bluuebunny/crossref_metadata_2025 huggingface dataset:
3‐D numerical simulations for polycondensation of poly(p‐phenylene terephthalamide) in twin screw extruder
Authors: Zong Yuan , Tang Hao , Zhao Ling
Published: January 2017

Poly(p‐phenylene terephthalamide) (PPTA) is a typical high‐performance fiber and usually synthesized by low temperature solution polycondensation in twin screw extruder. During the reactive extrusion, flow behavior, rheokinetics, and temperature are highly coupled, which makes it difficult to ensure the quality of product. In the present work, the rheokinetics of the PPTA solution is established by experiments and its reactive extrusion is investigated via 3‐D numerical simulation. The flow pattern, molecular weight distribution and temperature have been investigated for the extruders with three different elements, i.e., full flight screw (FF), kneading block (KB), and screw mixing element (SME). The results indicate that the unique flow characteristic of different screw elements affects mixing experience of the reactants and further the PPTA qualities. By numerical simulation, it shows the temperature increase within the tested extrusion stage is 7 K and reaction heat is found the main energy source for extrusion stage. Furthermore, heat removal method is verified with consideration of industrial production process. The numerical simulation work also discusses the reaction and mixing process in the extruders with three combined screws. The results show the introduction of more reverse FF and KB elements can lead to higher quality of PPTA. POLYM. ENG. SCI., 57:1252–1261, 2017. © 2017 Society of Plastics Engineers
Quantitative iTRAQ‐based proteomic analysis of rice grains to assess high night temperature stress
Authors: Zhang Hong‐Yu , Lei Gang , Zhou Hui‐Wen , He Chao , Liao Jiang‐Lin , Huang Ying‐Jin
Published: January 2017

Rice yield and quality are adversely affected by increasing global surface temperature, and are strongly attributed to high night temperature (HNT) than high daytime temperature. However, the molecular mechanism underlying the heat‐tolerant characteristics of rice remains unclear. In the present study, we compared the proteomes of heat‐tolerant and ‐sensitive lines of rice at early milky stage using an iTRAQ method. We have identified 38 differentially expressed proteins between the two lines, of which 32 proteins have been functionally annotated in NCBI and/or the UniProt database. These proteins were then classified into seven functional subgroups, which include signal transduction, transcript regulation, oxidation, defense response, transport, energy metabolism, and biosynthesis. Further analysis indicated that HNT stress could disrupt the redox equilibrium of plant cells, which in turn triggers the calcium‐dependent protein kinase and COP9 signalosome, thereby regulating downstream genes/proteins that are involved in the HNT response. The candidate proteins may provide genetic resources for the improvement of heat‐tolerant characteristics in rice, and the proposed model for signal transduction and transcriptional regulation may facilitate in the elucidation of the molecular mechanism underlying the response to HNT stress in rice.
Model for the deep defect‐related emission bands between 1.4 and 2.4 eV in AlN
Authors: Lamprecht M. , Jmerik V. N. , Collazo R. , Sitar Z. , Ivanov S. V. , Thonke K.
Published: January 2017

We report on defect‐related photoluminescence bands in the range from 1.4 to 2.4 eV in aluminum nitride bulk crystals and layers. Using continuous photoluminescence, photoluminescence excitation, and time‐resolved photoluminescence spectroscopy, we assign these bands to donor–acceptor pair transitions between shallow donor states or related slightly deeper states of silicon or oxygen donors, and three different types of deep acceptors. These three different acceptors are most likely a ()) complex, a () complex, and an aluminum vacancy , or different charge states of these.
Fault diagnosis and compensation for two‐dimensional discrete time systems with sensor faults and time‐varying delays
Authors: Zhao Dong , Shen Dong , Wang Youqing
Published: January 2017

