bluuebunny/crossref_metadata_2025 huggingface dataset:
Serine 105 phosphorylation of transcription factor GATA4 is necessary for stress-induced cardiac hypertrophy in vivo
Authors: van Berlo Jop H. , Elrod John W. , Aronow Bruce J. , Pu William T. , Molkentin Jeffery D.
Published: July 2011

Cardiac hypertrophy is an adaptive growth process that occurs in response to stress stimulation or injury wherein multiple signal transduction pathways are induced, culminating in transcription factor activation and the reprogramming of gene expression. GATA4 is a critical transcription factor in the heart that is known to induce/regulate the hypertrophic program, in part, by receiving signals from MAPKs. Here we generated knock-in mice in which a known MAPK phosphorylation site at serine 105 (S105) in
Gata4
that augments activity was mutated to alanine. Homozygous
Gata4
-
S105A
mutant mice were viable as adults, although they showed a compromised stress response of the myocardium. For example, cardiac hypertrophy in response to phenylephrine agonist infusion for 2 wk was largely blunted in
Gata4
-
S105A
mice, as was the hypertrophic response to pressure overload at 1 and 2 wk of applied stimulation.
Gata4
-
S105A
mice were also more susceptible to heart failure and cardiac dilation after 2 wk of pressure overload. With respect to the upstream pathway, hearts from
Gata4
-
S105A
mice did not efficiently hypertrophy following direct ERK1/2 activation using an activated MEK1 transgene in vivo. Mechanistically, GATA4 mutant protein from these hearts failed to show enhanced DNA binding in response to hypertrophic stimulation. Moreover, hearts from
Gata4
-
S105A
mice had significant changes in the expression of hypertrophy-inducible, fetal, and remodeling-related genes.
Contextual learning requires synaptic AMPA receptor delivery in the hippocampus
Authors: Mitsushima Dai , Ishihara Kouji , Sano Akane , Kessels Helmut W. , Takahashi Takuya
Published: July 2011

The hippocampus plays a central role in learning and memory. Although synaptic delivery of AMPA-type glutamate receptors (AMPARs) contributes to experience-dependent synaptic strengthening, its role in hippocampus-dependent learning remains elusive. By combining viral-mediated in vivo gene delivery with in vitro patch-clamp recordings, we found that the inhibitory avoidance task, a hippocampus-dependent contextual fear-learning paradigm, delivered GluR1-containing AMPARs into CA3-CA1 synapses of the dorsal hippocampus. To block the synaptic delivery of endogenous AMPARs, we expressed a fragment of the GluR1-cytoplasmic tail (the 14-aa GluR1 membrane-proximal region with two serines mutated to phospho-mimicking aspartates: MPR-DD). MPR-DD prevented learning-driven synaptic AMPAR delivery in CA1 neurons. Bilateral expression of MPR-DD in the CA1 region of the rat impaired inhibitory avoidance learning, indicating that synaptic GluR1 trafficking in the CA1 region of the hippocampus is required for encoding contextual fear memories. The fraction of CA1 neurons that underwent synaptic strengthening positively correlated with the performance in the inhibitory avoidance fear memory task. These data suggest that the robustness of a contextual memory depends on the number of hippocampal neurons that participate in the encoding of a memory trace.
Ligation of Fc gamma receptor IIB inhibits antibody-dependent enhancement of dengue virus infection
Authors: Chan Kuan Rong , Zhang Summer Li-Xin , Tan Hwee Cheng , Chan Ying Kai , Chow Angelia , Lim Angeline Pei Chiew , Vasudevan Subhash G. , Hanson Brendon J. , Ooi Eng Eong
Published: July 2011

The interaction of antibodies, dengue virus (DENV), and monocytes can result in either immunity or enhanced virus infection. These opposing outcomes of dengue antibodies have hampered dengue vaccine development. Recent studies have shown that antibodies neutralize DENV by either preventing virus attachment to cellular receptors or inhibiting viral fusion intracellularly. However, whether the antibody blocks attachment or fusion, the resulting immune complexes are expected to be phagocytosed by Fc gamma receptor (FcγR)-bearing cells and cleared from circulation. This suggests that only antibodies that are able to block fusion intracellularly would be able to neutralize DENV upon FcγR-mediated uptake by monocytes whereas other antibodies would have resulted in enhancement of DENV replication. Using convalescent sera from dengue patients, we observed that neutralization of the homologous serotypes occurred despite FcγR-mediated uptake. However, FcγR-mediated uptake appeared to be inhibited when neutralized heterologous DENV serotypes were used instead. We demonstrate that this inhibition occurred through the formation of viral aggregates by antibodies in a concentration-dependent manner. Aggregation of viruses enabled antibodies to cross-link the inhibitory FcγRIIB, which is expressed at low levels but which inhibits FcγR-mediated phagocytosis and hence prevents antibody-dependent enhancement of DENV infection in monocytes.
Autoimmune regulator (AIRE)-deficient CD8+CD28lowregulatory T lymphocytes fail to control experimental colitis
Authors: Pomié Céline , Vicente Rita , Vuddamalay Yirajen , Lundgren Brita Ardesjö , van der Hoek Mark , Enault Geneviève , Kagan Jérémy , Fazilleau Nicolas , Scott Hamish S. , Romagnoli Paola , van Meerwijk Joost P. M.
Published: July 2011

