bluuebunny/crossref_metadata_2025 huggingface dataset:
Verification of Requirements: System of Systems Theory, Framework, Formalisms, Validity
Authors: Langford Gary O.
Published: August 2017

Building on the success of systems verification, a new approach and method were developed to improve verification of requirements for system of systems. Following the formal logic (mereology) of Leśniewski, an integrative framework was structured on ontology‐based artifacts built from objects and processes within the problem domain. Meta‐structures of systems and system of systems artifacts were extracted to form a model of verification to a system of systems and its constituent systems.
Acquisition System Development: A Complex System Governance Perspective
Authors: Keating Charles B. , Katina Polinpapilinho F. , Jaradat Ra'ed , Bradley Joseph M. , Gheorghe Adrian V.
Published: August 2017

The acquisition field is experiencing increasing levels of system complexity, environmental turbulence, and uncertainty. This is representative of the reality facing the acquisition field and practitioners. This paper examines the potential contributions that Complex System Governance (CSG) can make to the challenges facing the acquisition field. CSG is an emerging field focused on the design, execution, and evolution of complex systems. CSG is drawn from the foundations of Systems Theory (principles that define behavior of systems), Management Cybernetics (science of effective system structural organization), and System Governance (provision of system direction, oversight, and accountability). CSG is targeted to systems such as acquisition that are struggling to sustain performance in the midst of an increasingly complex environment, unrelenting expectations, and difficult circumstances. Following a brief introduction, we pursue three primary objectives, including: (1) examination of the foundations and fundamental concepts of CSG, (2) exploration of the contributions that CSG can offer for enhancing the acquisition field, and (3) suggestion of a path forward for further exploration of CSG to improve acquisition capabilities and performance. The paper concludes with a set of specific acquisition challenges for incorporation of CSG to advance the acquisition field.
Value based Architecture of Digital Product‐Service Systems
Authors: Kumar Anand , Lokku Doji Samson , Zope Nikhil R , Reddypogu Jose Kumar
Published: August 2017

Today, innovating new systems, solutions and services at unprecedented rates is critical for the survival of businesses in any industry sector. Increasingly, such innovations are enabled by digital technologies. This is evident by the increasing digital components in products‐service systems. As a result, the world at large is witnessing a massive pace of digitization, wherein, businesses are adopting digital as the vehicle to innovate their business offerings. While there exists numerous architecture frameworks, processes and reference models for architecture of enterprises, systems, products, software and services, it is often the case that most of these artefacts are not suited for architecting digital product‐service systems. This paper presents a value based approach for architecting digital product‐service systems. This approach is based on the premise that any business offering should provide superior customer experience, increase customer delight and assert customer satisfaction and its architecture should address how it contributes to achieving these outcomes.
The myths and the reality of problem‐solving
Authors: Kasser Joseph , Zhao Yang‐Yang
Published: August 2017

Observations of the ubiquitous problem‐solving process have identified the existence of six myths and their corresponding realities. These myths hamper the problem‐solver and an understanding of the reality will help the problem‐solver to solve problems in a more effective and innovative manner. This paper documents and discusses six myths and their corresponding realities.
An Innovative Program to Further the Careers of Women as Leaders in Engineering
Authors: Hahn Heidi Ann , Lynn Barbara A.
Published: August 2017

This paper describes an initiative of the Los Alamos National Laboratory (LANL), the objective of which is to create a pipeline of female engineers to fill needs for a diverse mid‐career workforce. The program focuses on recruiting high‐performing junior‐level female engineering students, from any discipline, with the goal of retaining them through at least two years post‐Master's degree employment. Among the interventions is an affinity group approach, with cohorts receiving specialized networking and professional development opportunities to ensure successful workplace socialization. Additionally, LANL believes it is important that all discipline engineers appreciate the need to consider systems as a whole and to be aware of the interrelationships among the parts. An R&D Engineering Primer, which includes systems engineering content, is used in the first year activities and Design Thinking is incorporated into the second year. Results are promising: 100% of the first cohort are returning. However, longitudinal studies will be required to confirm the program's effectiveness in retaining women in engineering throughout their careers.
System Engineering Analysis of Construction Equipment Operation in the Latin America
Authors: Azevedo Kurt , Olsen Daniel
Published: August 2017

The Latin American region has many important ongoing infrastructure projects. It is a global source of mining materials such as copper and iron. Thus, the region is an important market for construction equipment manufacturers such as Caterpillar, John Deere, Komatsu, Volvo, and CNH. However, it is not financially feasible for these manufactures to test construction machines in all 33 countries. Consequently, there is a significant lack of engine system understanding in this region due to its diverse operating conditions. This research provides a system engineering analysis of how diesel engine durability is affected by the environmental factors such as altitude and fuel quality in Latin America. Examination of engine oil analyses shows that oil condition provides a leading indicator of premature internal engine wear in Latin America. The study further relates environment factors in Latin America such as altitude to machine diagnostic trouble codes.
A Systematic Approach to Influencing System Security Standards
Authors: Kepchar Kenneth J
Published: August 2017

