bluuebunny/crossref_metadata_2025 huggingface dataset:
Your Wish, My Command – Speeding up Projects in the Transportation Industry Using Ontologies
Authors: Chalé Góngora Hugo Guillermo , Llorens Juan , Gallego Elena
Published: August 2017

This paper presents the results of an exploratory study conducted at ALSTOM on the application of knowledge‐centric approaches to the requirements definition process. The original scope of the study concerned the application of ontologies to analyze and improve the quality of specification documents in an industrial context. An additional idea quickly emerged as a collateral benefit of the study to extend the usage of the gathered knowledge base in order to perform computer‐assisted identification of requirements from structured and unstructured documents. The purpose of this new approach is to improve the execution of projects in railway transportation by accelerating the requirements management and development processes and, in particular, the stakeholder requirements capture and elicitation activities.
Conducting a Model Based Systems Engineering Tool Trade Study Using a Systems Engineering Approach
Authors: Friedland Brittany , Herrold John , Ferguson Glendora , Malone Robert
Published: August 2017

Evaluating and choosing a comprehensive Commercial‐Off‐The‐Shelf (COTS) platform to serve as the basis for a deployable large scale Model Based Systems Engineering (MBSE) tool suite is a challenging task with many factors to take into account. Applying a Systems Engineering approach to the problem gives a highly useful roadmap for choosing an effective solution. Boeing evaluated 25 candidate COTS platforms against end users processes and accompanying business requirements that were used to identify and specify the desired tool suite functionality, desired behavior, and design constraints. Design constraints included a range of considerations from scalability concerns to implementation specific needs. This paper outline the criteria against which the candidates solutions were evaluated and the results of the evaluations.
On the Use of the Terms Verification and Validation
Authors: Ryan Michael J. , Wheatcraft Louis S.
Published: August 2017

While the concepts of verification and validation are commonplace, in practice the terms are often used interchangeably and the context of their use is not made clear, resulting in the meaning of the concepts frequently being misunderstood. This paper addresses the use of the terms verification and validation and identifies their various meanings in terms of the context in which they are used, particularly as defined in the relevant standards and literature, as well as everyday usage. In particular, it is identified that both terms are ambiguous unless a modifier is included in front of the word, clearly indicating to which context the term is referring. This paper illustrates that failing to use a modifier—thus assuming the reader understands the context in which the terms are used—is the most common reason for ambiguity and misunderstanding. The paper presents a simple model of the system design process to allow the nature of verification and validation to be understood better within a given context. Definitions are then proposed in order to disambiguate the various uses of the terms.
A Proposal for Standardized Use of the Term “Module” in Systems Engineering
Authors: Efatmaneshnik Mahmoud , Shoval Shraga , Ryan Michael J
Published: August 2017

The terms “module” and “modularity” are used extensively in the Product Engineering literature. Today, modularity is an essential core competency of leading product designs, enabling organizations to maintain a competitive edge in the marketplace. However, these terms have very context‐specific definitions in System Engineering (SE) literature. “Module” is not part of the technical taxonomy in any of the SE standards, which do not regard a module as a part of the formal system breakdown structure. In this paper, we redefine “module,” as a unit composed of a set of components with an specific interface, which must also serve one or more purely non‐functional goals, such as flexibility, evolvability, manufacturability, and maintainability. A configuration item, a subsystem, an assembly, a subassembly or a component can all be regarded as modules because their creation could have served non‐functional goals such as design tractability, tradesapce searchability, assembility etc., however, the important assertion here is that a module's boundaries do not necessarily coincide with those dictated by the functional system decomposition and functional hierarchy.
Robotic Satellite Servicing Trade Space Down‐Selection
Authors: Knizhnik Jessica , Austin Mark , Carignan Craig
Published: August 2017

As remote robotic space satellite servicing technologies develop, each servicer satellite will need to account for a number of servicing scenarios and consider a variety of alternate design solutions to best meet the most servicing scenario requirements. This paper presents a graph transformation method for systematically down‐selecting the number of design options available, and highlighting trade‐offs in sets of design solutions which best meet satellite servicing task requirements while also reducing total mass, maximum power needed and servicing time. In the test case examined, the proposed method successfully identifies for further consideration, seven best design solutions from a set of over 100,000 potential solutions.
Reusable Modules to Support Rapid Model Building: A Case Study of Defence Force Design
Authors: Bowers Joshua , Elsawah Sondoss , Ryan Michael
Published: August 2017

This work is motivated by the lack of research in the area of developing generic and domain‐specific system dynamics (SD) modules. Unlike traditional modelling approaches where an expert modeller builds the model from low‐level modelling constructs, modules allow for rapid construction of simulations by providing components that can be quickly parametrised and assembled to test different strategies. This approach has the potential to improve the efficiency and effectiveness of SD modelling by minimizing time and costs, sharing domain knowledge, and improving user involvement in the modelling process. This paper presents a working set of eight reusable modules in the domain of defence force planning and design. We illustrate the use of modules with a hypothetical scenario based on our experience with projects' clients. Finally, we conclude with suggestions for future work in the research areas related to the development, use, and evaluation of SD modules.
Control Theoretic Modeling and Simulation of Supply Chain Management System
Authors: Rehman Obaid Ur , Ryan Michael J.
Published: August 2017

