bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonsynaptic glycine release is involved in the early KCC2 expression
Authors: Allain Anne‐Emilie , Cazenave William , Delpy Alain , Exertier Prisca , Barthe Christophe , Meyrand Pierre , Cattaert Daniel , Branchereau Pascal
Published: October 2015

The cation‐chloride co‐transporters are important regulators of the cellular Cl‐ homeostasis. Among them the Na+‐K+−2Cl− co‐transporter (NKCC1) is responsible for intracellular chloride accumulation in most immature brain structures, whereas the K+‐Cl− co‐transporter (KCC2) extrudes chloride from mature neurons, ensuring chloride‐mediated inhibitory effects of GABA/glycine. We have shown that both KCC2 and NKCC1 are expressed at early embryonic stages (E11.5) in the ventral spinal cord (SC). The mechanisms by which KCC2 is prematurely expressed are unknown. In this study, we found that chronically blocking glycine receptors (GlyR) by strychnine led to a loss of KCC2 expression, without affecting NKCC1 level. This effect was not dependent on the firing of Na+ action potentials but was mimicked by a Ca2+‐dependent PKC blocker. Blocking the vesicular release of neurotransmitters did not impinge on strychnine effect whereas blocking volume‐sensitive outwardly rectifying (VSOR) chloride channels reproduced the GlyR blockade, suggesting that KCC2 is controlled by a glycine release from progenitor radial cells in immature ventral spinal networks. Finally, we showed that the strychnine treatment prevented the maturation of rhythmic spontaneous activity. Thereby, the GlyR‐activation is a necessary developmental process for the expression of functional spinal motor networks. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 764–779, 2016
Hydrological controls on productivity of regenerating Sphagnum in a cutover peatland
Authors: Taylor Neil , Price Jonathan , Strack Maria
Published: October 2015

Recent research into the production of Sphagnum biomass in extracted peatlands, an alternative to ecological restoration as a post‐industrial use of peatlands, has highlighted the need for an improved understanding of the ecohydrology of Sphagnum regenerating in these environments. Previous work suggested that limited connectivity between surficial layers and the underlying partially decomposed plant matter and peat would result in water stress and inhibited growth. This study links the soil water dynamics of regenerated layers ranging in age from 3 to 43 years and from 3 to 40 cm in thickness to the productivity of Sphagnum in order to determine the hydrological controls on productivity and the optimal range of water content for producing Sphagnum biomass. Productivity was never observed to be limited by insufficient supply of water, including during periods where water table was >40 cm below the surface and periods of 16 days without measured precipitation. While layers of different ages and thicknesses were able to sustain adequate water supply to remain productive under a range of conditions, the ability of layers to transmit water upwards differed greatly. Water content in the near‐surface inhibited productivity during wetter periods, especially at newly regenerating sites where the layer was <5 cm thick. This has important implications for biomass production using the Sphagnum species studied here. Using a mixed linear modelling approach to isolate the effects of water content on variance in productivity from those of other measured variables, a volumetric water content of 0.10 is identified as optimal. Copyright © 2015 John Wiley & Sons, Ltd.
Inverse γ‐Turn‐Inspired Peptide: Synthesis and Analysis of Segetalin A Indole Hemi­aminal
Authors: Lamping Matthias , Enck Sebastian , Geyer Armin
Published: October 2015

Substitution of a peptide bond for an imine transforms the irreversible macrocyclization of peptides into a reversible process. The inherent cyclization tendency of a linear peptide is then analyzable through the equilibrium between the aldehyde and the imine by virtue of the higher reactivity of the corresponding linear peptide aldehyde. The tryptophan side chain of segetalin A aldehyde forms a 12‐membered cyclic indole hemiaminal instead of the 18‐membered macrocyclic imine expected. Herein, we analyzed this uncommon hemiaminal that shows that the biosynthesis of cyclic peptides is not necessarily based on linear precursor peptides with a high inherent macrolactamization tendency.
Egg-laying sequence influences egg mercury concentrations and egg size in three bird species: Implications for contaminant monitoring programs
Authors: Ackerman Joshua T. , Eagles-Smith Collin A. , Herzog Mark P. , Yee Julie L. , Hartman C. Alex
Published: October 2015

Bird eggs are commonly used in contaminant monitoring programs and toxicological risk assessments, but intraclutch variation and sampling methodology could influence interpretability. The authors examined the influence of egg-laying sequence on egg mercury concentrations and burdens in American avocets, black-necked stilts, and Forster's terns. The average decline in mercury concentrations between the first and last eggs laid was 33% for stilts, 22% for terns, and 11% for avocets, and most of this decline occurred between the first and second eggs laid (24% for stilts, 18% for terns, and 9% for avocets). Trends in egg size with egg-laying order were inconsistent among species, and overall differences in egg volume, mass, length, and width were <3%. The authors summarized the literature, and among 17 species studied, mercury concentrations generally declined by 16% between the first and second eggs laid. Despite the strong effect of egg-laying sequence, most of the variance in egg mercury concentrations still occurred among clutches (75–91%) rather than within clutches (9%–25%). Using simulations, the authors determined that accurate estimation of a population's mean egg mercury concentration using only a single random egg from a subset of nests would require sampling >60 nests to represent a large population (10% accuracy) or ≥14 nests to represent a small colony that contained <100 nests (20% accuracy). Environ Toxicol Chem 2016;35:1458–1469. Published 2015 Wiley Periodicals Inc. on behalf of SETAC. This article is a US Government work and, as such, is in the public domain in the United States of America.
Epigenetic role of CCAAT box‐binding transcription factor NF‐Y on ID gene family in human embryonic carcinoma cells
Authors: Moeinvaziri Farideh , Shahhoseini Maryam
Published: October 2015