A fault diagnosis and compensation problem for two‐dimensional discrete time systems with time‐varying state delays is studied in this paper. The concerned two‐dimensional systems are described by the Fornasisi–Marchesini second model and are subject to unknown disturbances. First, a fault detection and diagnosis module is designed to obtain the information on sensor faults; a new fault detection and diagnosis integrated design, using the observer based on descriptor system approach, is proposed to detect and estimate the sensor faults. The integrated design can maximize the fault detection rate for a given false alarm rate. Sufficient conditions for the existence of the integrated fault detection and diagnosis design are derived in the context of norm evaluation and provided in terms of matrix inequalities. Second, a fault‐tolerant control module is proposed upon an existing output feedback controller. When the sensor fault occurs, the faulty measurement can be identified and corrected by the proposed fault detection and diagnosis module. In this case, the feedback controller can guarantee the performance of the closed‐loop system even when encountering sensor faults. Finally, the proposed method is applied to a thermal process to illustrate its effectiveness. Copyright © 2017 John Wiley & Sons, Ltd.
Unbiased split variable selection for random survival forests using maximally selected rank statistics
Authors: Wright Marvin N. , Dankowski Theresa , Ziegler Andreas
Published: January 2017

The most popular approach for analyzing survival data is the Cox regression model. The Cox model may, however, be misspecified, and its proportionality assumption may not always be fulfilled. An alternative approach for survival prediction is random forests for survival outcomes. The standard split criterion for random survival forests is the log‐rank test statistic, which favors splitting variables with many possible split points. Conditional inference forests avoid this split variable selection bias. However, linear rank statistics are utilized by default in conditional inference forests to select the optimal splitting variable, which cannot detect non‐linear effects in the independent variables. An alternative is to use maximally selected rank statistics for the split point selection. As in conditional inference forests, splitting variables are compared on the p‐value scale. However, instead of the conditional Monte‐Carlo approach used in conditional inference forests, p‐value approximations are employed. We describe several p‐value approximations and the implementation of the proposed random forest approach. A simulation study demonstrates that unbiased split variable selection is possible. However, there is a trade‐off between unbiased split variable selection and runtime. In benchmark studies of prediction performance on simulated and real datasets, the new method performs better than random survival forests if informative dichotomous variables are combined with uninformative variables with more categories and better than conditional inference forests if non‐linear covariate effects are included. In a runtime comparison, the method proves to be computationally faster than both alternatives, if a simple p‐value approximation is used. Copyright © 2017 John Wiley & Sons, Ltd.
Disease severity classification using quantitative magnetic resonance imaging data of cartilage in femoroacetabular impingement
Authors: Henn Lisa L. , Hughes John , Iisakka Eleena , Ellermann Jutta , Mortazavi Shabnam , Ziegler Connor , Nissi Mikko J. , Morgan Patrick
Published: January 2017

Femoroacetabular impingement (FAI) is a condition in which subtle deformities of the femoral head and acetabulum (hip socket) result in pathological abutment during hip motion. FAI is a common cause of hip pain and can lead to acetabular cartilage damage and osteoarthritis. For some patients with FAI, surgical intervention is indicated, and it can improve quality of life and potentially delay the onset of osteoarthritis. For other patients, however, surgery is contraindicated because significant cartilage damage has already occurred. Unfortunately, current imaging modalities (X‐rays and conventional MRI) are subjective and lack the sensitivity to distinguish these two groups reliably. In this paper, we describe the pairing of T2* mapping data (an investigational, objective MRI sequence) and a spatial proportional odds model for surgically obtained ordinal outcomes (Beck's scale of cartilage damage). Each hip in the study is assigned its own spatial dependence parameter, and a Dirichlet process prior distribution permits clustering of said parameters. Using the fitted model, we produce a six‐color, patient‐specific predictive map of the entire acetabular cartilage. Such maps will facilitate patient education and clinical decision making. Copyright © 2017 John Wiley & Sons, Ltd.
Choose to Fight or Choose to Flee? A Network Embeddedness Perspective of Executive Ship Jumping in Declining Firms
Authors: Jiang Han , Cannella Albert A. , Xia Jun , Semadeni Matthew
Published: January 2017

