bluuebunny/crossref_metadata_2025 huggingface dataset:
A role for actin in aging and apoptosis
Authors: Gourlay C.W. , Ayscough K.R.
Published: August 2015

The actin cytoskeleton is central to many cell processes including membrane trafficking and generation of cell polarity. We have identified a role for actin in cell death and in promoting longevity of the budding yeast, Saccharomyces cerevisiae. Aging in yeast appears to occur via an apoptotic-like pathway with changes including DNA fragmentation, loss of mitochondrial membrane permeability, increase in levels of ROS (reactive oxygen species) and exposure of phosphatidylserine in the outer leaflet of the plasma membrane. This pathway can be induced by alterations in actin dynamics, such that reduced dynamics correlates with increased levels of ROS and decreased viability. Conversely, increased actin dynamics correlates with low ROS levels and increased survival. Our current studies have focused on identifying pathways which couple changes in actin dynamics to cell death.
Interactions between Sla1p, Lsb5p and Arf3p in yeast endocytosis
Authors: Costa R. , Ayscough K.R.
Published: August 2015

Endocytosis is critical for controlling the protein–lipid composition of the plasma membrane, uptake of nutrients as well as pathogens, and also plays an important role in regulation of cell signalling. While a number of pathways for endocytosis have been characterized in different organisms, all of these require remodelling of the cell cortex. The importance of a dynamic actin cytoskeleton for facilitating endocytosis has been recognized for many years in budding yeast, and is increasingly supported by studies in mammalian cells. Our studies have focused on proteins that we have shown to act at the interface between the actin cytoskeleton and the endocytic machinery. In particular, we have studied interactions of Sla1p, which binds to both activators of actin dynamics, i.e. Abp1p, Las17p and Pan1p, and to cargo proteins such as the pheromone receptor Ste2p. More recently we have mapped the interaction of Sla1p with Lsb5p, a protein that has a similar structure to the GGA [Golgi-localizing, γ-adaptin ear homology domain, Arf (ADP-ribosylation factor)-binding] family of proteins with an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGAs and TOM1) domain. We show that Lsb5p can interact with yeast Arf3p (orthologous with mammalian Arf6) and we demonstrate a requirement for Arf3p expression in order to localize Lsb5p to the cell cortex.
The regulation of membrane to cytosol partitioning of signalling proteins by phosphoinositides and their soluble headgroups
Authors: Downes C.P. , Gray A. , Fairservice A. , Safrany S.T. , Batty I.H. , Fleming I.
Published: August 2015

Inositol phospholipids [PIs (phosphoinositides)] represent a group of membrane-tethered signalling molecules which differ with respect to the number and distribution of monoester phosphate groups around the inositol ring. They function by binding to proteins which possess one of several domains that bind a particular PI species, often with high affinity and specificity. PH (pleckstrin homology) domains for example possess ligand-binding pockets that are often lined with positively charged residues and which bind PIs with varying degrees of specificity. Several PH domains bind not only PIs, but also their cognate headgroups, many of which occur naturally in cells as relatively abundant cytosolic inositol phosphates. The subcellular distributions of proteins possessing such PH domains are therefore determined by the relative levels of competing membrane-bound and soluble ligands. A classic example of the latter is the PH domain of phospholipase Cδ1, which binds both phosphatidylinositol 4,5-bisphosphate and inositol 1,4,5-trisphosphate. We have shown that the N-terminal PH domain of the Rho family guanine nucleotide-exchange factor, Tiam 1, binds PI ligands promiscuously allowing multiple modes of regulation. We also recently analysed the ligand-binding specificity of the PH domain of PI-dependent kinase 1 and found that it could bind abundant inositol polyphosphates such as inositol hexakisphosphate. This could explain the dual distribution of this key signalling component, which needs to access substrates at both the plasma membrane and in the cytosol.
Cyclic nucleotide signalling: a molecular approach to drug discovery for Alzheimer's disease
Authors: McPhee I. , Gibson L.C.D. , Kewney J. , Darroch C. , Stevens P.A. , Spinks D. , Cooreman A. , MacKenzie S.J.
Published: August 2015

The EPAC (exchange protein directly activated by cAMP) proteins are GEFs (guanine nucleotide-exchange factors) that activate Rap GTPases upon binding to cAMP. The involvement of these proteins in a number of diseases, neurodegenerative, inflammatory and metabolic, has started to show how they may prove to be important targets for therapeutic intervention. We first became interested in EPAC when we discovered that the expression levels of both EPAC1 and EPAC2 were altered in those regions of the brain associated with Alzheimer's disease [McPhee, Breslin, Kewney, MacKenzie, Cooreman, Gibson and Hammond (2004) International Patent number WO 2004/096199 A2]. It was known that compounds could be designed to be selective for EPAC over PKA (protein kinase A); however, these compounds were all based around the core structure of cAMP. We decided to screen a small compound library (10000 compounds) to investigate the possibility of developing a compound series outside of the cAMP structure. We subsequently developed a novel, high-throughput screen based on the displacement of [3H]cAMP from the EPAC cAMP-binding site and identified small molecule hits from the Scottish Biomedical Lead Generation Library. These compounds selectively bind to the cAMP-binding sites of EPAC1 and EPAC2 and are structurally dissimilar to cAMP. They have similar affinities for both EPAC1 and EPAC2 and have a high degree of specificity for EPAC over PKA. We believe that these compounds provide a valuable starting point for a drug optimization programme.
Genetic manipulation and functional analysis of cAMP signalling in cardiac muscle: implications for a new target of pharmacotherapy
Authors: Ishikawa Y. , Iwatsubo K. , Tsunematsu T. , Okumura S.
Published: August 2015

