation.