bluuebunny/crossref_metadata_2025 huggingface dataset:
Silymarin Improves Vascular Function of Aged Ovariectomized Rats
Authors: Demirci Buket , Dost Turhan , Gokalp Filiz , Birincioglu Mustafa
Published: October 2013

Both aging and estrogen depletion lead to endothelial dysfunction, which is the main reason of many cardiovascular diseases. Previous reports have shown that cell protective effect of silymarin (SM) depends on its antioxidant and phytoestrogenic properties. We investigated the effect of SM on vascular stiffness of aged menopausal rats and the involvement of estrogenic activity in this effect. Isolated rat aortas were obtained from 22‐month‐old rats, after 18 months of ovariectomy (OVX) follow‐up. Each ring was incubated in tissue bath either with SM (50 mg/L) and 17β‐estradiol (10 μM, E2) or in the presence of SM/fulvestrant (50 mg/L, 10 μM). Endothelium‐intact rings were precontracted with phenylephrine (0.001–30 μM) or high potassium (40 mM); endothelium‐dependent/independent relaxant responses were obtained using acetylcholine (0.001–30 μM) and sodium nitroprusside (0.0001–3 μM), respectively. While phenylephrine sensitivity was significantly increased in OVX rats, relaxations were significantly less in aged OVX rats compared with young rats. In spite of the presence of estrogen antagonist, immediate SM treatment restored the endothelial function and vascular tone better than estrogen replacement. Additionally, as a complementary and alternative medicine, it does not cause estrogenic side effects when taken acutely. Copyright © 2013 John Wiley & Sons, Ltd.
The Effect of Black Seed (Nigella sativa) Extract on FOXO3 Expression in HepG2 Cells
Authors: Haas Michael J. , Onstead‐Haas Luisa , Naem Emad , Arnold Alexis , Rohrbaugh Nathcelly , Flowers Megan , Mooradian Arshag D.
Published: October 2013

Black seed extracts are known to alter cellular metabolism through multiple signaling pathways. Since Forkhead box transcription factor 3 (FOXO3) has a significant role in regulating cellular metabolism, the effect of lipid extracts of black seed (Sativa nigella) on FOXO3 levels and AKT and 5‐AMP activated protein kinase α (AMPKα) signaling was measured in HepG2 hepatoma cells. FOXO3 levels, phosphorylation, and nuclear exclusion were measured by Western blot, as were AKT and AMPK expression and activity using phosphorylation‐specific antibodies. Apolipoprotein A‐I expression, a black seed‐responsive gene, was measured by Western blot. Treatment with black seed extract increased FOXO3 phosphorylation and decreased its expression. In contrast to control cells where FOXO3 was located primarily in the nucleus, in black seed‐treated HepG2 cells, FOXO3 was localized primarily to the cytoplasm. These changes in FOXO3 phosphorylation, expression, and localization were accompanied by increased AKT activity. Black seed also decreased AMPKα activity but increased AMPKα expression. Lipid extracts from black seeds inhibit FOXO3 activity and thereby modulate the expression of FOXO3‐dependent genes. Copyright © 2013 John Wiley & Sons, Ltd.
Ferns and Lycopods—A Potential Treasury of Anticancer Agents but Also a Carcinogenic Hazard
Authors: Tomšík Pavel
Published: October 2013

Many species of seedless vascular plants—ferns and lycopods—have been used as food and folk medicine since ancient times. Some of them have become the focus of intensive research concerning their anticancer properties. Studies on the anticancer effect of crude extracts are being increasingly replaced by bioactivity‐guided fractionation, as well as detailed assessment of the mechanism of action. Numerous compounds—especially flavonoids such as amentoflavone and protoapigenone, and also simpler phenolic compounds, steroids, alkaloids and terpenoids—were isolated and found to be cytotoxic, particularly pro‐apoptotic, or to induce cell cycle arrest in cancer cell lines in vitro. In in vivo experiments, some fern‐derived compounds inhibited tumour growth with little toxicity. On the other hand, many ferns—not only the well‐known Bracken (Pteridium)—may pose a significant hazard to human health due to the fact that they contain carcinogenic sesquiterpenoids and their analogues. The objective of this review is to summarise the recent state of research on the anticancer properties of ferns and lycopods, with a focus on their characteristic bioactive constituents. The carcinogenic hazard posed by ferns is also mentioned. Copyright © 2013 John Wiley & Sons, Ltd.
Effect of Terminalia chebula Extract and Chlorhexidine on Salivary pH and Periodontal Health: 2 Weeks Randomized Control Trial
Authors: Gupta Devanand , Bhaskar D. J. , Gupta Rajendra Kumar , Karim Bushra , Gupta Vipul , Punia Himanshu , Batra Manu , Jain Ankita , Agarwal Amit , Singh Pradeep
Published: October 2013

