bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Polymeric Microcapsules Containing a Low Molecular Weight Peptide for Controlled Release
Authors: Moore Keith , Amos Jennifer , Davis Jeffrey , Gourdie Robert , Potts Jay D.
Published: January 2013

A need exists to prolong the release of rapidly metabolized peptides of a low molecular weight, while delivering this peptide without environmental interference. Previous studies have used bovine serum albumin (BSA) as a model peptide to study release characteristics from alginate microcapsules. BSA is 66 kDa in size, while the peptide of interest here, connexin-43 carboxyl-terminus mimetic peptide (αCT1), is only 3.4 kDa. Such a change in size results in a much different set of release parameters. Our overall goal is a sustained release over a 24+ h period. Prolonged application of the peptide to a wound site to investigate therapeutic effects is ideal. As a result, a diffusion method using alginate microcapsules, along with the addition of poly-l-lysine and poly-l-ornithine, has been explored. We first aimed to establish and characterize our parameters through a set of parametric tests. Variations in polymer coating, change in pH, and changes in loading ratio have previously been shown to effect release using model compounds. Here we test specific changes in these parameters to show effects on the release of αCT1. Additionally, the microcapsules were attached to several biomaterials and surgical implants by ultraviolet cross-linking to study the effectiveness of attachment and delivery. Analysis and measurements using phase contrast microscopy, scanning electron microscopy, and atomic force microscopy were used to characterize changes in microcapsule morphology.
Regulation of Bacillus subtilis DesK thermosensor by lipids
Authors: Martín Mariana , de Mendoza Diego
Published: January 2013

Temperature sensing is essential for the survival of living cells. The membrane-bound thermosensor DesK from Bacillus subtilis is a key representative of histidine kinases receptors able to remodel membrane lipid composition when the temperature drops below ~30°C. Although the receptor is well studied, a central issue remains: how does the compositional and functional diversity of the surrounding membrane modulate receptor function? Reconstituting full-length DesK into proteoliposomes of well-defined and controlled lipid composition represents a minimal synthetic approach to systematically address this question. Thus DesK has been reconstituted in a variety of phospholipid bilayers and its temperature-regulated autokinase activity determined as function of fatty acyl chain length, lipid head-group structure and phase preference. We show that the head group structure of lipids (both in vitro and in vivo) has little effect on DesK thermosensing, whereas properties determined by the acyl chain of lipids, such as membrane thickness and phase separation into coexisting lipid domains, exert a profound regulatory effect on kinase domain activation at low temperatures. These experiments suggest that the non-polar domain of glycerolipids is essential to regulate the allosteric structural transitions of DesK, by activating the autophosphorylation of the intracellular kinase domain in response to a decrease in temperature.
The ATP synthase: the understood, the uncertain and the unknown
Authors: Walker John E.
Published: January 2013

The ATP synthases are multiprotein complexes found in the energy-transducing membranes of bacteria, chloroplasts and mitochondria. They employ a transmembrane protonmotive force, Δp, as a source of energy to drive a mechanical rotary mechanism that leads to the chemical synthesis of ATP from ADP and Pi. Their overall architecture, organization and mechanistic principles are mostly well established, but other features are less well understood. For example, ATP synthases from bacteria, mitochondria and chloroplasts differ in the mechanisms of regulation of their activity, and the molecular bases of these different mechanisms and their physiological roles are only just beginning to emerge. Another crucial feature lacking a molecular description is how rotation driven by Δp is generated, and how rotation transmits energy into the catalytic sites of the enzyme to produce the stepping action during rotation. One surprising and incompletely explained deduction based on the symmetries of c-rings in the rotor of the enzyme is that the amount of energy required by the ATP synthase to make an ATP molecule does not have a universal value. ATP synthases from multicellular organisms require the least energy, whereas the energy required to make an ATP molecule in unicellular organisms and chloroplasts is higher, and a range of values has been calculated. Finally, evidence is growing for other roles of ATP synthases in the inner membranes of mitochondria. Here the enzymes form supermolecular complexes, possibly with specific lipids, and these complexes probably contribute to, or even determine, the formation of the cristae.
Palmitoylation of influenza virus proteins
Authors: Veit Michael , Serebryakova Marina V. , Kordyukova Larisa V.
Published: January 2013