Adenylate cyclase is a membrane-bound enzyme that catalyses the conversion of ATP into cAMP upon activation of cell-surface G-protein-coupled receptors, such as β-adrenergic receptors, and initiates a cascade of phosphorylation reactions within the cell. Type 5 adenylate cyclase is a major isoform in the heart as well as in the striatum of the brain. Mice with a disrupted type 5 adenylate cyclase gene exhibited normal cardiac function under basal conditions, but a decreased response to isoprenaline stimulation. When mice were subjected to pressure overload stress with aortic banding, they developed cardiac hypertrophy, but with a significant reduction in the number of apoptotic cardiac myocytes as well as preserved cardiac function. When type 5 adenylate cyclase activity was inhibited pharmacologically, by the use of a novel P-site inhibitor with enhanced selectivity for this isoform, there were no changes in cardiac myocyte contractility, but the development of cardiac myocyte apoptosis induced by isoprenaline stimulation was effectively prevented. These results indicate that type 5 adenylate cyclase may serve as a better target of pharmacotherapy to prevent the development of cardiac myocyte apoptosis and thus failure in response to various cardiac stresses.
Myocardial phenotyping using isotopomer analysis of metabolic fluxes
Authors: Des Rosiers C. , Chatham J.C.
Published: August 2015

Over the past 20 years, stable isotopes combined with isotopomer analysis have proven to be a powerful approach to probe the dynamics of metabolism in various biological systems, including the heart. The aim of this paper is to demonstrate how isotopomer analysis of metabolic fluxes can provide novel insights into the myocardial phenotype. Specifically, building on our past experience using NMR spectroscopy and GC–MS as applied to investigations of cardiac energy metabolism, we highlight specific complex metabolic networks that would not be predicted by classical biochemistry or by static measurements of metabolite, protein and mRNA levels.
Recent advances in understanding structure–function relationships in the type II topoisomerase mechanism
Authors: Schoeffler A.J. , Berger J.M.
Published: August 2015

DNA topos (topoisomerases) are complex, multisubunit enzymes that remodel DNA topology. Members of the type II topo family function by passing one segment of duplex DNA through a transient break in another, a process that consumes two molecules of ATP and requires the co-ordinated action of multiple domains. Recent structural data on type II topo ATPase regions, which activate and enforce the directionality of DNA strand passage, have highlighted how ATP physically controls the catalytic cycle of the enzyme. Structural and biochemical studies of specialized DNA-binding domains in two paralogous bacterial type IIA topos (DNA gyrase and topo IV) show how these enzymes selectively negatively supercoil or decatenate DNA. Taken together, these findings expand our understanding of how disparate functional elements work together to co-ordinate the type II topo mechanism.
The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells
Authors: Yates A. , Chambers I.
Published: August 2015

Intrinsic regulators of the pluripotency of mouse ES (embryonic stem) cells include the homeodomain proteins Oct4 and the recently identified Nanog. When overexpressed, Nanog displays the unique attribute of robustly sustaining ES cell self-renewal in the absence of the otherwise requisite extracellular stimulation by LIF (leukaemia inhibitory factor) and BMP (bone morphogenetic protein). Here, we review our current understanding of the function of Nanog in pluripotent stem cells both in vitro and in vivo.
Role of the phosphoinositide 3-kinase pathway in mouse embryonic stem (ES) cells
Authors: Takahashi K. , Murakami M. , Yamanaka S.
Published: August 2015

Mouse ES (embryonic stem) cells maintain pluripotency with robust proliferation in vitro. ES cells share some similarities with cancer cells, such as anchorage-independent growth, loss of contact inhibition and tumour formation. After differentiation, ES cells lose pluripotency and tumorigenicity. Recent studies showed that the PI3K (phosphoinositide 3-kinase) pathway is important for proliferation, survival and maintenance of pluripotency in ES cells. The PI3K pathway is activated by growth factors and cytokines including insulin and leukaemia inhibitory factor. In addition to these exogenous factors, the PI3K pathway is endogenously activated by the constitutively active Ras family protein ERas (ES cell-expressed Ras). The PI3K pathway utilizes multiple downstream effectors including mTOR (mammalian target of rapamycin), which we have shown to be essential for proliferation in mouse ES cells and early embryos.
The impact of phage lambda: from restriction to recombineering
Authors: Murray Noreen E.
Published: August 2015

Experiments using phage lambda provided early insights into important molecular mechanisms, including genetic recombination and the control of gene expression. Before recombinant DNA technology, the use of lambda, most particularly lambda transducing phages, illustrated the importance of cloning bacterial genes, already providing some insight into how to use cloned genes to advantage. Subsequently, lambda made significant contributions to recombinant DNA technology, including the early generation of genomic and cDNA libraries. More recently, lambda genes associated with recombination have enabled techniques referred to as ‘recombineering’ to be developed. These techniques permit the refined manipulation, including mutation, of foreign genes in Escherichia coli and their subsequent return to the donor organism.
Enantioselective formation and ring-opening of epoxides catalysed by halohydrin dehalogenases
Authors: Janssen D.B. , Majerić-Elenkov M. , Hasnaoui G. , Hauer B. , Spelberg J.H. Lutje
Published: August 2015