Nuclear factor Y (NF‐Y) is a histone substitute protein that specifically binds to the CCAAT box of the target genes and thereby promotes their regulation. NF‐Y transcription factor, with defined CCAAT element‐binding activities, target a gene family that encodes a group of basic helix–loop–helix ID factors (ID1–ID4), with or without CCAAT box at their promoter region. In this study, the expressions of NF‐Y in mRNA and protein level were evaluated in a human embryonic carcinoma cell line, named NTera2, before and after 7 days induction of differentiation. We also looked into expression levels of ID genes in NTera2 cells during differentiation because of their critical role in development. By using chromatin immunoprecipitation coupled with real‐time polymerase chain reaction, NF‐Y incorporation and acetylation/dimethylation of histone H3 at lysine 9 (H3K9ac/me2) was quantitatively evaluated on the regulatory regions of considered genes to monitor the changes in epigenetic markers at ID gene promoters throughout differentiation. The results demonstrated a marked down‐regulation of ID1, ID2, and ID3 genes, parallel to a loss of NF‐Y binding to the promoters of these genes. The data show that although the genes encoding NF‐Y complex remained expressed at mRNA level, NF‐YC is lost at the protein level onset of differentiation. Additionally, the epigenetic marks of H3K9ac and H3K9me2 at the target gene promoters decreased and increased, respectively, after 1 day of differentiation. It is suggested that, in the absence of NF‐Y binding, the corresponding regions adopt a heterochromatic nature, whereas when NF‐Y comes back after 7 days of differentiation, the ID1–3 promoters become again converted into active chromatin. The ID4 gene, lacking a CCAAT box, behaves differently and does not show any incorporation. This experiment implies for the first time that the presence of NF‐Y transcription factor plays a pivotal role in transcriptional regulation of ID genes in development. © 2015 IUBMB Life, 67(11):880–887, 2015
On the Definition of Terms in a Requirements Expression
Authors: Ryan Michael J. , Wheatcraft Louis S. , Dick Jeremy , Zinni Richard
Published: October 2015

The purpose of a requirement expression is to communicate clearly the needs of various entities into a formal language such that the intent is clearly understood by all involved: those whose job it is to implement the requirement, those responsible for proving the built system meets the requirement, and those responsible for proving the resulting system meets the needs of the relevant entity. Although many sources provide definitions of the terms associated with a requirement expression, there are only occasional agreements on common definitions, and the defined terms are too narrowly focused to be useful across the full requirements engineering domain. This paper proposes a cohesive set of definitions of the terms associated with a requirement expression. First, a framework for the transformation of needs into requirements is briefly discussed and existing definitions are presented from major relevant sources. These definitions are then analyzed and a cohesive set of definitions is offered for the key terms associated with a requirements expression: entity; need; requirement statement; and the requirement attributes that, along with the requirement statement itself, comprise the requirement expressions in a requirement set.
An Initial Ontology for System Qualities
Authors: Boehm Barry , Kukreja Nupul
Published: October 2015

This paper presents an initial ontology for reasoning about a system's System Qualities (SQs), ilities, or non‐functional requirements (reliability, usability, affordability, etc.). The need for such an ontology is based primarily on two factors. One is the importance of getting the SQs sufficiently well defined that the system's definition, development and evolution result in a satisfactory balance of SQ values for the system's success‐critical stakeholders, given the frequent system shortfalls and overruns that occur when this balance is not achieved. The other is that current system acquisition and evolution guidance descriptions have numerous deficiencies and inconsistencies in their coverage of SQ considerations. This situation is becoming more serious as systems and their stakeholders become increasingly complex, dynamic, and diverse. This paper provides an elaboration of the needs, a set of initial SQ ontology elements and definitions, examples of their application to some key SQs and their relationships, and an identification of further research and development needed to make the ontology fully useful and evolvable.
Model‐Based System Patterns for Automated Ground Vehicle Platforms
Authors: Peterson Troy , Schindel William D.
Published: October 2015

Automated Ground Vehicle (AGV) platform research and engineering is proliferating across commercial, military, and consumer applications. Beyond diversity of form and application, AGVs can be manned or unmanned, and exhibit a broad range of automated control, from partial to full autonomy, making these vehicles strikingly diverse.

This paper reports on application of Pattern‐Based Systems Engineering (PBSE) to representation of automated ground vehicle platforms. PBSE is based upon reusable, configurable S*Models conforming to the S*Metamodel, expressed in any modeling language and toolset. The INCOSE MBSE Initiative Patterns Challenge Team has been practicing PBSE across applications, reported in this and other IS2015 papers.