A double blind, randomized, controlled study with three parallel treatment groups was done to evaluate the efficacy of a Terminalia chebula 10% mouth rinse compared with chlorhexidine 0.12% mouth rinse, applied two times daily for 2 weeks, in the treatment of dental plaque and gingivitis. Seventy‐eight patients were included in the study. The efficacy variables were periodontal indices on days 0, 7 and 14 after commencement of therapy. Twenty six patients received chlorhexidine mouth rinse, twenty six Terminalia chebula mouth rinse and twenty six received saline solution. The clinical parameters were significantly reduced by both chlorhexidine and Terminalia chebula mouth rinse although no significant difference was seen between the two groups (P > 0.05). This study demonstrated that Terminalia chebula mouth rinse is effective in reducing microbial plaque, gingival inflammation and neutralizing salivary pH. Copyright © 2013 John Wiley & Sons, Ltd.
Compound‐specific δ13C analysis of monosaccharides from soil extracts by high‐performance liquid chromatography/isotope ratio mass spectrometry
Authors: Basler A. , Dyckmans J.
Published: October 2013

RATIONALE

Carbohydrates represent up to 25% of soil organic matter and derive from fresh plant input or organic matter transformation within the soil. Compound‐specific isotope analysis (CSIA) of monosaccharides (sugars) extracted from soil provides a powerful tool to disentangle the dynamics of different carbohydrate pools of soils. The use of high‐performance liquid chromatography/oxidation/isotope ratio mass spectrometry (HPLC/o/IRMS) allows isotope measurements without the need for derivatisation and thus increasing accuracy and precision of the isotopic measurement, compared with gas chromatography/combustion/isotope ratio mass spectrometry (GC/c/IRMS).

METHODS

The CSIA of soil carbohydrates was performed using a HPLC/o/IRMS system. The chromatographic and mass spectrometric subunits were coupled with a LC–Isolink interface. Soil sugars were extracted after mild hydrolysis using 4 M trifluoroacetic acid (TFA). Chromatographic separation of the sugars was achieved using a low strength 0.25 mM NaOH solution as mobile phase at a flow rate of 250 μL min–1 at 10 °C.

RESULTS

The chromatographic conditions allowed the baseline separation of the seven most abundant sugars in soil. Complete removal of TFA from the soil hydrolysate ensured chromatographic stability. The accuracy was better than 0.66 ‰ for amounts of >2.5 nM sugar on column. The sugars extracted from an agricultural soil appeared to be more enriched in 13C than the soil organic carbon, and to have a similar isotopic signature to the soil microbial biomass.

CONCLUSIONS

The proposed method proved to be suitable for the analysis of the common sugars in soil extracts and represents a precise tool for the study of carbohydrate dynamics. Copyright © 2013 John Wiley & Sons, Ltd.
Radar imaging with compressed sensing
Authors: Harding Brian J. , Milla Marco
Published: October 2013

A novel technique for radar‐imaging inversions is proposed which leverages ideas from the emerging field of compressed sensing. This new method takes advantage of the transform sparsity inherent in natural images. Theoretical recovery results are promising and are borne out by simulations in which this technique outperforms Capon's method and the Maximum Entropy method. Preliminary results using data collected at the Jicamarca Radio Observatory are also presented.
Multiple comprehension strategies instruction in the intermediate grades: three remarks about content and pedagogy in the intervention literature
Authors: Davis Dennis S.
Published: October 2013

This conceptual article provides an overview and critique of the major versions of multiple comprehension strategies instruction (MCSI) that have been studied since 1980. The author argues thatMCSIis a multifaceted instructional approach that takes on many different forms in the research literature. Even intervention studies that ostensibly examine the same brand ofMCSIcan have drastic variability in content and pedagogy. The author claims that independent and self‐regulated reading practices are underemphasized in this literature despite strong conceptual roots in self‐regulation and metacognitive learning theory. Finally, the author concludes that manyMCSIstudies present a proceduralized view of strategic reading, characterized by repeated use of common strategies taught to students in a prescribed sequence. While previous reviews and critiques of the reading comprehension literature have focused on the effectiveness ofMCSIand the way it has been inadequately translated into typical practice, this article comments on the wayMCSIis carried out in the intervention literature itself with the goal of understanding the pedagogical features that are prioritized byMCSIresearchers. The interpretive remarks in this article provide directions for future work on reading comprehension instruction.
Additive‐state‐decomposition‐based tracking control framework for a class of nonminimum phase systems with measurable nonlinearities and unknown disturbances
Authors: Quan Quan , Cai Kai‐Yuan , Lin Hai
Published: October 2013

This paper aims to propose an additive‐state‐decomposition‐based tracking control framework, based on which the output feedback tracking problem is solved for a class of nonminimum phase systems with measurable nonlinearities and unknown disturbances. This framework is to ‘additively’ decompose the output feedback tracking problem into two more tractable problems, namely an output feedback tracking problem for a linear time invariant system and a state feedback stabilization problem for a nonlinear system. Then, one can design a controller for each problem respectively using existing methods, and these two designed controllers are combined together to achieve the original control goal. The main contribution of the paper lies on the introduction of an additive state decomposition scheme and its implementation to mitigate the design difficulty of the output feedback tracking control problem for nonminimum phase nonlinear systems. To demonstrate the effectiveness, an illustrative example is given. Copyright © 2013 John Wiley & Sons, Ltd.
Bounded consensus tracking for sampled‐data second‐order multi‐agent systems with fixed and Markovian switching topology
Authors: Xie Dongmei , Cheng Yongli
Published: October 2013

