bluuebunny/crossref_metadata_2025_split huggingface dataset:
Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers
Authors: Henninger Christian , Fritz Gerhard 
Published: January 2017

AbstractCancer patients receiving anthracycline-based chemotherapy are at risk to develop life-threatening chronic cardiotoxicity with the pathophysiological mechanism of action not fully understood. Besides the most common hypothesis that anthracycline-induced congestive heart failure (CHF) is mainly caused by generation of reactive oxygen species, recent data point to a critical role of topoisomerase II beta (TOP2B), which is a primary target of anthracycline poisoning, in the pathophysiology of CHF. As the use of the only clinically approved cardioprotectant dexrazoxane has been limited by the FDA in 2011, there is an urgent need for alternative cardioprotective measures. Statins are anti-inflammatory and anti-oxidative drugs that are clinically well established for the prevention of cardiovascular diseases. They exhibit pleiotropic beneficial properties beyond cholesterol-lowering effects that most likely rest on the indirect inhibition of small Ras homologous (Rho) GTPases. The Rho GTPase Rac1 has been shown to be a major factor in the regulation of the pro-oxidative NADPH oxidase as well as in the regulation of type II topoisomerase. Both are discussed to play an important role in the pathophysiology of anthracycline-induced CHF. Therefore, off-label use of statins or novel Rac1 inhibitors might represent a promising pharmacological approach to gain control over chronic cardiotoxicity by interfering with key mechanisms of anthracycline-induced cardiomyocyte cell death.
p-wave triggered superconductivity in single-layer graphene on an electron-doped oxide superconductor
Authors: Di Bernardo A. , Millo O. , Barbone M. , Alpern H. , Kalcheim Y. , Sassi U. , Ott A. K. , De Fazio D. , Yoon D. , Amado M. , Ferrari A. C. , Linder J. , Robinson J. W. A. 
Published: January 2017

AbstractElectron pairing in the vast majority of superconductors follows the Bardeen–Cooper–Schrieffer theory of superconductivity, which describes the condensation of electrons into pairs with antiparallel spins in a singlet state with an s-wave symmetry. Unconventional superconductivity was predicted in single-layer graphene (SLG), with the electrons pairing with a p-wave or chiral d-wave symmetry, depending on the position of the Fermi energy with respect to the Dirac point. By placing SLG on an electron-doped (non-chiral) d-wave superconductor and performing local scanning tunnelling microscopy and spectroscopy, here we show evidence for a p-wave triggered superconducting density of states in SLG. The realization of unconventional superconductivity in SLG offers an exciting new route for the development of p-wave superconductivity using two-dimensional materials with transition temperatures above 4.2 K.
Glucocorticoid receptor signalling activates YAP in breast cancer
Authors: Sorrentino Giovanni , Ruggeri Naomi , Zannini Alessandro , Ingallina Eleonora , Bertolio Rebecca , Marotta Carolina , Neri Carmelo , Cappuzzello Elisa , Forcato Mattia , Rosato Antonio , Mano Miguel , Bicciato Silvio , Del Sal Giannino 
Published: January 2017

AbstractThe Hippo pathway is an oncosuppressor signalling cascade that plays a major role in the control of cell growth, tissue homoeostasis and organ size. Dysregulation of the Hippo pathway leads to aberrant activation of the transcription co-activator YAP (Yes-associated protein) that contributes to tumorigenesis in several tissues. Here we identify glucocorticoids (GCs) as hormonal activators of YAP. Stimulation of glucocorticoid receptor (GR) leads to increase of YAP protein levels, nuclear accumulation and transcriptional activity in vitro and in vivo. Mechanistically, we find that GCs increase expression and deposition of fibronectin leading to the focal adhesion-Src pathway stimulation, cytoskeleton-dependent YAP activation and expansion of chemoresistant cancer stem cells. GR activation correlates with YAP activity in human breast cancer and predicts bad prognosis in the basal-like subtype. Our results unveil a novel mechanism of YAP activation in cancer and open the possibility to target GR to prevent cancer stem cells self-renewal and chemoresistance.
Global and local selection acting on the pathogen Stenotrophomonas maltophilia in the human lung
Authors: Chung Hattie , Lieberman Tami D. , Vargas Sara O. , Flett Kelly B. , McAdam Alexander J. , Priebe Gregory P. , Kishony Roy 
Published: January 2017

