bluuebunny/crossref_metadata_2025 huggingface dataset:
Transplant tourism versus proper travel for transplantation
Authors: Gill John S. , Delmonico Francis L.
Published: October 2015

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Multitarget Strategy to Address Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and Computational Studies of Coumarin‐Based Derivatives
Authors: Montanari Serena , Bartolini Manuela , Neviani Paolo , Belluti Federica , Gobbi Silvia , Pruccoli Letizia , Tarozzi Andrea , Falchi Federico , Andrisano Vincenza , Miszta Przemysław , Cavalli Andrea , Filipek Sławomir , Bisi Alessandra , Rampa Angela
Published: October 2015

Alzheimer's disease (AD) is a major public health challenge that faces an aging global population. Current drug treatment has demonstrated only symptomatic efficacy, leaving an unmet medical need for a new generation of disease‐modifying therapies. Following the multitarget‐directed ligand approach, a small library of coumarin‐based derivatives was designed and synthesized as a follow‐up to our studies on AP2238, aimed at expanding its biological profile. The coumarin substitution pattern at the 6‐ or 7‐position was modified by introducing alkyl chains of variable lengths and with different terminal amino functional groups. 3‐(4‐{[Benzyl(ethyl)amino]methyl}phenyl)‐6‐({5‐[(7‐methoxy‐6H‐indeno[2,1‐b]quinolin‐11‐yl)amino]pentyl}oxy)‐2H‐chromen‐2‐one, bearing the bulkiest amine, emerged as a non‐neurotoxic dual acetylcholinesterase (AChE)/butyrylcholinesterase (BuChE) inhibitor, potentially suitable for the treatment of the middle stage of AD. Furthermore, the introduction of a diethylamino spacer, as in 3‐(4‐{[benzyl(ethyl)amino]methyl}phenyl)‐6‐{[5‐(diethylamino)pentyl]oxy}‐2H‐chromen‐2‐one and 3‐(4‐{[benzyl(ethyl)amino]methyl}phenyl)‐7‐[4‐(diethylamino)butoxy]‐2H‐chromen‐2‐one, led to nanomolar human AChE inhibitors endowed with significant inhibitory activity toward Aβ42 self‐aggregation, whereas the reference compound was completely ineffective. Furthermore, 3‐(4‐{[benzyl(ethyl)amino]methyl}phenyl)‐7‐[4‐(diethylamino)butoxy]‐2H‐chromen‐2‐one also showed promising neuroprotective behavior, which makes it a potential candidate for development into a disease‐modifying agent.
We Need 2C but Not 2B: Developing Serotonin 2C (5‐HT2C) Receptor Agonists for the Treatment of CNS Disorders
Authors: Cheng Jianjun , Kozikowski Alan P.
Published: October 2015

The serotonin 2C (5‐HT2C) receptor has been identified as a potential drug target for the treatment of a variety of central nervous system (CNS) disorders, such as obesity, substance abuse, and schizophrenia. In this Viewpoint article, recent progress in developing selective 5‐HT2C agonists for use in treating these disorders is summarized, including the work of our group. Challenges in this field and the possible future directions are described. Homology modeling as a method to predict the binding modes of 5‐HT2C ligands to the receptor is also discussed. Compared to known ligands, the improved pharmacological profiles of the 2‐phenylcyclopropylmethylamine‐based 5‐HT2C agonists make them preferred candidates for further studies.
Dual‐Responsive Mechanized Mesoporous Silica Nanoparticles Based on Sulfonatocalixarene Supramolecular Switches
Authors: Zhou Ting , Song Nan , Xu Shi‐Han , Dong Biao , Yang Ying‐Wei
Published: October 2015

Mesoporous silica nanoparticles (MSNs) have been functionalized with supramolecular switches, composed of cleavable disulfide bond‐containing alkylammonium stalks encircled by water‐soluble sulfonatocalix[4,6]arenes, to result in smart mechanized MSNs. Cargo can be encased tightly in the nanopores of these mechanized MSNs in their closed state, but are released efficiently either in response to L‐glutathione (GSH), by cleaving the disulfide bonds in the stalks, or in response to pH variation, by turning on the calixarene‐based supramolecular switches. The higher concentration of GSH in cancer cell cytosol and the relatively lower pH value of cancer cell lysosome can simultaneously activate the mechanized MSNs, enabling them to release the pre‐loaded cargo in place. This sufficient use of the different environment of cancer cells and normal healthy cells can enhance the targeting effect of delivery vehicles and effectively lower the side effects of delivered anti‐cancer drugs. In vitro cytotoxicity tests suggest good biocompatibility and low toxicity of these newly developed drug‐delivery systems.
Electron Density Analysis of Hyperconjugation
Authors: Azami S. M.
Published: October 2015

Hyperconjugation is analyzed through the electron density of orbitals responsible for hyperconjugative interactions, which cannot be detected by means of conventional electron‐density‐based calculations. This interaction is detected through the π electron density topology, by excluding σ electron density from the total. As the presence of the hyperconjugation phenomenon in carbocation systems is well understood, several carbocations are benchmarked, and the results show that the positive carbon atom establishes a hyperconjugative critical point with the adjacent methyl group(s). Also, π localization and delocalization indices are employed to support the conclusions made by the topological analysis.
Lignin Modification for Biopolymer/Conjugated Polymer Hybrids as Renewable Energy Storage Materials
Authors: Nilsson Ting Yang , Wagner Michal , Inganäs Olle
Published: October 2015