Influenza viruses contain two palmitoylated (S-acylated) proteins: the major spike protein HA (haemagglutinin) and the proton-channel M2. The present review describes the fundamental biochemistry of palmitoylation of HA: the location of palmitoylation sites and the fatty acid species bound to HA. Finally, the functional consequences of palmitoylation of HA and M2 are discussed regarding association with membrane rafts, entry of viruses into target cells by HA-mediated membrane fusion as well as the release of newly assembled virus particles from infected cells.
Recent advances in understanding GLP-1R (glucagon-like peptide-1 receptor) function
Authors: Koole Cassandra , Pabreja Kavita , Savage Emilia E. , Wootten Denise , Furness Sebastian G.B. , Miller Laurence J. , Christopoulos Arthur , Sexton Patrick M.
Published: January 2013

Type 2 diabetes is a major global health problem and there is ongoing research for new treatments to manage the disease. The GLP-1R (glucagon-like peptide-1 receptor) controls the physiological response to the incretin peptide, GLP-1, and is currently a major target for the development of therapeutics owing to the broad range of potential beneficial effects in Type 2 diabetes. These include promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin sensitivity and promotion of weight loss. Despite this, our understanding of GLP-1R function is still limited, with the desired spectrum of GLP-1R-mediated signalling yet to be determined. We review the current understanding of GLP-1R function, in particular, highlighting recent contributions in the field on allosteric modulation, probe-dependence and ligand-directed signal bias and how these behaviours may influence future drug development.
Fluorescent ligands to investigate GPCR binding properties and oligomerization
Authors: Cottet Martin , Faklaris Orestis , Falco Amadine , Trinquet Eric , Pin Jean-Philippe , Mouillac Bernard , Durroux Thierry
Published: January 2013

Fluorescent ligands for GPCRs (G-protein-coupled receptors) have been synthesized for a long time but their use was usually restricted to receptor localization in the cell by fluorescent imaging microscopy. During the last two decades, the emergence of new fluorescence-based strategies and the concomitant development of fluorescent measurement apparatus have dramatically widened the use of fluorescent ligands. Among the various strategies, TR (time-resolved)-FRET (fluorescence resonance energy transfer) approaches exhibit an interesting potential to study GPCR interactions with various partners. We have derived various sets of ligands that target different GPCRs with fluorophores, which are compatible with TR-FRET strategies. Fluorescent ligands labelled either with a fluorescent donor (such as europium or terbium cryptate) or with a fluorescent acceptor (such as fluorescein, dy647 or Alexa Fluor® 647), for example, kept high affinities for their cognate receptors. These ligands turn out to be interesting tools to develop FRET-based binding assays. We also used these fluorescent ligands to analyse GPCR oligomerization by measuring FRET between ligands bound to receptor dimers. In contrast with FRET strategies, on the basis of receptor labelling, the ligand-based approach we developed is fully compatible with the study of wild-type receptors and therefore with receptors expressed in native tissues. Therefore, by using fluorescent analogues of oxytocin, we demonstrated the existence of oxytocin receptor dimers in the mammary gland of lactating rats.
Extracellular vesicles in the circulation: are erythrocyte microvesicles a confounder in the plasma haemoglobin assay?
Authors: de Vooght Karen M.K. , Lau Cedric , de Laat Pim P.M. , van Wijk Richard , van Solinge Wouter W. , Schiffelers Raymond M.
Published: January 2013

Blood contains a mixture of extracellular vesicles from different cell types, primarily platelets, endothelial cells, leucocytes and erythrocytes. Erythrocytes are the most abundant cell type in blood and could, especially in certain pathologies, represent an important source of vesicles. Since erythrocytes contain the haemoglobin components iron and haem, which are potentially toxic, it is important to investigate the contribution of vesicle-associated haemoglobin to total cell-free haemoglobin levels. To our knowledge, this is the first time that cell-free plasma haemoglobin has been differentiated into vesicle-associated and molecular species. We investigated the contribution of vesicle-associated haemoglobin in residual patient material that was routinely analysed for total cell-free plasma haemoglobin. All patient samples included in the study were haemolytic with total cell-free haemoglobin concentration ranging from 80 to 2500 mg/l. In the majority of the samples, total cell-free haemoglobin concentration was between 100 and 200 mg/l. No haemoglobin could be detected in the vesicle fraction, indicating that the contribution of vesicle-associated haemoglobin to total cell free-haemoglobin levels in plasma is negligible. It is important to investigate whether erythrocyte vesicles are not formed in blood or that their production is not increased during pathologies associated with haemolysis or that the clearance rate of the vesicles surpasses the formation rate.
Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes)
Authors: Whiteside Theresa L.
Published: January 2013