System Security Engineering is a specialty domain of System Engineering as defined in the INCOSE System Engineering Handbook V4. To effectively integrate security practices, processes, and concepts into System Engineering requires considerable thought and effort. One of the opportunities to accomplish this is in the standards domain. This paper discusses an ongoing INCOSE initiative to influence the contents of security standards under development for compatibility with Systems Engineering principles and practices.
Improving the Systems Thinking Skills of the Systems Architect via Aesthetic Interpretation of Art
Authors: McDermott Tom , Salado Alejandro
Published: August 2017

Systems engineering has been considered for a long time both an art and a science. In fact, previous work has shown that principles and practices of systems engineering are exhibited in the creation of a film original score, a major artistic endeavor, and that some of the concepts employed in artistic painting to convey beauty are also used by system architects to reduce complexity and achieve elegance. Reflecting on the authors' experience as practitioners and educators of systems thinking and systems architecting, this paper discusses a common linkage between art and systems engineering through a third discipline, systems thinking, which has a unique role in helping us understand the dynamic nature of complex systems. Then we elaborate a learning model that relates art, systems thinking, and systems architecture, which results in a number of propositions to improve the systems thinking skills of systems architects via learning aesthetic interpretation of art.
A Complete Set of Systems Thinking Skills
Authors: Arnold Ross D. , Wade Jon P.
Published: August 2017

This paper proposes a complete set of systems thinking skills for use across many different disciplines. The paper places particular emphasis on the ability to assess each of the skills quantitatively, a comprehensible description of the skills, and the completeness of the set. The proposed skills were derived from a review of the literature, the application of systems thinking experience, and the application of systems thinking to itself. Several different sets of systems thinking skills can be found throughout the systems community, but common key concepts can be distilled from these sets. When combinations of these concepts are considered separately, holistically, and together as a system, a single, cohesive set of skills emerges.

Systems thinking is widely believed to be of critical importance across many different fields; it has been said that skillful use of systems thinking skills could have prevented such disasters as World War II, the Great Depression, and the Challenger space shuttle disaster, as well as lessened or avoided the effects of many major environmental disasters. At the opposite send of the spectrum, systems thinking can be used to enhance health care, improve the economy, improve technology, laws, international and interpersonal relationships, schools, organizations, and so much more. However, this very useful skill set still lingers outside mainstream education. To address this problem, a set of assessable, comprehensible systems thinking skills is required. Such skills are defined, described, and detailed in this paper.
Integrated Data as the Foundation of Systems Engineering
Authors: Wheatcraft Louis S. , Ryan Michael J. , Svensson Carl
Published: August 2017

This paper was written from the perspective that requirements, along with all work products, models, designs, documents, diagrams, drawings, etc.) generated during the performance of System Engineering (SE) lifecycle process activities are represented by underlying data and information that must be linked together and integrated into a common, integrated dataset. Using this perspective, the common, integrated dataset can be viewed as the foundation of Systems Engineering.

The authors feel this data‐centric perspective of SE provides a better lens through which to acquire a complete understanding of the SE lifecycle process activities and resulting work products and underlying data and information needed to manage the development of increasingly complex systems of the future. This perspective aids in acquiring a practical understanding of the SE lifecycle processes from the perspective of not only models, but all work products that are generated from activities conducted during each of the SE lifecycle processes and the underlying data and information used to represent these work products.

Expanding on the concept of SE from a data‐centric perspective, the goal of this paper is to present a broader data‐centric perspective of SE that meets that will aid readers in successfully meeting the challenges associated with today's ever increasingly complex systems, meeting the intent of the MBSE Initiative, and helping organizations move toward INCOSE's Vision 2025.
Developing A Systems Engineering Capability That Meets the Needs of Your Organization
Authors: Wheatcraft Louis S. , Svensson Carl , Ryan Michael J.
Published: August 2017

This paper was written from the perspective that requirements, along with all work products (models, designs, documents, diagrams, drawings, etc.) generated during the performance of System Engineering (SE) lifecycle process activities are represented by underlying data and information that must be integrated into a common, integrated dataset. From this data‐centric perspective, the common, integrated dataset can be viewed as the foundation of Systems Engineering. Based on this perspective, this paper discusses what it means to practice SE from a data‐centric perspective and provides the reader guidance that can be used to understand and successfully create and manage an integrated dataset within their organization.
Trains, Planes and Endoscopes: Using Capability Systems Engineering to reduce hospital‐acquired infections
Authors: O'Neil Meaghan , Kemp Duncan
Published: August 2017

Capability Systems Engineering can be used to reduce healthcare‐acquired infections caused by contaminated medical devices. We use examples from rail and defence systems to illustrate how this approach can include operational capabilities and systems of systems. We also provide a demonstration of techniques used to create improvements in the development, regulation and reprocessing of reusable medical devices, and provide a case study of preventing infections associated with endoscopes. This work reflects an ongoing collaboration between INCOSE and the Association for the Advancement for Medical Instrumentation (AAMI). It has been undertaken in support of the AAMI initiative to use a systems approach to reduce healthcare‐acquired infections.
Applying Bayesian Networks to TRL Assessments – Innovation in Systems Engineering
Authors: Austin Marc F. , Homberger Cheyne , Ahalt Virginia , Doolittle Erin , Polacek George A. , York Donald M.
Published: August 2017