Control theoretic modelling approaches are very effective in developing a dynamical model of a system. A supply chain system is a dynamical system which contains a number of lead times among supply nodes and is susceptible to demand variation. Control theoretic modelling approaches are proved to be very effective in developing ordering policies for such systems. In this work, we developed a linear discrete time model of a supply chain with multiple supply nodes and pure delays. The model presented here can be used to develop an optimal ordering and distribution policy so that the entire system remains stable. In addition to the mathematical model of the supply chain, a simulation model is also developed using Simulink® toolbox SimEvents®. The simulation model can be used to test various ordering policies to determine system stability. In this work the simulation model is used to test system stability and can be further used to find optimum ordering and optimum routing policies under uncertainty by running a Monte Carlo type simulation using the developed simulation model.
Tailoring a ConOps for NASA LSP Integrated Operations
Authors: Owens Clark V.
Published: August 2017

An integral part of the Systems Engineering process is the creation of a Concept of Operations (ConOps) for a given system, with the ConOps initially established early in the system design process and evolved as the system definition and design matures. As Integration Engineers in NASA's Launch Services Program (LSP) at Kennedy Space Center (KSC), our job is to manage the interface requirements for all the robotic space missions that come to our Program for a Launch Service. LSP procures and manages a launch service from one of our many commercial Launch Vehicle Contractors (LVCs) and these commercial companies are then responsible for developing the Interface Control Document (ICD), the verification of the requirements in that document, and all the services pertaining to integrating the spacecraft and launching it into orbit. However, one of the systems engineering tools that have not been employed within LSP to date is a Concept of Operations. The goal of this paper is to research the format and content that goes into these various aerospace industry ConOps and tailor the format and content into template form, so the template may be used as an engineering tool for spacecraft integration with future LSP procured launch services. This tailoring effort was performed as the author's final Masters Project in the Spring of 2016 for the Stevens Institute of Technology and modified for publication with INCOSE (Owens, 2016).
Fortune Telling, Estimating & Systems Engineering
Authors: Nolan Andy , Vlad Olimpia , Pickard Andrew C , Beasley Richard
Published: August 2017

Estimating the cost of a system is an essential aspect of Systems Engineering. Both the recurring and non‐recurring costs will need to be understood before a business can make a commitment. Often systems will be constrained by affordability and when the system will be needed and such constraints will need to be understood by the Systems Engineer. There is little point developing a system that will take too long to build and would likely bankrupt the company or customer. So a Systems Engineer will also need to explore trade options to optimize the system for cost and schedule.

Fortune tellers profess to know the future and assure business leaders that the system is a good idea and will be affordable. Evidence presented in this paper shows that fortune telling can be inaccurate and that unless robust estimation practices are applied, most systems will overshoot their budgets and deadlines. Often it is too late when a business finds out the true cost of the system they are committed to. A Systems Engineer must employ proven estimating practices if they are to avoid customer dissatisfaction and business losses

Success leaves clues and successful estimates are no accident. Success is defined here as an accurate estimate, one where the final system costs and schedules come in acceptably close to the estimate.

When we asked Systems Engineers for their views on the factors that lead to an accurate estimate, we hear answers like; clear requirements, accurate historic data, and robust estimation techniques. But how important are these and is it possible to quantify their value, their contribution, towards a successful estimate?

The authors developed a calibrated scoring mechanism to quantify the “maturity” of an estimate to help business leaders understand the “goodness” of an estimate before they make a commitment. The concept is called Estimate Readiness Level and is a score between 1 and 9 representing the maturity of the estimate. This paper summarizes how the authors calibrated the Estimate Readiness Level assessment so that business leaders can now predict the risk and uncertainty in an estimate before the project launches, and therefore be confident that the system being proposed is affordable and that the business case can be believed.
Integration and Framing between System Engineering, Enterprise Engineering and Whole of Society
Authors: Erasmus Louwrence , Greeff Braam
Published: August 2017

This paper proposes the integration between the domains of product development, systems engineering, enterprise engineering & architecture and the whole of society. The effort addresses the following systems engineering imperatives as per INCOSE Vision 2025: “Expanding the application of systems engineering across industry domains, applying systems engineering to help shape policy related to social and natural systems, expanding the theoretical foundation for systems engineering, advancing the tools and methods to address complexity.” Formal theoretical structures in the form of mathematical predicates are used from the structuralist programme in the philosophy of science to frame the integration. The formal structures make future simulations of the identified integration possible.
Systematic Capacity‐Based Risk Assessment: Application to Water Service Project in Kassala, Sudan
Authors: Magpili Luna , Pinto C. Ariel , Bharathy Gnana , Babiker Mohammed
Published: August 2017

Inhabitants of sub‐Saharan Africa suffer disproportionately from lack of access to improved drinking water sources than the rest of the world. Previous studies have established capacity‐related success factors (or enablers) of infrastructure development projects, including drinking water supply. However, these enablers when not well established can also be indicators of risks to the sustainability and overall success of such water projects. The riskiness for success of a water project in Kassala, Sudan was assessed using the eight enablers, resulting in explicit documentation of capacity deficiencies, which may be considered as risk factors for the sustainability, and ultimately, the overall success of the water project. These capacity deficiencies may also serve as risk checklist for project managers and systems engineers involved in projects in similar environments.
MicroRNA‐142‐5p induces cancer stem cell‐like properties of cutaneous squamous cell carcinoma via inhibiting PTEN
Authors: Bai Xinping , Zhou Yu , Chen Ping , Yang Ming , Xu Jiang
Published: August 2017