Research summary:Executives in declining firms may engage in ship‐jumping behavior (i.e., voluntarily move to new employers before the failure occurs) to avoid the stigma of failure. However, it is unclear how executives decide whether or not to jump ship. Building on a network embeddedness perspective, we highlight how three network‐based indicators (i.e., executive social capital, the social capital of other peers in the declining firm, and the declining firm's alliance network) influence the executive‐level ship‐jumping decision by shaping its benefits and opportunity costs. Using data from executives at failing firms inChina, we find support for our hypothesized relationships. Our research provides important insight into the network mechanisms driving the ship‐jumping decision.

Managerial summary:Executives at failing firms have a choice: stay and attempt to rescue the firm from failure or exit and avoid the stigma of the failure (i.e., jump ship). Yet, little is known about what factors affect this choice. We propose that social capital plays an important role in the decision. Our evidence from specially treated (*ST) public firms inChina finds that ship jumping is lowest at low and high values of social capital, and highest at moderate levels of social capital (an invertedU‐shaped relationship). In addition, higher levels of peer social capital (in the declining firm) as well as a well‐established firm‐level alliance network discourage the ship‐jumping choice. Copyright © 2017 John Wiley & Sons, Ltd.
Epidermal growth factor receptor (EGFR)—MAPK—nuclear factor(NF)‐κB—IL8: A possible mechanism of particulate matter(PM) 2.5‐induced lung toxicity
Authors: Jeong Seung‐Chan , Cho Yoon , Song Mi‐Kyung , Lee Eunil , Ryu Jae‐Chun
Published: January 2017

Airway inflammation plays a central role in the pathophysiology of diverse pulmonary diseases. In this study, we investigated whether exposure to particulate matter (PM) 2.5, a PM with an aerodynamic diameter of less than 2.5 µm, enhances inflammation‐related toxicity in the human respiratory system through activation of the epidermal growth factor receptor (EGFR) signaling pathway. Through cytokine antibody array analysis of two extracts of PM2.5 [water (W‐PM2.5) and organic (O‐PM2.5) soluble extracts] exposed to A549 (human alveolar epithelial cell), we identified eight cytokines changed their expression with W‐PM2.5 and three cytokines with O‐PM2.5. Among them, epidermal growth factor (EGF) was commonly up‐regulated by W‐PM2.5 and O‐PM2.5. Then, in both groups, we can identify the increase in EGF receptor protein levels. Likewise, increases in the phosphorylation of ERK1/2 MAP kinase and acetylation of nuclear factor(NF)‐κB were detected. We also detected an increase in IL‐8 that was related to inflammatory response. And using the erlotinib as an inhibitor of EGFR, we identified the erlotinib impaired the phosphorylation of EGFR, ERK1/2, acetylation of NF‐κB proteins and decreased IL‐8. Furthermore, at in vivo model, we were able to identify similar patterns. These results suggest that PM2.5 may contribute to an abnormality in the human respiratory system through EGFR, MAP kinase, NF‐κB, and IL‐8 induced toxicity signaling. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1628–1636, 2017.
Retracted: Chronic nasal exposure to nanoparticulate TiO2 causes pulmonary tumorigenesis in male mice
Authors: Hong Fashui , Ji Li , Zhou Yingjun , Wang Ling
Published: January 2017