Currently, Technology Readiness Assessments (TRAs) are used in determining the maturity of the Critical Technology Elements (CTEs) of a system as it moves forward in the system development life cycle. The TRA method uses Technology Readiness Levels (TRLs) as the decision metric. TRL values are assessed and determined by Subject Matter Experts (SMEs). Since expert evaluators often differ in their judgment when scoring a system element against the TRL scale criteria, this paper argues for the use of a Bayesian network model to provide a mathematical method to consistently combine and validate the judgment of these SMEs and increase the confidence in the determination of the readiness of system components and their technologies.
Breaking Out: Systems Engineering To Go
Authors: Scott Zane
Published: August 2017

Systems engineering grew up in the mil‐aero market space. This shaped the discipline in a number of ways. For several decades, the practice developed and grew in a space with plenty of opportunity and revenue for practitioners. But the market space is changing. Funding is shrinking and the nature of warfare is swinging away from the need for large, complex physical systems. This is pressuring the traditional systems engineering market space.

This paper explores some of the possible response to this pressure and the obstacles to those responses. Systems engineers are faced with the need to think differently about their discipline. Meeting the challenges of breaking out of the traditional space is no insignificant undertaking. Some suggestions regarding how to approach this situation are the main thrust of the paper.

The purpose here is to help practitioners see opportunities in non‐traditional markets and enable communication with potential customers. There has already been excellent work in leveraging communication between systems practitioners in different areas (Martin et al, 2013) It is not the object to repeat or expand on those but to focus on the practitioners themselves and how they see and interact with their new markets.
A Graph Theory Approach to Functional Failure Propagation in Early Complex Cyber‐Physical Systems (CCPSs)
Authors: O'Halloran Bryan M. , Papakonstantinou Nikolaos , Giammarco Kristin , Van Bossuyt Douglas L.
Published: August 2017

This paper presents a framework to quantify failure propagation potential for complex, cyber‐physical systems (CCPSs) during the conceptual stages of design. This method is referred to as the Function Failure Propagation Potential Methodology (FFPPM). This research is motivated by recent trends in engineering design. As systems become increasingly connected, an open area of research for CCPSs is to move reliability and failure assessments earlier in the engineering design process. This allows practitioners to make decisions at a point in the design process where the decision has a high impact and a low cost. Standard methods are limited by the availability of data and often rely on detailed representations of the system. As such, they have not addressed failure propagation in the functional design prior to selecting candidate architectures. To develop the metrics, graph theory is used to model and quantify the connectedness of the functional block diagram (FBD). These metrics quantify (1) the summation of the reachability matrix and (2) the summation of the number of paths between nodes (functions within system models) i and j for all i and j. From a practical standpoint, these metrics quantify the reachability between functions in the graph and the number of paths between functions defines the failure propagation potential of that failure. The unique contribution of this research is to quantify failure propagation potential during conceptual design prior to selecting candidate architectures. The goal of these metrics is to produce derived system requirements, based on an analysis, that focus on minimizing the impact of failures.
Apps to Bridge the Gap: Developing the Third Space With Apps
Authors: Thomas Katie M.
Published: August 2017

This forum highlights and evaluates apps, computer programs, and websites that teachers, students, and other interested parties can use to explore, research, and engage in content learning and literacy practices.
Reading the World: Toward a Praxis of Inquiry, Critical Literacy, and Cultural Knowledge
Authors: Kazembe Lasana
Published: August 2017

Most people have struggled with reading in one situation or another, depending on their appreciation for the content, their prior experiences, and the texts. This department column shares ways for educators to help literacy learners unlock their potential with instruction anchored in their skills, knowledge, ways of learning, interests, and attitudes.
Imaging lymphatics in human normal and lymphedema limbs—Usefulness of various modalities for evaluation of lymph and edema fluid flow pathways and dynamics
Authors: Zaleska Marzanna T. , Olszewski Waldemar L.
Published: August 2017

The human lymphatic system morphology and function still remain largely unknown to clinicians and biologists. How does the lymphatic vascular system look like in comparison to the blood transport system, how does lymph flow, where does capillary filtrate accumulate in cases with lymphatic obstruction caused by inflammation, trauma, and cancer therapy, remain as basic questions. Visualization of the lymphatic pathways and dynamics of lymph flow, and in cases of obstruction, the localization of the capillary filtrate/edema fluid accumulation becomes indispensable. The contemporary methods only partly meet these requirements. Since the early 1950s of the 20th century only few specific clinical methods of imaging of limb lymphatics are being used in human clinic. Each of the applied modalities provides different images due to different physical chemistry and distribution of tracer, methods used for its detection in tissues, their sensitivity and specificity and clinical type of lymph vessel pathology. Here, the advantages and disadvantages of the most commonly used 3 methods of imaging: the iodinated oil X‐ray, isotopic, and fluorescent lympangiographies are presented. The study is based on retrospective and recent collections of lymphangiograms from large cohorts of patients. Imaging of lymph nodes has not been included as it is requiring different interpretation compared with vessels. Composite evaluation of X‐ray, isotopic, and fluorescent lymphographic images or, as it is practiced now the isotope and indocyanine green near infrared lymphographies, provide most clinically important information. Special attention was directed at methods enabling early diagnosis of imminent lymphedema especially in cases with cancer therapy‐related lymphedema. Groups of typical images obtained with the 3 methods are presented.
High Bone Turnover in Mice Carrying a Pathogenic Notch2 Mutation Causing Hajdu-Cheney Syndrome
Authors: Vollersen Nele , Hermans-Borgmeyer Irm , Cornils Kerstin , Fehse Boris , Rolvien Tim , Triviai Ioanna , Jeschke Anke , Oheim Ralf , Amling Michael , Schinke Thorsten , Yorgan Timur Alexander
Published: August 2017