Cutaneous squamous cell carcinoma (cSCC) is a malignancy of keratinocyte‐derived skin tumor, which is regarded as the second most common skin cancer worldwide. Accumulating evidence has established that microRNAs (miRNAs) can play a critical role in tumor initiation, progression, and metastasis including cSCC. Abnormal expression of hsa‐miR‐142‐5p has been elaborated in various tumors. Nevertheless, its expression and function in the development of cSCC remain unclear. In our study, we found that the expression of hsa‐miR‐142‐5p in cSCC cells were greatly overexpressed compared to human benign epidermal keratinocyte cells. Moreover, inhibited hsa‐miR‐142‐5p can repress cSCC cell growth and induce apoptosis while upregulated hsa‐miR‐142‐5p exhibited a reverse phenomenon. Recently, cancer stem cells (CSCs) which possess the ability of self‐renewal and proliferation and are able to produce cancer cells have been widely reported. However, the correlation between hsa‐miR‐142‐5p and CSCs in cSCC is still unknown. Interestingly, we observed that overexpressing hsa‐miR‐142‐5p can induce CSC‐like properties in cSCC via activating Wnt signaling. In addition, the luciferase reporter assay data and bioinformatics analysis demonstrated that hsa‐miR‐142‐5p can target the 3′UTR of PTEN mRNA. Taken these together, we draw a conclusion that hsa‐miR‐142‐5p can trigger cancer stem cell‐like properties of cSCC through inhibition of PTEN. Our findings may provide hsa‐miR‐142‐5p as a new therapeutic target for cSCC.
Silencing of SOCS‐1 and SOCS‐3 suppresses renal interstitial fibrosis by alleviating renal tubular damage in a rat model of hydronephrosis
Authors: Zheng Gui‐Hong , Wang Yong‐Jian , Wen Xin , Han Xin‐Rui , Shen Min , Wang Shan , Zhuang Juan , Zhang Zi‐Feng , Wang Liang , Hu Bin , Sun Chun‐Hui , Mao Xiao‐Yun , Yi Lan‐Ni , Wu Dong‐Mei , Lu Jun , Zheng Yuan‐Lin
Published: August 2017

Our study was performed to elucidate how SOCS‐1/3 silencing suppresses renal interstitial fibrosis (RIF) by alleviating renal tubular damage in rat models affected by hydronephrosis. Male Wistar rats were randomly selected to establish hydronephrosis rat model, after which all rats were classified into normal, model, negative control (NC), siRNA‐SOCS‐1, siRNA‐SOCS‐3, and siRNA‐SOCS‐1 + siRNA‐SOCS‐3 groups. The levels of urine protein, serum creatinine (Scr), and blood urea nitrogen (BUN) were detected. ELISA was performed to determine levels of cystatin (CysC), β2‐microglobulin (β2‐MG), interleukin (IL)‐6, and tumor necrosis factor (TNF)‐α. RT‐qPCR and Western blotting were used for mRNA and protein expressions of SOCS‐1, SOCS‐3, α‐smooth muscle actin (α‐SMA), and transforming Growth Factor (TGF)‐β1. Compared with the normal group, the levels of Scr, BUN, urine protein, NAG, CysC, β2‐MG, IL‐6, and TNF‐α were increased in other groups, as well as elevated mRNA and protein expressions of SOCS‐1, SOCS‐3, α‐SMA, and TGF‐β1. The siRNA‐SOCS‐1, siRNA‐SOCS‐3, and siRNA‐SOCS‐1 + siRNA‐SOCS‐3 groups were found with decreased levels of Scr, BUN, urine protein, NAG, CysC, β2‐MG, IL‐6, and TNF‐α, as well as mRNA and protein expressions of SOCS‐1, SOCS‐3, α‐SMA, and TGF‐β1, including positive rates of SOCS‐1 and SOCS‐3 proteins in comparison with the model and NC groups. In comparison with the siRNA‐SOCS‐1 and siRNA‐SOCS‐3 groups, the siRNA‐SOCS‐1 + siRNA‐SOCS‐3 group exhibited decreased levels of Scr, BUN, urine protein, NAG, CysC, β2‐MG, IL‐6, and TNF‐α. Our study demonstrated that silencing of SOCS‐1/3 may suppress RIF by alleviating the renal tubular damage in rat models affected by hydronephrosis.
Sleep deprivation induces pathological changes in rat masticatory muscles: Role of Toll like signaling pathway and atrophy
Authors: Yujra Veronica Q. , Antunes Hanna K. M. , Mônico‐Neto Marcos , Pisani Luciana P. , Santamarina Aline B. , Quintana Hananiah T. , de Oliveira Flavia , Oshima Celina T. F. , Ribeiro Daniel A.
Published: August 2017