A specialized class of Cyber‐Physical Systems, AGVs are subject to intense interest, creating new opportunities, risks, and complexities. To address the diversity and complexity of these systems, the Embedded Intelligence (EI) Pattern, another S*Pattern, is being applied by the team to illustrate its applicability to an AGV Platform Pattern.
Studying Flexible Design and Management Decision‐Making in Engineering Systems Using Simulation Games
Authors: Cardin Michel‐Alexandre , Yixin Jiang , Yue Howard Ka‐Ho , Haidong Fu
Published: October 2015

This paper presents the results of an empirical study of training procedures enabling flexibility in the design and management of emergency medical services (EMS) systems – an example of complex engineering system. The study relies on the development and use of a simulation gaming environment to study decision‐making dynamics under different treatment conditions. Evaluation of short‐term (explicit vs. control), long‐term (explicit vs. control), and in‐game (with vs. without) flexibility training procedures was completed to assess the main and interaction effects on lifecycle performance score (ΔS). Controlled experiments were conducted with forty‐six participants working on the design and management of an EMS system. Results show that in‐game training produces a statistically significant improvement on lifecycle performance score (ΔS). It means that in‐game training may be more effective than others at improving the quantitative performance (i.e. lifecycle performance score). The empirical study provides insights for developing and evaluating novel training approaches for flexibility in engineering systems
Do Teams Using Agile Methodology Need Modeling?
Authors: Osvalds Gundars , Lempia David L.
Published: October 2015

System modeling, simulation and visualization enable the understanding of complex systems, an INCOSE Systems Engineering Vision for 2025. Modeling improves understand‐ing, increases quality and improves team performance. Agile Methodologies are used in de‐veloping complex systems. These Agile Methodologies improve quality and team performance with a shorter time to market and improved customer satisfaction. The approach described in this paper builds on the Agile Systems Engineering Framework by investigating who benefits from models on Agile Teams and what type and fidelity of models provide the benefits. As proposed in this paper the combination of agile development and modeling is a new concept that requires further data gathering and investigation to determine if it will result in im‐provement in productivity and risk reduction without losing the benefits of agile methodology.
System Life Cycle Trajectories: Tracking Innovation Paths Using System DNA
Authors: Schindel William D.
Published: October 2015

Systems change configuration across life cycles. Systems in development change in‐progress developmental configurations. Evolving product lines and competing product models change configurations, over lives of product lines. Understanding system trajectories (paths of changing configurations) is important to understanding installation history, developmental progress, and competitive evolution.

What to track? For living systems, physical form (phenotype) was the initial focus, but the study of genetic information (genotype) became vital. MBSE, Configuration Management (CM), Product Lifecycle Management (PLM), Model Management (MM) disciplines and tools partially address engineered system needs. However, cyberwar, epidemics, and other threats raise pressure to accelerate rates and efficacy of system evolution, enhancing agility.

This paper, part II of an IS2015 case for stronger MBSE semantics, applies “system DNA” trajectories, extends work reported by a System Sciences Working Group project at IW2014, and supports the IW2015 MBSE Workshop session on Agile Systems and the INCOSE Agile Systems Engineering Project.
Guidelines for creating systems
Authors: Kasser Joseph
Published: October 2015

A review of the INCOSE literature on systems engineering has shown that publications in systems engineering especially in systems engineering education tend to assume the system exists and then go on from there. Hence there is a need for guidance on conceptualizing and creating the system. This paper, written for both educators and practitioners provides some of that guidance by introducing and describing an iterative holistic process for conceptualizing and creating a system and/or situation, and determining which elements of the situation belong inside the system boundary and which elements remain outside, namely the paper describes the S2 process in the Nine‐System Model (Kasser and Zhao, 2014).
Differentiating System Architectures: Applying Architecture Measures
Authors: Carson Ronald S.
Published: October 2015

Having the right system architecture can facilitate system development and help manage life‐cycle costs. The wrong system architecture can make these more challenging because there may be missing program activities to address the key features of the selected architecture. For example, integrated architectures may require more design integration and analysis compared with federated (modular) architectures because of the tight coupling among subsystems. In the extreme case, the wrong architecture can lead to failure to satisfy all the requirements or obviate the possibility of future enhancements.

How do we select the right system architecture? Can we differentiate a “good” from a “bad” system architecture, or a “better” vs. a “worse” one? When or why should we prefer “modular”, “open”, “service‐oriented”, or “integrated” as an architecture approach? The answers to such questions can help us with the system design of aircraft, space systems, networks, and other complex systems.

This paper applies recent work of the National Defense Industrial Association (NDIA) and International Council on Systems Engineering (INCOSE) to evaluate examples of system architectures for different life‐cycle criteria. The paper reviews industry standard definitions of “architecture”, identifies the latest industry work on system architecture measurement, and applies the measurements to specific examples of system architectures. From this analysis an analyst can identify “acceptable” and “better” system architectures. It is shown that there is no universal statement of a “better” architecture because most selection criteria are program‐specific.
An Architecture‐based Enterprise Planning Process
Authors: Martin James N
Published: October 2015

There is a need to augment the traditional enterprise portfolio management process with a more robust process for managing the evolution of enterprise, program and system architectures. These architectures need to evolve towards a desired end state that best meets the needs and concerns of various stakeholders for the enterprise and the extent and variety of systems under its purview. This paper describes a six‐step process for managing architectures under these conditions. It has been implemented at some large government agencies and is based on best practices from government and industry. This process is one of those essential to implementing the relatively new practice of enterprise systems engineering.
Cooks, Recipes and Ingredients
Authors: Nolan Andy J. , Pickard Andrew C.
Published: October 2015

To make a meal, you need ingredients and a recipe. A recipe defines sequencing, quantities, timing etc. This is analogous to a project's processes (ingredients) and life‐cycle (recipe).