This paper studies the bounded consensus tracking problems of second‐order multi‐agent systems with fixed and Markovian switching topology in a sampling setting. It is assumed that all the agents can only obtain the approximative value of the leader's acceleration instead of the actual value. Moreover, only a portion of agents can have the access to the leader and obtain the leader's position and velocity directly. By virtue of matrix analysis and perturbation theory, we present necessary and sufficient conditions for boundedness of tracking error system and show the ultimate bound of tracking errors under fixed and Markovian switching topology, respectively. Finally, a simulation example is given to illustrate the effectiveness of the results. Copyright © 2013 John Wiley & Sons, Ltd.
Precise modeling of aging populations
Authors: Eberlein Robert L. , Thompson James P.
Published: October 2013

Aggregate continuous time formulations used in system dynamics models result in the implicit mixing of individual constituents of levels. Normally, this is acceptable as the heterogeneous nature of model variables implies that some individuals counted in a level's value will pass others and exit earlier. In models with a focus on chronological aging and age‐related characteristics, this phenomenon, which we call cohort blending, can result in large distortions. Using aging chains can reduce these distortions, but cohort blending persists even with one‐year groupings. As an alternative, we introduce an approach we call “continuous cohorting” in which populations are tracked with cohorts sized the same as the computational interval of the model. This approach eliminates the blending problem with minimal notational and moderate computational burden. The resulting models display quantitative, though limited qualitative, differences from their traditional counterparts and are more easily defensible with demographers and others who study population dynamics. Copyright © 2013 System Dynamics Society
Hidden attribute‐based signcryption scheme for lattice
Authors: Xiang Xinyin , Li Hui , Wang Mingyu , Liu Zhenhua
Published: October 2013

As a novel cryptographic primitive, signcryption realizes the function of digital signature and public‐key encryption simultaneously, at a cost significantly lower than that of the traditional sign‐then‐encrypt approach. To the best of the authors’ knowledge, there is little works focusing on attribute‐based signcryption (ABSC), especially in the setting of lattice‐based cryptography. In this paper, we show that it is possible to construct hidden ABSC schemes based on lattice problems by presenting an ABSC scheme. In the random oracle model, the proposed scheme is proved to be indistinguishable against adaptively chosen ciphertext attacks under the learning with errors assumption and existentially unforgeable against adaptively chosen message attacks under the short integer solution assumption, respectively. Copyright © 2013 John Wiley & Sons, Ltd.
Depth profiling with SNMS and SIMS of Zn(O,S) buffer layers for Cu(In,Ga)Se2 thin‐film solar cells
Authors: Eicke Axel , Ciba Thomas , Hariskos Dimitrios , Menner Richard , Tschamber Carsten , Witte Wolfram
Published: October 2013

Zn(O,S) is a promising candidate to replace the commonly used CdS buffer layer for Cu(In,Ga)Se2 (CIGS) thin‐film solar cells due to its non‐toxicity and its potential to enhance the conversion efficiency of the CIGS solar cell. The composition of chemical bath deposited (CBD) and sputtered Zn(O,S) layers with thicknesses well below 100 nm was determined by sputtered neutral and secondary ion mass spectrometry (SNMS and SIMS). Despite numerous mass interferences of double‐charged atoms and dimers with single Zn, O and S isotopes, we developed an evaluation algorithm for quantification of SNMS depth profiles of Zn(O,S) layers. In particular, the superposition of double‐charged S and Zn atoms with O and S isotopes is accounted for numerically in the quantification procedure. For sputtered Zn(O,S) layers, the S/(S + O) atomic ratio and the vertical composition profile can be controlled by the O2 content in the gas flow and the substrate temperature during sputtering whereas for CBD Zn(O,S) the S/(S + O) ratio is constant around 0.7–0.8. A Cu‐depleted layer of about 5 nm on the CIGS surface after buffer deposition was observed for both preparation methods. With negative SIMS, we found more hydroxides and carbon residues in CBD Zn(O,S) as compared to sputtered layers. Best cell performance with sputtered Zn(O,S) layers was achieved for S/(S + O) ratios of 0.25–0.40, yielding efficiencies up to 13%. Our solar cells with CBD Zn(O,S) buffers exhibit higher efficiencies due to an improved open‐circuit voltage. Copyright © 2013 John Wiley & Sons, Ltd.
C K‐edge NEXAFS study of fluorocarbon formation on carbon anodes in molten NaF–AlF3–CaF2
Authors: Haverkamp Richard G. , Cowie Bruce C. C.
Published: October 2013

Operational instability from processes occurring at the anode during the production of aluminum in the commercial Hall‐Héroult process may lead to an increase in undesirable fluorocarbon emissions, higher energy use, and shorter plant life. One contribution to this instability may be the possible formation of a fluorocarbon film at the electrode interface. Here, the surface composition of graphite anodes after electrolysis in molten NaF–AlF3–CaF2 at 990 °C is investigated for evidence of fluorocarbon formation using C K‐edge near edge X‐ray absorption fine structure. Fluorocarbon is identified on an anode surface after prolonged anode effect (very high overpotential with increased cell resistance) and also on an anode surface after normal electrolysis without anode effect. This provides evidence that fluorocarbon formation may occur prior to anode effect lowering the surface tension of the anode and therefore resulting in dewetting to contribute to the onset of the anode effect. Confirmation that such compounds form furthers our understanding of electrochemical reactions of graphite with fluoride and of the fundamental processes that occur in an aluminum smelter cell. Copyright © 2013 John Wiley & Sons, Ltd.
Regression analysis of multivariate current status data with dependent censoring: application to ankylosing spondylitis data
Authors: Chen Chyong‐Mei , Wei James Cheng‐Chung , Hsu Chao‐Min , Lee Ming‐Yung
Published: October 2013