Mutations in the gene encoding the transcription factor autoimmune regulator (AIRE) are responsible for autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome. AIRE directs expression of tissue-restricted antigens in the thymic medulla and in lymph node stromal cells and thereby substantially contributes to induction of immunological tolerance to self-antigens. Data from experimental mouse models showed that AIRE deficiency leads to impaired deletion of autospecific T-cell precursors. However, a potential role for AIRE in the function of regulatory T-cell populations, which are known to play a central role in prevention of immunopathology, has remained elusive. Regulatory T cells of CD8+CD28lowphenotype efficiently control immune responses in experimental autoimmune and colitis models in mice. Here we show that CD8+CD28lowregulatory T lymphocytes from AIRE-deficient mice are transcriptionally and phenotypically normal and exert efficient suppression of in vitro immune responses, but completely fail to prevent experimental colitis in vivo. Our data therefore demonstrate that AIRE plays an important role in the in vivo function of a naturally occurring regulatory T-cell population.
Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer
Authors: Cheung Hiu Wing , Cowley Glenn S. , Weir Barbara A. , Boehm Jesse S. , Rusin Scott , Scott Justine A. , East Alexandra , Ali Levi D. , Lizotte Patrick H. , Wong Terence C. , Jiang Guozhi , Hsiao Jessica , Mermel Craig H. , Getz Gad , Barretina Jordi , Gopal Shuba , Tamayo Pablo , Gould Joshua , Tsherniak Aviad , Stransky Nicolas , Luo Biao , Ren Yin , Drapkin Ronny , Bhatia Sangeeta N. , Mesirov Jill P. , Garraway Levi A. , Meyerson Matthew , Lander Eric S. , Root David E. , Hahn William C.
Published: July 2011

A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overexpressed in ovarian cancer cell lines. One such gene,
PAX8
, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of
PAX8
selectively induces apoptotic cell death of ovarian cancer cells. These results identify
PAX8
as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.
tRNA-dependent peptide bond formation by the transferase PacB in biosynthesis of the pacidamycin group of pentapeptidyl nucleoside antibiotics
Authors: Zhang Wenjun , Ntai Ioanna , Kelleher Neil L. , Walsh Christopher T.
Published: July 2011

Pacidamycins are a family of uridyl tetra/pentapeptide antibiotics with antipseudomonal activities through inhibition of the translocase MraY in bacterial cell wall assembly. The biosynthetic gene cluster for pacidamycins has recently been identified through genome mining of the producer
Streptomyces coeruleorubidus
, and the highly dissociated nonribosomal peptide assembly line for the uridyl tetrapeptide scaffold of pacidamycin has been characterized. In this work a hypothetical protein PacB, conserved in known uridyl peptide antibiotics gene clusters, has been characterized by both genetic deletion and enzymatic analysis of the purified protein. PacB catalyzes the transfer of the alanyl residue from alanyl-tRNA to the
N
terminus of the tetrapeptide intermediate yielding a pentapeptide on the thio-templated nonribosomal peptide synthetase (NRPS) assembly line protein PacH. PacB thus represents a new group of tRNA-dependent peptide bond-forming enzymes in secondary metabolite biosynthesis in addition to the recently identified cyclodipeptide synthases. The characterization of PacB completes the assembly line reconstitution of pacidamycin pentapeptide antibiotic scaffolds, bridging the primary and secondary metabolic pathways by hijacking an aminoacyl-tRNA to the antibiotic biosynthetic pathway.
The Effects of Transnational Environmentalism on Domestic Environmental Coalitions: Thick Conservation Networks and Thin Pollution Networks in Ecuador
Authors: Lewis Tammy L.
Published: July 2011

Ecuador's environmental movement has engaged in the international environmental network since 1978. This article examines how transnationalism has affected Ecuadorian environmental organizations by comparing two issue networks: the conservation network and the pollution network. Data from an on-line organizational survey of Ecuadorian organizations and interviews show that the transnational conservation network, a resource-rich vertical network, has encouraged the growth of horizontal/domestic networks in Ecuador, but the domestic network is dysfunctional. By contrast, the relatively poor transnational pollution network did not generate growth in horizontal/domestic networks. Instead, independent organizations emerged domestically. This organizational network may prove more functional.
Network Governance as Adaptive Institutional Response: The Case of Multifunctional Forested Landscapes
Authors: Wolf Steven A.
Published: July 2011