The aim of this study was to evaluate the Toll like signaling pathway and atrophy after sleep deprivation (SD) in rat masticatory muscles: masseter and temporal. A total of 24 animals was distributed into three groups: Control group (CTL, n = 8), subjected to SD for 96 h (SD96, n = 8) and subjected to SD for 96 h more 96 h of sleep recovery (SD96 + R, n = 8). Histopathological analysis revealed the presence of acute inflammatory cells, congested vessels, fibrosis, and high cellularity in the skeletal muscle fibers from masseter and temporal submitted to SD. These morphological alterations were not observed in the control group since neither inflammatory cells nor congested vessels were observed to this group. In the group SD96 + R, the absence of inflammation was noticed to the masseter only. In this group, COX‐2 and TNF‐alpha downregulation were detected when comparing to control group. MyD88 and pIKK decreased in SD96 and SD96 + R groups being pNFKBp50 downregulatated in SD96 + R. MyD88 expression increased in rats submitted to SD96 and SD96 + R in temporal when compared to control group. On the other hand, pIKK decreased the protein expression in groups SD96 and SD96 + R while pNFKBp50 showed a decreased protein expression in group SD96 only. The activation of atrophy by means of MAFbx upregulation was detected in temporal muscle in SD96 and SD96 + R when compared to control. In summary, our results show that SD is able to induce morphological alterations in rat masticatory muscles. Toll like signaling pathway and atrophy play important roles in ethiopathogenesis induced by SD, being dependent of skeletal muscle type.
Effect of Combination Therapy of Ezetimibe and Atorvastatin on Remnant Lipoprotein Versus Double Atorvastatin Dose in Egyptian Diabetic Patients
Authors: El‐Tamalawy Mona Mohammed , Ibrahim Osama Mohamed , Hassan Timour Mostafa , El‐Barbari Ali Ali
Published: August 2017

A high level of remnant lipoprotein cholesterol (RLP‐C) is a predominant feature in diabetic patients with atherosclerosis. This study aimed to investigate the effect of ezetimibe added to statin therapy compared to doubling standard statin dose. Sixty‐five eligible patients were recruited then prospectively randomized to receive ezetimibe 10 mg/day plus their 40 mg daily atorvastatin dose (group 1) or atorvastatin 80 mg/day (group 2) for 3 months. Efficacy was evaluated using plasma levels of RLP‐C, apolipoprotein B, non–high‐density lipoprotein cholesterol (non‐HDL), percentage of brachial artery flow‐mediated dilation, and lipid profile. Forty patients completed the study and provided efficacy data. Group 1 showed more reduction in RLP‐C (45.7% vs 31.7%, P = .02), apolipoprotein B (28.5% vs 9.5%, P = .01), total cholesterol (34.7% vs 24.6%, P = .003), triglycerides (49% vs 24.4%, P = .000), non‐HDL (49.3% vs 33%, P = .002), and low‐density lipoprotein cholesterol (49.6% vs 35.2%, P = .02) compared to group 2. Group 1 showed a greater increase in HDL (66% vs 35%, P = .002); and flow‐mediated dilation (30% vs 17%, P = .01) compared to group 2. It is concluded that adding ezetimibe 10 mg to atorvastatin 40 mg may be a better choice than doubling atorvastatin dose in improving RLPs, endothelial function, and lipid profile in diabetic cardiovascular patients who could not achieve their therapeutic treatment goals with the standard atorvastatin dose.
Effect of different implant abutment surfaces on OBA‐09 epithelial cell adhesion
Authors: Rigolin Maria Sílvia M. , de Avila Erica Dorigatti , Basso Fernanda G. , Hebling Josimeri , de S. Costa Carlos Alberto , Mollo Junior Francisco de Assis
Published: August 2017

For the long‐term success of implants, it is necessary to achieve a direct contact between the implant and the subjacent bone. To avoid bacterial penetration that could adversely affect the initial wound healing as well as the long‐term behavior of the implants, an early tissue barrier must form that is able to protect the biological peri‐implant structures. Given the need of an effective tissue early barrier around dental implants, the present study evaluated, in vitro, the influence of physical and chemical characteristics of two implant abutment surfaces on gingival epithelial cells (OBA‐9) adhesion. To this end, titanium (Ti) and zirconia (ZrO2) disk‐shaped specimens were used mimicking the abutment components surfaces, while bovine enamel (BE) and glass cover slips (GCS) disks served as positive and negative controls, respectively. Roughness and surface free energy (SFE) of all materials were evaluated previously to cellular adhesion step. In sequence, the effect of each material on cells morphology and viability was analyzed after 1 and 24 hr. The results showed that roughness and SFE had no effect on the cell viability data or on their interaction (p = .559), independent of a post‐contact analysis of 1 or 24 hr. However, cells attachment and spreading increased after 24 hr on Ti and ZrO2 than BE, corresponding to the highest SFE values. SFE appears to be an important property interfering on the quality of the soft tissue surrounding dental implants. These data can be considered a trigger point for developing new material surfaces.
Synthesis, Characterization, and Fluorescence Studies of Novel Heterocyclic Azo Dyes Derived from Benzothiazole
Authors: Şener Nesrin , Erişkin Selinay , Şahin Çiğdem , Yılmaz Mehmet , Şener İzzet
Published: August 2017

Ten novel fluorescent azo disperse dyes2a–e(open forms) and3a–e(closed forms) were obtained by the coupling reaction of carbocyclic amine based diazonium chloride with compounds2and3. The synthesized dyes were characterized by elemental analysis, high‐resolution mass spectrometry, Fourier transform infrared, and NMR spectral techniques. Moreover, we investigated the substituent effect and solvatochromic properties of the dyes on absorption and fluorescence spectra. At the same time, the absorption and emission spectral data of the closed form dyes3a–ewere compared with the open form dyes2a–edue to more planarity of the closed form dyes that lead to the extension of the π–electron conjugation.
The Impact of Fiscal Consolidation on Human Development
Authors: Agnello Luca , Castro Vitor , Jalles João Tovar , Sousa Ricardo M.
Published: August 2017