Chronic inhalation bioassays in rodents are used to assess pulmonary carcinogenicity for purposes of hazard identification and potentially for risk characterization. Numerous studies have been confirmed that exposure to titanium dioxide nanoparticles (TiO2 NPs) may result in chronic pulmonary inflammation in both mice and rats. However, very few studies have focused on the pulmonary tumorigenesis. In this study, to examine whether chronic TiO2 NP exposure induce tumorigenesis in the lung, forty mice (each group) were nasally exposed to 1.25, 2.5, and 5 mg/kg body weight TiO2 NPs for nine consecutive months, lung pathology was then evaluated, and the biochemical function parameters in bronchoalveolar lavage (BAL) and tumor markers in the serum were investigated using an ELISA method. We observed that nasal exposure to TiO2 NPs caused infiltration of inflammatory cells, tumorigenesis in the lung, and accompanied by significant increases of lactate dehydrogenase, alkaline phosphatase, and total protein levels in BLAF, significant increases in tumor markers including cytokeratin 19, neuron‐specific enolase, carcinoembryonic antigen, squamous cell carcinoma antigen, and cancer antigen‐125 in the serum. It implies that chronic inhaled TiO2 NPs may increase possibility of pulmonary tumor formation for human. Therefore, the production and application of TiO2 NPs should be paid more attention. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1651–1657, 2017.
Neonatal blockade of GABA‐A receptors alters behavioral and physiological phenotypes in adult mice
Authors: Salari Ali‐Akbar , Amani Mohammad
Published: January 2017

Gamma‐aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA‐A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA‐A receptors by bicuculline can alter anxiety‐ and depression‐like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80–95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300 μg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety‐ (elevated plus‐maze and light‐dark box) and depression‐like behaviors (tail suspension test and forced swim test). Stress‐induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300 μg/kg decreased anxiety‐like behavior, stress‐induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression‐like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA‐A receptors affects anxiety‐like behavior, physiological and hormonal parameters in a sex‐dependent manner in mice. Taken together, these data corroborate the concept that GABA‐A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood.
Nuclear Politics
Authors: Debs Alexandre , Monteiro Nuno P.
Published: January 2017

When do states acquire nuclear weapons? Overturning a decade of scholarship focusing on other factors, Debs and Monteiro show in Nuclear Politics that proliferation is driven by security concerns. Proliferation occurs only when a state has both the willingness and opportunity to build the bomb. A state has the willingness to nuclearize when it faces a serious security threat without the support of a reliable ally. It has the opportunity when its conventional forces or allied protection are sufficient to deter preventive attacks. This explains why so few countries have developed nuclear weapons. Unthreatened or protected states do not want them; weak and unprotected ones cannot get them. This powerful theory combined with extensive historical research on the nuclear trajectory of sixteen countries will make Nuclear Politics a standard reference in international security studies, informing scholarly and policy debates on nuclear proliferation - and US non-proliferation efforts - for decades to come.
The Russian Revolution, 1917
Authors: Wade Rex A.
Published: January 2017

Rex A. Wade presents an essential overview of the Russian Revolution from its beginning in February 1917, through the numerous political crises under Kerensky, to the victory of Lenin and the Bolsheviks in the October Revolution. This thoroughly revised and expanded third edition introduces students to new approaches to the Revolution's political history and clears away many of the myths and misconceptions that have clouded studies of the period. It also gives due space to the social history of the Revolution, incorporating people and places too often left out of the story, including women, national minority peoples, peasantry, and front soldiers. The third edition has been updated to include new scholarship on topics such as the coming of the Revolution and the beginning of Bolshevik rule, as well as the Revolution's cultural context. This highly readable book is an invaluable guide to one of the most important events of modern history.
Resilient Organizations
Authors: Pirotti Guia Beatrice , Venzin Markus
Published: January 2017

Recent financial crises have shown that firms need to create more robust business models. However, it seems that the task of developing resilience - a firm's ability to adapt, endure, bounce back and then thrive, despite the shock - appears on most managers' strategic issue list only after such a shock has occurred. Managers, through responsible leadership, can make explicit choices that will enhance their firm's resilience, increasing their chances of anticipating and avoiding these shocks. This book is the result of a three-year research project across seven industries, and is aimed at improving the understanding of why some firms are better than others in dealing with market turbulence. Pirotti and Venzin develop a measure for organizational resilience, identifying resilience drivers and demonstrating how firms can appropriate value from high resilience levels. It is a valuable read for graduates taking a course in strategy and global management and for reflective practitioners.
IS THERE A MARKET FOR BRANDED GULF OF MEXICO OYSTERS?
Authors: PETROLIA DANIEL R. , WALTON WILLIAM C. , YEHOUENOU LAURIANE
Published: January 2017