Multivariate current‐status failure time data consist of several possibly related event times of interest, in which the status of each event is determined at a single examination time. If the examination time is intrinsically related to the event times, the examination is referred to as dependent censoring and needs to be taken into account. Such data often occur in clinical studies and animal carcinogenicity experiments. To accommodate for possible dependent censoring, this paper proposes a joint frailty model for event times and dependent censoring time. We develop a likelihood approach using Gaussian quadrature techniques for obtaining maximum likelihood estimates. We conduct extensive simulation studies for investigating finite‐sample properties of the proposed method. We illustrate the proposed method with an analysis of patients with ankylosing spondylitis, where the examination time may be dependent on the event times of interest. Copyright © 2013 John Wiley & Sons, Ltd.
A model for repeated clustered data with informative cluster sizes
Authors: Iosif Ana‐Maria , Sampson Allan R.
Published: October 2013

Many chronic diseases or health conditions manifest with recurring episodes, each of which can be characterized by a measure of intensity or severity. Both the number of episodes and the severity of each episode can depend on the latent severity of an individual's underlying condition. Data such as this are commonly gathered repeatedly at fixed follow‐up intervals. An example is a study of the association between stressful life events and the onset of depression. Stress exposure is assessed through the frequency and intensity of stressful life events occurring each month. Both the number of events and the intensity of each event at each measurement occasion are informative about the underlying severity of stress over time. One might hypothesize that people that approach the onset of a depressive episode have worse stress profiles than the controls, reflected by both more frequent and more intense stressors. We propose models to analyze data collected repeatedly on both the frequency of an event and its severity when both of these are informative about the underlying latent severity. Maximum likelihood estimators are developed, and simulations with small to moderate sample sizes show that the estimators also have good finite sample properties, and they are robust against misspecification of the model. This method is applied to a psychiatric data set. Copyright © 2013 John Wiley & Sons, Ltd.
An introduction with medical applications to functional data analysis
Authors: Sørensen Helle , Goldsmith Jeff , Sangalli Laura M.
Published: October 2013

Functional data are data that can be represented by suitable functions, such as curves (potentially multi‐dimensional) or surfaces. This paper gives an introduction to some basic but important techniques for the analysis of such data, and we apply the techniques to two datasets from biomedicine. One dataset is about white matter structures in the brain in multiple sclerosis patients; the other dataset is about three‐dimensional vascular geometries collected for the study of cerebral aneurysms. The techniques described are smoothing, alignment, principal component analysis, and regression. Copyright © 2013 John Wiley & Sons, Ltd.
Variance reduction in randomised trials by inverse probability weighting using the propensity score
Authors: Williamson Elizabeth J. , Forbes Andrew , White Ian R.
Published: October 2013

In individually randomised controlled trials, adjustment for baseline characteristics is often undertaken to increase precision of the treatment effect estimate. This is usually performed using covariate adjustment in outcome regression models. An alternative method of adjustment is to use inverse probability‐of‐treatment weighting (IPTW), on the basis of estimated propensity scores. We calculate the large‐sample marginal variance of IPTW estimators of the mean difference for continuous outcomes, and risk difference, risk ratio or odds ratio for binary outcomes. We show that IPTW adjustment always increases the precision of the treatment effect estimate. For continuous outcomes, we demonstrate that the IPTW estimator has the same large‐sample marginal variance as the standard analysis of covariance estimator. However, ignoring the estimation of the propensity score in the calculation of the variance leads to the erroneous conclusion that the IPTW treatment effect estimator has the same variance as an unadjusted estimator; thus, it is important to use a variance estimator that correctly takes into account the estimation of the propensity score. The IPTW approach has particular advantages when estimating risk differences or risk ratios. In this case, non‐convergence of covariate‐adjusted outcome regression models frequently occurs. Such problems can be circumvented by using the IPTW adjustment approach. © 2013 The authors. Statistics in Medicine published by John Wiley & Sons, Ltd.
Phase I design for completely or partially ordered treatment schedules
Authors: Wages Nolan A. , O'Quigley John , Conaway Mark R.
Published: October 2013

The majority of methods for the design of phase I trials in oncology are based upon a single course of therapy, yet in actual practice, it may be the case that there is more than one treatment schedule for any given dose. Therefore, the probability of observing a dose‐limiting toxicity may depend upon both the total amount of the dose given, as well as the frequency with which it is administered. The objective of the study then becomes to find an acceptable combination of both dose and schedule. Past literature on designing these trials has entailed the assumption that toxicity increases monotonically with both dose and schedule. In this article, we relax this assumption for schedules and present a dose‐schedule finding design that can be generalized to situations in which we know the ordering between all schedules and those in which we do not. We present simulation results that compare our method with other suggested dose‐schedule finding methodology. Copyright © 2013 John Wiley & Sons, Ltd.
Semiparametric Bayesian joint modeling of a binary and continuous outcome with applications in toxicological risk assessment
Authors: Hwang Beom Seuk , Pennell Michael L.
Published: October 2013