Halohydrin dehalogenases catalyse the conversion of vicinal halohydrins into their corresponding epoxides, while releasing halide ions. They can be found in several bacteria that use halogenated alcohols or compounds that are degraded via halohydrins as a carbon source for growth. Biochemical and structural studies have shown that halohydrin dehalogenases are evolutionarily and mechanistically related to enzymes of the SDR (short-chain dehydrogenase/reductase) superfamily. In the reverse reaction, which is epoxide-ring opening, different nucleophiles can be accepted, including azide, nitrite and cyanide. This remarkable catalytic promiscuity allows the enzymatic production of a broad range of β-substituted alcohols from epoxides. In these oxirane-ring-opening reactions, the halohydrin dehalogenase from Agrobacterium radiobacter displays high enantioselectivity, making it possible to use the enzyme for the preparation of enantiopure building blocks for fine chemicals.
Synthesizing cellular networks from evolved ribosome–mRNA pairs
Authors: Rackham O. , Chin J.W.
Published: August 2015

We describe cellular engineering for the creation of multiple new cellular modules each composed of an orthogonal ribosome and orthogonal mRNA. These modules operate independently of the endogenous ribosome and mRNA. We discuss some of the applications of orthogonal pairs and highlight the expression of Boolean logic in gene regulation using multiple orthogonal pairs.
Alu elements: at the crossroads between disease and evolution
Authors: Ule Jernej
Published: August 2015

The cost of DNA sequencing is decreasing year by year, and the era of personalized medicine and the $1000 genome seems to be just around the corner. In order to link genetic variation to gene function, however, we need to learn more about the function of the non-coding genomic elements. The advance of high-throughput sequencing enabled rapid progress in mapping the functional elements in our genome. In the present article, I discuss how intronic mutations acting at Alu elements enable formation of new exons. I review the mutations that cause disease when promoting a major increase in the inclusion of Alu exon into mature transcripts. Moreover, I present the mechanism that represses such a major inclusion of Alu exons and instead enables a gradual evolution of Alu elements into new exons.
Mutations in cytoplasmic dynein and its regulators cause malformations of cortical development and neurodegenerative diseases
Authors: Lipka Joanna , Kuijpers Marijn , Jaworski Jacek , Hoogenraad Casper C.
Published: August 2015

Neurons are highly specialized for the processing and transmission of electrical signals and use cytoskeleton-based motor proteins to transport different vesicles and cellular materials. Abnormalities in intracellular transport are thought to be a critical factor in the degeneration and death of neurons in both the central and peripheral nervous systems. Several recent studies describe disruptive mutations in the minus-end-directed microtubule motor cytoplasmic dynein that are directly linked to human motor neuropathies, such as SMA (spinal muscular atrophy) and axonal CMT (Charcot–Marie–Tooth) disease or malformations of cortical development, including lissencephaly, pachygyria and polymicrogyria. In addition, genetic defects associated with these and other neurological disorders have been found in multifunctional adaptors that regulate dynein function, including the dynactin subunit p150Glued, BICD2 (Bicaudal D2), Lis-1 (lissencephaly 1) and NDE1 (nuclear distribution protein E). In the present paper we provide an overview of the disease-causing mutations in dynein motors and regulatory proteins that lead to a broad phenotypic spectrum extending from peripheral neuropathies to cerebral malformations.
Induced pluripotent stem cell (iPSC)-derived dopaminergic models of Parkinson's disease
Authors: Beevers Joel E. , Caffrey Tara M. , Wade-Martins Richard
Published: August 2015

iPSCs (induced pluripotent stem cells) are the newest tool used to model PD (Parkinson's disease). Fibroblasts from patients carrying pathogenic mutations that lead to PD have been reprogrammed into iPSCs, which can subsequently be differentiated into important cell types. Given the characteristic loss of dopaminergic neurons in the substantia nigra pars compacta of PD patients, iPSC-derived midbrain dopaminergic neurons have been generated to investigate pathogenic mechanisms in this important cell type as a means of modelling PD. iPSC-derived cultures studied so far have been made from patients carrying mutations in LRRK2 (leucine-rich repeat kinase 2), PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced putative kinase 1], PARK2 (encodes parkin) or GBA (β-glucocerebrosidase), in addition to those with SNCA (α-synuclein) multiplication and idiopathic PD. In some cases, isogenic control lines have been created to minimize inherent variability between lines from different individuals. Disruptions in autophagy, mitochondrial function and dopamine biology at the synapse have been described. Future applications for iPSC-derived models of PD beyond modelling include drug testing and the ability to investigate the genetic diversity of PD.
GCN2, an old dog with new tricks
Authors: Grallert Beáta , Boye Erik
Published: August 2015

Gcn2 was first described in budding yeast as a serine/threonine protein kinase involved in the response to amino acid starvation and this is its best characterized role to date. Recent work has revealed new and exciting roles for Gcn2, which affect many aspects of cellular physiology in response to a number of stresses in addition to starvation. Furthermore, the Gcn2 pathway has been implicated in diseases such as cancer and Alzheimer’s disease, and therefore elucidating the new roles of Gcn2 seems ever more important.
Copper transport and regulation in Schizosaccharomyces pombe
Authors: Beaudoin Jude , Ekici Seda , Daldal Fevzi , Ait-Mohand Samia , Guérin Brigitte , Labbé Simon
Published: August 2015