AbstractBacterial populations diversify during infection into distinct subpopulations that coexist within the human body. Yet, it is unknown to what extent subpopulations adapt to location-specific selective pressures as they migrate and evolve across space. Here we identify bacterial genes under local and global selection by testing for spatial co-occurrence of adaptive mutations. We sequence 552 genomes of the pathogen Stenotrophomonas maltophilia across 23 sites of the lungs from a patient with cystic fibrosis. We show that although genetically close isolates colocalize in space, distant lineages with distinct phenotypes separated by adaptive mutations spread throughout the lung, suggesting global selective pressures. Yet, for one gene (a distant homologue of the merC gene implicated in metal resistance), mutations arising independently in two lineages colocalize in space, providing evidence for location-specific selection. Our work presents a general framework for understanding how selection acts upon a pathogen that colonizes and evolves across the complex environment of the human body.
SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers
Authors: Tagal Vural , Wei Shuguang , Zhang Wei , Brekken Rolf A. , Posner Bruce A. , Peyton Michael , Girard Luc , Hwang TaeHyun , Wheeler David A. , Minna John D. , White Michael A. , Gazdar Adi F. , Roth Michael G. 
Published: January 2017

AbstractMutations in the SMARCA4/BRG1 gene resulting in complete loss of its protein (BRG1) occur frequently in non-small cell lung cancer (NSCLC) cells. Currently, no single therapeutic agent has been identified as synthetically lethal with SMARCA4/BRG1 loss. We identify AURKA activity as essential in NSCLC cells lacking SMARCA4/BRG1. In these cells, RNAi-mediated depletion or chemical inhibition of AURKA induces apoptosis and cell death in vitro and in xenograft mouse models. Disc large homologue-associated protein 5 (HURP/DLGAP5), required for AURKA-dependent, centrosome-independent mitotic spindle assembly is essential for the survival and proliferation of SMARCA4/BRG1 mutant but not of SMARCA4/BRG1 wild-type cells. AURKA inhibitors may provide a therapeutic strategy for biomarker-driven clinical studies to treat the NSCLCs harbouring SMARCA4/BRG1-inactivating mutations.
Indefinitely stable iron(IV) cage complexes formed in water by air oxidation
Authors: Tomyn Stefania , Shylin Sergii I. , Bykov Dmytro , Ksenofontov Vadim , Gumienna-Kontecka Elzbieta , Bon Volodymyr , Fritsky Igor O. 
Published: January 2017

AbstractIn nature, iron, the fourth most abundant element of the Earth’s crust, occurs in its stable forms either as the native metal or in its compounds in the +2 or +3 (low-valent) oxidation states. High-valent iron (+4, +5, +6) compounds are not formed spontaneously at ambient conditions, and the ones obtained synthetically appear to be unstable in polar organic solvents, especially aqueous solutions, and this is what limits their studies and use. Here we describe unprecedented iron(IV) hexahydrazide clathrochelate complexes that are assembled in alkaline aqueous media from iron(III) salts, oxalodihydrazide and formaldehyde in the course of a metal-templated reaction accompanied by air oxidation. The complexes can exist indefinitely at ambient conditions without any sign of decomposition in water, nonaqueous solutions and in the solid state. We anticipate that our findings may open a way to aqueous solution and polynuclear high-valent iron chemistry that remains underexplored and presents an important challenge.
Fibronectin-guided migration of carcinoma collectives
Authors: Gopal Sandeep , Veracini Laurence , Grall Dominique , Butori Catherine , Schaub Sébastien , Audebert Stéphane , Camoin Luc , Baudelet Emilie , Radwanska Agata , Beghelli-de la Forest Divonne Stéphanie , Violette Shelia M. , Weinreb Paul H. , Rekima Samah , Ilie Marius , Sudaka Anne , Hofman Paul , Van Obberghen-Schilling Ellen 
Published: January 2017