For a project, the attributes of cost, schedule and quality are properties that emerge from the recipes and ingredients. But how important is the recipe? This paper has found instances where a project's recipe had a 16‐fold cost difference using the exact same ingredients. This suggests that a good cook can make a great meal almost regardless of the ingredients.

Many Project Managers inadvertently become chiefs of their projects and create new recipes in their attempt to recover their project. However, few managers are aware of the outcome of the recipes they create. When things turn out unexpectedly, generally badly, they blame the ingredients and not the recipe.

This paper shows how a business can characterize a recipe to meet business goals, define it in a structured way (a reference model) and then use that definition to plan and monitor a project. The method has been used at Rolls‐Royce since 2002 and has been shown to improve project success, halving the level of scrap and rework whilst holding schedule. In one case, this method brought a 45% cost reduction to a project with only a small increase to schedule.

The concepts behind this paper are not new, but the notation used made it easy to define the ideal recipe, plan projects and to track them against the ideal recipe. This paper describes the background, benefits and methods to develop your own project recipes.

This paper is aimed at project managers, process architects and systems engineers. It defines a unified language to bridge all three needs in a language that can be understood by all.
A Systems Engineering Framework for R&D Organizations
Authors: Lombardo Nicholas , Millard David , Sturges Mark
Published: October 2015

Research and development (R&D) organizations such as the U.S. Department of Energy national laboratories span the spectrum of R&D from basic science to operational support. They must address a wide range of project types (e.g., projects that produce knowledge as their primary product or that develop a first‐of‐a‐kind system), technology readiness levels, and client demands. Application of formal systems engineering processes (such as those supporting U.S. Department of Defense acquisitions) is often not warranted or affordable, particularly where it is uncertain whether a technology can meet key performance goals. To address these challenges, the Pacific Northwest National Laboratory has developed and is implementing a systems engineering framework that is highly tailorable and adaptable for the wide range of R&D that the laboratory executes. The framework applies the concepts of systems development‐related risk and technology maturity levels to tailor the systems engineering effort. This paper describes the framework and its implementation.
Change Agency for Systems Engineers
Authors: McKinney Dorothy , Arnold Eileen , Sheard Sarah
Published: October 2015

INCOSE aims to establish thought leadership and help the world tackle large problems and complex issues. Systems engineering can enable rational problem solving that considers multiple stakeholder needs and interconnections of many interacting parts. Yet many systems engineers have trouble influencing decisions within their own organization, leaving doubt as to the path from engineering technical systems to establishing thought leadership in the greater world.

This paper describes the process of leading change, called “change agency,” as an evolution of a technical systems engineering career. Change agency makes use of skills learned in engineering, as extended to the social world. Learning change agency requires systems engineers to identify new skills, acquire new knowledge, and adapt to new philosophies, in order to prepare for, plan, and implement intelligent and lasting change.

This paper begins with two stories of change that systems engineers have participated in, and asks whether standard, technical systems engineering would be enough to ensure the change is implemented. Then it shows the evolution required from standard systems engineering knowledge and skills to the knowledge and skills required to be a good Change Agent. Steps required to identify, plan, and implement a change are discussed. The story endings are shared with an explanation of the results. An appendix describes a self‐assessment tool to help the systems engineer identify which aspects of change agency should be the first to be developed further.
Addressing the Rural Context in Literacies Research
Authors: Azano Amy Price
Published: October 2015

The article features a discussion about rural contexts in literacy research. Rural students compose a significant portion of K–12 students, and rural schools have unique challenges, such as limited funding and resources. However, as a field of literacy researchers, we do not privilege place equitably across multiple contexts. The article serves as a call to action for literacy researchers and educators to promote greater social justice and address educational inequities for rural students.
Synthesis of self‐assembled IL‐1Ra‐presenting nanoparticles for the treatment of osteoarthritis
Authors: Agarwal Rachit , Volkmer Tiago M. , Wang Peiyi , Lee L. Andrew , Wang Qian , García Andrés J.
Published: October 2015

Osteoarthritis is a progressive joint disease that results in degradation of cartilage in load‐bearing joints. Pain and inflammation in the joint are the hallmarks of this condition, which further exacerbate the cartilage destruction and health of the patient. It is hence imperative to treat the joint inflammation at the earliest. Interleukin 1 (IL‐1) blockade by IL‐1 receptor antagonist (IL‐1Ra) has shown promise in the clinic but this therapy suffers from rapid clearance, high doses, and frequent intervention. Use of carrier particles that result in longer residence time has been proposed. Here we have synthesized a new class of nanoparticles presenting IL‐1Ra on the surface and with tunable size from 300 to 700 nm. These IL‐1Ra‐poly(2‐hydroxyethyl methacrylate)‐pyridine nanoparticles are cytocompatible and stable in serum‐containing solutions for several days. Our results further demonstrate that these nanoparticles are capable of blocking IL‐1β signaling in an NF‐κB inducible reporter cell line. These engineered nanoparticles are promising for localized intra‐articular delivery in joint space to reduce inflammation in osteoarthritis and other inflammatory diseases. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 595–599, 2016.
Trichostatin A, an Inhibitor of Histone Deacetylase, Inhibits the Viability and Invasiveness of Hypoxic Rheumatoid Arthritis Fibroblast‐Like Synoviocytes via PI3K/Akt Signaling
Authors: Zhang Yong , Zhang Bo
Published: October 2015