The fission yeast Schizosaccharomyces pombe has been successfully used as a model to gain fundamental knowledge in understanding how eukaryotic cells acquire copper during vegetative growth. These studies have revealed the existence of a heteromeric Ctr4–Ctr5 plasma membrane complex that mediates uptake of copper within the cells. Furthermore, additional studies have led to the identification of one of the first vacuolar copper transporters, Ctr6, as well as the copper-responsive Cuf1 transcription factor. Recent investigations have extended the use of S. pombe to elucidate new roles for copper metabolism in meiotic differentiation. For example, these studies have led to the discovery of Mfc1, which turned out to be the first example of a meiosis-specific copper transporter. Whereas copper-dependent transcriptional regulation of the Ctr family members is under the control of Cuf1 during mitosis or meiosis, meiosis-specific copper transporter Mfc1 is regulated by the recently discovered transactivator Mca1. It is foreseeable that identification of novel meiotic copper-related proteins will serve as stepping stones to unravel fundamental aspects of copper homoeostasis.
High-resolution free energy landscape analysis of protein folding
Authors: Banushkina Polina V. , Krivov Sergei V.
Published: August 2015

The free energy landscape can provide a quantitative description of folding dynamics, if determined as a function of an optimally chosen reaction coordinate. The profile together with the optimal coordinate allows one to directly determine such basic properties of folding dynamics as the configurations of the minima and transition states, the heights of the barriers, the value of the pre-exponential factor and its relation to the transition path times. In the present study, we review the framework, in particular, the approach to determine such an optimal coordinate, and its application to the analysis of simulated protein folding dynamics.
Activation of the E3 ubiquitin ligase Parkin
Authors: Caulfield Thomas R. , Fiesel Fabienne C. , Springer Wolfdieter
Published: August 2015

The PINK1 (phosphatase and tensin homologue-induced putative kinase 1)/Parkin-dependent mitochondrial quality control pathway mediates the clearance of damaged organelles, but appears to be disrupted in Parkinson's disease (PD) [Springer and Kahle (2011) Autophagy 7, 266–278]. Upon mitochondrial stress, PINK1 activates the E3 ubiquitin (Ub) ligase Parkin through phosphorylation of the Ub-like (UBL) domain of Parkin and of the small modifier Ub itself at a conserved residue [Sauvé and Gehring (2014) Cell Res. 24, 1025–1026]. Recently resolved partial crystal structures of Parkin showed a ‘closed’, auto-inhibited conformation, consistent with its notoriously weak enzymatic activity at steady state [Wauer and Komander (2013) EMBO J. 32, 2099–2112; Riley et al. (2013) Nat. Commun. 4, 1982; Trempe et al. (2013) Science 340, 1451–1455; Spratt et al. (2013) Nat. Commun. 4, 1983]. It has thus become clear that Parkin must undergo major structural rearrangements in order to unleash its catalytic functions. Recent published findings derived from X-ray structures and molecular modelling present a complete structural model of human Parkin at an all-atom resolution [Caulfield et al. (2014) PLoS Comput. Biol. 10, e1003935]. The results of the combined in silico simulations-based and experimental assay-based study indicates that PINK1-dependent Ser65 phosphorylation of Parkin is required for its activation and triggering of ‘opening’ conformations. Indeed, the obtained structures showed a sequential release of Parkin's intertwined domains and allowed docking of an Ub-charged E2 coenzyme, which could enable its enzymatic activity. In addition, using cell-based screening, select E2 enzymes that redundantly, cooperatively or antagonistically regulate Parkin's activation and/or enzymatic functions at different stages of the mitochondrial autophagy (mitophagy) process were identified [Fiesel et al. (2014) J. Cell Sci. 127, 3488–3504]. Other work that aims to pin-point the particular pathogenic dysfunctions of Parkin mis-sense mutations have been recently disseminated (Fabienne C. Fiesel, Thomas R. Caulfield, Elisabeth L. Moussaud-Lamodiere, Daniel F.A.R. Dourado, Kotaro Ogaki, Owen A. Ross, Samuel C. Flores, and Wolfdieter Springer, submitted). Such a structure–function approach provides the basis for the dissection of Parkin's regulation and a targeted drug design to identify small-molecule activators of this neuroprotective E3 Ub ligase.
Linking microtubules to Parkinson's disease: the case of parkin
Authors: Cappelletti Graziella , Casagrande Francesca , Calogero Alessandra , De Gregorio Carmelita , Pezzoli Gianni , Cartelli Daniele
Published: August 2015

Microtubules (MTs) are dynamic polymers consisting of α/β tubulin dimers and playing a plethora of roles in eukaryotic cells. Looking at neurons, they are key determinants of neuronal polarity, axonal transport and synaptic plasticity. The concept that MT dysfunction can participate in, and perhaps lead to, Parkinson's disease (PD) progression has been suggested by studies using toxin-based and genetic experimental models of the disease. Here, we first learn lessons from MPTP and rotenone as well as from the PD related genes, including SNCA and LRRK2, and then look at old and new evidence regarding the interplay between parkin and MTs. Data from experimental models and human cells point out that parkin regulates MT stability and strengthen the link between MTs and PD paving the way to a viable strategy for the management of the disease.
TSPO as a target for glioblastoma therapeutics
Authors: Werry Eryn L. , Barron Melissa L. , Kassiou Michael
Published: August 2015