AbstractFunctional interplay between tumour cells and their neoplastic extracellular matrix plays a decisive role in malignant progression of carcinomas. Here we provide a comprehensive data set of the human HNSCC-associated fibroblast matrisome. Although much attention has been paid to the deposit of collagen, we identify oncofetal fibronectin (FN) as a major and obligate component of the matrix assembled by stromal fibroblasts from head and neck squamous cell carcinomas (HNSCC). FN overexpression in tumours from 435 patients corresponds to an independent unfavourable prognostic indicator. We show that migration of carcinoma collectives on fibrillar FN-rich matrices is achieved through αvβ6 and α9β1 engagement, rather than α5β1. Moreover, αvβ6-driven migration occurs independently of latent TGF-β activation and Smad-dependent signalling in tumour epithelial cells. These results provide insights into the adhesion-dependent events at the tumour–stroma interface that govern the collective mode of migration adopted by carcinoma cells to invade surrounding stroma in HNSCC.
Optimality and sub-optimality in a bacterial growth law
Authors: Towbin Benjamin D. , Korem Yael , Bren Anat , Doron Shany , Sorek Rotem , Alon Uri 
Published: January 2017

AbstractOrganisms adjust their gene expression to improve fitness in diverse environments. But finding the optimal expression in each environment presents a challenge. We ask how good cells are at finding such optima by studying the control of carbon catabolism genes in Escherichia coli. Bacteria show a growth law: growth rate on different carbon sources declines linearly with the steady-state expression of carbon catabolic genes. We experimentally modulate gene expression to ask if this growth law always maximizes growth rate, as has been suggested by theory. We find that the growth law is optimal in many conditions, including a range of perturbations to lactose uptake, but provides sub-optimal growth on several other carbon sources. Combining theory and experiment, we genetically re-engineer E. coli to make sub-optimal conditions into optimal ones and vice versa. We conclude that the carbon growth law is not always optimal, but represents a practical heuristic that often works but sometimes fails.
High-fidelity entangling gate for double-quantum-dot spin qubits
Authors: Nichol John M. , Orona Lucas A. , Harvey Shannon P. , Fallahi Saeed , Gardner Geoffrey C. , Manfra Michael J. , Yacoby Amir 
Published: January 2017

AbstractElectron spins in semiconductors are promising qubits because their long coherence times enable nearly 109 coherent quantum gate operations. However, developing a scalable high-fidelity two-qubit gate remains challenging. Here, we demonstrate an entangling gate between two double-quantum-dot spin qubits in GaAs by using a magnetic field gradient between the two dots in each qubit to suppress decoherence due to charge noise. When the magnetic gradient dominates the voltage-controlled exchange interaction between electrons, qubit coherence times increase by an order of magnitude. Using randomized benchmarking, we measure single-qubit gate fidelities of ~ 99%, and through self-consistent quantum measurement, state, and process tomography, we measure an entangling gate fidelity of 90%. In the future, operating double quantum dot spin qubits with large gradients in nuclear-spin-free materials, such as Si, should enable a two-qubit gate fidelity surpassing the threshold for fault-tolerant quantum information processing.
HD Physiology Project—Japanese efforts to promote multilevel integrative systems biology and physiome research
Authors: Furutani Kazuharu , Tsumoto Kunichika , Kurachi Yoshihisa ,   for HD physiology project investigators
Published: January 2017

AbstractThe HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research.
A novel dominant GJB2 (DFNA3) mutation in a Chinese family
Authors: Wang Hongyang , Wu Kaiwen , Yu Lan , Xie Linyi , Xiong Wenping , Wang Dayong , Guan Jing , Wang Qiuju 
Published: January 2017