This study was undertaken to explore the effects of trichostatin A (TSA), an inhibitor of histone deacetylase, on the viability, apoptosis, and invasiveness of hypoxic rheumatoid arthritis fibroblast‐like synoviocytes (RA FLSs). RA FLSs were exposed to hypoxia for 24 h in the presence or absence of 2 μM TSA and tested for cell viability, apoptosis, invasion, and gene expression. The involvement of the phosphatidylinositol‐3‐kinase (PI3K)/Akt pathway was checked. TSA significantly inhibited the viability and induced apoptosis of hypoxic RA FLSs, compared to vehicle control. TSA blocked hypoxia‐induced invasion of RA FLSs during Matrigel invasion assays and reduced the expression of matrix metalloproteinases (MMP‐2 and MMP‐9) and PI3K and phosphorylation of Akt. Overexpression of constitutively active Akt reversed TSA‐mediated suppression of invasiveness and downregulation of MMP‐2 and MMP‐9. Our results indicate the antisurvival and antiinvasive activities of TSA in hypoxic RA FLSs, which is associated with inactivation of PI3K/Akt signaling.
Elevated Expression of Hepatoma Up‐Regulated Protein Inhibits γ‐Irradiation‐Induced Apoptosis of Prostate Cancer Cells
Authors: Hassan Mohamed , El Khattouti Abdelouahid , Ejaeidi Ahmed , Ma Tangeng , Day William A. , Espinoza Ingrid , Vijayakumar Srinivasan , Gomez Christian R.
Published: October 2015

Despite progression in diagnosis and treatment, prostate cancer (PCa) still represents the main cause of cancer‐related mortality and morbidity in men. Although radiation therapy offers clinical benefit over other therapeutic modalities, the success of this therapeutic modality is commonly hampered by the resistance of advanced tumors. So far, the mechanisms governing tumor resistance to radiotherapy are not discussed in detail. Here, we demonstrate for the first time that the resistance of PCa to radiation therapy is attributed to elevated expression of Hepatoma Up‐Regulated Protein (HURP). In PCa cells, the induction of HURP expression suppresses γ‐irradiation‐induced apoptosis. γ‐irradiation‐induced apoptosis of PCa cells is associated with expression of E2F1, p53, p21 proteins together with the phosphorylation of apoptosis signal‐regulating kinase1 (ASK1), c‐jun‐N‐terminal kinase (JNK) and Ataxia‐telangiectasia mutated (ATM) and histone family member X (H2AX). Whereas, the induction of HURP expression is able to suppress γ‐irradiation‐induced effects on E2F1, p53, p21, ATM, ASK1, JNK and ATM, and H2AX. Also, inhibition of γ‐irradiation‐induced‐ cytochrome c release, cleavage of caspase‐9, caspase‐3, PARP, and reactive oxygen species (ROS) were noted in PCa cells induced for HURP expression. The observed radio‐resistance of PCa is thought to be the consequence of HURP‐mediated destabilization of p53 and ATM proteins that are essential for the modulation of γ‐irradiation‐induced apoptosis. Thus, based on our findings, PCa resistance to radiation therapy results from the deregulation of ASK1/ JNK; ATM/ H2AX; ATM/p53 and checkpoint kinase 2 (Chk2)/ E2F‐1 in response to the elevated expression of HURP. J. Cell. Biochem. 117: 1308–1318, 2016. © 2015 Wiley Periodicals, Inc.
Investigating lung responses with functional hyperpolarized xenon‐129 MRI in an ex vivo rat model of asthma
Authors: Lilburn David M.L. , Tatler Amanda L. , Six Joseph S. , Lesbats Clémentine , Habgood Anthony , Porte Joanne , Hughes‐Riley Theodore , Shaw Dominick E. , Jenkins Gisli , Meersmann Thomas
Published: October 2015

Purpose

Asthma is a disease of increasing worldwide importance that calls for new investigative methods. Ex vivo lung tissue is being increasingly used to study functional respiratory parameters independent of confounding systemic considerations but also to reduce animal numbers and associated research costs. In this work, a straightforward laboratory method is advanced to probe dynamic changes in gas inhalation patterns by using an ex vivo small animal ovalbumin (OVA) model of human asthma.

Methods

Hyperpolarized (hp) 129Xe was actively inhaled by the excised lungs exposed to a constant pressure differential that mimicked negative pleural cavity pressure. The method enabled hp 129Xe MRI of airway responsiveness to intravenous methacholine (MCh) and airway challenge reversal through salbutamol.