Body fluids of cancer patients contain TEXs (tumour-derived exosomes). Tumours release large quantities of TEXs, and the protein content of exosome or MV (microvesicle) fractions isolated from patients’ sera is high. TEXs down-regulate functions of immune cells, thus promoting tumour progression. We isolated TEXs from tumour cell supernatants and sera of patients with solid tumours or AML (acute myelogenous leukaemia). The molecular profile of TEXs was distinct from that of circulating exosomes derived from normal cells. TEXs were co-incubated with activated T-cells, conventional CD4+CD25neg T-cells or CD56+CD16+ NK (natural killer) cells respectively. TEXs down-regulated CD3ζ and JAK3 (Janus kinase 3) expression in primary activated T-cells and mediated Fas/FasL (Fas ligand)-driven apoptosis of CD8+ T-cells. TEXs promoted CD4+CD25neg T-cell proliferation and their conversion into CD4+CD25hiFOXP3+ (FOXP3 is forkhead box P3) Treg cells (regulatory T-cells), which also expressed IL-10 (interleukin 10), TGFβ1 (transforming growth factor β1), CTLA-4 (cytotoxic T-lymphocyte antigen 4), GrB (granzyme B)/perforin and effectively mediated suppression. Neutralizing antibodies specific for TGFβ1 and/or IL-10 inhibited the ability of TEXs to expand Treg cells. TEXs obtained at diagnosis from AML patients’ sera were positive for blast-associated markers CD33, CD34, CD117 and TGFβ1, and they decreased cytotoxic activity of NK cells isolated from NC (normal control) donors, induced Smad phosphorylation and down-regulated NKG2D receptor expression. Correlations between the TEX molecular profile or TEX protein levels and clinical data in cancer patients suggest that TEX-mediated effects on immune cells are prognostically important. In contrast with exosomes released by normal cells, TEXs have immunosuppressive properties and are involved in regulating peripheral tolerance in patients with cancer.
How ligands and signalling proteins affect G-protein-coupled receptors' conformational landscape
Authors: Mary Sophie , Fehrentz Jean-Alain , Damian Marjorie , Verdié Pascal , Martinez Jean , Marie Jacky , Banères Jean-Louis
Published: January 2013

The dynamic character of GPCRs (G-protein-coupled receptors) is essential to their function. However, the details of how ligands and signalling proteins stabilize a receptor conformation to trigger the activation of a given signalling pathway remain largely unexplored. Multiple data, including recent results obtained with the purified ghrelin receptor, suggest a model where ligand efficacy and functional selectivity are directly related to different receptor conformations. Importantly, distinct effector proteins (G-proteins and arrestins) as well as ligands are likely to affect the conformational landscape of GPCRs in different manners, as we show with the isolated ghrelin receptor. Such modulation of the GPCR conformational landscape by pharmacologically distinct ligands and effector proteins has major implications for the design of new drugs that activate specific signalling pathways.
Chemical approaches for profiling dynamic palmitoylation
Authors: Martin Brent R.
Published: January 2013

Protein palmitoylation is a critical post-translational modification important for membrane compartmentalization, trafficking and regulation of many key signalling proteins. Recent non-radioactive chemo-proteomic labelling methods have enabled a new focus on this emerging regulatory modification. Palmitoylated proteins can now be profiled in complex biological systems by MS for direct annotation and quantification. Based on these analyses, palmitoylation is clearly widespread and broadly influences the function of many cellular pathways. The recent introduction of selective chemical labelling approaches has opened new opportunities to revisit long-held questions about the enzymatic regulation of this widespread post-translational modification. In the present review, we discuss the impact of new chemical labelling approaches and future challenges for the dynamic global analysis of protein palmitoylation.
Archaeology of RNA polymerase: factor swapping during the transcription cycle
Authors: Blombach Fabian , Daviter Tina , Fielden Daniel , Grohmann Dina , Smollett Katherine , Werner Finn
Published: January 2013