Contemporary interest in networks in natural resources management reflects the increasing complexity of social regulation of the environment. This complexity stems from differentiation of social demand for environmental goods and services, and an accompanying search for both technical and institutional innovation. Rather than implying sustained coherence, network governance refers to new patterns of engagement, interdependence, and flows of information and resources among state, market and civil society actors. In identifying network forms of governance as an institutional innovation arising in response to environmental change, and by suggesting that networks can reshape the material environment, I invoke a co-evolutionary analysis. This general argument is developed through consideration of the particular challenges of construction of multifunctional forested landscapes in the US.
Networking to Conserve Biodiversity: The Case of Chicago Wilderness
Authors: McCance Elizabeth
Published: July 2011

Looking at Chicago Wilderness, a network of more than 250 organizational members working to conserve biodiversity in metropolitan Chicago, this article examines the factors that promote and inhibit adoption of collaboration as a conservation strategy. While collaboration is essential for ecosystem management, it is not easy. A function of Chicago Wilderness is to promote collaboration. Testing this network function, this study of Chicago Wilderness illustrates how patterns of network participation, as well as organizational type and perceptions of leadership support, influence attitudes towards collaboration.
Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice
Authors: Oh Keunhee , Park Hyung-Bae , Byoun Ok-Jin , Shin Dong-Myung , Jeong Eui Man , Kim Young Whan , Kim Yon Su , Melino Gerry , Kim In-Gyu , Lee Dong-Sup
Published: July 2011

Pulmonary fibrosis is a potentially life-threatening disease that may be caused by overt or asymptomatic inflammatory responses. However, the precise mechanisms by which tissue injury is translated into inflammation and consequent fibrosis remain to be established. Here, we show that in a lung injury model, bleomycin induced the secretion of IL-6 by epithelial cells in a transglutaminase 2 (TG2)–dependent manner. This response represents a key step in the differentiation of IL-17–producing T cells and subsequent inflammatory amplification in the lung. The essential role of epithelial cells, but not inflammatory cells, TG2 was confirmed in bone marrow chimeras; chimeras made in TG2-deficient recipients showed reduced inflammation and fibrosis, compared with those in wild-type mice, regardless of the bone marrow cell phenotype. Epithelial TG2 thus appears to be a critical inducer of inflammation after noninfectious pulmonary injury. We further demonstrated that fibroblast-derived TG2, acting downstream of transforming growth factor-β, is also important in the effector phase of fibrogenesis. Therefore, TG2 represents an interesting potential target for therapeutic intervention.
Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination
Authors: Jeevan-Raj Beena Patricia , Robert Isabelle , Heyer Vincent , Page Adeline , Wang Jing H. , Cammas Florence , Alt Frederick W. , Losson Régine , Reina-San-Martin Bernardo
Published: July 2011

Immunoglobulin class switch recombination (CSR) is initiated by double-stranded DNA breaks (DSBs) in switch regions triggered by activation-induced cytidine deaminase (AID). Although CSR correlates with epigenetic modifications at the IgH locus, the relationship between these modifications and AID remains unknown. In this study, we show that during CSR, AID forms a complex with KAP1 (KRAB domain–associated protein 1) and HP1 (heterochromatin protein 1) that is tethered to the donor switch region (Sμ) bearing H3K9me3 (trimethylated histone H3 at lysine 9) in vivo. Furthermore, in vivo disruption of this complex results in impaired AID recruitment to Sμ, inefficient DSB formation, and a concomitant defect in CSR but not in somatic hypermutation. We propose that KAP1 and HP1 tether AID to H3K9me3 residues at the donor switch region, thus providing a mechanism linking AID to epigenetic modifications during CSR.
IFN-γ– and IL-10–expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis
Authors: Zhao Jingxian , Zhao Jincun , Fett Craig , Trandem Kathryn , Fleming Erica , Perlman Stanley
Published: July 2011

Foxp3+ CD4 regulatory T cells (T reg cells) are important in limiting immunopathology in infections. However, identifying pathogen-specific epitopes targeted by these cells has been elusive. Using MHC class II/peptide tetramers and intracellular cytokine staining, we identify T reg cells recognizing two virus-specific CD4 T cell epitopes in the coronavirus-infected central nervous system as well as naive T cell precursor pools. These T reg cells are detected at the same time as effector T cells (T eff cells) exhibiting the same specificity and can suppress T eff cell proliferation after stimulation with cognate peptide. These virus-specific T reg cells may be especially effective in inhibiting the immune response during the peak of infection, when virus antigen is maximal. Furthermore, these T reg cells express both IL-10 and IFN-γ after peptide stimulation. IFN-γ expression is maintained during both acute and chronic phases of infection. Identification of T reg cell target epitopes by cytokine production is also applicable in autoimmune disease because myelin oligodendrocyte glycoprotein–specific Foxp3+ T reg cells express IL-10 and IL-17 at the peak of disease in mice with experimental autoimmune encephalomyelitis. These results show that pathogen epitope-specific Foxp3+ T reg cells can be identified on the basis of cytokine production.
An automaton model for the cell cycle
Authors: Altinok Atilla , Gonze Didier , Lévi Francis , Goldbeter Albert
Published: July 2011