Many dose–response studies collect data on correlated outcomes. For example, in developmental toxicity studies, uterine weight and presence of malformed pups are measured on the same dam. Joint modeling can result in more efficient inferences than independent models for each outcome. Most methods for joint modeling assume standard parametric response distributions. However, in toxicity studies, it is possible that response distributions vary in location and shape with dose, which may not be easily captured by standard models. To address this issue, we propose a semiparametric Bayesian joint model for a binary and continuous response. In our model, a kernel stick‐breaking process prior is assigned to the distribution of a random effect shared across outcomes, which allows flexible changes in distribution shape with dose shared across outcomes. The model also includes outcome‐specific fixed effects to allow different location effects. In simulation studies, we found that the proposed model provides accurate estimates of toxicological risk when the data do not satisfy assumptions of standard parametric models. We apply our method to data from a developmental toxicity study of ethylene glycol diethyl ether. Copyright © 2013 John Wiley & Sons, Ltd.
An analytic method for the placebo‐based pattern‐mixture model
Authors: Lu Kaifeng
Published: October 2013

Pattern‐mixture models provide a general and flexible framework for sensitivity analyses of nonignorable missing data. The placebo‐based pattern‐mixture model (Little and Yau, Biometrics 1996; 52:1324–1333) treats missing data in a transparent and clinically interpretable manner and has been used as sensitivity analysis for monotone missing data in longitudinal studies. The standard multiple imputation approach (Rubin, Multiple Imputation for Nonresponse in Surveys, 1987) is often used to implement the placebo‐based pattern‐mixture model. We show that Rubin's variance estimate of the multiple imputation estimator of treatment effect can be overly conservative in this setting. As an alternative to multiple imputation, we derive an analytic expression of the treatment effect for the placebo‐based pattern‐mixture model and propose a posterior simulation or delta method for the inference about the treatment effect. Simulation studies demonstrate that the proposed methods provide consistent variance estimates and outperform the imputation methods in terms of power for the placebo‐based pattern‐mixture model. We illustrate the methods using data from a clinical study of major depressive disorders. Copyright © 2013 John Wiley & Sons, Ltd.
Creating Technological Boundaries to Protect Bedtime: Examining Work–Home Boundary Management, Psychological Detachment and Sleep
Authors: Barber Larissa K. , Jenkins Jade S.
Published: October 2013

This study examined the mechanism by which information and communication technology (ICT) use at home for work purposes may affect sleep. In this investigation, data from 315 employees were used to examine the indirect effect of ICT use at home on sleep outcomes through psychological detachment, and how boundary creation may moderate this effect. Results revealed the indirect effect of increased work–home boundary crossing on sleep (quantity, quality and consistency) through psychological detachment occurred only among individuals with low boundaries around ICT use and not among those with high boundaries. These results suggest that creating boundaries around work‐relevant ICT use while at home is beneficial to sleep as a recovery process through being able to psychologically disengage from work. Copyright © 2013 John Wiley & Sons, Ltd.
Nanobodies and Nanocrystals: Highly Sensitive Quantum Dot‐Based Homogeneous FRET Immunoassay for Serum‐Based EGFR Detection
Authors: Wegner K. David , Lindén Stina , Jin Zongwen , Jennings Travis L. , Khoulati Rachid el , van Bergen en Henegouwen Paul M. P. , Hildebrandt Niko
Published: October 2013

Semiconductor quantum dot nanocrystals (QDs) for optical biosensing applications often contain thick polyethylene glycol (PEG)‐based coatings in order to retain the advantageous QD properties in biological media such as blood, serum or plasma. On the other hand, the application of QDs in Förster resonance energy transfer (FRET) immunoassays, one of the most sensitive and most common fluorescence‐based techniques for non‐competitive homogeneous biomarker diagnostics, is limited by such thick coatings due to the increased donor‐acceptor distance. In particular, the combination with large IgG antibodies usually leads to distances well beyond the common FRET range of approximately 1 to 10 nm. Herein, time‐gated detection of Tb‐to‐QD FRET for background suppression and an increased FRET range is combined with single domain antibodies (or nanobodies) for a reduced distance in order to realize highly sensitive QD‐based FRET immunoassays. The “(nano)2” immunoassay (combination of nanocrystals and nanobodies) is performed on a commercial clinical fluorescence plate reader and provides sub‐nanomolar (few ng/mL) detection limits of soluble epidermal growth factor receptor (EGFR) in 50 μL buffer or serum samples. Apart from the first demonstration of using nanobodies for FRET‐based immunoassays, the extremely low and clinically relevant detection limits of EGFR demonstrate the direct applicability of the (nano)2‐ assay to fast and sensitive biomarker detection in clinical diagnostics.
Comparing text‐based and dependence‐based approaches for determining the origins of bugs
Authors: Davies Steven , Roper Marc , Wood Murray
Published: October 2013