All RNAPs (RNA polymerases) repeatedly make use of their DNA template by progressing through the transcription cycle multiple times. During transcription initiation and elongation, distinct sets of transcription factors associate with multisubunit RNAPs and modulate their nucleic-acid-binding and catalytic properties. Between the initiation and elongation phases of the cycle, the factors have to be exchanged by a largely unknown mechanism. We have shown that the binding sites for initiation and elongation factors are overlapping and that the binding of the factors to RNAP is mutually exclusive. This ensures an efficient exchange or ‘swapping’ of factors and could furthermore assist RNAP during promoter escape, enabling robust transcription. A similar mechanism applies to the bacterial RNAP system. The elongation factors are evolutionarily conserved between the bacterial (NusG) and archaeo-eukaryotic (Spt5) systems; however, the initiation factors [σ and TBP (TATA-box-binding protein)/TF (transcription factor) B respectively] are not. Therefore we propose that this factor-swapping mechanism, operating in all three domains of life, is the outcome of convergent evolution.
C/D box sRNA, CRISPR RNA and tRNA processing in an archaeon with a minimal fragmented genome
Authors: Richter Hagen , Mohr Sabine , Randau Lennart
Published: January 2013

The analysis of deep sequencing data allows for a genome-wide overview of all the small RNA molecules (the ‘sRNome’) that are present in a single organism. In the present paper, we review the processing of CRISPR (clustered regularly interspaced short palindromic repeats) RNA, C/D box sRNA (small non-coding RNA) and tRNA in Nanoarchaeum equitans. The minimal and fragmented genome of this tiny archaeon permits a sequencing depth that enables the identification of processing intermediates in the study of RNA processing pathways. These intermediates include circular C/D box sRNA molecules and tRNA half precursors.
A brief history of the discovery of hyperthermophilic life
Authors: Stetter Karl O.
Published: January 2013

Hyperthermophiles, growing optimally at 80°C and above were first discovered in 1981. They represent the upper temperature border of life and are found within water-containing terrestrial and submarine environments of active volcanism and geothermally heated subterranean rocks. The energy-yielding reactions represent mainly anaerobic and aerobic types of respiration rather than fermentation. Within the ss (single-stranded) rRNA phylogenetic tree, hyperthermophiles occupy all of the short deep branches closest to the root. Members of the deepest branch-offs are represented by the newly found Nanoarchaeota and Korarchaeota.
Characterization of the dynamic events of GPCRs by automated computational simulations
Authors: Gutiérrez-de-Terán Hugo , Bello Xabier , Rodríguez David
Published: January 2013

The recent advances in membrane protein crystallography have provided extremely valuable structural information of the superfamily of GPCRs (G-protein-coupled receptors). This has been particularly true for a few receptors whose structure was solved several times under different biochemical conditions. It follows that the mechanisms of receptor conformational equilibrium and related dynamic events can be explored by computational simulations. In the present article, we summarize our recent understanding of several dynamic features of GPCRs, accomplished through the use of MD (molecular dynamics) simulations. Our pipeline for the MD simulations of GPCRs, implemented in the web service http://gpcr.usc.es, is updated in the present paper and illustrated by recent applications. Special emphasis is put on the A2A adenosine receptor, one of the selected cases where crystal structures in several conformations and conditions exist, and on the dimerization process of the CXCR4 (CXC chemokine receptor 4).
From archaeon to eukaryote: the evolutionary dark ages of the eukaryotic cell
Authors: Martijn Joran , Ettema Thijs J.G.
Published: January 2013