Results

Significant differences were demonstrated between control and OVA challenged animals on global lung hp 129Xe gas inhalation with P < 0.05 at MCh dosages above 460 μg. Spatial mapping of the regional hp gas distribution revealed an approximately three‐fold increase in heterogeneity for the asthma model organs.

Conclusion

The experimental results from this proof of concept work suggest that the ex vivo hp noble gas imaging arrangement and the applied image analysis methodology may be useful as an adjunct to current diagnostic techniques. Magn Reson Med 76:1224–1235, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Bloch‐Siegert ‐mapping for human cardiac 31P‐MRS at 7 Tesla
Authors: Clarke William T. , Robson Matthew D. , Rodgers Christopher T.
Published: October 2015

Purpose

Phosphorus MR spectroscopy (31P‐MRS) is a powerful tool for investigating tissue energetics in vivo. Cardiac 31P‐MRS is typically performed using surface coils that create an inhomogeneous excitation field across the myocardium. Accurate measurements of
(and hence flip angle) are necessary for quantitative analysis of 31P‐MR spectra. We demonstrate a Bloch‐Siegert
‐mapping method for this purpose.

Theory and Methods

We compare acquisition strategies for Bloch‐Siegert
‐mapping when there are several spectral peaks. We optimize a Bloch‐Siegert sensitizing (Fermi) pulse for cardiac 31P‐MRS at 7 Tesla (T) and apply it in a three‐dimensional (3D) chemical shift imaging sequence. We validate this in phantoms and skeletal muscle (against a dual‐TR method) and present the first cardiac 31P
‐maps at 7T.

Results

The Bloch‐Siegert method correlates strongly (Pearson's r = 0.90 and 0.84) and has bias <25 Hz compared with a multi‐TR method in phantoms and dual‐TR method in muscle. Cardiac 3D
‐maps were measured in five normal volunteers.
maps based on phosphocreatine and alpha‐adenosine‐triphosphate correlated strongly (r = 0.62), confirming that the method is T1 insensitive.

Conclusion

The 3D 31P Bloch‐Siegert
‐mapping is consistent with reference methods in phantoms and skeletal muscle. It is the first method appropriate for 31P
‐mapping in the human heart at 7T. Magn Reson Med 76:1047–1058, 2016. © 2015 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Free‐breathing variable flip angle balanced SSFP cardiac cine imaging with reduced SAR at 3T
Authors: Srinivasan Subashini , Kroeker Randall M. , Gabriel Simon , Plotnik Adam , Godinez Sergio R. , Hu Peng , Halnon Nancy , Finn J. Paul , Ennis Daniel B.
Published: October 2015

Purpose

To develop a free‐breathing variable flip angle (VFA) balanced steady‐state free precession (bSSFP) cardiac cine imaging technique with reduced specific absorption rate (SAR) at 3 Tesla.

Methods

Free‐breathing VFA (FB‐VFA) images in the short‐axis and four‐chamber views were acquired using an optimal VFA scheme, then compared with conventional breath‐hold constant flip angle (BH‐CFA) acquisitions. Two cardiac MRI experts used a 5‐point scale to score images from healthy subjects (N = 10). The left ventricular ejection fraction, end diastolic volume (LVEDV), end systolic volume, stroke volume (LVSV), and end diastolic myocardial mass (LVEDM) were determined by manual contour analysis for BH‐CFA and FB‐VFA. A pilot evaluation of FB‐VFA was performed in one patient with Duchenne muscular dystrophy.

Results

FB‐VFA SAR was 25% lower than BH‐CFA with similar blood–myocardium contrast. The qualitative FB‐VFA score was lower than the BH‐CFA for the short‐axis (3.1 ± 0.5 versus 4.3 ± 0.8; P < 0.05) and the four‐chamber view (3.4 ± 0.4 versus 4.6 ± 0.6; P < 0.05). The LVEDV and the LVSV were 5% and 12% larger (P < 0.05) for FB‐VFA compared with BH‐CFA. There was no difference in LVEDM.

Conclusion

FB‐VFA bSSFP cardiac cine imaging decreased the SAR at 3T with image quality sufficient to perform cardiac functional analysis. Magn Reson Med 76:1210–1216, 2016. © 2015 Wiley Periodicals, Inc.
Array‐compressed parallel transmit pulse design
Authors: Cao Zhipeng , Yan Xinqiang , Grissom William A.
Published: October 2015

Purpose

To design array‐compressed parallel transmit radiofrequency (RF) pulses and compare them to pulses designed with existing transmit array compression strategies.

Theory and Methods

Array‐compressed parallel RF pulse design is proposed as the joint optimization of a matrix of complex‐valued compression weights that relate a full‐channel physical array to a reduced‐channel virtual array, along with a set of RF pulses for the virtual array. In this way, the physics of the RF pulse application determine the coil combination weights. Array‐compressed pulse design algorithms are described for four parallel transmit applications: accelerated two‐dimensional spiral excitation, multislice RF shimming, small‐tip‐angle kT‐points excitation, and slice‐selective spokes refocusing. Array‐compressed designs are compared in simulations and an experiment to pulses designed using four existing array compression strategies.