Identifying bug origins – the point where erroneous code was introduced – is crucial for many software engineering activities, from identifying process weaknesses to gathering data to support bug detection tools. Unfortunately, this information is not usually recorded when fixing bugs, and recovering it later is challenging. Recently, the text approach and the dependence approach have been developed to tackle this problem. Respectively, they examine textual and dependence‐related changes that occurred prior to a bug fix. However, only limited evaluation has been carried out, partially because of a lack of available implementations and of datasets linking bugs to origins. To address this, origins of 174 bugs in three projects were manually identified and compared to a simulation of the approaches. Both approaches were partially successful across a variety of bugs – achieving 29–79% precision and 40–70% recall. Results suggested the precise definition of program dependence could affect performance, as could whether the approaches identified a single or multiple origins. Some potential improvements are explored in detail and identify pragmatic strategies for combining techniques along with simple modifications. Even after adopting these improvements, there remain many challenges: large commits, unrelated changes and long periods between origins and fixes all reduce effectiveness. Copyright © 2013 John Wiley & Sons, Ltd.
FaultTracer: a spectrum‐based approach to localizing failure‐inducing program edits
Authors: Zhang Lingming , Kim Miryung , Khurshid Sarfraz
Published: October 2013

Detecting faults in evolving systems is important. Change impact analysis has been shown to be effective for finding faults during software evolution. For example, Chianti represents program edits as atomic changes, selects affected tests, and determines a subset of affecting changes that might have caused test failures. However, the number of affecting changes related to each test failure in practice may still be overwhelming for manual inspection. In this paper, we present a novel approach, FaultTracer, which ranks program edits according to their suspiciousness to reduce developer effort in manually inspecting affecting changes. FaultTracer adapts spectrum‐based fault localization techniques, which assume the statements that are primarily executed by failed tests are more suspicious, and applies them in tandem with an enhanced change impact analysis to identify failure‐inducing edits more precisely. We conducted an experimental study using 23 real versions of four real‐world Java programs from the Software Infrastructure Repository. The experimental results show that FaultTracer localizes a real regression fault within top three atomic changes for 14 out of 22 studied real failures. When ranking only method‐level changes, compared to the existing ranking heuristic, FaultTracer reduces the number of changes to be manually inspected by more than 50% on the data set of real regression faults, and by more than 60% on the data set of seeded faults. The fault localization component of FaultTracer is 80% more effective than traditional spectrum‐based fault localization, and enables similar benefits when using either our enhanced change impact analysis or Chianti. The runtime overhead for FaultTracer to collect extended call graphs is 49.83 s for each subject on average and is only 8.26% more than that for Chianti to collect traditional call graph information. Copyright © 2013 John Wiley & Sons, Ltd.
A conceptual framework for SPI evaluation
Authors: Unterkalmsteiner Michael , Gorschek Tony , Islam A. K. M. Moinul , Cheng Chow Kian , Permadi Rahadian Bayu , Feldt Robert
Published: October 2013

Software Process Improvement (SPI) encompasses the analysis and modification of the processes within software development, aimed at improving key areas that contribute to the organizations' goals. The task of evaluating whether the selected improvement path meets these goals is challenging. On the basis of the results of a systematic literature review on SPI measurement and evaluation practices, we developed a framework (SPI Measurement and Evaluation Framework (SPI‐MEF)) that supports the planning and implementation of SPI evaluations. SPI‐MEF guides the practitioner in scoping the evaluation, determining measures, and performing the assessment. SPI‐MEF does not assume a specific approach to process improvement and can be integrated in existing measurement programs, refocusing the assessment on evaluating the improvement initiative's outcome. Sixteen industry and academic experts evaluated the framework's usability and capability to support practitioners, providing additional insights that were integrated in the application guidelines of the framework. Copyright © 2013 John Wiley & Sons, Ltd.
Using System Dynamics for Grand Challenges: The ESDMA Approach
Authors: Kwakkel Jan H. , Pruyt Erik
Published: October 2013

In this paper, we argue and show how system dynamics modelling can be combined with exploratory modelling and analysis in order to address grand societal challenges, which are almost without exception characterized by dynamic complexity and deep uncertainty. Addressing such issues requires the systematic exploration of different hypotheses related to model formulation and model parametrization and their effect on the kinds of behavioral dynamics that can occur. Through two cases, we illustrate the combination of system dynamics and exploratory modelling. The first case illustrates its use for discovering different types of dynamics related to metal and mineral scarcity. The second case illustrates its use for worst‐case discovery in water scarcity. We conclude that exploratory system dynamics modelling represents a promising approach for addressing deeply uncertain dynamically complex societal challenges. Copyright © 2013 John Wiley & Sons, Ltd.
Systemic Mediation: Moral Reasoning and Boundaries of Concern
Authors: Midgley Gerald , Pinzón Luis A.
Published: October 2013

This paper outlines a new systemic mediation approach, based on the idea that the most important thing for many participants in mediation is to have their moral reasoning understood and appreciated. This is frequently more important to people than financial reparation. We compare our mediation approach with others to demonstrate that many previous approaches share the assumption that once the interests of a participant have been identified, these should not be questioned. In contrast, our systemic mediation approach encourages participants to explore their own and other people's moral frameworks to enable critical reflection on their interests. Indeed, the concept of an ‘interest’ can be reframed as the boundary that a participant uses to delimit his or her concerns, and boundaries can be shifted in response to moral reasoning. Our mediation approach aims to generate both personal insights and improvements in mutual understanding. The mediator plays a facilitative role but cannot be neutral: the morality of the mediator unavoidably influences his or her facilitative interventions. Therefore, personal reflection by the mediator on his or her own moral framework is essential, so that its influences can be made visible and the facilitator can thereby be held accountable for them in dialogue with his or her peers. Tools are provided in our systemic mediation approach to support reflection on moral frameworks and boundaries of concern, and a practical example of their use in Colombian mediation practice is provided. Copyright © 2013 John Wiley & Sons, Ltd.
Rethinking Systems Thinking: Learning and Coevolving with the World
Authors: Ing David
Published: October 2013