The evolutionary origin of the eukaryotic cell represents an enigmatic, yet largely incomplete, puzzle. Several mutually incompatible scenarios have been proposed to explain how the eukaryotic domain of life could have emerged. To date, convincing evidence for these scenarios in the form of intermediate stages of the proposed eukaryogenesis trajectories is lacking, presenting the emergence of the complex features of the eukaryotic cell as an evolutionary deus ex machina. However, recent advances in the field of phylogenomics have started to lend support for a model that places a cellular fusion event at the basis of the origin of eukaryotes (symbiogenesis), involving the merger of an as yet unknown archaeal lineage that most probably belongs to the recently proposed ‘TACK superphylum’ (comprising Thaumarchaeota, Aigarchaeota, Crenarchaeota and Korarchaeota) with an alphaproteobacterium (the protomitochondrion). Interestingly, an increasing number of so-called ESPs (eukaryotic signature proteins) is being discovered in recently sequenced archaeal genomes, indicating that the archaeal ancestor of the eukaryotic cell might have been more eukaryotic in nature than presumed previously, and might, for example, have comprised primitive phagocytotic capabilities. In the present paper, we review the evolutionary transition from archaeon to eukaryote, and propose a new model for the emergence of the eukaryotic cell, the ‘PhAT (phagocytosing archaeon theory)’, which explains the emergence of the cellular and genomic features of eukaryotes in the light of a transiently complex phagocytosing archaeon.
Translation initiation in the crenarchaeon Sulfolobus solfataricus: eukaryotic features but bacterial route
Authors: La Teana Anna , Benelli Dario , Londei Paola , Bläsi Udo
Published: January 2013

The formation of the translation initiation complex represents the rate-limiting step in protein synthesis. Translation initiation in the crenarchaeon Sulfolobus solfataricus depends on several translation IFs (initiation factors), some of which have eukaryal but no bacterial counterparts. In the present paper, we review the current knowledge of the structure, function and evolution of the IFs in S. solfataricus in the context of eukaryotic and bacterial orthologues. Despite similarities between eukaryotic and S. solfataricus IFs, the sequence of events in translation initiation in S. solfataricus follows the bacterial mode.
End-resection at DNA double-strand breaks in the three domains of life
Authors: Blackwood John K. , Rzechorzek Neil J. , Bray Sian M. , Maman Joseph D. , Pellegrini Luca , Robinson Nicholas P.
Published: January 2013

During DNA repair by HR (homologous recombination), the ends of a DNA DSB (double-strand break) must be resected to generate single-stranded tails, which are required for strand invasion and exchange with homologous chromosomes. This 5′–3′ end-resection of the DNA duplex is an essential process, conserved across all three domains of life: the bacteria, eukaryota and archaea. In the present review, we examine the numerous and redundant helicase and nuclease systems that function as the enzymatic analogues for this crucial process in the three major phylogenetic divisions.
CoA biosynthesis in archaea
Authors: Atomi Haruyuki , Tomita Hiroya , Ishibashi Takuya , Yokooji Yuusuke , Imanaka Tadayuki
Published: January 2013

CoA is a ubiquitous molecule in all three domains of life and is involved in various metabolic pathways. The enzymes and reactions involved in CoA biosynthesis in eukaryotes and bacteria have been identified. By contrast, the proteins/genes involved in CoA biosynthesis in archaea have not been fully clarified, and much has to be learned before we obtain a general understanding of how this molecule is synthesized. In the present paper, we review the current status of the research on CoA biosynthesis in the archaea, and discuss important questions that should be addressed in the near future.
Genomics and biology of Rudiviruses, a model for the study of virus–host interactions in Archaea
Authors: Prangishvili David , Koonin Eugene V. , Krupovic Mart
Published: January 2013

Archaeal viruses, especially viruses that infect hyperthermophilic archaea of the phylum Crenarchaeota, constitute one of the least understood parts of the virosphere. However, owing to recent substantial research efforts by several groups, archaeal viruses are starting to gradually reveal their secrets. In the present review, we summarize the current knowledge on one of the emerging model systems for studies on crenarchaeal viruses, the Rudiviridae. We discuss the recent advances towards understanding the function and structure of the proteins encoded by the rudivirus genomes, their role in the virus life cycle, and outline the directions for further research on this model system. In addition, a revised genome annotation of SIRV2 (Sulfolobus islandicus rod-shaped virus 2) is presented. Future studies on archaeal viruses, combined with the knowledge on viruses of bacteria and eukaryotes, should lead to a better global understanding of the diversity and evolution of virus–host interactions in the viral world.
Evolutionary advantages of polyploidy in halophilic archaea
Authors: Soppa Jörg
Published: January 2013