Hajdu-Cheney syndrome (HCS) is a rare autosomal-dominant disorder primarily characterized by acro-osteolysis and early-onset osteoporosis. Genetically, HCS is caused by nonsense or deletion mutations within exon 34 of the NOTCH2 gene, resulting in premature translational termination and production of C-terminally truncated NOTCH2 proteins that are predicted to activate NOTCH2-dependent signaling. To understand the role of Notch2 in bone remodeling, we developed a mouse model of HCS by introducing a pathogenic mutation (6272delT) into the murine Notch2 gene. By μCT and undecalcified histology, we observed generalized osteopenia in two independent mouse lines derived by injection of different targeted embryonic stem (ES) cell clones, yet acro-osteolysis did not occur until the age of 52 weeks. Cellular and dynamic histomorphometry revealed a high bone turnover situation in Notch2+/HCS mice, since osteoblast and osteoclast indices were significantly increased compared with wild-type littermates. Whereas ex vivo cultures failed to uncover cell-autonomous gain-of-functions within the osteoclast or osteoblast lineage, an unbiased RNA sequencing approach identified Tnfsf11 and Il6 as Notch-signaling target genes in bone marrow cells cultured under osteogenic conditions. Because we further observed that the high-turnover pathology of Notch2+/HCS mice was fully normalized by alendronate treatment, our results demonstrate that mutational activation of Notch2 does not directly control osteoblast activity but favors a pro-osteoclastic gene expression pattern, which in turn triggers high bone turnover. © 2017 American Society for Bone and Mineral Research.
Increased Risk of Breast Cancer at a Young Age in Women with Fibrous Dysplasia
Authors: Majoor Bas CJ , Boyce Alison M , Bovée Judith VMG , Smit Vincent THBM , Collins Michael T , Cleton-Jansen Anne-Marie , Dekkers Olaf M , Hamdy Neveen AT , Dijkstra PD Sander , Appelman-Dijkstra Natasha M
Published: August 2017

Fibrous dysplasia (FD) is a rare bone disorder caused by mutations of the GNAS gene, which are also identified in malignancies. We explored the potential relationship between breast cancer and fibrous dysplasia in two fibrous dysplasia cohorts from the Netherlands and the United States. Data on fibrous dysplasia and breast cancer diagnosis were retrieved from hospital records of 134 (Netherlands) and 121 (US) female patients. Results were validated with breast cancer data of 645 female fibrous dysplasia patients from the Dutch Pathology Registry (PALGA). Standardized morbidity ratios for breast cancer were estimated with data from Dutch and US general population registries. GNAS mutation was analyzed in 9 available breast cancer specimens. A combined total of 15 patients (6 polyostotic, 9 McCune-Albright Syndrome) had breast cancer (87% thoracic localizations). In the Netherlands, a breast cancer incidence rate of 7.5% at median age of 46 years was validated in PALGA (6.5% at age 51 years). Breast cancer risk was 3.4-fold increased (95% confidence interval [CI] 1.6–5.9) compared with the Dutch general population; OR 13.2-fold (95% CI 6.2–22.8) in thoracic disease. In the US cohort, breast cancer incidence rate was 4.5% at a median age of 36 years. Breast cancer risk was 3.9-fold increased (95% CI 1.2–8.2) compared with the general population; 5.7-fold (95% CI 1.4–13.0) in thoracic disease. GNAS mutation was positive in 4 breast cancer specimens (44%). Risk of breast cancer is increased at a younger age, particularly in polyostotic FD, suggesting that screening for breast cancer should be considered in this particular group at a younger age than currently advocated by national guidelines. © 2017 American Society for Bone and Mineral Research.
Leucine supplementation after mechanical stimulation activates protein synthesis via L‐type amino acid transporter 1 in vitro
Authors: Nakai Naoya , Kawano Fuminori , Murakami Taro , Nakata Ken , Higashida Kazuhiko
Published: August 2017