We find that fiscal austerity is associated with a reduction of human development standards, with the negative effect being particularly severe in the case of spending‐driven consolidation episodes. Fiscal adjustments are especially damaging for human development in developing countries (namely, African and Latin American countries). Additionally, the empirical evidence shows that (i) government stability is a crucial institutional determinant of human development, and (ii) while investment in physical capital can boost human development, government consumption and inflation are detrimental to it. Copyright © 2017 John Wiley & Sons, Ltd.
Reduced activation and proliferation of human lymphocytes exposed to respiratory syncytial virus compared to cells exposed to influenza virus
Authors: Fleming Elisa H. , Ochoa Eliana E. , Nichols Joan E. , O'Banion M. Kerry , Salkind Alan R. , Roberts Norbert J.
Published: August 2017

Both respiratory syncytial virus (RSV) and influenza A virus (IAV) may infect human peripheral blood mononuclear leukocytes (PBMC) during the immune response to viral challenge as the cells are recruited to the respiratory tract. The current studies demonstrated differences in PBMC responses to the two viruses very early after exposure, including reduced fos protein and CD69 expression and IL‐2 production by RSV‐exposed T lymphocytes. Exposure to RSV resulted in reduced lymphocyte proliferation despite evidence of a virus‐specific T lymphocyte frequency equivalent to that for influenza virus. Reduced RSV‐induced proliferation was not due to apoptosis, which was itself reduced relative to that of influenza virus‐exposed T lymphocytes. The data indicate that differential immune responses to RSV and influenza virus are determined early after exposure of human PBMC and support the concept that the anamnestic immune response that might prevent clinically evident reinfection is attenuated very soon after exposure to RSV. Thus, candidate RSV vaccines should be expected to reduce but not prevent clinical illness upon subsequent infection by RSV. Furthermore, effective therapeutic agents for RSV are likely to be needed, especially for high‐risk populations, even after vaccine development.
A piecewise spectral method for solving the chaotic control problems of hyperchaotic finance system
Authors: Karimi Mohammad , Saberi Nik Hassan
Published: August 2017

This work presents an accurate algorithm for solving the chaotic control (optimal and adaptive control) problems of hyperchaotic finance system. A modification of the spectral homotopy analysis method technique is proposed for solving the hyperchaotic finance system and the extreme conditions obtained from the Pontryagin minimum principle. The proposed method is based on implementing the spectral homotopy analysis method on a sequence of multiple intervals thereby increasing its radius of convergence to yield highly accurate method that is referred to as the piecewise spectral homotopy analysis method. Finally, piecewise spectral homotopy analysis method is used to solve the problem of Lyapunov stabilization of the hyperchaotic finance system. Numerical simulations are given to illustrate and verify effectiveness of the proposed strategy.
Modeling of the hERG K+ Channel Blockage Using Online Chemical Database and Modeling Environment (OCHEM)
Authors: Li Xiao , Zhang Yuan , Li Huanhuan , Zhao Yong
Published: August 2017

Human ether‐a‐go‐go related gene (hERG) K+ channel plays an important role in cardiac action potential. Blockage of hERG channel may result in long QT syndrome (LQTS), even cause sudden cardiac death. Many drugs have been withdrawn from the market because of the serious hERG‐related cardiotoxicity. Therefore, it is quite essential to estimate the chemical blockage of hERG in the early stage of drug discovery. In this study, a diverse set of 3721 compounds with hERG inhibition data was assembled from literature. Then, we make full use of the Online Chemical Modeling Environment (OCHEM), which supplies rich machine learning methods and descriptor sets, to build a series of classification models for hERG blockage. We also generated two consensus models based on the top‐performing individual models. The consensus models performed much better than the individual models both on 5‐fold cross validation and external validation. Especially, consensus model II yielded the prediction accuracy of 89.5 % and MCC of 0.670 on external validation. This result indicated that the predictive power of consensus model II should be stronger than most of the previously reported models. The 17 top‐performing individual models and the consensus models and the data sets used for model development are available at https://ochem.eu/article/103592.
Novel Method Proposing Chemical Structures with Desirable Profile of Activities Based on Chemical and Protein Spaces
Authors: Maeda Iwao , Hasegawa Kiyoshi , Kaneko Hiromasa , Funatsu Kimito
Published: August 2017

Active molecules among numerous chemical structures in a chemical database can be searched easily by statistical prediction of compound–protein interactions. However, constructing a simple prediction model against one protein does not aid drug design, because detecting chemical structures that act similarly against multiple proteins is necessary for preventing side effects of the potential drug. To tackle this problem, we propose a new method that visualizes chemical and protein spaces.

For simultaneous visualization of both spaces, we employ a counterpropagation neural network (CPNN) and develop a new visualization method named multi‐input CPNN (MICPNN). In a case study of the kinase protein family, the MICPNN model predicted accurately the complex relationships between compounds and proteins. The proposed method identified chemical structures with promising activity against kinases. Our proposed method is also applicable to other protein families, such as G‐protein coupled receptors, ion channels and transporters.
Local incompressible registration for liver ablation surgery assessment
Authors: Fu Tianyu , Li Qin , Liu Dingkun , Ai Danni , Song Hong , Liang Ping , Wang Yongtian , Yang Jian
Published: August 2017

Purpose

In liver microwave ablation (MWA) surgery, the ablation area covers the tumor to generate tissue necrosis and treat the cancer. As the liver deforms during the operation, deviation between the target area determined during preoperative planning and the resultant ablation area is inevitable. Therefore, an accurate assessment of tumor coverage is crucial for treatment. Through registration between the pre‐ and postoperative livers, the ablation area is warped on the preoperative liver for the computation of tumor coverage. However, large deformations between the pre‐ and postoperative livers are caused by multiple factors, and these diverse deformations make registration a challenging task. The purpose of this paper was to develop an automatic method that can accurately register post‐ to preoperative livers.