Much of systems thinking, as commonly espoused today, was developed by a generation in the context of the 1950s–1980s. In the 2010s, has systems thinking changed with the world in which it is to be applied? Is systems thinking learning and coevolving with the world? Some contemporary systems thinkers continue to push the frontiers of theory, methods and practice. Others situationally increment the traditions of their preferred gurus, where approaches proven successful in prior experiences are replicated for new circumstances. Founded on interactions with a variety of systems communities over the past 15 years, three ways to rethink systems thinking are proposed:

‘parts and wholes’ snapshots → ‘learning and coevolving’ over time

social and ecological → emerged environments of the service economy and the Anthropocene

episteme and techne → phronesis for the living and nonliving

These proposed ways are neither exhaustive nor sufficient. The degree to which systems thinking should be rethought may itself be controversial. If, however, systems thinking is to be authentic, the changed world of the 21st century should lead systems thinkers to engage in a reflective inquiry. Copyright © 2013 John Wiley & Sons, Ltd.
Inhibition of EGFR Induces a c-MET-Driven Stem Cell Population in Glioblastoma
Authors: Jun Hyun Jung , Bronson Roderick T. , Charest Alain
Published: October 2013

Glioblastoma multiforme (GBM) is the most lethal form of primary brain tumors, characterized by highly invasive and aggressive tumors that are resistant to all current therapeutic options. GBMs are highly heterogeneous in nature and contain a small but highly tumorigenic and self-renewing population of stem or initiating cells (glioblastoma stem cells or GSCs). GSCs have been shown to contribute to tumor propagation and resistance to current therapeutic modalities. Recent studies of human GBMs have elucidated the genetic alterations common in these tumors, but much remains unknown about specific signaling pathways that regulate GSCs. Here we identify a distinct fraction of cells in a genetically engineered mouse model of EGFR-driven GBM that respond to anti-EGFR therapy by inducing high levels of c-MET expression. The MET-positive cells displayed clonogenic potential and long-term self-renewal ability in vitro and are capable of differentiating into multiple lineages. The MET-positive GBM cells are resistant to radiation and highly tumorigenic in vivo. Activation of MET signaling led to an increase in expression of the stemness transcriptional regulators Oct4, Nanog, and Klf4. Pharmacological inhibition of MET activity in GSCs prevented the activation of Oct4, Nanog, and Klf4 and potently abrogated stemness. Finally, the MET expressing cells were preferentially localized in perivascular regions of mouse tumors consistent with their function as GSCs. Together, our findings indicate that EGFR inhibition in GBM induces MET activation in GSCs, which is a functional requisite for GSCs activity and thus represents a promising therapeutic target. Stem Cells  2014;32:338–348
CCAAT/Enhancer-Binding ProteinβExpressed by Bone Marrow Mesenchymal Stromal Cells Regulates Early B-Cell Lymphopoiesis
Authors: Yoshioka Satoshi , Miura Yasuo , Yao Hisayuki , Satake Sakiko , Hayashi Yoshihiro , Tamura Akihiro , Hishita Terutoshi , Ichinohe Tatsuo , Hirai Hideyo , Takaor-Kondo Akifumi , Maekawa Taira
Published: October 2013

The transcription factor CCAAT/enhancer-binding protein β (C/EBPβ) regulates the differentiation of a variety of cell types. Here, the role of C/EBPβ expressed by bone marrow mesenchymal stromal cells (BMMSCs) in B-cell lymphopoiesis was examined. The size of the precursor B-cell population in bone marrow was reduced in C/EBPβ-knockout (KO) mice. When bone marrow cells from C/EBPβ-KO mice were transplanted into lethally irradiated wild-type (WT) mice, which provide a normal bone marrow microenvironment, the size of the precursor B-cell population was restored to a level equivalent to that generated by WT bone marrow cells. In coculture experiments, BMMSCs from C/EBPβ-KO mice did not support the differentiation of WT c-Kit+ Sca-1+ Lineage− hematopoietic stem cells (KSL cells) into precursor B cells, whereas BMMSCs from WT mice did. The impaired differentiation of KSL cells correlated with the reduced production of CXCL12/stromal cell-derived factor-1 by the cocultured C/EBPβ-deficient BMMSCs. The ability of C/EBPβ-deficient BMMSCs to undergo osteogenic and adipogenic differentiation was also defective. The survival of leukemic precursor B cells was poorer when they were cocultured with C/EBPβ-deficient BMMSCs than when they were cocultured with WT BMMSCs. These results indicate that C/EBPβ expressed by BMMSCs plays a crucial role in early B-cell lymphopoiesis. Stem Cells  2014;32:730–740
Spontaneous Reactivation of Clusters of X-Linked Genes Is Associated with the Plasticity of X-Inactivation in Mouse Trophoblast Stem Cells
Authors: Dubois Agnès , Deuve Jane Lynda , Navarro Pablo , Merzouk Sarra , Pichard Sylvain , Commere Pierre-Henri , Louise Anne , Arnaud Danielle , Avner Philip , Morey Céline
Published: October 2013