Several species of haloarchaea have been shown to be polyploid and thus this trait might be typical for and widespread in haloarchaea. In the present paper, nine different possible evolutionary advantages of polyploidy for haloarchaea are discussed, including low mutation rate, radiation/desiccation resistance, gene redundancy and survival over geological times and at extraterrestrial sites. Experimental indications exist for all but one of these evolutionary advantages. Several of the advantages require gene conversion, which has been shown to be present and active in haloarchaea.
Molecular sampling of the allosteric binding pocket of the TSH receptor provides discriminative pharmacophores for antagonist and agonists
Authors: Hoyer Inna , Haas Ann-Karin , Kreuchwig Annika , Schülein Ralf , Krause Gerd
Published: January 2013

The TSHR (thyrotropin receptor) is activated endogenously by the large hormone thyrotropin and activated pathologically by auto-antibodies. Both activate and bind at the extracellular domain. Recently, SMLs (small-molecule ligands) have been identified, which bind in an allosteric binding pocket within the transmembrane domain. Modelling driven site-directed mutagenesis of amino acids lining this pocket led to the delineation of activation and inactivation sensitive residues. Modified residues showing CAMs (constitutively activating mutations) indicate signalling-sensitive positions and mark potential trigger points for agonists. Silencing mutations lead to an impairment of basal activity and mark contact points for antagonists. Mapping these residues on to a structural model of TSHR indicates locations where an SML may switch the receptor to an inactive or active conformation. In the present article, we report the effects of SMLs on these signalling-sensitive amino acids at the TSHR. Surprisingly, the antagonistic effect of SML compound 52 was reversed to an agonistic effect, when tested at the CAM Y667A. Switching agonism to antagonism and the reverse by changing either SMLs or residues covering the binding pocket provides detailed knowledge about discriminative pharmacophores. It prepares the basis for rational optimization of new high-affinity antagonists to interfere with the pathogenic activation of the TSHR.
Mechanism and function of DHHC S-acyltransferases
Authors: Linder Maurine E. , Jennings Benjamin C.
Published: January 2013

Protein S-palmitoylation is a reversible post-translational modification of proteins with fatty acids. In the last 5 years, improved proteomic methods have increased the number of proteins identified as substrates for palmitoylation from tens to hundreds. Palmitoylation regulates protein membrane interactions, activity, trafficking and stability and can be constitutive or regulated by signalling inputs. A family of PATs (protein acyltransferases) is responsible for modifying proteins with palmitate or other long-chain fatty acids on the cytoplasmic face of cellular membranes. PATs share a signature DHHC (Asp-His-His-Cys) cysteine-rich domain that is the catalytic centre of the enzyme. The biomedical importance of members of this family is underscored by their association with intellectual disability, Huntington's disease and cancer in humans, and raises the possibility of DHHC PATs as targets for therapeutic intervention. In the present paper, we discuss recent progress in understanding enzyme mechanism, regulation and substrate specificity.
Sulfolobus islandicus: a model system for evolutionary genomics
Authors: Zhang Changyi , Krause David J. , Whitaker Rachel J.
Published: January 2013

Sulfolobus islandicus has been developed as a model system for combining approaches of evolutionary and molecular biology in Archaea. We describe how the application of this interdisciplinary approach can lead to novel hypotheses derived from patterns of natural variation that can be tested in the laboratory when combined with a diversity of natural variants and versatile genetic markers. We review how this approach has highlighted the importance of recombination as an evolutionary parameter and provided insight into a molecular mechanism of recombination that may be unique in the archaeal domain. We review the development and improvement of the model system S. islandicus that will enable us to study the mechanism and genomic architecture of recombination guided by evolutionary genomic analysis of Nature's ongoing experiments in wild populations.
Arresting inflammation: contributions of plasma membrane and endosomal signalling to neuropeptide-driven inflammatory disease
Authors: Cattaruzza Fiore , Poole Daniel P. , Bunnett Nigel W.
Published: January 2013