Methods

In the proposed method, nonrigid deformations caused by respiratory movement and edema are separately considered and estimated by the local incompressible model in the registration of livers. The pre‐ and postoperative livers are first aligned by a rigid registration based on a convex hull. In the nonrigid registrations, local incompressible constraints are then set on the liver and the ablation area to estimate the deformations caused by respiratory movement and edema, respectively. The concatenation of the rigid and nonrigid deformations is used to warp the ablation area on the preoperative liver.

Results

The proposed method was evaluated using clinical CT datasets from 20 patients. The Dice similarity coefficient (DSC) between the preoperative and warped postoperative livers is 94.35%, the mean surface distance (MSD) between the livers is 1.65 mm, the mean Hausdorff distance (HDD) between the livers is 3.36 mm, and the mean corresponding distance (MCD) between the corresponding landmarks is 1.70 mm. Compared with five other state‐of‐the‐art methods, the proposed method achieves automatic ablation assessment with highly accurate registration.

Conclusions

The proposed method achieves a high accuracy for registering the livers. The sizes and positions of the ablation area and tumor are accurately compared for the assessment of ablation surgery.
Feasibility of quantitative regional ventilation and perfusion mapping with phase‐resolved functional lung (PREFUL) MRI in healthy volunteers and COPD, CTEPH, and CF patients
Authors: Voskrebenzev Andreas , Gutberlet Marcel , Klimeš Filip , Kaireit Till F. , Schönfeld Christian , Rotärmel Alexander , Wacker Frank , Vogel‐Claussen Jens
Published: August 2017

Purpose

In this feasibility study, a phase‐resolved functional lung imaging postprocessing method for extraction of dynamic perfusion (Q) and ventilation (V) parameters using a conventional 1H lung MRI Fourier decomposition acquisition is introduced.

Methods

Time series of coronal gradient‐echo MR images with a temporal resolution of 288 to 324 ms of two healthy volunteers, one patient with chronic thromboembolic hypertension, one patient with cystic fibrosis, and one patient with chronic obstructive pulmonary disease were acquired at 1.5 T. Using a sine model to estimate cardiac and respiratory phases of each image, all images were sorted to reconstruct full cardiac and respiratory cycles. Time to peak (TTP), V/Q maps, and fractional ventilation flow‐volume loops were calculated.

Results

For the volunteers, homogenous ventilation and perfusion TTP maps (V‐TTP, Q‐TTP) were obtained. The chronic thromboembolic hypertension patient showed increased perfusion TTP in hypoperfused regions in visual agreement with dynamic contrast‐enhanced MRI, which improved postpulmonary endaterectomy surgery. Cystic fibrosis and chronic obstructive pulmonary disease patients showed a pattern of increased V‐TTP and Q‐TTP in regions of hypoventilation and decreased perfusion. Fractional ventilation flow‐volume loops of the chronic obstructive pulmonary disease patient were smaller in comparison with the healthy volunteer, and showed regional differences in visual agreement with functional small airways disease and emphysema on CT.

Conclusions

This study shows the feasibility of phase‐resolved functional lung imaging to gain quantitative information regarding regional lung perfusion and ventilation without the need for ultrafast imaging, which will be advantageous for future clinical translation. Magn Reson Med 79:2306–2314, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Heme Biosynthetic Pathway is Functionally Linked to Adipogenesis via Mitochondrial Respiratory Activity
Authors: Moreno‐Navarrete José María , Rodríguez Amaia , Ortega Francisco , Becerril Sara , Girones Jordi , Sabater‐Masdeu Mònica , Latorre Jéssica , Ricart Wifredo , Frühbeck Gema , Fernández‐Real José Manuel
Published: August 2017

Objective

To investigate key enzymes of heme biosynthesis in human adipocytes and adipose tissue (AT).

Methods

Heme biosynthesis‐related gene expression (ALAS1, ALAD, HMBS) was investigated in whole AT from humans (n = 178 and n = 75) and rats according to obesity status and during adipogenesis of human preadipocytes. The effects of aminotriazole (an ALAD inhibitor) and of ALAD knockdown were also studied.

Results

Consistent heme biosynthesis‐related gene expression was detected in both subcutaneous AT (SAT) and visceral AT (VAT) and was significantly increased in SAT. ALAS1, ALAD, and HMBS mRNAs were positively associated with adipogenic gene expression in human AT and significantly decreased in subjects with obesity. These results were replicated in an independent cohort. Both SAT and VAT heme levels were positively correlated with ALAS1, ALAD, and HMBS mRNAs. ALAD and HMBS were mainly expressed in adipocytes and increased during differentiation of human adipocytes in parallel to adipogenic genes. In rats, high‐fat diet‐induced weight gain resulted in decreased Alad and Hmbs mRNAs in a similar way to what was observed with Adipoq. Aminotriazole administration or ALAD knockdown attenuated adipogenesis in parallel with decreased glucose uptake and impaired mitochondrial respiratory function during human adipocyte differentiation.