Lignin derivatives, which arise as waste products from the pulp and paper industry and are mainly used for heating, can be used as charge storage materials. The charge storage function is a result of the quinone groups formed in the lignin derivative. Herein, we modified lignins to enhance the density of such quinone groups by covalently linking monolignols and quinones through phenolation. The extra guaiacyl, syringyl, and hydroquinone groups introduced by phenolation of kraft lignin derivatives were monitored by 31P nuclear magnetic resonance and size exclusion chromatography. Electropolymerization in ethylene glycol/tetraethylammonium tosylate electrolyte was used to synthesize the kraft lignin/polypyrrole hybrid films. These modifications changed the phenolic content of the kraft lignin with attachment of hydroquinone units yielding the highest specific capacity (around 70 mA h g−1). The modification of softwood and hardwood lignin derivatives yielded 50 % and 23 % higher charge capacity than the original lignin, respectively.
Infant and adult pupil dilation in response to unexpected sounds
Authors: Wetzel Nicole , Buttelmann David , Schieler Andy , Widmann Andreas
Published: October 2015

Surprisingly occurring sounds outside the focus of attention can involuntarily capture attention. This study focuses on the impact of deviant sounds on the pupil size as a marker of auditory involuntary attention in infants. We presented an oddball paradigm including four types of deviant sounds within a sequence of repeated standard sounds to 14‐month‐old infants and to adults. Environmental and noise deviant sounds elicited a strong pupil dilation response (PDR) in both age groups. In contrast, moderate frequency deviants elicited a significant PDR in adults only. Moreover, a principal component analysis revealed two components underlying the PDR. Component scores differ, depending on deviant types, between age groups. Results indicate age effects of parasympathetic inhibition and sympathetic activation of the pupil size caused by deviant sounds with a high arousing potential. Results demonstrate that the PDR is a sensitive tool for the investigation of involuntary attention to sounds in preverbal children. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 58: 382–392, 2016.
The past, present, and future of basal insulins
Authors: Pettus Jeremy , Santos Cavaiola Tricia , Tamborlane William V. , Edelman Steven
Published: October 2015

Insulin production by the pancreas follows a basic pattern where basal levels of insulin are secreted during fasting periods, with prandial increases in insulin associated with food ingestion. The aim of insulin therapy in patients with diabetes is to match the endogenous pattern of insulin secretion as closely as possible without causing hypoglycaemia. There are several optimal pharmacokinetic and pharmacodynamic properties of long‐acting basal insulins that can help to achieve this aim, namely, as follows: activity that is flat and as free of peaks as possible, a duration of action of ≥24‐h, and as little day‐to‐day variation as possible. The long‐acting basal insulins are a fundamental therapy for patients with type 1 and type 2 diabetes, and those that are currently available have many benefits; however, the development of even longer‐acting insulins and improved insulin delivery techniques may lead to better glycemic control for patients in the future. Established long‐acting basal insulins available in the United States and Europe include insulin glargine 100 units/mL and insulin detemir, both of which exhibit similar glycemic control to that of the intermediate‐acting neutral protamine Hagedorn insulin, but with a reduction in hypoglycaemia. Newer insulin products available include new insulin glargine 300 units/mL (United States and Europe) and the ultra‐long‐acting insulin degludec (Europe) with basal insulin peglispro currently in development. These new insulins demonstrate different pharmacokinetic/pharmacodynamic profiles and longer durations of action (>24 h) compared with insulin glargine 100 units/mL, which may lead to potential benefits. The introduction of biosimilar insulins may also broaden access to insulins by reducing treatment costs. Copyright © 2015 John Wiley & Sons, Ltd.
Valproic acid stimulates proliferation of glial precursors during cortical gliogenesis in developing rat
Authors: Lee Hee Jae , Dreyfus Cheryl , DiCicco‐Bloom Emanuel
Published: October 2015

Valproic acid (VPA) is a neurotherapeutic drug prescribed for seizures, bipolar disorder, and migraine, including women of reproductive age. VPA is a well‐known teratogen that produces congenital malformations in many organs including the nervous system, as well as later neurodevelopmental disorders, including mental retardation and autism. In developing brain, few studies have examined VPA effects on glial cells, particularly astrocytes. To investigate effects on primary glial precursors, we developed new cell culture and in vivo models using frontal cerebral cortex of postnatal day (P2) rat. In vitro, VPA exposure elicited dose‐dependent, biphasic effects on DNA synthesis and proliferation. In vivo VPA (300 mg/kg) exposure from P2 to P4 increased both DNA synthesis and cell proliferation, affecting primarily astrocyte precursors, as >75% of mitotic cells expressed brain lipid‐binding protein. Significantly, the consequence of early VPA exposure was increased astrocytes, as both S100‐β+ cells and glial fibrillary acidic protein were increased in adolescent brain. Molecularly, VPA served as an HDAC inhibitor in vitro and in vivo as enhanced proliferation was accompanied by increased histone acetylation, whereas it elicited changes in culture in cell‐cycle regulators, including cyclin D1 and E, and cyclin‐dependent kinase (CDK) inhibitors, p21 and p27. Collectively, these data suggest clinically relevant VPA exposures stimulate glial precursor proliferation, though at higher doses can elicit inhibition through differential regulation of CDK inhibitors. Because changes in glial cell functions are proposed as mechanisms contributing to neuropsychiatric disorders, these observations suggest that VPA teratogenic actions may be mediated through changes in astrocyte generation during development. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 780–798, 2016
Scabrous overexpression in the eye affects R3/R4 cell fate specification and inhibits notch signaling
Authors: Muñoz‐Soriano Verónica , Santos Diego , Durupt Fabrice C. , Casani Sandra , Paricio Nuria
Published: October 2015