The translocator protein (TSPO) is an 18-kDa five-transmembrane protein, which is primarily found in the outer mitochondrial membrane. Levels of this protein are up-regulated in the most aggressive and common glioma, glioblastoma multiforme (GM). Levels of TSPO also correlate with GM clinical outcome, suggesting that TSPO may be a novel GM diagnostic imaging agent. Therapeutically, targeting the TSPO may provide a mechanism to abrogate the apoptotic-resistant, invasive and aggressive nature of GM and may also provide a way of targeting other anti-cancer treatments to GM sites. This review highlights recent progress in research on TSPO-based diagnostic imaging and therapeutics for GM.
TSPO: functions and applications of a mitochondrial stress response pathway
Authors: Campanella Michelangelo , Turkheimer Federico E.
Published: August 2015

The mitochondrial outer membrane protein TSPO (translocator protein) lies in a privileged position at the interface between mitochondrion and cytosol. Since the initially discovery, nearly forty years ago, it has generated major interest among various disciplines of modern experimental and applied biomedicine. The focused meeting we have organized aimed at summarizing the state of the art knowledge on TSPO and the discipline-based segregated concepts that have made this an exciting and active field of science. The scientists who have generously contributed the event have agreed to generate a special issue here published—stemmed from the discussion of the vent. This consists in a series of contributions via which the know-how is shared aiming to inspire current and future endeavours to validate and accelerate the impact of TSPO science in human pathophysiology and clinical applications.
Metabolic signatures linked to macrophage polarization: from glucose metabolism to oxidative phosphorylation
Authors: Boscá Lisardo , González-Ramos Silvia , Prieto Patricia , Fernández-Velasco María , Mojena Marina , Martín-Sanz Paloma , Alemany Susana
Published: August 2015

Macrophages are present in a large variety of locations, playing distinct functions that are determined by its developmental origin and by the nature of the activators of the microenvironment. Macrophage activation can be classified as pro-inflammatory (M1 polarization) or anti-inflammatory-pro-resolution-deactivation (M2), these profiles coexisting in the course of the immune response and playing a relevant functional role in the onset of inflammation (Figure 1). Several groups have analysed the metabolic aspects associated with macrophage activation to answer the question about what changes in the regulation of energy metabolism and biosynthesis of anabolic precursors accompany the different types of polarization and to what extent they are necessary for the expression of the activation phenotypes. The interest of these studies is to regulate macrophage function by altering their metabolic activity in a ‘therapeutic way’.
Comparative study of 0° X-cut and Y + 36°-cut lithium niobate high-voltage sensing
Authors: Patel N. , Branch D. W. , Schamiloglu E. , Cular S.
Published: August 2015

A comparison study between Y + 36° and 0° X-cut lithium niobate (LiNbO3) was performed to evaluate the influence of crystal cut on the acoustic propagation to realize a piezoelectric high-voltage sensor. The acoustic time-of-flight for each crystal cut was measured when applying direct current (DC), alternating current (AC), and pulsed voltages. Results show that the voltage-induced shift in the acoustic wave propagation time scaled quadratically with voltage for DC and AC voltages applied to X-cut crystals. For the Y + 36° crystal, the voltage-induced shift scales linearly with DC voltages and quadratically with AC voltages. When applying 5 μs voltage pulses to both crystals, the voltage-induced shift scaled linearly with voltage. For the Y + 36° cut, the voltage-induced shift from applying DC voltages ranged from 10 to 54 ps and 35 to 778 ps for AC voltages at 640 V over the frequency range of 100 Hz–100 kHz. Using the same conditions as the Y + 36° cut, the 0° X-cut crystal sensed a shift of 10–273 ps for DC voltages and 189–813 ps for AC voltage application. For 5 μs voltage pulses, the 0° X-cut crystal sensed a voltage induced shift of 0.250–2 ns and the Y + 36°-cut crystal sensed a time shift of 0.115–1.6 ns. This suggests a frequency sensitive response to voltage where the influence of the crystal cut was not a significant contributor under DC, AC, or pulsed voltage conditions. The measured DC data were compared to a 1-D impedance matrix model where the predicted incremental length changed as a function of voltage. When the voltage source error was eliminated through physical modeling from the uncertainty budget, the combined uncertainty of the sensor (within a 95% confidence interval) decreased to 0.0033% using a Y + 36°-cut crystal and 0.0032% using an X-cut crystal for all the voltage conditions used in this experiment.
Liquid pressure wireless sensor based on magnetostrictive microwires for applications in cardiovascular localized diagnostic
Authors: Aragón A. M. , Hernando-Rydings M. , Hernando A. , Marín P.
Published: August 2015

In this letter, we report a method to measure changes in a fluid pressure, flowing through a flexible pipeline, by means of a ring of magnetic microwire concentric to the pipeline. The detection is based on the modulated scattering of electromagnetic waves by the magnetoelastic ring. This modulation is driven by applying a low frequency bias magnetic field able to tune the magnetic permeability of the ferromagnetic microwire. Pressure detection, by means of magnetic permeability changes, is possible due to the magnetostrictive character of the sample. The experimental work developed has, also, allowed fluid pressure detection in a hydraulic circuit connected to ventricular assist system where a fluid with a viscosity close to blood flows.
Ionic charge transport between blockages: Sodium cation conduction in freshly excised bulk brain tissue
Authors: Emin David , Akhtari Massoud , Ellingson B. M. , Mathern G. W.
Published: August 2015