Random epigenetic silencing of the X-chromosome in somatic tissues of female mammals equalizes the dosage of X-linked genes between the sexes. Unlike this form of X-inactivation that is essentially irreversible, the imprinted inactivation of the paternal X, which characterizes mouse extra-embryonic tissues, appears highly unstable in the trophoblast giant cells of the placenta. Here, we wished to determine whether such instability is already present in placental progenitor cells prior to differentiation toward lineage-specific cell types. To this end, we analyzed the behavior of a GFP transgene on the paternal X both in vivo and in trophoblast stem (TS) cells derived from the trophectoderm of XXGFP blastocysts. Using single-cell studies, we show that not only the GFP transgene but also a large number of endogenous genes on the paternal X are subject to orchestrated cycles of reactivation/de novo inactivation in placental progenitor cells. This reversal of silencing is associated with local losses of histone H3 lysine 27 trimethylation extending over several adjacent genes and with the topological relocation of the hypomethylated loci outside of the nuclear compartment of the inactive X. The “reactivated” state is maintained through several cell divisions. Our study suggests that this type of “metastable epigenetic” states may underlie the plasticity of TS cells and predispose specific genes to relaxed regulation in specific subtypes of placental cells. Stem Cells  2014;32:377–390
Nanotubular Crosstalk with Distressed Cardiomyocytes Stimulates the Paracrine Repair Function of Mesenchymal Stem Cells
Authors: Figeac Florence , Lesault Pierre-François , Coz Olivier , Damy Thibaud , Souktani Richard , Trébeau Céline , Schmitt Alain , Ribot Jonathan , Mounier Rémi , Guguin Aurélie , Manier Céline , Surenaud Mathieu , Hittinger Luc , Dubois-Randé Jean-Luc , Rodriguez Anne-Marie
Published: October 2013

Mesenchymal stem cells (MSC) are known to repair broken heart tissues primarily through a paracrine fashion while emerging evidence indicate that MSC can communicate with cardiomyocytes (CM) through tunneling nanotubes (TNT). Nevertheless, no link has been so far established between these two processes. Here, we addressed whether cell-to-cell communication processes between MSC and suffering cardiomyocytes and more particularly those involving TNT control the MSC paracrine regenerative function. In the attempt to mimic in vitro an injured heart microenvironment, we developed a species mismatch coculture system consisting of terminally differentiated CM from mouse in a distressed state and human multipotent adipose derived stem cells (hMADS). In this setting, we found that crosstalk between hMADS and CM through TNT altered the secretion by hMADS of cardioprotective soluble factors such as VEGF, HGF, SDF-1α, and MCP-3 and thereby maximized the capacity of stem cells to promote angiogenesis and chemotaxis of bone marrow multipotent cells. Additionally, engraftment experiments into mouse infarcted hearts revealed that in vitro preconditioning of hMADS with cardiomyocytes increased the cell therapy efficacy of naïve stem cells. In particular, in comparison with hearts treated with stem cells alone, those treated with cocultured ones exhibited greater cardiac function recovery associated with higher angiogenesis and homing of bone marrow progenitor cells at the infarction site. In conclusion, our findings established the first relationship between the paracrine regenerative action of MSC and the nanotubular crosstalk with CM and emphasize that ex vivo manipulation of these communication processes might be of interest for optimizing current cardiac cell therapies. Stem Cells  2014;32:216–230
Pax6 Mediates ß-Catenin Signaling for Self-Renewal and Neurogenesis by Neocortical Radial Glial Stem Cells
Authors: Gan Qini , Lee Albert , Suzuki Ryusuke , Yamagami Takashi , Stokes Arjun , Nguyen Bao Chau , Pleasure David , Wang Junjiang , Chen Hong-Wu , Zhou Chengji J.
Published: October 2013

The Wnt/ß-catenin pathway is a critical stem cell regulator and plays important roles in neuroepithelial cells during early gestation. However, the role of Wnt/ß-catenin signaling in radial glia, a major neural stem cell population expanded by midgestation, remains poorly understood. This study shows that genetic ablation of ß-catenin with hGFAP-Cre mice inhibits neocortical formation by disrupting radial glial development. Reduced radial glia and intermediate progenitors are found in the ß-catenin-deficient neocortex during late gestation. Increased apoptosis and divergent localization of radial glia in the subventricular zone are also observed in the mutant neocortex. In vivo and in vitro proliferation and neurogenesis as well as oligodendrogenesis by cortical radial glia or by dissociated neural stem cells are significantly defective in the mutants. Neocortical layer patterning is not apparently altered, while astrogliogenesis is ectopically increased in the mutants. At the molecular level, the expression of the transcription factor Pax6 is dramatically diminished in the cortical radial glia and the sphere-forming neural stem cells of ß-catenin-deficient mutants. Chromatin immunoprecipitation and luciferase assays demonstrate that ß-catenin/Tcf complex binds to Pax6 promoter and induces its transcriptional activities. The forced expression of Pax6 through lentiviral transduction partially rescues the defective proliferation and neurogenesis by ß-catenin-deficient neural stem cells. Thus, Pax6 is a novel downstream target of the Wnt/ß-catenin pathway, and ß-catenin/Pax6 signaling plays critical roles in self-renewal and neurogenesis of radial glia/neural stem cells during neocortical development. Stem Cells  2014;32:45–58