Conclusions

Current data suggest a possible role of heme biosynthesis in human adipogenesis.
Flame‐retardant performance and mechanism of epoxy thermosets modified with a novel reactive flame retardant containing phosphorus, nitrogen, and sulfur
Authors: Huo Siqi , Wang Jun , Yang Shuang , Chen Xi , Zhang Bin , Wu Qilei , Zhang Bo
Published: August 2017

A novel phosphorus‐containing, nitrogen‐containing, and sulfur‐containing reactive flame retardant (BPD) was successfully synthesized by 1‐pot reaction. The intrinsic flame‐retardant epoxy resins were prepared by blending different content of BPD with diglycidyl ether of bisphenol‐A (DGEBA). Thermal stability, flame‐retardant properties, and combustion behaviors of EP/BPD thermosets were investigated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), limited oxygen index (LOI) measurement, UL94 vertical burning test, and cone calorimeter test. The flame‐retardant mechanism of BPD was studied by TGA/infrared spectrometry (TGA‐FTIR), pyrolysis‐gas chromatography/mass spectrometry (Py‐GC/MS), morphology, and chemical component analysis of the char residues. The results demonstrated that EP/BPD thermosets not only exhibited outstanding flame retardancy but also kept high glass transition temperature. EP/BPD‐1.0 thermoset achieved LOI value of 39.1% and UL94 V‐0 rating. In comparison to pure epoxy thermoset, the average of heat release rate (av‐HRR), total heat release (THR), and total smoke release (TSR) of EP/BPD‐1.0 thermoset were decreased by 35.8%, 36.5% and 16.5%, respectively. Although the phosphorus content of EP/BPD‐0.75 thermoset was lower than that of EP/DOPO thermoset, EP/BPD‐0.75 thermoset exhibited better flame retardancy than EP/DOPO thermoset. The significant improvement of flame retardancy of EP/BPD thermosets was ascribed to the blocking effect of phosphorus‐rich intumescent char in condensed phase, and the quenching and diluting effects of abundant phosphorus‐containing free radicals and nitrogen/sulfur‐containing inert gases in gaseous phase. There was flame‐retardant synergism between phosphorus, nitrogen, and sulfur of BPD.
Complexation of bis‐crown stilbene with alkali and alkaline‐earth metal cations. Ultrafast excited state dynamics of the stilbene‐viologen analogue charge transfer complex
Authors: Volchkov Valery V. , Rusalov Mikhail V. , Gostev Fedor E. , Shelaev Ivan V. , Nadtochenko Viktor A. , Vedernikov Artem I. , Efremova Asya A. , Kuz'mina Lyudmila G. , Gromov Sergey P. , Alfimov Michael V. , Ya. Melnikov Mikhail
Published: August 2017

The complex formation of bis(18‐crown‐6)stilbene (1) and its supramolecular donor‐acceptor complex with N,N′‐bis(ammonioethyl) 1,2‐di(4‐pyridyl)ethylene derivative (2) with alkali and alkaline‐earth metal perchlorates has been studied using absorption, steady‐state fluorescence, and femtosecond transient absorption spectroscopy. The formation of 1∙Mn+ and 1∙(Mn+)2 complexes in acetonitrile was demonstrated. The weak long‐wavelength charge‐transfer absorption band of 1·2 completely vanishes upon complexation with metal cations because of disruption of the pseudocyclic structure. The spectroscopic and luminescence parameters, stability constants, and 2‐stage dissociation constants were calculated. The initial stage of a recoordination process was found in the excited complexes 1∙M+ and 1∙(M+)2 (M = Li, Na). The pronounced fluorescence quenching of 1·2 is explained by very fast back electron transfer (τet = 0.397 ps). The structure of complex 1·2 was studied by X‐ray diffraction; stacked (1·2)m polymer in which the components were connected by hydrogen bonding and stacking was found in the crystal. These compounds can be considered as novel optical molecular sensors for alkali and alkaline‐earth metal cations.
Rigid diol bearing 6‐6‐6 fused ring system derived from naturally occurring myo‐inositol and its polyaddition with diisocyanates
Authors: Yoshida Arata , Sudo Atsushi
Published: August 2017

Naturally occurring myo‐inositol was developed into a highly rigid diol by converting its 3,4‐ and 1,6‐vicinal diols in trans configuration into the corresponding butane‐2,3‐diacetals. The resulting diol bearing 6‐6‐6 fused ring system, in which conformational change is strictly suppressed, was combined with diisocyanates to perform polyadditions. The resulting polyurethanes were analyzed by differential scanning calorimetry, and it was found that their glass transition temperatures were much higher than those of the previously reported myo‐inositol‐derived polyurethanes, which were synthesized from a myo‐inositol‐derived diol bearing 5‐6‐5 fused ring system. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017, 55, 3798–3803
Effect of Sandpaper and Grain Size on Non‐Shock Initiated Reactions in HMX
Authors: Reynolds John G. , Hsu Peter C. , Hust Gary A. , Strout Stephen A. , Hoffman D. Mark , Springer H. Keo
Published: August 2017