We analyze the transient-dc and frequency-dependent electrical conductivities between blocking electrodes. We extend this analysis to measurements of ions’ transport in freshly excised bulk samples of human brain tissue whose complex cellular structure produces blockages. The associated ionic charge-carrier density and diffusivity are consistent with local values for sodium cations determined non-invasively in brain tissue by MRI (NMR) and diffusion-MRI (spin-echo NMR). The characteristic separation between blockages, about 450 microns, is very much shorter than that found for sodium-doped gel proxies for brain tissue, >1 cm.
Low contact resistance in epitaxial graphene devices for quantum metrology
Authors: Yager Tom , Lartsev Arseniy , Cedergren Karin , Yakimova Rositsa , Panchal Vishal , Kazakova Olga , Tzalenchuk Alexander , Kim Kyung Ho , Park Yung Woo , Lara-Avila Samuel , Kubatkin Sergey
Published: August 2015

We investigate Ti/Au contacts to monolayer epitaxial graphene on SiC (0001) for applications in quantum resistance metrology. Using three-terminal measurements in the quantum Hall regime we observed variations in contact resistances ranging from a minimal value of 0.6 Ω up to 11 kΩ. We identify a major source of high-resistance contacts to be due bilayer graphene interruptions to the quantum Hall current, whilst discarding the effects of interface cleanliness and contact geometry for our fabricated devices. Moreover, we experimentally demonstrate methods to improve the reproducibility of low resistance contacts (<10 Ω) suitable for high precision quantum resistance metrology.
Shootin1–cortactin interaction mediates signal–force transduction for axon outgrowth
Authors: Kubo Yusuke , Baba Kentarou , Toriyama Michinori , Minegishi Takunori , Sugiura Tadao , Kozawa Satoshi , Ikeda Kazushi , Inagaki Naoyuki
Published: August 2015

Motile cells transduce environmental chemical signals into mechanical forces to achieve properly controlled migration. This signal–force transduction is thought to require regulated mechanical coupling between actin filaments (F-actins), which undergo retrograde flow at the cellular leading edge, and cell adhesions via linker “clutch” molecules. However, the molecular machinery mediating this regulatory coupling remains unclear. Here we show that the F-actin binding molecule cortactin directly interacts with a clutch molecule, shootin1, in axonal growth cones, thereby mediating the linkage between F-actin retrograde flow and cell adhesions through L1-CAM. Shootin1–cortactin interaction was enhanced by shootin1 phosphorylation by Pak1, which is activated by the axonal chemoattractant netrin-1. We provide evidence that shootin1–cortactin interaction participates in netrin-1–induced F-actin adhesion coupling and in the promotion of traction forces for axon outgrowth. Under cell signaling, this regulatory F-actin adhesion coupling in growth cones cooperates with actin polymerization for efficient cellular motility.
Right Ventricular Protein Expression Profile in End‐Stage Heart Failure
Authors: Su Yan Ru , Chiusa Manuel , Brittain Evan , Hemnes Anna R. , Absi Tarek S. , Lim Chee Chew , Di Salvo Thomas G.
Published: August 2015

Little is known about the right ventricular (RV) proteome in human heart failure (HF), including possible differences compared to the left ventricular (LV) proteome. We used 2‐dimensional differential in‐gel electrophoresis (pH: 4–7, 10–150 kDa), followed by liquid chromatography tandem mass spectrometry, to compare the RV and LV proteomes in 12 explanted human hearts. We used Western blotting and multiple‐reaction monitoring for protein verification and RNA sequencing for messenger RNA and protein expression correlation. In all 12 hearts, the right ventricles (RVs) demonstrated differential expression of 11 proteins relative to the left ventricles (LVs), including lesser expression of CRYM, TPM1, CLU, TXNL1, and COQ9 and greater expression of TNNI3, SAAI, ERP29, ACTN2, HSPB2, and NDUFS3. Principal‐components analysis did not suggest RV‐versus‐LV proteome partitioning. In the nonischemic RVs (n = 6), 7 proteins were differentially expressed relative to the ischemic RVs (n = 6), including increased expression of CRYM, B7Z964, desmin, ANXA5, and MIME and decreased expression of SERPINA1 and ANT3. Principal‐components analysis demonstrated partitioning of the nonischemic and ischemic RV proteomes, and gene ontology analysis identified differences in hemostasis and atherosclerosis‐associated networks. There were no proteomic differences between RVs with echocardiographic dysfunction (n = 8) and those with normal function (n = 4). Messenger RNA and protein expression did not correlate consistently, suggesting a major role for RV posttranscriptional protein expression regulation. Differences in contractile, cytoskeletal, metabolic, signaling, and survival pathways exist between the RV and the LV in HF and may be related to the underlying HF etiology and differential posttranscriptional regulation.
Design and feasibility of integrating personalized PRO dashboards into prostate cancer care
Authors: Hartzler Andrea L , Izard Jason P , Dalkin Bruce L , Mikles Sean P , Gore John L
Published: August 2015

Objective Patient-reported outcomes (PROs) are a valued source of health information, but prior work focuses largely on data capture without guidance on visual displays that promote effective PRO use in patient-centered care. We engaged patients, providers, and design experts in human-centered design of “PRO dashboards” that illustrate trends in health-related quality of life (HRQOL) reported by patients following prostate cancer treatment.