Background: Planar cell polarity (PCP) in the Drosophila eye is generated when immature ommatidial preclusters acquire opposite chirality in the dorsal and ventral halves of the eye imaginal disc and rotate 90 ° toward the equator. The scabrous (sca) gene is involved in R8 differentiation and in the correct spacing of ommatidial clusters in eye imaginal discs, but it was also suggested to be required during ommatidial rotation. However, no clear relationships between sca and other genes involved in the process were established. Results: To explore the role of Sca in PCP establishment, we performed an RNAi‐based modifier genetic screen using the rough eye phenotype of sca‐overexpressing flies. We found that sca overexpression mainly affects R3/R4 cell specification as it was reported in Notch mutants. Of the 86 modifiers identified in the screen, genes encoding components of Notch signaling and proteins involved in intracellular transport were of particular interest. Conclusions: These and other results obtained with a reporter line of Notch activity indicate that sca overexpression antagonizes Notch signaling in the Drosophila eye, and are inconsistent with Sca being an ommatidial rotation‐specific factor. We also found that microtubule motors and other proteins involved in intracellular transport are related with Sca function. Developmental Dynamics 245:166–174, 2016. © 2015 Wiley Periodicals, Inc.
From actomyosin oscillations to tissue‐level deformations
Authors: Gorfinkiel Nicole
Published: October 2015

Pulsatile actomyosin contractility driving cell shape oscillations is a common feature of actomyosin networks present in a variety of tissues undergoing morphogenetic processes. The origin of this oscillatory dynamics, how it is stabilized over time to give rise to net cell shape changes and how it is spatially coordinated across a tissue, are questions that have being extensively investigated in recent years. In this work, I review how genetics, cell biology, and quantitative and theoretical approaches have started to give a comprehensive understanding of these problems revealing that both biochemical and mechanical regulation play an important role in the emergence, coordination and stabilization of this activity. Developmental Dynamics 245:268–275, 2016. © 2015 Wiley Periodicals, Inc.
Growth–climate relationships across topographic gradients in the northern Great Lakes
Authors: Dymond S. F. , D'Amato A. W. , Kolka R. K. , Bolstad P. V. , Sebestyen S. D. , Bradford J. B.
Published: October 2015

Climatic conditions exert important control over the growth, productivity, and distribution of forests, and characterizing these relationships is essential for understanding how forest ecosystems will respond to climate change. We used dendrochronological methods to develop climate–growth relationships for two dominant species, Populus tremuloides (quaking aspen) and Pinus resinosa (red pine), in the upper Great Lakes region to understand how climate and water availability influence annual forest productivity. Trees were sampled along a topographic gradient at the Marcell Experimental Forest (Minnesota, USA) to assess growth response to variations in temperature and different water availability metrics (precipitation, potential evapotranspiration (PET), cumulative moisture index (CMI), and soil water storage). Climatic variables were able to explain 33–58% of the variation in annual growth (as measured by ring‐width increment) for quaking aspen and 37–74% of the variation for red pine. Climate–growth relationships were influenced by topography for quaking aspen but not for red pine. Annual ring growth for quaking aspen decreased with June CMI on ridges, decreased with temperature in the November prior to the growing season on sideslopes, and decreased with June PET on toeslopes. Red pine growth increased with increasing July PET across all topographic positions. These results indicate the sensitivity of both quaking aspen and red pine to local climate and show several vulnerabilities of these species to shifts in water supply and temperature because of climate change. Copyright © 2015 John Wiley & Sons, Ltd.
Incidence of heart failure in 6083 elderly hypertensive patients: the Second Australian National Blood Pressure Study (ANBP2)
Authors: Sahle Berhe W. , Owen Alice J. , Krum Henry , Reid Christopher M. ,   on behalf of the Second Australian National Blood Pressure Study Management Committee
Published: October 2015

Aims

Hypertension is a known risk factor for the development of heart failure (HF); however, few data are available on the magnitude of short‐ and long‐term progression from hypertension to HF. The present study aims to determine the short‐ and long‐term incidence of HF, and identify factors associated with onset of HF in elderly hypertensive patients.

Methods and results

The incidence of HF was measured in 6083 hypertensive patients, in the Second Australian National Blood Pressure Study (ANBP2), followed for a median of 10.8 years (4.1 years during the trial and 6.7 years during post‐trial follow‐up). A total of 373 cases of HF were identified over 59 581 person‐years of follow‐up (PY). The overall cumulative incidence of HF was 6.26 per 1000 PY; 5.33 per 1000 PY during the ANBP2 clinical trial and 7.04 per 1000 PY during the post‐trial follow‐up. HF was 63% higher among men [incidence rate ratios (IRR) 1.63, P < 0.01]. Older age, male sex, obesity, and history of cardiovascular disease independently predicted HF during both the short‐ and long‐term follow‐up. In addition, diabetes and smoking were associated with onset of HF in the short‐term follow‐up, and higher systolic blood pressure in the long‐term follow‐up. Median survival following diagnosis with HF was 3.94 years, and women (6.06 years) had a survival advantage over men (3.32 years).