Results

In all cases, array‐compressed pulses achieved the lowest root‐mean‐square excitation error among the array compression approaches. Low errors were generally achieved without increasing root‐mean‐square RF amplitudes or maximum local 10‐gram specific absorption rate. Leave‐one‐out multisubject shimming simulations demonstrated that array‐compressed RF shimming can identify useful fixed coil combination weights that perform well across a population.

Conclusion

Array‐compressed pulse design jointly identifies the transmit coil array compression weights and RF pulses that perform best for a specific parallel excitation application. Magn Reson Med 76:1158–1169, 2016. © 2015 Wiley Periodicals, Inc.
Capillary zone electrophoresis for bottom‐up analysis of complex proteomes
Authors: Sun Liangliang , Zhu Guijie , Yan Xiaojing , Zhang Zhenbin , Wojcik Roza , Champion Matthew M. , Dovichi Norman J.
Published: October 2015

Capillary zone electrophoresis (CZE) is emerging as a useful tool in proteomic analysis. Interest arises from dramatic improvements in performance that result from improvements in the background electrolyte used for the separation, the incorporation of advanced sample injection methods, the development of robust and sensitive electrospray interfaces, and the coupling with Orbitrap mass spectrometers with high resolution and sensitivity. The combination of these technologies produces performance that is rapidly approaching the performance of UPLC‐based methods for microgram samples and exceeds the performance of UPLC‐based methods for mid‐ to low nanogram samples. These systems now produce over 10 000 peptide IDs in a single 100‐min analysis of the HeLa proteome.
Twisted olefinic building blocks for low bandgap polymers in solar cells and ambipolar field‐effect transistors
Authors: Chiu Chien‐Yang , Wang Hengbin , Phan Hung , Shiratori Kazuya , Nguyen Thuc‐Quyen , Hawker Craig J.
Published: October 2015

A series of polymers based on 8,8′‐biindeno[2,1‐b]thiophenylidene for use in photovoltaic devices and field‐effect transistors are reported. These structurally twisted olefins are effective building blocks for preparation of low bandgap polymers with optical bandgaps of 1.2–1.5 eV. Device performance, such as Voc and Jsc, in solar cell devices could be successfully modulated by incorporation of a variety of comonomers. Ambipolar properties in field‐effect transistors using Au electrodes were also studied, with PtBTPDPP exhibiting balanced charge transport properties with hole and electron mobilities of 0.09 and 0.12 cm2·V−1·s−1, respectively. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 889–899
Theory of optical properties of graphene quantum dots
Authors: Ozfidan Isil , Güçlü A. D. , Korkusinski Marek , Hawrylak Pawel
Published: October 2015

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We present here a theory of the optical properties of graphene quantum dots (GQDs) with tunable band gaps by lateral size confinement, from UV to THz. Starting from the Hartree–Fock ground state, we construct the correlated many‐body ground and excited states of GQDs as a linear combination of a finite number of electron–hole pair excitations. We discuss the evolution of the band gap with size and its renormalization by self‐energy and excitonic effects. We calculate and analyze the dipole moments of graphene quantum dots that possess a degenerate valence and conduction band edge, and construct a characteristic exciton and biexciton spectrum. We find an exciton band consisting of a pair of robust, spin singlet bright exciton states and a band of dark, spin singlet and spin triplet, exciton states at lower energies. We predict a characteristic band of biexciton levels at the band edge, discuss the Auger processes and identify a biexciton–exciton cascade. Our theoretical results are compared with experimental linear absorption and non‐linear transient absorption spectra of colloidal GQDs. We next discuss the optical properties of triangular GQDs with zigzag edges whose magnetic moment can be controlled by gates. The control over the magnetic moment through carrier density manipulation results in optical spin blockade and gate tunable optical properties over a wide range of photon energies. (© 2015 WILEY‐VCH Verlag GmbH &Co. KGaA, Weinheim)
The moderating effects of coping and self-esteem on the relationship between defeat, entrapment and suicidality in a sample of prisoners at high risk of suicide
Authors: Gooding P. , Tarrier N. , Dunn G. , Shaw J. , Awenat Y. , Ulph F. , Pratt D.
Published: October 2015

Background

Research is sparse which examines pathways to suicide, and resilience to suicide, in people who are particularly vulnerable to suicide, for example, prison inmates. The purpose of this study was to examine the ways in which perceptions of self-esteem and coping ability interacted with defeat and entrapment to both amplify suicidal thoughts and feelings, and to act as a buffer against suicidal thoughts and feelings.

Methods

Participants were 65 male prisoners at high risk of suicide. A cross-sectional questionnaire design was used. Questionnaire measures of depression, defeat, entrapment, self-esteem, coping ability and suicidal probability were administered.

Results

For the hopelessness component of the suicide probability measure, high levels of coping ability together with low levels of defeat resulted in the lowest levels of suicidality indicative of a resilience factor. In contrast, low levels of coping skills together with high levels of entrapment were a high risk factor for this hopelessness component of suicide. This pattern of results pertained when controlling for depression levels.

Conclusions

This is the first study to examine interactions between defeat, entrapment and appraisals of self-esteem and coping ability. Therapeutic interventions would benefit from boosting perceptions and appraisals of coping ability, in particular, in people who are at high risk for suicide.
Patterns of long-term and short-term responses in adult patients with attention-deficit/hyperactivity disorder in a completer cohort of 12 weeks or more with atomoxetine
Authors: Sobanski E. , Leppämäki S. , Bushe C. , Berggren L. , Casillas M. , Deberdt W.
Published: October 2015

Background

Atomoxetine is a well-established pharmacotherapy for adult ADHD. Long-term studies show incremental reductions in symptoms over time. However, clinical experience suggests that patients differ in their response patterns.