We administered an online choice experiment to a sample of U.S. raw-oyster consumers to identify factors influencing preferences for Gulf of Mexico oysters, determined the extent of preference heterogeneity, and estimated marginal willingness to pay for specific varieties and other key attributes. Results indicate significant preference heterogeneity among select varieties, with non-Gulf respondents estimated to require a price discount on Gulf oyster varieties on the order of $3–$6/half dozen. Gulf respondents were found to be less sensitive to oyster variety, and estimated to be willing to pay a price premium only for select Gulf varieties on the order of $0–$3/half dozen.
Model granularity in engineering design – concepts and framework
Authors: Maier Jakob F. , Eckert Claudia M. , John Clarkson P.
Published: January 2017

In many engineering design contexts models are indispensable. They offer decision support and help tackle complex and interconnected design projects, capturing the underlying structure of development processes or resulting products. Because managers and engineers base many decisions on models, it is crucial to understand their properties and how these might influence their behaviour. The level of detail, or granularity, of a model is a key attribute that results from how reality is abstracted in the modelling process. Despite the direct impact granularity has on the use of a model, the general topic has so far only received limited attention and is therefore not well understood or documented. This article provides background on model theory, explores relevant terminology from a range of fields and discusses the implications for engineering design. Based on this, a classification framework is synthesised, which outlines the main manifestations of model granularity. This research contributes to theory by scrutinising the nature of model granularity. It also illustrates how this may manifest in engineering design models, using Design Structure Matrices as an example, and discusses associated challenges to provide a resource for modellers navigating decisions regarding granularity.
Vortex-induced rotations of a rigid square cylinder at low Reynolds numbers
Authors: Ryu Sungmin , Iaccarino Gianluca
Published: January 2017

A numerical investigation of vortex-induced rotations (VIRs) of a rigid square cylinder, which is free to rotate in the azimuthal direction in a two-dimensional uniform cross-flow, is presented. Two-dimensional simulations are performed in a range of Reynolds numbers between 45 and 150 with a fixed mass and moment of inertia of the cylinder. The parametric investigation reveals six different dynamic responses of the square cylinder (expanding on those reported by Zaki et al. (J. Fluids Struct., vol. 8, 1994, pp. 555–582)) and their coupled vortex patterns at low Reynolds numbers. In each characteristic regime, moment generating mechanisms are elucidated with investigations of instantaneous flow fields and surface pressure distributions at chosen time instants in a period of rotation response. Our simulation results also elucidate that VIRs significantly influence the statistics of drag and lift force coefficients: (i) the onset of a rapid increases of the two coefficients at $Re=80$ and (ii) their step increases in the autorotation regime.
Characterisation of fatty acid metabolism in different insulin-resistant phenotypes by means of stable isotopes
Authors: Blaak Ellen E.
Published: January 2017

The obese insulin resistant and/or prediabetic state is characterised by systemic lipid overflow, mainly driven by an impaired lipid buffering capacity of adipose tissue, and an impaired capacity of skeletal muscle to increase fat oxidation upon increased supply. This leads to the accumulation of bioactive lipid metabolites in skeletal muscle interfering with insulin sensitivity via various mechanisms. In this review, the contribution of dietary v. endogenous fatty acids to lipid overflow, their extraction or uptake by skeletal muscle as well as the fractional synthetic rate, content and composition of the muscle lipid pools is discussed in relation to the development or presence of insulin resistance and/or an impaired glucose metabolism. These parameters are studied in vivo in man by combining a dual stable isotope methodology with [2H2]- and [U-13C]-palmitate tracers with the arterio-venous balance technique across forearm muscle and biochemical analyses in muscle biopsies. The insulin-resistant state is characterised by an elevated muscle TAG extraction, despite similar supply, and a reduced skeletal muscle lipid turnover, in particular after intake of a high fat, SFA fat meal, but not after a high fat, PUFA meal. Data are placed in the context of current literature, and underlying mechanisms and implications for long-term nutritional interventions are discussed.
Childhood maltreatment and eating disorder pathology: a systematic review and dose-response meta-analysis
Authors: Molendijk M. L. , Hoek H. W. , Brewerton T. D. , Elzinga B. M.
Published: January 2017