Materials and Methods We designed and assessed the feasibility of integrating dashboards into care in 3 steps: (1) capture PRO needs of patients and providers through focus groups and interviews; (2) iteratively build and refine a prototype dashboard; and (3) pilot test dashboards with patients and their provider during follow-up care.

Results Focus groups ( n = 60 patients) prioritized needs for dashboards that compared longitudinal trends in patients’ HRQOL with “men like me.” Of the candidate dashboard designs, 50 patients and 50 providers rated pictographs less helpful than bar charts, line graphs, or tables ( P < .001) and preferred bar charts and line graphs most. Given these needs and the design recommendations from our Patient Advisory Board ( n = 7) and design experts ( n = 7), we built and refined a prototype that charts patients’ HRQOL compared with age- and treatment-matched patients in personalized dashboards. Pilot testing dashboard use ( n = 12 patients) improved compliance with quality indicators for prostate cancer care ( P < .01).

Conclusion PRO dashboards are a promising approach for integrating patient-generated data into prostate cancer care. Informed by human-centered design principles, this work establishes guidance on dashboard content, tailoring, and clinical use that patients and providers find meaningful.
Directional reversals enableMyxococcus xanthuscells to produce collective one-dimensional streams during fruiting-body formation
Authors: Thutupalli Shashi , Sun Mingzhai , Bunyak Filiz , Palaniappan Kannappan , Shaevitz Joshua W.
Published: August 2015

The formation of a collectively moving group benefits individuals within a population in a variety of ways. The surface-dwelling bacteriumMyxococcus xanthusforms dynamic collective groups both to feed on prey and to aggregate during times of starvation. The latter behaviour, termed fruiting-body formation, involves a complex, coordinated series of density changes that ultimately lead to three-dimensional aggregates comprising hundreds of thousands of cells and spores. How a loose, two-dimensional sheet of motile cells produces a fixed aggregate has remained a mystery as current models of aggregation are either inconsistent with experimental data or ultimately predict unstable structures that do not remain fixed in space. Here, we use high-resolution microscopy and computer vision software to spatio-temporally track the motion of thousands of individuals during the initial stages of fruiting-body formation. We find that cells undergo a phase transition from exploratory flocking, in which unstable cell groups move rapidly and coherently over long distances, to a reversal-mediated localization into one-dimensional growing streams that are inherently stable in space. These observations identify a new phase of active collective behaviour and answer a long-standing open question inMyxococcusdevelopment by describing how motile cell groups can remain statistically fixed in a spatial location.
Diagnosing psychiatric disorders in people with intellectual disabilities: issues and achievements
Authors: Bertelli Marco O. , Rossi Michele , Scuticchio Daniela , Bianco Annamaria
Published: August 2015

Purpose

– Diagnosing psychiatric disorders (PD) in adults with Intellectual Disability (ID) presents several issues and need specific skills and tools. The purpose of this paper is to provide a detailed description of the current status of art through a systematic mapping of the literature.

Design/methodology/approach

– The authors reviewed the international literature on the basis of the following questions: what are the issues in the psychiatric diagnostic process for adults with ID? What methods and procedures have been used for psychiatric assessment in ID? To date, is it possible to identify some most effective procedures?

Findings

– The analysis of the literature indicates that main issues of the psychiatric diagnostic process in adults with ID are the following: identification of psychiatric symptoms, behavioural equivalents, diagnostic criteria, setting, source of information, screening, and diagnostic tools. The evidence base is only emerging and although many relevant achievements have been reached in the last two decades, no definitive guideline has been produced. Most recent acquisition also allowed to identify some assessment procedures that are currently considered the most effective. Individualised assessment remains the best way to meet the needs of this heterogeneous and variable patient group.

Originality/value

– This paper offers a comprehensive and updated description of current achievements and issues towards the assessment of PD in people with ID.
Mental health and intellectual disability: integrating different approaches in the neurodevelopmental perspective
Authors: Bertelli Marco O.
Published: August 2015

Purpose

– The purpose of this paper is to provide a critical overview of some main implications of the neurodevelopmental perspective for the field of the mental health in intellectual disability and autism spectrum disorders.

Design/methodology/approach

– A discussion surrounding the importance of integrating different approaches in the neurodevelopmental perspective, drawing on sources from the paper proposals to the 10th International Congress of the European Association in Mental Health and Intellectual Disability (EAMHID), and the literature.

Findings

– At present, the neurodevelopmental perspective seems to be the most appropriate and valued conceptual framework to support multi-level, interdisciplinary approaches in understanding the aetiologies of mental health problems as well as when and how to intervene. It inherently exemplifies a dimensional approach, which can capture variations between individuals, their developmental time course, brain-behaviours associations and functional significance better than categorical approaches, and diagnostic measures.

Originality/value

– This editorial outlines a special issue that offers a comprehensive and varied collection of papers from the contributions to the 10th International Congress of the EAMHID.
Homogenization of selective laser melting cellular material for impact performance simulation
Authors: Labeas G. , Ptochos Evangelos
Published: August 2015

Purpose

– The purpose of this paper is to present, the global behaviour of sandwich structures comprising cellular cores is predicted by finite element (FE) analysis. Two modelling approaches are investigated, providing different levels of accuracy; in both approaches, the sandwich structure is idealised as a layered stack with the skin modelled using shell elements; while the core is either modelled with fine detail using beam micro-elements representing the cell struts, or is modelled by three-dimensional solid elements after an appropriate core homogenisation.