Methods

From 13 Eli Lilly-sponsored studies, we pooled and analyzed data for adults with ADHD whocompletedatomoxetine treatment at long-term (24 weeks;n= 1443) and/or short-term (12 weeks;n= 2830) time-points, and had CAARS-Inv:SV total and CGI-S data up to or after these time-points and at Week 0 (i.e. at baseline, when patients first received atomoxetine). The goal was to identify and describe distinct trajectories of response to atomoxetine using hierarchical clustering methods and linear mixed modelling.

Results

Based on the homogeneity of changes in CAARS-Inv:SV total scores, 5 response clusters were identified for patients who completed long-term (24 weeks) treatment with atomoxetine, and 4 clusters were identified for patients who completed short-term (12 weeks) treatment. Four of the 5 long-term clusters (comprising 95% of completer patients) showed positive trajectories: 2 faster responding clusters (L1 and L2), and 2 more gradually responding clusters (L3 and L4). Responses (i.e. ≥ 30% reduction in CAARS-Inv:SV total score, and CGI-S score ≤ 3) were observed at 8 and 24 weeks in 80% and 95% of completers in Cluster L1, versus 5% and 48% in Cluster L4.

Conclusions

While many adults with ADHD responded relatively rapidly to atomoxetine, others responded more gradually without a clear plateau at 24 weeks. Longer-term treatment may be associated with greater numbers of responders.
The closed conformation of the LDL receptor is destabilized by the low Ca++ concentration but favored by the high Mg++ concentration in the endosome
Authors: Martínez-Oliván Juan , Arias-Moreno Xabier , Hurtado-Guerrero Ramón , Carrodeguas José Alberto , Miguel-Romero Laura , Marina Alberto , Bruscolini Pierpaolo , Sancho Javier
Published: October 2015

The LDL receptor (LDLR) internalizes LDL and VLDL particles. In the endosomes, it adopts a closed conformation important for recycling, by interaction of two modules of the ligand binding domain (LR4–5) and a β‐propeller motif. Here, we investigate by SPR the interactions between those two modules and the β‐propeller. Our results indicate that the two modules cooperate to bind the β‐propeller. The binding is favored by low pH and by high [Ca++]. Our data show that Mg++, at high concentration in the endosome, favors the formation of the closed conformation by replacing the structuring effect of Ca++ in LR5. We propose a sequential model of LDL release where formation of the close conformation follows LDL release.
PIP1 aquaporins: Intrinsic water channels or PIP2 aquaporin modulators?
Authors: Yaneff Agustín , Vitali Victoria , Amodeo Gabriela
Published: October 2015

The highly conserved plant aquaporins, known as Plasma membrane Intrinsic Proteins (PIPs), are the main gateways for cell membrane water exchange. Years of research have described in detail the properties of the PIP2 subfamily. However, characterizing the PIP1 subfamily has been difficult due to the failure to localize to the plasma membrane. In addition, the discovery of the PIP1–PIP2 interaction suggested that PIP1 aquaporins could be regulated by a complex posttranslational mechanism that involves trafficking, heteromerization and fine‐tuning of channel activity. This review not only considers the evidence and findings but also discusses the complexity of PIP aquaporins. To establish a new benchmark in PIP regulation, we propose to consider PIP1–PIP2 pairs as functional units for the purpose of future research into their physiological roles.
Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson's disease
Authors: Haddad Dominik , Nakamura Ken
Published: October 2015

Mitochondria are undoubtedly changed in Parkinson's disease (PD), and mitochondrial functions are disrupted in genetic and pharmacologic models of PD. However, many of these changes might not truly drive neurodegeneration. PD is defined by the particular susceptibility of nigrostriatal dopamine (DA) neurons, but little is understood about the mitochondria in these cells. Here, we critically review the evidence that mitochondrial stressors cause PD. We then consider how changes in the intrinsic function of mitochondria and in their mass, distribution, and dynamics might synergize with an increased need for mitochondria and produce PD, and the importance of understanding how mitochondria contribute to its pathogenesis.
CAR T‐cell immunotherapy: The path from the by‐road to the freeway?
Authors: Whilding Lynsey M. , Maher John
Published: October 2015

Chimeric antigen receptors are genetically encoded artificial fusion molecules that can re‐program the specificity of peripheral blood polyclonal T‐cells against a selected cell surface target. Unparallelled clinical efficacy has recently been demonstrated using this approach to treat patients with refractory B‐cell malignancy. However, the approach is technically challenging and can elicit severe toxicity in patients. Moreover, solid tumours have largely proven refractory to this approach. In this review, we describe the important structural features of CARs and how this may influence function. Emerging clinical experience is summarized in both solid tumours and haematological malignancies. Finally, we consider the particular challenges imposed by solid tumours to the successful development of CAR T‐cell immunotherapy, together with a number of innovative strategies that have been developed in an effort to reverse the balance in favour of therapeutic benefit.