AbstractTo decipher the phenotype and genotype of a Chinese family with autosomal dominant non-syndromic hearing loss (ADNSHL) and a novel dominant missense mutation in the GJB2 gene (DFNA3), mutation screening of GJB2 was performed on the propositus from a five-generation ADNSHL family through polymerase chain reaction amplification and Sanger sequencing. The candidate variation and the co-segregation of the phenotype were verified in all ascertained family members. Targeted genes capture and next-generation sequencing (NGS) were performed to explore additional genetic variations. We identified the novel GJB2 mutation c.524C > A (p.P175H), which segregated with high frequency and was involved in progressive sensorineural hearing loss. One subject with an additional c.235delC mutation showed a more severe phenotype than did the other members with single GJB2 dominant variations. Four patients diagnosed with noise-induced hearing loss did not carry this mutation. No other pathogenic variations or modifier genes were identified by NGS. In conclusion, a novel missense mutation in GJB2 (DFNA3), affecting the second extracellular domain of the protein, was identified in a family with ADNSHL.
Bioactive compounds and antioxidant activity of wolfberry infusion
Authors: Sun Yujing , Rukeya Japaer , Tao Wenyang , Sun Peilong , Ye Xingqian 
Published: January 2017

AbstractAn infusion of the wolfberry (Lycium barbarum L.) is a traditional Asian herbal tea. This is the most commonly consumed form of dried wolfberry worldwide, yet little scientific information on wolfberry infusions is available. We investigated the effects of making infusions with hot water on the color, the content of bioactive compounds (polysaccharides, polyphenols, flavonoids and carotenoids) and the antioxidant ability of wolfberry infusions. The contents of bioactive compounds and the antioxidant activity of a wolfberry infusion increased with increased infusion temperature and time. Total polysaccharides content (TPOC), total polyphenols (TPC), total flavonoids (TFC) and total carotenoids contents (TCC) were important for determining the antioxidant capacity of wolfberry infusions with the contribution to antioxidant activity in the order TPC > TFC > TCC > TPOC. Hierarchical cluster analysis indicated preparation conditions of 100 °C for 1~3 h, 90 °C for 2~3 h and 80 °C for 2.5~3 h were equivalent as regards the value of TPC, TPOC, TFC, TCC, FRAP, DPPH and ABTS. The results of this study suggest the length of time of making a wolfberry infusion in actual real life practice is too short and different dietary habits associated with the intake of wolfberry infusion might provide the same bioactive nutrients.
Investigating causality in associations between smoking initiation and schizophrenia using Mendelian randomization
Authors: Gage Suzanne H. , Jones Hannah J. , Taylor Amy E. , Burgess Stephen , Zammit Stanley , Munafò Marcus R. 
Published: January 2017

AbstractSmoking is strongly associated with schizophrenia. Although it has been widely assumed that this reflects self-medication, recent studies suggest that smoking may be a risk factor for schizophrenia. We performed two-sample bi-directional Mendelian randomization using summary level genomewide association data from the Tobacco And Genetics Consortium and Psychiatric Genomics Consortium. Variants associated with smoking initiation and schizophrenia were combined using an inverse-variance weighted fixed-effects approach. We found evidence consistent with a causal effect of smoking initiation on schizophrenia risk (OR 1.73, 95% CI 1.30–2.25, p < 0.001). However, after relaxing the p-value threshold to include variants from more than one gene and minimize the potential impact of pleiotropy, the association was attenuated (OR 1.03, 95% CI 0.97–1.09, p = 0.32). There was little evidence in support of a causal effect of schizophrenia on smoking initiation (OR 1.01, 95% CI 0.98–1.04, p = 0.32). MR Egger regression sensitivity analysis indicated no evidence for pleiotropy in the effect of schizophrenia on smoking initiation (intercept OR 1.01, 95% CI 0.99–1.02, p = 0.49). Our findings provide little evidence of a causal association between smoking initiation and schizophrenia, in either direction. However, we cannot rule out a causal effect of smoking on schizophrenia related to heavier, lifetime exposure, rather than initiation.
Predicting Drug Combination Index and Simulating the Network-Regulation Dynamics by Mathematical Modeling of Drug-Targeted EGFR-ERK Signaling Pathway
Authors: Huang Lu , Jiang Yuyang , Chen Yuzong 
Published: January 2017