Design/methodology/approach

– The applied homogenisation methodology, as well as the all important modelling issues are presented in detail. Experimental tests performed using a mass-drop testing machine are used for the successful validation of the simulation models.

Findings

– It was concluded that the core microscale models having detailed FE modelling of the core unit cells geometry with fine scale beam elements are suitable for the analysis of the core failure modes and the prediction of the basic core stiffness and strength properties. It was demonstrated that the homogenised core model provides significant advantages with respect to computing time and cost, although they require additional calculations in order to define the homogenised stress-strain curves.

Research limitations/implications

– Special microscale material tests are required for the determination of appropriate materials parameters of the core models, as steel selective laser melting (SLM) microstrut properties differ from the constitutive steel material ones, due to the core manufacturing SLM technique. Stress interactions were not taken into account in the homogenisation, as the applied core material model supports the introduction of independent stress-strain curves; however, the predicted load deflection results appeared to be very close to those obtained from the detailed core micromodels.

Originality/value

– The paper is original. The dynamic behaviour of conventional sandwich structures comprising conventional honeycomb type cores has been extensively studied, using simple mass-spring models, energy based models, as well as FE models. However, the response of sandwich panels with innovative SLM cellular cores has been limited. In the present paper, novel modelling approaches for the simulation of the structural response of sandwich panels having innovative open lattice cellular cores produced by SLM are investigated.
A global reference for caesarean section rates (C‐Model): a multicountry cross‐sectional study
Authors: Souza JP , Betran AP , Dumont A , de Mucio B , Gibbs Pickens CM , Deneux‐Tharaux C , Ortiz‐Panozo E , Sullivan E , Ota E , Togoobaatar G , Carroli G , Knight H , Zhang J , Cecatti JG , Vogel JP , Jayaratne K , Leal MC , Gissler M , Morisaki N , Lack N , Oladapo OT , Tunçalp Ö , Lumbiganon P , Mori R , Quintana S , Costa Passos AD , Marcolin AC , Zongo A , Blondel B , Hernández B , Hogue CJ , Prunet C , Landman C , Ochir C , Cuesta C , Pileggi‐Castro C , Walker D , Alves D , Abalos E , Moises ECD , Vieira EM , Duarte G , Perdona G , Gurol‐Urganci I , Takahiko K , Moscovici L , Campodonico L , Oliveira‐Ciabati L , Laopaiboon M , Danansuriya M , Nakamura‐Pereira M , Costa ML , Torloni MR , Kramer MR , Borges P , Olkhanud PB , Pérez‐Cuevas R , Agampodi SB , Mittal S , Serruya S , Bataglia V , Li Z , Temmerman M , Gülmezoglu AM
Published: August 2015

Objective

To generate a global reference for caesarean section (CS) rates at health facilities.

Design

Cross‐sectional study.

Setting

Health facilities from 43 countries.

Population/Sample

Thirty eight thousand three hundred and twenty‐four women giving birth from 22 countries for model building and 10 045 875 women giving birth from 43 countries for model testing.

Methods

We hypothesised that mathematical models could determine the relationship between clinical‐obstetric characteristics and CS. These models generated probabilities of CS that could be compared with the observed CS rates. We devised a three‐step approach to generate the global benchmark of CS rates at health facilities: creation of a multi‐country reference population, building mathematical models, and testing these models.

Main outcome measures

Area under the ROC curves, diagnostic odds ratio, expected CS rate, observed CS rate.

Results

According to the different versions of the model, areas under the ROC curves suggested a good discriminatory capacity of C‐Model, with summary estimates ranging from 0.832 to 0.844. The C‐Model was able to generate expected CS rates adjusted for the case‐mix of the obstetric population. We have also prepared an e‐calculator to facilitate use of C‐Model (www.who.int/reproductivehealth/publications/maternal_perinatal_health/c-model/en/).

Conclusions

This article describes the development of a global reference for CS rates. Based on maternal characteristics, this tool was able to generate an individualised expected CS rate for health facilities or groups of health facilities. With C‐Model, obstetric teams, health system managers, health facilities, health insurance companies, and governments can produce a customised reference CS rate for assessing use (and overuse) of CS.

Tweetable abstract

The C‐Model provides a customized benchmark for caesarean section rates in health facilities and systems.
The Use of Entheseal Changes in the Femur and Os Coxa for Age Assessment
Authors: Listi Ginesse A.
Published: August 2015

This study examined the relationship between age and entheseal modifications in the femur and os coxa for estimating age at death. Five areas on the os coxa and four on the femur were scored in 200 white individuals over 40 years of age. Statistical analyses assessed the relationship between age and entheseal modification using both raw scores and scores adjusted for body size, for each sex, and for sexes combined. Results indicate that significant relationships exist between age and entheseal modification at three sites on the femur and four on the os coxae, but the relationships are not strong enough to generate age predictions. Conversely, the most severe entheseal modifications show promise as an indicator of age in older adults. Although further research is needed using larger samples for robust statistical analyses, current data indicate these modifications can suggest an age >60, or in some cases 70, years.