Conclusion

Heart failure is a frequent long‐term outcome in treated elderly hypertensive patients. Development of HF was predicted by patient characteristics and co‐morbidities, with the effect of some predictors varying over the short‐ and long‐term follow‐up.
Immunoactivation induced by chronic viral infection inhibits viral replication and drives immunosuppression through sustained IFN‐I responses
Authors: Honke Nadine , Shaabani Namir , Merches Katja , Gassa Asmae , Kraft Anke , Ehrhardt Katrin , Häussinger Dieter , Löhning Max , Dittmer Ulf , Hengel Hartmut , Recher Mike , Lang Philipp A. , Lang Karl S.
Published: October 2015

Acute or chronic viral infections can lead to generalized immunosuppression. Several mechanisms, such as immunopathology of CD8+ T cells, inhibitory receptors, or regulatory T (Treg) cells, contribute to immune dysfunction. Moreover, patients with chronic viral infections usually do not respond to vaccination, a finding that has not been previously explained. Recently, we reported that CD169+ macrophages enforce viral replication, which is essential for guaranteeing antigen synthesis and efficient adaptive immune responses. In the present study, we used a chronic lymphocytic choriomeningitis virus infection mouse model to determine whether this mechanism is affected by chronic viral infection, which may impair the activation of adaptive immunity. We found that enforced viral replication of a superinfecting virus is completely blunted in chronically infected mice. This absence of enforced viral replication in CD169+ macrophages is not explained by CD8+ T‐cell‐mediated immunopathology but rather by prolonged IFN‐I responses. Consequently, the absence of viral replication impairs both antigen production and the adaptive immune response against the superinfecting virus. These findings indicate that chronic infection leads to sustained IFN‐I action, which is responsible for the absence of an antiviral immune response against a secondary viral infection.
Convenient Synthesis of Functionalized 6‐Styryl‐1,4,5,6‐tetrahydropyridines through a Domino [2+2+2] Cycloaddition Reaction
Authors: Zhang Jing , Yang Wen‐Juan , Sun Jing , Yan Chao‐Guo
Published: October 2015

The domino [2+2+2] cycloaddition reaction of α,β‐unsaturated N‐arylaldimines, dialkyl acetylenedicarboxylates, and arylidenemalononitriles in dry acetonitrile at room temperature afforded polysubstituted 6‐styryl‐1,4,5,6‐tetrahydropyridines in good yields with various cis/trans‐isomer ratios. The similar three‐component reaction that contains ethyl arylidenecyanoacetates or arylidenepivaloylacetonitriles also resulted in polysubstituted 6‐styryl‐1,4,5,6‐tetrahydropyridines, which can be separated into pure cis‐ and trans‐isomers. The stereochemistry of the obtained polysubstituted 1,4,5,6‐tetrahydropyridines is clearly elucidated on the basis of 1H NMR spectroscopy and single‐crystal structures.
Self‐Assembly of n‐Alkyl‐ and Aryl‐Side Chain Ureas and Their Derivatives as Evidenced by SEM and X‐ray Analysis
Authors: Kulikov Oleg V. , Siriwardane Dumindika A. , McCandless Gregory T. , Barnes Charles , Sevryugina Yulia V. , DeSousa Joseph D. , Wu Jingbo , Sommer Roger , Novak Bruce M.
Published: October 2015

A small library of ureas and related compounds was synthesized and examined by scanning electron microscopy (SEM), single‐crystal X‐ray diffraction, powder X‐ray (pXRD), and polarized optical microscopy (POM) techniques in order to elucidate the factors controlling their self‐assembly in the solid state. Inspection of the 12 solid‐state structures revealed that molecules in the crystal lattice are held together by intermolecular H‐bonding, π–π stacking as well as C‐H/π interactions. The same interactions are likely responsible for the formation of supramolecular aggregates (e.g. sheet‐like assemblies, micro‐ and nano‐fibers, and the porous networks easily identifiable by SEM technique) and in certain cases led to the small molecules gelation.
Application of a Monte‐Carlo simulation approach for the probabilistic assessment of seismic hazard for geographically distributed portfolio
Authors: Akkar Sinan , Cheng Yin
Published: October 2015

The conventional integral approach is very well established in probabilistic seismic hazard assessment (PSHA). However, Monte‐Carlo (MC) simulations can become an efficient and flexible alternative against conventional PSHA when more complicated factors (e.g. spatial correlation of ground shaking) are involved. This study aims at showing the implementation of MC simulation techniques for computing the annual exceedance rates of dynamic ground‐motion intensity measures (GMIMs) (e.g. peak ground acceleration and spectral acceleration). We use multi‐scale random field technique to incorporate spatial correlation and near‐fault directivity while generating MC simulations to assess the probabilistic seismic hazard of dynamic GMIMs. Our approach is capable of producing conditional hazard curves as well. We show various examples to illustrate the potential use of the proposed procedures in the hazard and risk assessment of geographically distributed structural systems. Copyright © 2015 John Wiley & Sons, Ltd.
Using biofilms for monitoring metal contamination in lotic ecosystems: The protective effects of hardness and pH on metal bioaccumulation
Authors: Leguay Sébastien , Lavoie Isabelle , Levy Jacqueline L. , Fortin Claude
Published: October 2015