Branched‐chain amino acid supplements consumed following exercise are widely used to increase muscle mass. Although both exercise (ie, mechanical stimulation) and branched‐chain amino acid leucine supplementation have been reported to stimulate muscle protein synthesis by activating the mammalian target of rapamycin (mTOR) signaling pathway independently, the mechanisms underlying their synergistic effects are largely unknown. Utilizing cultured differentiated C2C12 myotubes, we established a combination treatment model in which the cells were subjected to cyclic uniaxial mechanical stretching (4 h, 15%, 1 Hz) followed by stimulation with 2 mM leucine for 45 min. Phosphorylation of p70 S6 kinase (p70S6K), an mTOR‐regulated marker of protein translation initiation, was significantly increased following mechanical stretching alone but returned to the baseline after 4 h. Leucine supplementation further increased p70S6K phosphorylation, with a greater increase observed in the stretched cells than in the non‐stretched cells. Notably, the expression of L‐type amino acid transporter 1 (LAT1), a stimulator of the mTOR pathway, was also increased by mechanical stretching, and siRNA‐mediated knockdown partially attenuated leucine‐induced p70S6K phosphorylation. These results suggest that mechanical stretching promotes LAT1 expression and, consequently, amino acid uptake, leading to enhanced leucine‐induced activation of protein synthesis. LAT1 has been demonstrated to be a point of crosstalk between exercise‐ and nutrition‐induced skeletal muscle growth.
Co‐expression analysis reveals key gene modules and pathway of human coronary heart disease
Authors: Tang Yu , Ke Zun‐Ping , Peng Yi‐Gen , Cai Ping‐Tai
Published: August 2017

Coronary heart disease is a kind of disease which causes great injury to people world‐widely. Although gene expression analyses had been performed previously, to our best knowledge, systemic co‐expression analysis for this disease is still lacking to date. Microarray data of coronary heart disease was downloaded from NCBI with the accession number of GSE20681. Co‐expression modules were constructed by WGCNA. Besides, the connectivity degree of eigengenes was analyzed. Furthermore, GO and KEGG enrichment analysis was performed on these eigengenes in these constructed modules. A total of 11 co‐expression modules were constructed by the 3000 up‐regulated genes from the 99 samples with coronary heart disease. The average number of genes in these modules was 270. The interaction analysis indicated the relative independence of gene expression in these modules. The functional enrichment analysis showed that there was a significant difference in the enriched terms and degree among these 11 modules. The results showed that modules 9 and 10 played critical roles in the occurrence of coronary disease. Pathways of hsa00190 (oxidative phosphorylation) and (hsa01130: biosynthesis of antibiotics) were thought to be closely related to the occurrence and development of coronary heart disease. Our result demonstrated that modules 9 and 10 were the most critical modules in the occurrence of coronary heart disease. Pathways as hsa00190 (oxidative phosphorylation) and (hsa01130: biosynthesis of antibiotics) had the potential to serve as the prognostic and predictive marker of coronary heart disease.
A novel splicing isoform of protein arginine methyltransferase 1 (PRMT1) that lacks the dimerization arm and correlates with cellular malignancy
Authors: Patounas Odysseas , Papacharalampous Ioanna , Eckerich Carmen , Markopoulos Georgios S. , Kolettas Evangelos , Fackelmayer Frank O.
Published: August 2017

Methylation of arginine residues is an important modulator of protein function that is involved in epigenetic gene regulation, DNA damage response and RNA maturation, as well as in cellular signaling. The enzymes that catalyze this post‐translational modification are called protein arginine methyltransferases (PRMTs), of which PRMT1 is the predominant enzyme. Human PRMT1 has previously been shown to occur in seven splicing isoforms, which are differentially abundant in different tissues, and have distinct substrate specificity and intracellular localization. Here we characterize a novel splicing isoform which does not affect the amino‐terminus of the protein like the seven known isoforms, but rather lacks exons 8 and 9 which encode the dimerization arm of the enzyme that is essential for enzymatic activity. Consequently, the isoform does not form catalytically active oligomers with the other endogenous PRMT1 isoforms. Photobleaching experiments reveal an immobile fraction of the enzyme in the nucleus, in accordance with earlier results from our laboratory that had shown a tight association of inhibited or inactivated PRMT1 with chromatin and the nuclear scaffold. Thus, it apparently is able to bind to the same substrates as catalytically active PRMT1. This isoform is found in a variety of cell lines, but is increased in those of cancer origin or after expression of the EMT‐inducing transcriptional repressor Snail1. We discuss that the novel isoform could act as a modulator of PRMT1 activity in cancer cells by acting as a competitive inhibitor that shields substrates from access to active PRMT1 oligomers.
Autophagy‐dependent crosstalk between GILT and PAX‐3 influences radiation sensitivity of human melanoma cells
Authors: Hathaway‐Schrader Jessica D. , Doonan Bently P. , Hossain Azim , Radwan Faisal F.Y. , Zhang Lixia , Haque Azizul
Published: August 2017

Melanoma represents an ever‐increasing problem in the western world as incidence rates continue to climb. Though manageable during early stages, late stage metastatic disease is highly resistant to current intervention. We have previously shown that gamma‐interferon‐inducible lysosomal thiol‐reductase (GILT) enhances HLA class II antigen processing and immune detection of human melanoma cells. Here we report that GILT expression inhibits a potential target, paired box‐3 (PAX‐3) protein, in late stage human metastatic melanoma. We also show that GILT transfection or induction by IFN‐γ, decreases PAX‐3 protein expression while upregulating the expression of Daxx, which is also a repressor of PAX‐3. Confocal microscopic analysis demonstrated that GILT co‐localizes with PAX‐3 protein, but not with Daxx within melanoma cells. Immunoprecipitation and immunoblotting studies suggest that GILT expression negatively regulates PAX‐3 through the autophagy pathway, potentially resulting in increased susceptibility to conventional treatment in the form of chemotherapy or radiotherapy. While high‐dose radiation is a common treatment for melanoma patients, our data suggest that GILT expression significantly increased the susceptibility of melanoma cells to low‐dose radiation therapy via upregulation of tumor suppressor protein p53. Overall, these data suggest that GILT has multiple roles in inducing human melanoma cells as better targets for radiation and immunotherapy.
Retracted: ZIC2 promotes viability and invasion of human osteosarcoma cells by suppressing SHIP2 expression and activating PI3K/AKT pathways
Authors: Huang Shuaihao , Jin Anmin
Published: August 2017