We consider an automaton model that progresses spontaneously through the four successive phases of the cell cycle: G1, S (DNA replication), G2 and M (mitosis). Each phase is characterized by a mean durationτand a variabilityV. As soon as the prescribed duration of a given phase has passed, the transition to the next phase of the cell cycle occurs. The time at which the transition takes place varies in a random manner according to a distribution of durations of the cell cycle phases. Upon completion of the M phase, the cell divides into two cells, which immediately enter a new cycle in G1. The duration of each phase is reinitialized for the two newborn cells. At each time step in any phase of the cycle, the cell has a certain probability to be marked for exiting the cycle and dying at the nearest G1/S or G2/M transition. To allow for homeostasis, which corresponds to maintenance of the total cell number, we assume that cell death counterbalances cell replication at mitosis. In studying the dynamics of this automaton model, we examine the effect of factors such as the mean durations of the cell cycle phases and their variability, the type of distribution of the durations, the number of cells, the regulation of the cell population size and the independence of steady-state proportions of cells in each phase with respect to initial conditions. We apply the stochastic automaton model for the cell cycle to the progressive desynchronization of cell populations and to their entrainment by the circadian clock. A simple deterministic model leads to the same steady-state proportions of cells in the four phases of the cell cycle.
Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients
Authors: Scully Christopher G. , Karaboué Abdoulaye , Liu Wei-Min , Meyer Joseph , Innominato Pasquale F. , Chon Ki H. , Gorbach Alexander M. , Lévi Francis
Published: July 2011

Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non-invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2–6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively
cool
had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules.
From petrochemistry to biotech: a European perspective on the bio-based economy
Authors: Landeweerd Laurens , Surette Monique , van Driel Corry
Published: July 2011

This paper gives an account of the issues at play in Europe with regard to the transition to a bio-based economy. Agricultural crops have always been used for the production of food, feed, fibre and fuel. The Model T Ford—the first mass produced car—originally ran on bioethanol, and wood has been in use as a source for energy ever since the discovery of fire. What is new is that the balance between agricultural uses is changing under the pressure of an increasing need for food and feed, as well as the new need for biofuels and biomaterials. At the basis of this change lie several serious issues related to the current use of bio-based feedstock to secure energy supply, the future depletion of natural resources and global climate change. Innovations in industrial biotechnology are expected to play a crucial role in dealing with these issues in biomass use.
How can land-use modelling tools inform bioenergy policies?
Authors: Davis Sarah C. , House Joanna I. , Diaz-Chavez Rocio A. , Molnar Andras , Valin Hugo , DeLucia Evan H.
Published: July 2011

Targets for bioenergy have been set worldwide to mitigate climate change. Although feedstock sources are often ambiguous, pledges in European nations, the United States and Brazil amount to more than 100 Mtoe of biorenewable fuel production by 2020. As a consequence, the biofuel sector is developing rapidly, and it is increasingly important to distinguish bioenergy options that can address energy security and greenhouse gas mitigation from those that cannot. This paper evaluates how bioenergy production affects land-use change (LUC), and to what extent land-use modelling can inform sound decision-making. We identified local and global internalities and externalities of biofuel development scenarios, reviewed relevant data sources and modelling approaches, identified sources of controversy about indirect LUC (iLUC) and then suggested a framework for comprehensive assessments of bioenergy. Ultimately, plant biomass must be managed to produce energy in a way that is consistent with the management of food, feed, fibre, timber and environmental services. Bioenergy production provides opportunities for improved energy security, climate mitigation and rural development, but the environmental and social consequences depend on feedstock choices and geographical location. The most desirable solutions for bioenergy production will include policies that incentivize regionally integrated management of diverse resources with low inputs, high yields, co-products, multiple benefits and minimal risks of iLUC. Many integrated assessment models include energy resources, trade, technological development and regional environmental conditions, but do not account for biodiversity and lack detailed data on the location of degraded and underproductive lands that would be ideal for bioenergy production. Specific practices that would maximize the benefits of bioenergy production regionally need to be identified before a global analysis of bioenergy-related LUC can be accomplished.
Multi-scale simulations of the dynamics of in-stent restenosis: impact of stent deployment and design
Authors: Tahir Hannan , Hoekstra Alfons G. , Lorenz Eric , Lawford Patricia V. , Hose D. Rodney , Gunn Julian , Evans David J.W.
Published: July 2011