Three grades of HMX samples, coarse (A), coarse with a small amount of fines (B), and ultra‐fine (F), were tested for impact sensitivity by ERL drop hammer. The Type 12A test used sandpapers of three different compositions, 120‐, 180‐grit Si/C and 180‐grit garnet. Reaction was accounted for by operator observation and microphone. The results showed different sensitivity for each of the HMX types. The F‐HMX was the smallest in average particle size and was the least sensitive to impact. The A‐HMX was the next most stable and the B‐HMX was the most sensitive to impact. The spent samples from the drop hammer testing of B‐HMX and F‐HMX were further evaluated with optical imaging. Conditions were selected that were near the DH50 values of the specific HMX. Previous literature has cited localized hot spot formation to be the probable cause of non‐shock initiated reactions leading to impact sensitivity. This study yielded a plethora of samples exhibiting hot spots for HMX materials, both without and with proximity to grit particles. Hot spots in the proximity of grit particles gave the most dramatic hot spots, but both types of hot spots were exhibited in samples considered reacted and non‐reacted. The F‐HMX, even though the most stable to impact sensitivity, exhibited the most and best resolved hot spots of all the samples and conditions. Foreign objects were also observed in some of the samples. Previous work has shown metal particles coming from wear of the anvils used in the drop hammer experiment can also form hot spots. However, none of the samples here with metal particles exhibited, in proximity, hot spot formation.
Capturing the photo‐signaling state of a photoreceptor in a steady‐state fashion by binding a transition metal complex
Authors: Yu Pengyun , Song Lei , Qin Jun , Wang Jianping
Published: August 2017

Binding a small molecule to proteins causes conformational changes, but often to a limited extent. Here, we demonstrate that the interaction of a CO‐releasing molecule (CORM3) with a photoreceptor photoactive yellow protein (PYP) drives large structural changes in the latter. The interaction of CORM3 and a mutant of PYP, Met100Ala, not only trigger the isomerization of its chromophore, p‐coumaric acid, from its anionic trans configuration to a protonated cis configuration, but also increases the content of β‐sheet at the cost of α‐helix and random coil in the secondary structure of the protein. The CORM3 derived Met100Ala is found to highly resemble the signaling state, which is one of the key photo‐intermediates of this photoactive protein, in both protein local conformation and chromophore configuration. The organometallic reagents hold promise as protein engineering tools. This work highlights a novel approach to structurally accessing short lived intermediates of proteins in a steady‐state fashion.
Identification of heteromolecular binding sites in transcription factors Sp1 and TAF4 using high‐resolution nuclear magnetic resonance spectroscopy
Authors: Hibino Emi , Inoue Rintaro , Sugiyama Masaaki , Kuwahara Jun , Matsuzaki Katsumi , Hoshino Masaru
Published: August 2017

The expression of eukaryotic genes is precisely controlled by interactions between general transcriptional factors and promoter‐specific transcriptional activators. The fourth element of TATA‐box binding protein‐associated factor (TAF4), an essential subunit of the general transcription factor TFIID, serves as a coactivator for various promoter‐specific transcriptional regulators. Interactions between TAF4 and site‐specific transcriptional activators, such as Sp1, are important for regulating the expression levels of genes of interest. However, only limited information is available on the molecular mechanisms underlying the interactions between these transcriptional regulatory proteins. We herein analyzed the interaction between the transcriptional factors Sp1 and TAF4 using high‐resolution solution nuclear magnetic resonance spectroscopy. We found that four glutamine‐rich (Q‐rich) regions in TAF4 were largely disordered under nearly physiological conditions. Among them, the first Q‐rich region in TAF4 was essential for the interaction with another Q‐rich region in the Sp1 molecule, most of which was largely disordered. The residues responsible for this interaction were specific and highly localized in a defined region within a range of 20–30 residues. Nevertheless, a detailed analysis of 13C‐chemical shift values suggested that no significant conformational change occurred upon binding. These results indicate a prominent and exceptional binding mode for intrinsically disordered proteins other than the well‐accepted concept of “coupled folding and binding.”
How will NICE's budget impact test affect new drug availability?
Authors: Ogden Joy
Published: August 2017

NICE's budget impact test – in which new drugs that will have a net impact of £20 million or more in any one of their first three years of use will trigger commercial negotiations between NHS England and the drug company – was introduced in April, amid much controversy. Many argue the threshold is too low and will have an unacceptable impact on the availability of new medicines.
Efficacy and side‐effects of oral contraceptives
Authors: MacGregor Anne
Published: August 2017

For the majority of women, oral contraception is safe, convenient and effective, but users should be counselled about potential adverse effects and the importance of good adherence. This review discusses the efficacy, advantages and disadvantages of both combined and progestogen‐only oral contraceptives.
Tofacitinib: a janus kinase inhibitor for rheumatoid arthritis
Authors: Chaplin Steve
Published: August 2017

Tofacitinib (Xeljanz) is an oral janus kinase (JAK) inhibitor indicated for the second‐line treatment of moderate to severe active rheumatoid arthritis in adults. This article discusses its properties, efficacy and adverse effects.
Diagnosis and management of spondyloarthritis in the over‐16s
Authors: Chaplin Steve
Published: August 2017

In February, NICE published its first clinical guideline on spondyloarthritis in adults (NG65). This article provides a short summary of the guidance.
A Polaronic View of Impact Ionization in Amorphous Se Films
Authors: Tanaka Keiji
Published: August 2017

In this letter, it is proposed that the impact ionization in amorphous Se films, which triggers avalanche carrier multiplications, occurs through transformations of electron and hole motions from polaronic to supersonic states, the situation resembling those envisaged for semiconducting one‐dimensional organic polymers. However, reflecting unique origins of the conduction and the valence band in Se, the electron–lattice interaction appears stronger than the hole–lattice interaction, which seems to be responsible for characteristic properties such as less efficient electron multiplication. The idea is consistent with the fact that a‐Si:H having three‐dimensional structures exhibits no corresponding phenomena.