AbstractSynergistic drug combinations enable enhanced therapeutics. Their discovery typically involves the measurement and assessment of drug combination index (CI), which can be facilitated by the development and applications of in-silico CI predictive tools. In this work, we developed and tested the ability of a mathematical model of drug-targeted EGFR-ERK pathway in predicting CIs and in analyzing multiple synergistic drug combinations against observations. Our mathematical model was validated against the literature reported signaling, drug response dynamics, and EGFR-MEK drug combination effect. The predicted CIs and combination therapeutic effects of the EGFR-BRaf, BRaf-MEK, FTI-MEK, and FTI-BRaf inhibitor combinations showed consistent synergism. Our results suggest that existing pathway models may be potentially extended for developing drug-targeted pathway models to predict drug combination CI values, isobolograms, and drug-response surfaces as well as to analyze the dynamics of individual and combinations of drugs. With our model, the efficacy of potential drug combinations can be predicted. Our method complements the developed in-silico methods (e.g. the chemogenomic profile and the statistically-inferenced network models) by predicting drug combination effects from the perspectives of pathway dynamics using experimental or validated molecular kinetic constants, thereby facilitating the collective prediction of drug combination effects in diverse ranges of disease systems.
Ocean warming and acidification synergistically increase coral mortality
Authors: Prada F. , Caroselli E. , Mengoli S. , Brizi L. , Fantazzini P. , Capaccioni B. , Pasquini L. , Fabricius K. E. , Dubinsky Z. , Falini G. , Goffredo S. 
Published: January 2017

AbstractOrganisms that accumulate calcium carbonate structures are particularly vulnerable to ocean warming (OW) and ocean acidification (OA), potentially reducing the socioeconomic benefits of ecosystems reliant on these taxa. Since rising atmospheric CO2is responsible for global warming and increasing ocean acidity, to correctly predict how OW and OA will affect marine organisms, their possible interactive effects must be assessed. Here we investigate, in the field, the combined temperature (range: 16–26 °C) and acidification (range: pHTS8.1–7.4) effects on mortality and growth of Mediterranean coral species transplanted, in different seasonal periods, along a natural pH gradient generated by a CO2vent. We show a synergistic adverse effect on mortality rates (up to 60%), for solitary and colonial, symbiotic and asymbiotic corals, suggesting that high seawater temperatures may have increased their metabolic rates which, in conjunction with decreasing pH, could have led to rapid deterioration of cellular processes and performance. The net calcification rate of the symbiotic species was not affected by decreasing pH, regardless of temperature, while in the two asymbiotic species it was negatively affected by increasing acidification and temperature, suggesting that symbiotic corals may be more tolerant to increasing warming and acidifying conditions compared to asymbiotic ones.
The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction
Authors: Sot Begoña , Rubio-Muñoz Alejandra , Leal-Quintero Ahudrey , Martínez-Sabando Javier , Marcilla Miguel , Roodveldt Cintia , Valpuesta José M. 
Published: January 2017

AbstractThe eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington’s disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson’s disease. We evaluated fibrillation blockade in α-synuclein A53T deletion mutants and CCT interactions of full-length A53T in distinct oligomeric states to define an inhibition mechanism specific for α-synuclein. CCT interferes with fibre assembly by interaction of its CCTζ and CCTγ subunits with the A53T central hydrophobic region (NAC). This interaction is specific to NAC conformation, as it is produced once soluble α-synuclein A53T oligomers form and blocks the reaction before fibres begin to grow. Finally, we show that this association inhibits α-synuclein A53T oligomer toxicity in neuroblastoma cells. In summary, our results and those for huntingtin suggest that CCT is a general modulator of amyloidogenesis via a specific mechanism.