Neointimal hyperplasia, a process of smooth muscle cell re-growth, is the result of a natural wound healing response of the injured artery after stent deployment. Excessive neointimal hyperplasia following coronary artery stenting results in in-stent restenosis (ISR). Regardless of recent developments in the field of coronary stent design, ISR remains a significant complication of this interventional therapy. The influence of stent design parameters such as strut thickness, shape and the depth of strut deployment within the vessel wall on the severity of restenosis has already been highlighted but the detail of this influence is unclear. These factors impact on local haemodynamics and vessel structure and affect the rate of neointima formation. This paper presents the first results of a multi-scale model of ISR. The development of the simulated restenosis as a function of stent deployment depth is compared with an
in vivo
porcine dataset. Moreover, the influence of strut size and shape is investigated, and the effect of a drug released at the site of injury, by means of a drug-eluting stent, is also examined. A strong correlation between strut thickness and the rate of smooth muscle cell proliferation has been observed. Simulation results also suggest that the growth of the restenotic lesion is strongly dependent on the stent strut cross-sectional profile.
@neurIST complex information processing toolchain for the integrated management of cerebral aneurysms
Authors: Villa-Uriol M. C. , Berti G. , Hose D. R. , Marzo A. , Chiarini A. , Penrose J. , Pozo J. , Schmidt J. G. , Singh P. , Lycett R. , Larrabide I. , Frangi A. F.
Published: July 2011

Cerebral aneurysms are a multi-factorial disease with severe consequences. A core part of the European project @neurIST was the physical characterization of aneurysms to find candidate risk factors associated with aneurysm rupture. The project investigated measures based on morphological, haemodynamic and aneurysm wall structure analyses for more than 300 cases of ruptured and unruptured aneurysms, extracting descriptors suitable for statistical studies. This paper deals with the unique challenges associated with this task, and the implemented solutions. The consistency of results required by the subsequent statistical analyses, given the heterogeneous image data sources and multiple human operators, was met by a highly automated toolchain combined with training. A testimonial of the successful automation is the positive evaluation of the toolchain by over 260 clinicians during various hands-on workshops. The specification of the analyses required thorough investigations of modelling and processing choices, discussed in a detailed analysis protocol. Finally, an abstract data model governing the management of the simulation-related data provides a framework for data provenance and supports future use of data and toolchain. This is achieved by enabling the easy modification of the modelling approaches and solution details through abstract problem descriptions, removing the need of repetition of manual processing work.
Contrasts and synergies in different biofuel reports
Authors: Michalopoulos A. , Landeweerd L. , Van der Werf-Kulichova Z. , Puylaert P. G. B. , Osseweijer P.
Published: July 2011

The societal debate on biofuels is characterised by increased complexity. This can hinder the effective governance of the field. This paper attempts a quantitative bird's eye meta-analysis of this complexity by mapping different stakeholder perspectives and expected outcomes as seen in the secondary literature on biofuels, along the lines of the People-Planet-Profit framework. Our analysis illustrates the tension between stated and actual drivers of large scale biofuel development, especially for first generation biofuels. Although environmental (Planet) aspects have dominated the biofuel debate, their overall assessment is mostly negative with regard to first generation biofuels. By contrast, economic (Profit) aspects are the only ones that are assessed positively with regard to first generation biofuels. Furthermore, positive and negative assessments of biofuel development are strongly influenced by the differences in focus between different stakeholder clusters. Stakeholders who appear generally supportive to biofuel development (industry) focus relatively more on aspects that are generally assessed as positive (Profit). By contrast, non-supportive stakeholders (NGO's) tend to focus mainly on aspects that are generally assessed as negative (Planet). Moreover, our analysis of reference lists revealed few citations of primary scientific data, and also that intergovernmental organizations produce the most influential publications in the debate. The surprising lack of listed references to scientific (primary) data reveals a need to assess in which arena the transition of scientific data towards secondary publications takes place, and how one can measure its quality. This work should be understood as a first effort to take some control over a complex and contradictory number of publications, and to allow the effective governance of the field through the identification of areas of overlapping consensus and persisting controversy, without reverting to claims on technical detail.
Coupled personalization of cardiac electrophysiology models for prediction of ischaemic ventricular tachycardia
Authors: Relan Jatin , Chinchapatnam Phani , Sermesant Maxime , Rhode Kawal , Ginks Matt , Delingette Hervé , Rinaldi C. Aldo , Razavi Reza , Ayache Nicholas
Published: July 2011