Biofilms can make good bioindicators and biomarkers, offering a convenient tool to monitor metal contamination in streams that results from mine tailing sites. Biofilm metal content (Cu, Zn, Cd, Pb) as well as diatom diversity and the presence of teratologies (diatom abnormalities) were determined for biofilms from rivers with a variety of physicochemical properties across a metal contamination gradient. The results of metal accumulation were highly consistent from year to year, with significant relationships between calculated free metal ion concentrations and biofilm metal contents for samples from different rivers. This indicates the “universal nature” of the metal accumulation process in biofilms. The authors observed that protons and major cations protected against metal accumulation. A very low number of diatom taxa were found at the most contaminated sites, and the highest proportions of deformities were observed at these sites. However, it was difficult to distinguish the effect of metal contamination from the effect of other parameters, especially pH. The results suggest that the development of biofilm-based proxies for metal bioavailability is useful and that incorporation of the effects of hardness and pH in this metal contamination monitoring tool is important. Environ Toxicol Chem 2016;35:1489–1501. © 2015 SETAC
Impacts of 2,4-dichlorophenoxyacetic acid aquatic herbicide formulations on reproduction and development of the fathead minnow (Pimephales promelas)
Authors: DeQuattro Zachary A. , Karasov William H.
Published: October 2015

The authors studied the effects of 2 formulations of 2,4-dichlorophenoxyacetic acid, dimethylamine salt (2,4-D) herbicide on fathead minnow reproduction, embryonic development, and larval survival. Groups of reproductively mature fathead minnows were exposed for 28 d to 0.00 ppm, 0.05 ppm, 0.50 ppm, and 2.00 ppm 2,4-D (target) in a flow-through system. Weedestroy® AM40 significantly (p ≤ 0.05) depressed male tubercle presence and significantly increased female gonadosomatic index, and there were statistical trends (0.05 ≤ p ≤ 0.10) for effects on fecundity and hepatic vitellogenin mRNA expression in females and males. The herbicide DMA® 4 IVM also significantly depressed male tubercle presence. Gonads of females exposed to DMA 4 IVM exhibited significantly depressed stage of oocyte maturation, significantly increased severity of oocyte atresia, and a significant presence of an unidentified tissue type. Also, DMA 4 IVM significantly decreased larval survival. It had no impact on hepatic vitellogenin mRNA expression or gonadosomatic index. No significant effects on fertilization, hatchability, or embryonic development were observed in either trial. The formulations tested exhibited different toxicological profiles from pure 2,4-D. These data suggest that the formulations have the potential for endocrine disruption and can exert some degree of chronic toxicity. The present use of 2,4-D formulations in lake management practices and their permitting based on the toxicological profile of 2,4-D pure compound should be reconsidered. Environ Toxicol Chem 2016;35:1478–1488. © 2015 SETAC
A new smoothness indicator for third‐order WENO scheme
Authors: Wu Xiaoshuai , Liang Jianhan , Zhao Yuxin
Published: October 2015

We present a new reference smoothness indicator for third‐order weighted essentially non‐oscillatory scheme to recover its design‐order convergence at critical points. This reference smoothness indicator, which involves both the candidate and global smoothness indicators in the weighted essentially non‐oscillatory framework, is devised according to a sufficient condition on the weights for third‐order convergence. The recovery of design‐order is verified by standard tests. Meanwhile, numerical results demonstrate that the present reference smoothness indicator produces sharper representation of the discontinuity owing to the combined effects of larger weight assignment to the discontinuous stencils and convergence rate recovery. Copyright © 2015 John Wiley & Sons, Ltd.
A consistent incompressible SPH method for internal flows with fixed and moving boundaries
Authors: Mamouri S. Jahangiri , Fatehi R. , Manzari M. T.
Published: October 2015

An improved incompressible smoothed particle hydrodynamics (ISPH) method is presented, which employs first‐order consistent discretization schemes both for the first‐order and second‐order spatial derivatives. A recently introduced wall boundary condition is implemented in the context of ISPH method, which does not rely on using dummy particles and, as a result, can be applied more efficiently and with less computational complexity. To assess the accuracy and computational efficiency of this improved ISPH method, a number of two‐dimensional incompressible laminar internal flow benchmark problems are solved and the results are compared with available analytical solutions and numerical data. It is shown that using smaller smoothing lengths, the proposed method can provide desirable accuracies with relatively less computational cost for two‐dimensional problems. Copyright © 2015 John Wiley & Sons, Ltd.
Sex‐specific associations between birth weight and adult primary liver cancer in a large cohort of Danish children
Authors: Zimmermann Esther , Berentzen Tina L. , Gamborg Michael , Sørensen Thorkild I. A. , Baker Jennifer L.
Published: October 2015