GPCR (G-protein-coupled receptor) signalling at the plasma membrane is under tight control. In the case of neuropeptides such as SP (substance P), plasma membrane signalling is regulated by cell-surface endopeptidases (e.g. neprilysin) that degrade extracellular neuropeptides, and receptor interaction with β-arrestins, which uncouple receptors from heterotrimeric G-proteins and mediate receptor endocytosis. By recruiting GPCRs, kinases and phosphatases to endocytosed GPCRs, β-arrestins assemble signalosomes that can mediate a second wave of signalling by internalized receptors. Endosomal peptidases, such as ECE-1 (endothelin-converting enzyme-1), can degrade SP in acidified endosomes, which destabilizes signalosomes and allows receptors, freed from β-arrestins, to recycle and resensitize. By disassembling signalosomes, ECE-1 terminates β-arrestin-mediated endosomal signalling. These mechanisms have been studied in model cell systems, and the relative importance of plasma membrane and endosomal signalling to complex pathophysiological processes, such as inflammation, pain and proliferation, is unclear. However, deletion or inhibition of metalloendopeptidases that control neuropeptide signalling at the plasma membrane and in endosomes has marked effects on inflammation. Neprilysin deletion exacerbates inflammation because of diminished degradation of pro-inflammatory SP. Conversely, inhibition of ECE-1 attenuates inflammation by preventing receptor recycling/resensitization, which is required for sustained pro-inflammatory signals from the plasma membrane. β-Arrestin deletion also affects inflammation because of the involvement of β-arrestins in pro-inflammatory signalling and migration of inflammatory cells. Knowledge of GPCR signalling in specific subcellular locations provides insights into pathophysiological processes, and can provide new opportunities for therapy. Selective targeting of β-arrestin-mediated endosomal signalling or of mechanisms of receptor recycling/resensitization may offer more effective and selective treatments than global targeting of cell-surface signalling.
Levitation of delocalized states at weak magnetic field: Critical exponents and phase diagram
Authors: Kagalovsky V.
Published: January 2013

We study numerically the form of the critical line in the disorder–magnetic field phase diagram of the p–q network model, constructed to study the levitation of extended states at weak magnetic fields. We use one-parameter scaling, keeping either q (related to magnetic field) or p (related to energy) constant, to calculate two critical exponents, describing the divergence of the localization length in each case. The ratio of those two exponents defines the form of the critical line close to zero magnetic field.
A microfabricated ion trap with integrated microwave circuitry
Authors: Allcock D. T. C. , Harty T. P. , Ballance C. J. , Keitch B. C. , Linke N. M. , Stacey D. N. , Lucas D. M.
Published: January 2013

We describe the design, fabrication, and testing of a surface-electrode ion trap, which incorporates microwave waveguides, resonators, and coupling elements for the manipulation of trapped ion qubits using near-field microwaves. The trap is optimised to give a large microwave field gradient to allow state-dependent manipulation of the ions' motional degrees of freedom, the key to multi-qubit entanglement. The microwave field near the centre of the trap is characterised by driving hyperfine transitions in a single laser-cooled  43Ca+ ion.
Effect of pre-impingement length and misalignment in the hydrodynamics of multijet impingement atomization
Authors: Panão M. R. O. , Delgado J. M. D.
Published: January 2013

The multijet impingement atomization strategy is proposed as a competitive one in designing atomizers with relatively simple geometries, producing sprays from the impact of multiple jets at low-flow rate conditions (<1.5 l/min). Most theoretical studies have been made for the spray produced by the impact of two jets. However, there are two important geometric issues related with the atomizer design, scarcely approached in the literature, which are the pre-impingement length of jets before impact and jet misalignment. This work analyses the influence of these parameters on the structure of the liquid sheet as well as on drop size. First, the liquid sheet structure has two hydrodynamic regimes: closed-rim and open-rim. The results evidence that higher pre-jet-impingement distances influence only the open-rim regime, namely, producing shorter liquid sheet breakup lengths, smaller drop sizes, and more droplets. The jet misalignment elongates the liquid sheet in the closed-rim regime, and anticipates breakup in the open-rim regime.
Rovibrational internal energy transfer and dissociation of $\mathbf { \rm N_2(^1\Sigma _g^+)-\rm N(^4S_u)}$N2(1Σg+)−N(4Su) system in hypersonic flows
Authors: Panesi Marco , Jaffe Richard L. , Schwenke David W. , Magin Thierry E.
Published: January 2013