In order to translate the important progress in cardiac electrophysiology modelling of the last decades into clinical applications, there is a requirement to make macroscopic models that can be used for the planning and performance of the clinical procedures. This requires model personalization, i.e. estimation of patient-specific model parameters and computations compatible with clinical constraints. Simplified macroscopic models can allow a rapid estimation of the tissue conductivity, but are often unreliable to predict arrhythmias. Conversely, complex biophysical models are more complete and have mechanisms of arrhythmogenesis and arrhythmia sustainibility, but are computationally expensive and their predictions at the organ scale still have to be validated. We present a coupled personalization framework that combines the power of the two kinds of models while keeping the computational complexity tractable. A simple eikonal model is used to estimate the conductivity parameters, which are then used to set the parameters of a biophysical model, the Mitchell–Schaeffer (MS) model. Additional parameters related to action potential duration restitution curves for the tissue are further estimated for the MS model. This framework is applied to a clinical dataset derived from a hybrid X-ray/magnetic resonance imaging and non-contact mapping procedure on a patient with heart failure. This personalized MS model is then used to perform an
in silico
simulation of a ventricular tachycardia (VT) stimulation protocol to predict the induction of VT. This proof of concept opens up possibilities of using VT induction modelling in order to both assess the risk of VT for a given patient and also to plan a potential subsequent radio-frequency ablation strategy to treat VT.
Model-driven therapeutic treatment of neurological disorders: reshaping brain rhythms with neuromodulation
Authors: Modolo Julien , Legros Alexandre , Thomas Alex W. , Beuter Anne
Published: July 2011

Electric stimulation has been investigated for several decades to treat, with various degrees of success, a broad spectrum of neurological disorders. Historically, the development of these methods has been largely empirical but has led to a remarkably efficient, yet invasive treatment: deep brain stimulation (DBS). However, the efficiency of DBS is limited by our lack of understanding of the underlying physiological mechanisms and by the complex relationship existing between brain processing and behaviour. Biophysical modelling of brain activity, describing multi-scale spatio-temporal patterns of neuronal activity using a mathematical model and taking into account the physical properties of brain tissue, represents one way to fill this gap. In this review, we illustrate how biophysical modelling is beginning to emerge as a driving force orienting the development of innovative brain stimulation methods that may move DBS forward. We present examples of modelling works that have provided fruitful insights in regards to DBS underlying mechanisms, and others that also suggest potential improvements for this neurosurgical procedure. The reviewed literature emphasizes that biophysical modelling is a valuable tool to assist a rational development of electrical and/or magnetic brain stimulation methods tailored to both the disease and the patient's characteristics.
Real-time quasi-static ultrasound elastography
Authors: Treece Graham , Lindop Joel , Chen Lujie , Housden James , Prager Richard , Gee Andrew
Published: July 2011

Ultrasound elastography is a technique used for clinical imaging of tissue stiffness with a conventional ultrasound machine. It was first proposed two decades ago, but active research continues in this area to the present day. Numerous clinical applications have been investigated, mostly related to cancer imaging, and though these have yet to prove conclusive, the technique has seen increasing commercial and clinical interest. This paper presents a review of the most widely adopted, non-quantitative, techniques focusing on technical innovations rather than clinical applications. The review is not intended to be exhaustive, concentrating instead on placing the various techniques in context according to the authors' perspective of the field.
Workflow for generating competing hypothesis from models with parameter uncertainty
Authors: Gomez-Cabrero David , Compte Albert , Tegner Jesper
Published: July 2011

Mathematical models are increasingly used in life sciences. However, contrary to other disciplines, biological models are typically over-parametrized and loosely constrained by scarce experimental data and prior knowledge. Recent efforts on analysis of complex models have focused on isolated aspects without considering an integrated approach—ranging from model building to derivation of predictive experiments and refutation or validation of robust model behaviours. Here, we develop such an integrative workflow, a sequence of actions expanding upon current efforts with the purpose of setting the stage for a methodology facilitating an extraction of core behaviours and competing mechanistic hypothesis residing within underdetermined models. To this end, we make use of optimization search algorithms, statistical (machine-learning) classification techniques and cluster-based analysis of the state variables' dynamics and their corresponding parameter sets. We apply the workflow to a mathematical model of fat accumulation in the arterial wall (atherogenesis), a complex phenomena with limited quantitative understanding, thus leading to a model plagued with inherent uncertainty. We find that the mathematical atherogenesis model can still be understood in terms of a few key behaviours despite the large number of parameters. This result enabled us to derive distinct mechanistic predictions from the model despite the lack of confidence in the model parameters. We conclude that building integrative workflows enable investigators to embrace modelling of complex biological processes despite uncertainty in parameters.
Three-dimensional ultrasound scanning
Authors: Fenster Aaron , Parraga Grace , Bax Jeff
Published: July 2011

The past two decades have witnessed developments of new imaging techniques that provide three-dimensional images about the interior of the human body in a manner never before available. Ultrasound (US) imaging is an important cost-effective technique used routinely in the management of a number of diseases. However, two-dimensional viewing of three-dimensional anatomy, using conventional two-dimensional US, limits our ability to quantify and visualize the anatomy and guide therapy, because multiple two-dimensional images must be integrated mentally. This practice is inefficient, and may lead to variability and incorrect diagnoses. Investigators and companies have addressed these limitations by developing three-dimensional US techniques. Thus, in this paper, we review the various techniques that are in current use in three-dimensional US imaging systems, with a particular emphasis placed on the geometric accuracy of the generation of three-dimensional images. The principles involved in three-dimensional US imaging are then illustrated with a diagnostic and an interventional application: (i) three-dimensional carotid US imaging for quantification and monitoring of carotid atherosclerosis and (ii) three-dimensional US-guided prostate biopsy.
Ultrasound-mediated optical tomography: a review of current methods
Authors: Elson Daniel S. , Li Rui , Dunsby Christopher , Eckersley Robert , Tang Meng-Xing
Published: July 2011