Whether the prenatal period is critical for the development of adult primary liver cancer (PLC) is sparsely investigated. Recently, attention has been drawn to potential sex‐differences in the early origins of adult disease. The association between birth weight and adult PLC, separately in men and women was investigated, using a large cohort of 217,227 children (51% boys), born from 1936 to 1980, from the Copenhagen School Health Records Register, and followed them until 2010 in national registers. Hazard ratios (95% confidence intervals) of PLC (30 years or older) were estimated by Cox regression models stratified by birth cohort. During 5.1 million person‐years of follow‐up, 185 men and 65 women developed PLC. Sex modified the association between birth weight and adult PLC (p values for interaction = 0.0005). Compared with a sex‐specific reference group of birth weights between 3.25 and 3.75 kg, men with birth weights between 2.00 and 3.25 kg and 3.75–5.50 kg, had HRs of 1.48 (1.06–2.05) and 0.85 (0.56–1.28), respectively. Among women the corresponding HRs were 1.71 (0.90–3.29) and 3.43 (1.73–6.82). Associations were similar for hepatocellular carcinoma only, across year of birth, and after accounting for diagnoses of alcohol‐related disorders, viral hepatitis and biliary cirrhosis. Prenatal exposures influenced the risk of adult PLC, and the effects at the high birth weight levels appeared to be sex‐specific. These findings underscore the importance of considering sex‐specific mechanisms in the early origins of adult PLC.
Genetic and epigenetic aberrations occurring in colorectal tumors associated with serrated pathway
Authors: Sakai Eiji , Fukuyo Masaki , Ohata Ken , Matsusaka Keisuke , Doi Noriteru , Mano Yasunobu , Takane Kiyoko , Abe Hiroyuki , Yagi Koichi , Matsuhashi Nobuyuki , Fukushima Junichi , Fukayama Masashi , Akagi Kiwamu , Aburatani Hiroyuki , Nakajima Atsushi , Kaneda Atsushi
Published: October 2015

To clarify molecular alterations in serrated pathway of colorectal cancer (CRC), we performed epigenetic and genetic analyses in sessile serrated adenoma/polyps (SSA/P), traditional serrated adenomas (TSAs) and high‐methylation CRC. The methylation levels of six Group‐1 and 14 Group‐2 markers, established in our previous studies, were analyzed quantitatively using pyrosequencing. Subsequently, we performed targeted exon sequencing analyses of 126 candidate driver genes and examined molecular alterations that are associated with cancer development. SSA/P showed high methylation levels of both Group‐1 and Group‐2 markers, frequent BRAF mutation and occurrence in proximal colon, which were features of high‐methylation CRC. But TSA showed low‐methylation levels of Group‐1 markers, less frequent BRAF mutation and occurrence at distal colon. SSA/P, but not TSA, is thus considered to be precursor of high‐methylation CRC. High‐methylation CRC had even higher methylation levels of some genes, e.g., MLH1, than SSA/P, and significant frequency of somatic mutations in nonsynonymous mutations (p < 0.0001) and insertion/deletions (p = 0.002). MLH1‐methylated SSA/P showed lower methylation level of MLH1 compared with high‐methylation CRC, and rarely accompanied silencing of MLH1 expression. The mutation frequencies were not different between MLH1‐methylated and MLH1‐unmethylated SSA/P, suggesting that MLH1 methylation might be insufficient in SSA/P to acquire a hypermutation phenotype. Mutations of mismatch repair genes, e.g., MSH3 and MSH6, and genes in PI3K, WNT, TGF‐β and BMP signaling (but not in TP53 signaling) were significantly involved in high‐methylation CRC compared with adenoma, suggesting importance of abrogation of these genes in serrated pathway.
Semantic‐based representation, enrichment and computation of product breakdown structures
Authors: Alvarez‐Rodríguez Jose María , Llorens Juan , Alejandres Manuela , Fuentes Jose Miguel
Published: October 2015

Product breakdown structures (PBS) are considered a cornerstone in the development of safety critical systems. In this context, the dramatic increase of the amount of applications, management platforms or services imply a tangled environment of data formats, models or protocols that prevent a proper re‐use of data and information resources. Recent times have seen the development of the Open Services for Lifecycle Collaboration (OSLC) initiative to exchange domain‐based knowledge under a common and shared data model (RDF) and to access services under web‐based protocols. The present paper introduces a method and a model to represent a PBS applying a profile‐based approach using RDF‐based vocabularies. Moreover, a hybrid method to validate data, information and structure of a PBS is also introduced. Finally, a case study is conducted to compare traditional PBS management methods to a Linked Data based PBS using the Analytical Hierarchy Process (AHP) and the Service Measurement Index (SMI).
Requirements Engineering for Control and Computing Systems at large research facilities: Process implementation and a case study
Authors: Friedrich Thilo , Reščič Miha , Törngren Martin
Published: October 2015

This paper explores the comprehensive implementation of requirements engineering processes in the controls and computing domain at large research facilities, made concrete in a case study on the world‐leading, accelerator‐based research facility for neutron science, the European Spallation Source (ESS). The implementation of requirements engineering establishes views (e.g. functional, data, hardware, etc.), informational structures, activity patterns, tools and services suitable for this domain. Adequate views and patterns for information related to requirements engineering need to be derived from the characteristics of the organizational environment, domain‐specific best practices, and target systems’ characteristics. All this forms the foundation for the design and application of requirements engineering activity patterns, tools and support services. Our key message is: For the successful deployment and operation of control and computing systems, a research facility needs to implement requirements engineering to provide views, informational structures, activity patterns, tools and services suitable to the domain. The RE implementation effort benefits from being managed as a multi‐faceted project itself, and has properties which render an Agile management approach beneficial.
On the Dynamics of Design of Future‐proof Systems
Authors: Rehman Obaid Ur , Ryan Michael J.
Published: October 2015