Osteosarcoma is a malignant tumor of the skeletal system. The zinc finger transcription factor ZIC2 has been reported to be highly expressed in human cancers. The present study evaluated the effects of ZIC2 and the possible underlying mechanisms in the human osteosarcoma cells. The expression levels of ZIC2 in human fetal osteoblastic cell line (hFOB1.19), osteosarcoma cell lines (U‐2OS, SaoS2, and MG63), normal bone tissue, and osteosarcoma tumor were analyzed by Western blot, and real‐time quantitative RT‐PCR (qRT‐PCR). Osteosarcoma cells with either overexpressed ZIC2 or suppressed ZIC2 were analyzed to determine cell viability, colony formation, and cell invasion. The expressions of SHIP2 and PI3K/AKT signal pathway‐related proteins were analyzed by Western blot and qRT‐PCR. We first showed that ZIC2 is highly expressed in osteosarcoma cells and tissues. Then we demonstrated that overexpression of ZIC2 promoted viability, migration, and invasion of osteosarcoma cells, whereas suppression of ZIC2 showed opposite effects. Furthermore, SHIP2 expression was negatively regulated by ZIC2. Importantly, ZIC2 overexpression activated the PI3K/AKT signal pathway; however, overexpressed SHIP2 inhibited these effects. Lastly, we showed that activation of the PI3K/AKT signal pathway is essential for the effects of ZIC2 on osteosarcoma cells, as the effects of ZIC2 on the osteosarcoma cells were reversed by a PI3K/AKT inhibitor. Overall, ZIC2 is highly expressed in osteosarcoma cells and tissues, and its overexpression promotes viability, invasion of osteosarcoma cells via SHIP2 suppression, and PI3K/AKT activation. Thus, ZIC2 can be considered as a novel drug target for osteosarcoma management.
Retracted: Down‐regulation of the long noncoding RNA‐HOX transcript antisense intergenic RNA inhibits the occurrence and progression of glioma
Authors: Yang Bin , Wei Zhen‐Yu , Wang Bang‐Qing , Yang Hua‐Chao , Wang Jun‐Yi , Bu Xing‐Yao
Published: August 2017

This study aims to explore the role of long noncoding RNA (lncRNA)‐HOX transcript antisense intergenic RNA (HOTAIR) in the occurrence and progression of glioma. Fresh glioma and normal brain tissues were classified into a glioma group (n = 67) and a normal group (n = 64) respectively. U87 cells were assigned into the blank, sh‐NC, and sh‐HOTAIR groups. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was utilized to determine HOTAIR expression. Cell proliferation, cell cycle and cell apoptosis rates were detected by cell counting kit‐8 (CCK‐8) and flow cytometry (FCM). Scratch test and transwell assay were conducted for cell migration and invasion. Orthotopic glioma tumor model in nude mice was established by inoculating tumor cell suspension. Hematoxylin‐Eosin (HE) staining was used to observe the growth and invasion of orthotopic glioma tumors. The expression of HOTAIR and cell viability was found to be lowest in the sh‐HOTAIR group among the three groups. The sh‐HOTAIR group exhibited a higher apoptotic rate and lower number of cell migration compared with the blank and sh‐NC groups. Additionally, the speed of wound healing was slower, the migration distance decreased and the survival time of nude mice was extended in the sh‐HOTAIR compared to the other groups. Moreover, the sh‐HOTAIR group demonstrated reduced lesion sizes and inflammation, no convulsions or hemiplegia and lesser number of satellite metastases. Our findings support that down‐regulation of HOTAIR could inhibit cell proliferation, promote cell apoptosis as well as suppress cell invasion and migration in the progression of glioma.
Rhorix: An interface between quantum chemical topology and the 3D graphics program blender
Authors: Mills Matthew J. L. , Sale Kenneth L. , Simmons Blake A. , Popelier Paul L. A.
Published: August 2017

Chemical research is assisted by the creation of visual representations that map concepts (such as atoms and bonds) to 3D objects. These concepts are rooted in chemical theory that predates routine solution of the Schrödinger equation for systems of interesting size. The method of Quantum Chemical Topology (QCT) provides an alternative, parameter‐free means to understand chemical phenomena directly from quantum mechanical principles. Representation of the topological elements of QCT has lagged behind the best tools available. Here, we describe a general abstraction (and corresponding file format) that permits the definition of mappings between topological objects and their 3D representations. Possible mappings are discussed and a canonical example is suggested, which has been implemented as a Python “Add‐On” named Rhorix for the state‐of‐the‐art 3D modeling program Blender. This allows chemists to use modern drawing tools and artists to access QCT data in a familiar context. A number of examples are discussed. © 2017 The Authors. Journal of Computational Chemistry Published by Wiley Periodicals, Inc.
Green's Function and Eigenvalue Representation of Time Lag for Absorptive Permeation Across a Heterogeneous Membrane
Authors: Chen Jenn‐Shing , Yeh Kwei‐Tin , Chang Wen‐Yih
Published: August 2017