Ultrasound-mediated optical tomography (UOT) is a hybrid technique that is able to combine the high penetration depth and high spatial resolution of ultrasound imaging to overcome the limits imposed by optical scattering for deep tissue optical sensing and imaging. It has been proposed as a method to detect blood concentrations, oxygenation and metabolism at depth in tissue for the detection of vascularized tumours or the presence of absorbing or scattering contrast agents. In this paper, the basic principles of the method are outlined and methods for simulating the UOT signal are described. The main detection methods are then summarized with a discussion of the advantages and disadvantages of each. The recent focus on increasing the weak UOT signal through the use of the acoustic radiation force is explained, together with a summary of our results showing sensitivity to the mechanical shear stiffness and optical absorption properties of tissue-mimicking phantoms.
Acoustic radiation force-based elasticity imaging methods
Authors: Palmeri Mark L. , Nightingale Kathryn R.
Published: July 2011

Conventional diagnostic ultrasound images portray differences in the acoustic properties of soft tissues, whereas ultrasound-based elasticity images portray differences in the elastic properties of soft tissues (i.e. stiffness, viscosity). The benefit of elasticity imaging lies in the fact that many soft tissues can share similar ultrasonic echogenicities, but may have different mechanical properties that can be used to clearly visualize normal anatomy and delineate pathological lesions. Acoustic radiation force-based elasticity imaging methods use acoustic radiation force to transiently deform soft tissues, and the dynamic displacement response of those tissues is measured ultrasonically and is used to estimate the tissue's mechanical properties. Both qualitative images and quantitative elasticity metrics can be reconstructed from these measured data, providing complimentary information to both diagnose and longitudinally monitor disease progression. Recently, acoustic radiation force-based elasticity imaging techniques have moved from the laboratory to the clinical setting, where clinicians are beginning to characterize tissue stiffness as a diagnostic metric, and commercial implementations of radiation force-based ultrasonic elasticity imaging are beginning to appear on the commercial market. This article provides an overview of acoustic radiation force-based elasticity imaging, including a review of the relevant soft tissue material properties, a review of radiation force-based methods that have been proposed for elasticity imaging, and a discussion of current research and commercial realizations of radiation force based-elasticity imaging technologies.
Vascular ultrasound for atherosclerosis imaging
Authors: de Korte Chris L. , Hansen Hendrik H. G. , van der Steen Anton F. W.
Published: July 2011

Cardiovascular disease is a leading cause of death in the Western world. Therefore, detection and quantification of atherosclerotic disease is of paramount importance to monitor treatment and possible prevention of acute events. Vascular ultrasound is an excellent technique to assess the geometry of vessel walls and plaques. The high temporal as well as spatial resolution allows quantification of luminal area and plaque size and volume. While carotid arteries can be imaged non-invasively, scanning of coronary arteries requires invasive intravascular catheters. Both techniques have already demonstrated their clinical applicability. Using linear array technology, detection of disease as well as monitoring of pharmaceutical treatment in carotid arteries are feasible. Data acquired with intravascular ultrasound catheters have proved to be especially beneficial in understanding the development of atherosclerotic disease in coronary arteries. With the introduction of vascular elastography not only the geometry of plaques but also the risk for rupture of plaques might be identified. These so-called vulnerable plaques are frequently not flow-limiting and rupture of these plaques is responsible for the majority of cerebral and cardiac ischaemic events. Intravascular ultrasound elastography studies have demonstrated a high correlation between high strain and vulnerable plaque features, both
ex vivo
and
in vivo
. Additionally, pharmaceutical intervention could be monitored using this technique. Non-invasive vascular elastography has recently been developed for carotid applications by using compound scanning. Validation and initial clinical evaluation is currently being performed. Since abundance of vasa vasorum (VV) is correlated with vulnerable plaque development, quantification of VV might be a unique tool to even prevent this from happening. Using ultrasound contrast agents, it has been demonstrated that VV can be identified and quantified. Although far from routine clinical application, non-invasive and intravascular ultrasound VV imaging might pave the road to prevent atherosclerotic disease in an early phase. This paper reviews the conventional vascular ultrasound techniques as well as vascular ultrasound strain and vascular ultrasound VV imaging.
Ultrasonic image analysis and image-guided interventions
Authors: Noble J. Alison , Navab Nassir , Becher H.
Published: July 2011