The ability to cope with uncertainty in the operation of a system is accounted for through appropriate bounds on the parameters set for the non‐functional requirements for the system. The ability to cater for changes throughout a long life, perhaps in a number of life cycles, is generally referred to as future‐proofing—that is, taking account in the current design of some aspect of the future use of the system such that, when the anticipated need does arise, the system will be prepared to some degree. The principal difference between design for uncertainty in non‐functional requirements and for uncertainty in future use is the time at which the system must be able to account for the uncertainty: on deployment for non‐functional requirements and at some time in the future for future‐proof design. This paper provides a brief preliminary investigation into the dynamics of design for uncertainty in non‐functional requirements (using robustness as an example) and for uncertainty in future‐proof design. Based on a simple model of system design and a definition of sufficiency in design and the notion of minimum sufficiency, we use design for robustness as an example of the design considerations required to address uncertainty in the non‐functional requirements of a system. Having addressed design for uncertainty required immediately on deployment of the system, we then show how design for future‐proofing of a system accommodates changes in future operations and support.
The Education Background of INCOSE Systems Engineering Professional Certification Program Applicants
Authors: Lipizzi Carlo , Manchanda Shipra , Kamil Monis , Pyster Art , Henry Deva , Hutchison Nicole , Hutchison Nicole , Barboza Christina , Wright Courtney
Published: October 2015

Helix is a multi‐year research project of the Systems Engineering Research Center (SERC) that is developing a theory of what makes those who perform systems engineering effective. To support that research, Helix is collecting data from a diverse set of systems engineers, others who perform some systems engineering activities but do not think of themselves as systems engineers, and those who work with systems engineers. Among the data sources available to Helix is the complete set of applications between 2004 and 2013 that were submitted to the INCOSE Systems Engineering Professional Certification Program. This paper reports on the education background of 2504 applicants and includes the number and types of university degrees and how the most popular degrees of applicants have changed over time. The applicants are very well educated, with almost 70% having an advanced college degree. With nearly three‐quarters of the applicants coming from the US, education from US universities dominates. At the bachelor level, classical engineering degrees dominate, but computer‐related majors are becoming increasingly popular. Two of the most popular masters degrees earned since 2000 are the Master of System Engineering and the Master of Business Administration.
Open Source Systems Engineering Guides, Deployment Packages and Support Tools for Very Small Enterprises ‐‐ A Case Study
Authors: Laporte Claude Y. , Houde Ronald
Published: October 2015

Very small entities (VSEs) play an increasingly important role in the global economy. The products they develop are often integrated into products made by larger enterprises. The “Big League” clients, furthermore, demand of the VSEs that they assume a much broader role, spanning the entire development life‐cycle of the product instead of being limited to a “build‐to‐print” approach. To address this new reality, to exploit the lean and efficient nature of VSEs and to adapt to their typical budget and resource constraints, the ISO/IEC 29110 systems engineering standards, management and engineering guides were developed from ISO/IEC/IEEE 15288. In addition, and by design, the standard is supported by Deployment Packages, software tools and training kits. The INCOSE VSE working group developed the deployment packages. A deployment package is a set of artefacts designed to facilitate the implementation of a standard or a set of practices in a VSE. In tune with the need for low cost and flexibility, Open Source software tools are emerging to complete “Big League” development life‐cycle toolsets, which are often out‐of‐reach to VSEs. Finally, to make the deployment of the standard possible in the VSE, training packages, supported by relevant pilot projects help VSE personnel learn how to apply all of the above.
A Set of Heuristics to Support Early Identification of Conflicting Requirements
Authors: Salado Alejandro , Nilchiani Roshanak
Published: October 2015

Conventional approaches to system design use requirements as boundary conditions against which the design activity occurs. Decisions at a given level of the architecture decomposition can result in the flowing down of conflicting requirements, which are easy to fulfill in isolation but extremely difficult when dealt with simultaneously. Designing against such sets of requirements considerably limits system affordability. Identification of such conflicts is usually performed in industry by subject matter experts. Such evaluations are primarily driven by experience. As a result, effectiveness in identifying conflicting requirements is strongly dependent on the person making the assessment. We propose in this paper a set of heuristics that supports identification of conflicting requirements by providing direction and focus in the identification effort. The heuristics have been derived from a combination of literature review and experience from practitioners. In particular, a set of practitioners was interviewed orally and through a questionnaire in order to abstract and generalize their individual experiences.
From initial investigations up to large‐scale rollout of an MBSE method and its supporting workbench: the Thales experience
Authors: Voirin Jean‐Luc , Bonnet Stéphane , Normand Véronique , Exertier Daniel
Published: October 2015