Background

Meta-analyses have established a high prevalence of childhood maltreatment (CM) in patients with eating disorders (EDs) relative to the general population. Whether the prevalence of CM in EDs is also high relative to that in other mental disorders has not yet been established through meta-analyses nor to what extent CM affects defining features of EDs, such as number of binge/purge episodes or age at onset. Our aim is to provide meta-analyses on the associations between exposure to CM (i.e. emotional, physical and sexual abuse) on the occurrence of all types of EDs and its defining features.

Method

Systematic review and meta-analyses. Databases were searched until 4 June 2016.

Results

CM prevalence was high in each type of ED (totalN= 13 059, prevalence rates 21–59%) relative to healthy (N= 15 092, prevalence rates 1–35%) and psychiatric (N= 7736, prevalence rates 5–46%) control groups. ED patients reporting CM were more likely to be diagnosed with a co-morbid psychiatric disorder [odds ratios (ORs) range 1.41–2.46,p< 0.05] and to be suicidal (OR 2.07,p< 0.001) relative to ED subjects who were not exposed to CM. ED subjects exposed to CM also reported an earlier age at ED onset [effect size (Hedges’g) = −0.32,p< 0.05], to suffer a more severe form of the illness (g= 0.29,p< 0.05), and to binge-purge (g= 0.31,p< 0.001) more often compared to ED patients who did not report any CM.

Conclusion

CM, regardless of type, is associated with the presence of all types of ED and with severity parameters that characterize these illnesses in a dose dependent manner.
Japanese encephalitis virus induces human neural stem/progenitor cell death by elevating GRP78, PHB and hnRNPC through ER stress
Authors: Mukherjee Sriparna , Singh Noopur , Sengupta Nabonita , Fatima Mahar , Seth Pankaj , Mahadevan Anita , Shankar Susarla Krishna , Bhattacharyya Arindam , Basu Anirban
Published: January 2017

Japanese encephalitis virus (JEV), which is a causative agent of sporadic encephalitis, harbours itself inside the neural stem/progenitor cells. It is a well-known fact that JEV infects neural stem/progenitor cells and decreases their proliferation capacity. With mass spectrometry-based quantitative proteomic study, it is possible to reveal the impact of virus on the stem cells at protein level. Our aim was to perceive the stem cell proteomic response upon viral challenge. We performed a two-dimensional gel electrophoresis-based proteomic study of the human neural stem cells (hNS1 cell line) post JEV infection and found that 13 proteins were differentially expressed. The altered proteome profile of hNS1 cell line revealed sustained endoplasmic reticulum stress, which deteriorated normal cellular activities leading to cell apoptosis. The proteomic changes found in hNS1 cell line were validatedin vivoin the subventricular zone of JE infected BALB/c mice. Congruent alterations were also witnessed in multipotent neural precursor cells isolated from human foetus and in autopsy samples of human brain clinically diagnosed as cases of JE patients. Endoplasmic reticulum resident chaperone GRP78, mitochondrial protein Prohibitin and heterogeneous nuclear ribonucleoprotein hnRNPC (C1/C2) have been shown to interact with viral RNA. Hence it is proposed that these are the principle candidates governing endoplasmic reticulum stress-induced apoptosis in JEV infection.
Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers
Authors: Henninger Christian , Fritz Gerhard
Published: January 2017

Cancer 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

Electron 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

The 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

Bacterial 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

Mutations 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

In 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

Functional 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

Organisms 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

Electron 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

The 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

To 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

An 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

Smoking 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

Synergistic 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

Organisms 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.