The time‐lag problem is treated for absorptive penetration across a heterogeneous membrane, where both the diffusivity D(x) and the partition coefficient K(x) depend on the coordinate x (0 ≦ x ≦  h), with 0 and h being the coordinates of the upstream and downstream faces, respectively. A new concept of time‐lag distribution is introduced, and the first (time) moment and the second (time) moment over this distribution are also difined and treated in the Lapalce domain in conjuction with the Green's function G(x,y), and eigenvalues associated with the time‐independent diffusion equation subject to the absorbing boundary condition at both ends of the membrane. Our central results include and , where λi is the ith eigenvalue of the aforementioned diffusion equation. The merits of these new resprentations and comparison with the treatments of Frisch or Eyring are also discussed.
Glycated hemoglobin: A powerful tool not used enough in primary care
Authors: Salinas Maria , López‐Garrigós Maite , Flores Emilio , Leiva‐Salinas Carlos ,   the Pilot Group of the Appropriate Utilization of Laboratory Tests
Published: August 2017

Background

Glycated haemoglobin (HbA1c) is one of the most useful and relevant laboratory tests currently available. The aim of the actual research was to study the variability and appropriateness in the request of HbA1c in primary care, and differences between regions, to assess if there would be an opportunity to improve the request.

Methods

A cross‐sectional study was conducted enrolling clinical Spanish laboratories. The number of HbA1c requested in 2014 by all general practitioners was reported by each participant. Test‐utilization rate was expressed as tests per 1000 inhabitants. The index of variability was calculated, as the top decile divided by the bottom decile. HbA1c per 1000 inhabitants was compared between the different regions. To investigate whether HbA1c was appropriately requested to manage patients with diabetes, the real request was compared to the theoretically ideal number, according to prevalence of known diabetes mellitus in Spain and guideline recommendations.

Results

A total of 110 laboratories participated in the study, corresponding to a catchment area of 27 798 262 inhabitants (59.8% of the Spanish population) from 15 different autonomous communities (AACCs). 2 655 547 HbA1c were requested, a median of 93.9 (interquartile range (IQR): 33.4) per 1000 inhabitants. The variability index was 1.97. The HbA1c/1000 inhabitants was significantly different among the AACCs, ranging from 73.4 to 126.3.

A total of 4 336 529 additional HbA1c would have been necessary to manage patients with diabetes according to guidelines, and 3 861 769 for diagnosis in asymptomatic patients.

Conclusions

There was a high variability and significant differences between Spanish AACCs. Also a significant under‐request of HbA1c was observed in Primary Care in Spain.
Syntheses of Some New N‐Linked Pyrimidine‐2‐amines with Pyrazinopyrimidines, Thienopyrimidines, and Benzazoles via Reactions of Various Nucleophiles with Cyanamides
Authors: Moustafa Amr Hassan , Ahmed Walaa Wefki , Khodairy Ahmed
Published: August 2017

New heterocycles containing 2‐aminopyrimidine moiety linked with pyrazino[1,2‐c]pyrimidines, thieno[2,3‐d]pyrimidines, benzimidazoles, benzothiazoles, and benzoxazoles have been prepared by an efficient method starting from N‐(pyrimidin‐2‐yl)cyanamides.
Synthesis, radiofluorination, and preliminary evaluation of the potential 5‐HT2A receptor agonists [18F]Cimbi‐92 and [18F]Cimbi‐150
Authors: Edgar Fraser Graeme , Hansen Hanne D. , Leth‐Petersen Sebastian , Ettrup Anders , Kristensen Jesper L. , Knudsen Gitte M. , Herth Matthias M.
Published: August 2017

An agonist PET tracer is of key interest for the imaging of the 5‐HT2A receptor, as exemplified by the previously reported success of [11C]Cimbi‐36. Fluorine‐18 holds several advantages over carbon‐11, making it the radionuclide of choice for clinical purposes. In this respect, an 18F‐labelled agonist 5‐HT2A receptor (5‐HT2AR) tracer is highly sought after. Herein, we report a 2‐step, 1‐pot labelling methodology of 2 tracer candidates. Both ligands display high in vitro affinities for the 5‐HT2AR. The compounds were synthesised from easily accessible labelling precursors, and radiolabelled in acceptable radiochemical yields, sufficient for in vivo studies in domestic pigs. PET images partially conformed to the expected brain distribution of the 5‐HT2AR; a notable exception however being significant uptake in the striatum and thalamus. Additionally, a within‐scan displacement challenge with a 5‐HT2AR antagonist was unsuccessful, indicating that the tracers cannot be considered optimal for neuroimaging of the 5‐HT2AR.
Purification and properties of beta‐cyclomaltodextrin glucanotransferase from Bacillus flexus SV 1
Authors: Reddy Shwetha V. , More Sunil S. , Annappa Goutham S.
Published: August 2017