Thales is today in the process of rolling out field‐proven model‐based systems engineering method and workbench, on a large scale throughout its different business domains and countries. This article looks back at the past decade of coming of age, describes a few practical deployment cases in Thales entities and analyses success factors, both at people and organization level as well as at technical level. The close loop between operational users, solution experts and tooling development are identified as a key success factor.
Model‐based Engineering of Emergence in a Collaborative SoS: Exploiting SysML & Formalism
Authors: Ingram Claire , Payne Richard , Fitzgerald John , Couto Luis Diogo
Published: October 2015

A collaborative SoS is a system composed of constituent systems (CSs), which are independent and voluntarily cooperate without an agreed SoS director. Engineering emergent behaviour is just one of the key engineering challenges for which support is needed. In this paper we illustrate for the first time an integrated collection of model‐based techniques for verifying behaviours and properties, with the aim of assisting the engineering of collaborative systems of systems (SoSs). We provide an illustration of an approach that flows from requirements and architectural modelling to the use of formal techniques, integrating methods drawn from software and systems engineering fields to tackle engineering challenges in SoS. The approach incorporates architectural modelling (implemented in SysML) before transitioning to a formal modelling notation which has been developed specifically for SoSs. This formal modelling approach supports a wide range of analysis and verification techniques, such as: design space exploration; requirements verification; and consistency checks. We also discuss how our approach can be incorporated into a standard systems engineering approach.
One Size Fits All?: A model of human growth and its application to systems thinking
Authors: Nolan Andy J. , Russell Jennifer L. , Pickard Andrew C. , Beasley Richard
Published: October 2015

The Graves Model was developed in the 1950's by Dr. Clare W. Graves. The model proposes a number of levels that describe how people think and behave. It describes how people change, organize, make choices, create strategies, and communicate. But, unlike other models of human behavior, the Graves Model applies not only to individuals but also to teams, projects, and even organizations.

The model was introduced into Rolls‐Royce in 2006 as a tool to increase the success of improvement/change projects. The model proved to be both simple and powerful at characterizing many situations we experienced over the years. The tool is useful for Systems Engineers, change leaders, managers and business leaders.

The Graves Model is a tool to help a Systems Engineer understand how to approach a problem, the team they will require, how to communicate ideas, and also understand the end‐user's likely response to a solution. The model can help diagnose problems in projects as well as anticipate likely problems in future projects. This understanding can then be used to change a project approach and the people involved.

This paper summarizes the Graves Model and provides examples of how it may be used in your organization.
Objects, Relations and Clusters for System Analysis
Authors: Simpson Joseph J. , Simpson Mary J
Published: October 2015

The use of Abstract Relation Types (ART) in the analysis of system structure and system component clustering is the primary focus of this paper. Two basic system definitions are presented along with two, object‐clustering definitions which were obtained from a literature search. Systems structuring mathematical properties, used in systems analysis, are outlined and discussed. The ART analysis approach is applied to classical N‐Squared Charts and Design Structure Matrices (DSM), with specific emphasis on clustering methods, types and meaning. The primary structuring relationship associated with N‐Squared ART and DSM ART are evaluated and discussed. Multiple DSM ART solution approaches and techniques are referenced and discussed.
Principles for Agile Development
Authors: Marbach Phyllis , Rosser Larri , Osvalds Gundars , Lempia David
Published: October 2015

The Manifesto for Agile Software Development [Beck 2001] and the Principles behind the Agile Manifesto were written specifically for software development teams. Since the manifesto does not appear to apply to systems or large programs with multiple teams of development, how it applies to systems engineers is not apparent. The Principles for Agile Development are recommended for cross‐functional teams that include Systems and Software Engineers working on customer “pull” projects to produce software products. These principles provide a foundation for the working relationship across the teams. We believe these principles apply to programs that include both hardware development and software development; however, we limit our examples to software intensive development for this discussion. As we strive to produce products more affordably in this ever‐increasing, global marketplace adopting these principles will serve as a foundation for working together to develop high‐value capabilities incrementally.
A practical guide to assuring the system resilience to operational errors
Authors: Zonnenshain Avigdor , Harel Avi
Published: October 2015

Studies about the sources of critical accidents in operating human‐made systems indicate that most of them are commonly attributed to errors made by the human operators. These findings motivated the development of a guide for designing and developing systems which are resilient to operational errors. This article reports on the development of such a guide by the Gordon Center for System Engineering at the Technion. Assuming the Human Factors variant of Murphy's Law, the guide applies the STAMP paradigm of self‐control in scenario‐based design, relying on a model of resilient operation. The guide suggests designing three firewalls, for preventing latent threats, preventing escalation and learning from incidents. The effectiveness of the guide was evaluated collaboratively in a special INCOSE_IL working group, by examination of its applicability to case studies. The guide was validated by scoring the guidelines applicability to failure modes observed in a special database of 67 mishaps.
Towards a Method to Describe Resilience to Assist System Specification
Authors: Jackson Scott , Cook Stephen C. , Ferris Timothy L.J.
Published: October 2015

This paper arose from the challenges inherent in defining and specifying the complicated, non‐functional system characteristic of resilience in the presence of competing definitions. The approach adopted is to specify the resilience of a system using a state‐machine. In this class of model, the state of the system is modelled by the states, the threat events that can be expected to result in altered operational states modelled by the definitions of the state transitions, and the result of the occurrence of a threat event modelled by the state to which the system would transition. The paper describes a generic model that can be tailored to form the basis for specifying a range of system types and illustrates its utility through two case studies.