The fields of medical image analysis and computer-aided interventions deal with reducing the large volume of digital images (X-ray, computed tomography, magnetic resonance imaging (MRI), positron emission tomography and ultrasound (US)) to more meaningful clinical information using software algorithms. US is a core imaging modality employed in these areas, both in its own right and used in conjunction with the other imaging modalities. It is receiving increased interest owing to the recent introduction of three-dimensional US, significant improvements in US image quality, and better understanding of how to design algorithms which exploit the unique strengths and properties of this real-time imaging modality. This article reviews the current state of art in US image analysis and its application in image-guided interventions. The article concludes by giving a perspective from clinical cardiology which is one of the most advanced areas of clinical application of US image analysis and describing some probable future trends in this important area of ultrasonic imaging research.
Minimum-drag shapes in magnetohydrodynamics
Authors: Zabarankin Michael
Published: July 2011

A necessary optimality condition for the minimum-drag shape for a non-magnetic solid body immersed in the uniform flow of an electrically conducting viscous incompressible fluid under the presence of a magnetic field is obtained. It is assumed that the flow and magnetic field are uniform and parallel at infinity, and that the body and fluid have the same magnetic permeability. The condition is derived based on the linearized magnetohydrodynamic (MHD) equations subject to a constraint on the body’s volume, and generalizes the existing optimality conditions for the minimum-drag shapes for the body in the Stokes and Oseen flows of a non-conducting fluid. It is shown that for any Hartmann number
M
, Reynolds number
Re
and magnetic Reynolds number
Re
m
, the minimum-drag shapes are fore-and-aft symmetric and have conic vertices with an angle of 2
π
/3. The minimum-drag shapes are represented in a function-series form, and the series coefficients are found iteratively with the derived optimality condition. At each iteration, the MHD problem is solved via the boundary integral equations obtained based on the Cauchy integral formula for generalized analytic functions. With respect to the equal-volume sphere, drag reduction as a function of the Cowling number S=
M
2
/(
Re
m
 
Re
) is smallest at S=1. Also, in the considered examples, the drag values for the minimum-drag shapes and equal-volume minimum-drag spheroids are sufficiently close.
Enhancement in crystalline perfection and optical properties of benzophenone single crystals: the remarkable effect of a liquid crystal
Authors: Kushwaha S. K. , Vijayan N. , Maurya K. K. , Kumar A. , Kumar B. , Somayajulu K. , Bhagavannarayana G.
Published: July 2011

The remarkable enhancement of the crystalline perfection of benzophenone (BP) crystals induced by liquid crystal (LC) doping has been investigated, and has in turn led to better optical properties. High-resolution X-ray diffractometry demonstrates that the structural grain boundaries present in pure crystals can be eliminated when the crystal is grown with LC doping. Thus, the high alignment capability of LCs has for the first time been utilized to enhance the quality of BP bulk single crystals. The LC-doped crystal exhibits higher optical transparency over its entire transparent region. The optical polarizing behaviour of the doped BP crystal is also improved.
Structural elucidation of β-(Y,Sc)2Si2O7: combined use of89Y MAS NMR and powder diffraction
Authors: Allix M. , Alba M. D. , Florian P. , Fernandez-Carrion A. J. , Suchomel M. R. , Escudero A. , Suard E. , Becerro A. I.
Published: July 2011

Although the structures of pure Sc2Si2O7and β-Y2Si2O7have been described in the literature using theC2/mspace group,29Si magic angle spinning (MAS) NMR measurements of the intermediate members of the Sc2Si2O7–β-Y2Si2O7system indicate a lowering of the symmetry to theC2 space group. Indeed, these compositions exhibit a unique Si crystallographic site and an Si—O—Si angle lower than 180°, incompatible with theC2/mspace group.C2 is the only possible alternative. Space groupCmcan be discarded with regard to its two different Si sites per unit cell. Moreover,89Y MAS NMR data have revealed the existence of two different Y sites in the structure of the intermediate members of the Sc2Si2O7–β-Y2Si2O7system, confirming the lowering of the symmetry to theC2 space group. The viability of theC2 model has therefore been tested and confirmed by refinement of synchrotron and neutron powder diffraction data for the different members of the system. The structural evolutions across the Sc2Si2O7–β-Y2Si2O7system are discussed.
gsaslanguage: aGSASscript language for automated Rietveld refinements of diffraction data
Authors: Vogel Sven C.
Published: July 2011

A description of the gsaslanguage software is presented. The software provides input to and processes output from theGSASpackage. It allows the development of scripts for the automatic evaluation of large numbers of data sets and provides documentation of the refinement strategies employed, thus fostering the development of efficient refinement strategies. Use of the bash shell and standard Unix text-processing tools, available natively on Linux and Mac OSX platforms andviathe freecygwinsoftware on Windows systems, make this software platform independent.