Cyclomaltodextrin glucanotransferase is a unique enzyme that degrades starch into cyclic oligosaccharides called cyclodextrins, which have numerous applications in various industries such as pharmaceutical, textile, agricultural, cosmetics etc. Due to its wide applications, microorganism producing one type of cyclodextrin is of interest as it simplifies the down streaming process of separating mixture of cyclodextrins. In the present study, β‐CGTase was isolated from Bacillus flexus SV 1 and biochemically characterized. Enzyme was purified by starch adsorption followed by DEAE cellulose column chromatography which resulted in a fold purification of 6.1, with a yield of 44.07%. Molecular weight of the purified enzyme was found to be 96.68 kDa, enzyme was monomeric in nature with a Km and Vmax of 0.08976 μmol mL−1 and 585.1 μmol/ml/min, respectively. Optimum pH and temperature of the purified enzyme was found to be 8.0 and 60 °C. Ca2+ showed significant increase in enzyme activity. The inhibition of enzyme by EDTA indicates that CGTase is a metalloenzyme. CGTase produced majorly β‐CD and was alkalotolarent and active at high temperatures which is a promising candidate for various industries such as textile, food, agriculture, and pharmaceuticals.
A multi‐layer, closed‐loop system for continuous measurement of soil CO2 concentration
Authors: Jochheim Hubert , Wirth Stephan , von Unold Georg
Published: August 2017

We present a setup of measurement devices that allow the continuous measurement of CO2 concentrations at different soil depths using small nondispersive infrared (NDIR) sensors within a 16‐channel closed‐loop system. Hydrophobic, gas‐permeable polypropylene membrane tubes allow an equilibrium of CO2 concentration of circulating air, driven by peristaltic pumps, with soil air. The advantage of this system over other systems is the option to measure up to 16 channels without a time shift between individual measurements, as occurs when using a multiplexer system. Furthermore, the system prevents carry‐over effects. A 16‐position multiplexer provides a connection to an isotopic CO2 analyzer for measurement campaigns. This approach aimed to detect vertical concentration profiles and temporal variation of soil CO2 concentration and δ13C‐CO2 signature in soils and to determine the impact of underlying environmental drivers based on concurrent measurements of soil temperature and moisture. The system was tested by applying it in a beech and a pine forest stand during a period of 15 d. Soil CO2 concentrations were mostly determined by soil temperature as well as by soil moisture at a biweekly scale. At diel scale, the dynamic of soil CO2 concentrations followed the shape of soil temperature, sometimes with some time shift. The observed values of δ13C‐CO2 at 10–30 cm soil depths ranged between –22.0 and –19.0‰ at the beech site and –22.4 and –21.8‰ at the pine site, with a distinct vertical gradient at the beech site. Our results show that the system is reliable in practical application, capable of continuously detecting soil CO2 concentrations and its isotopic signature (δ13C‐CO2) with high temporal resolution.
Assessment of the effect of silver nanoparticles on the relevant soil protozoan genus Acanthamoeba
Authors: Grün Anna-Lena , Scheid Patrick , Hauröder Bärbel , Emmerling Christoph , Manz Werner
Published: August 2017

Silver nanoparticles (AgNP) are used in a broad range of consumer products and industrial applications. During the regular product life cycle and disposal, AgNP are continuously released into the environment. Hence, the aim of this study was to investigate the potential ecotoxicological effects of AgNP exposure on amoebae. The Acanthamoeba castellanii ATCC 30234 strain and environmental isolate Acanthamoeba strain C5/2, which are both affiliated with genotype T4, were chosen as representatives of ecologically important soil protozoan organisms. The amoebae were exposed to citrate‐stabilized AgNP (30 and 70 nm in size) for 24 h and 96 h at concentrations ranging from 600 µg L−1 to 20 mg L−1. A newly adopted cell culture based microscopic assay was applied to assess the adherence ability of the amoeba trophozoites. The general metabolic activity of Acanthamoeba was determined to be a second independent endpoint by means of intracellular reduction of the redox dye AlamarBlue®. The fate of AgNP within the amoebae and test solutions was visualized by light‐ and transmission electron microscopy (TEM). Both Acanthamoeba strains showed a significant dose‐dependent decrease of adherence ability (p < 0.04) and metabolic activity (p < 0.01) after 96 h of AgNP exposure. The environmental Acanthamoeba strain C5/2 lost both its adherence ability and metabolic activity at lower AgNP concentrations than the type strain, indicating a higher sensitivity to ionic silver. This was confirmed by the application of AgNO3, provoking a higher effect level in strain C5/2. AgNP was visualized intracellularly by transmission electron microscopy within the cytoplasm of Acanthamoeba. This is the first report to show the ecotoxicological effects of short‐term AgNP exposure on the soil protist Acanthamoeba, causing both changes in the adherence ability and metabolic activity of this amoeba. This combined approach may be a powerful tool in the future for predicting potential harmful ecotoxicological effects of AgNP exposure using soil protozoans.