A rovibrational collisional model is developed to study energy transfer and dissociation of \documentclass[12pt]{minimal}\begin{document}$\rm N_2(^1\Sigma _g^+)$\end{document}N2(1Σg+) molecules interacting with \documentclass[12pt]{minimal}\begin{document}$\rm N(^4S_u)$\end{document}N(4Su) atoms in an ideal isochoric and isothermal chemical reactor. The system examined is a mixture of molecular nitrogen and a small amount of atomic nitrogen. This mixture, initially at room temperature, is heated by several thousands of degrees Kelvin, driving the system toward a strong non-equilibrium condition. The evolution of the population densities of each individual rovibrational level is explicitly determined via the numerical solution of the master equation for temperatures ranging from 5000 to 50 000 K. The reaction rate coefficients are taken from an ab initio database developed at NASA Ames Research Center. The macroscopic relaxation times, energy transfer rates, and dissociation rate coefficients are extracted from the solution of the master equation. The computed rotational-translational (RT) and vibrational-translational (VT) relaxation times are different at low heat bath temperatures (e.g., RT is about two orders of magnitude faster than VT at T = 5000 K), but they converge to a common limiting value at high temperature. This is contrary to the conventional interpretation of thermal relaxation in which translational and rotational relaxation timescales are assumed comparable with vibrational relaxation being considerable slower. Thus, this assumption is questionable under high temperature non-equilibrium conditions. The exchange reaction plays a very significant role in determining the dynamics of the population densities. The macroscopic energy transfer and dissociation rates are found to be slower when exchange processes are neglected. A macroscopic dissociation rate coefficient based on the quasi-stationary distribution, exhibits excellent agreement with experimental data of Appleton et al. [J. Chem. Phys. 48, 599–608 (1968)]10.1063/1.1668690. However, at higher temperatures, only about 50% of dissociation is found to take place under quasi-stationary state conditions. This suggest the necessity of explicitly including some rovibrational levels, when solving a global kinetic rate equation.
Mesoscopic states in graphene in a magnetic field: Collapse and revival of wave packets
Authors: Demikhovskii V. Ya. , Telezhnikov A. V. , Frolova E. V. , Kravets N. A.
Published: January 2013

The effects of collapse and revival of wave packets in monolayer and bilayer graphene in the presence of an external perpendicular magnetic field are investigated. An evolution of the electron wave packets, which are a superposition of states with quantum numbers n near the Landau level n0, are studied. The probability density and the average velocity of the center of packets were calculated analytically and visualized. The initial wave packet, which includes only states with positive energy, loses spatial localization, and splits into several sub-packets at the moments t = (m/n)TR, where TR is the revival time, m and n are co-primes. In addition, it is shown that a behavior of the wave packet, which consists of states of two energy bands (with En > 0 and En < 0) is more complex. Such a packet splits into two parts, which rotate with a cyclotron frequency in opposite directions. The nature of electromagnetic radiation of wave packets, undergoing periodic collapse and revival is discussed.
Fano effect upon tunneling of a spin-polarized electron through a single magnetic impurity
Authors: Val'kov V. V. , Aksenov S. V. , Ulanov E. A.
Published: January 2013

The calculations of transport characteristics of a single magnetic impurity showed that the presence of different effective channels for electron transmission results in the Fano effect. It was noticed that the external magnetic field and gate voltage allow controlling the conducting properties, which are governed by the configuration interaction between the states of the system.
The generalized identification of truly interfacial molecules (ITIM) algorithm for nonplanar interfaces
Authors: Sega Marcello , Kantorovich Sofia S. , Jedlovszky Pál , Jorge Miguel
Published: January 2013

We present a generalized version of the ITIM algorithm for the identification of interfacial molecules, which is able to treat arbitrarily shaped interfaces. The algorithm exploits the similarities between the concept of probe sphere used in ITIMand the circumsphere criterion used in the α-shapes approach, and can be regarded either as a reference-frame independent version of the former, or as an extended version of the latter that includes the atomic excluded volume. The new algorithm is applied to compute the intrinsic orientational order parameters of water around a dodecylphosphocholine and a cholic acid micelle in aqueous environment, and to the identification of solvent-reachable sites in four model structures for soot. The additional algorithm introduced for the calculation of intrinsic density profiles in arbitrary geometries proved to be extremely useful also for planar interfaces, as it allows to solve the paradox of smeared intrinsic profiles far from the interface.
Resistive switching mechanism in silicon highly rich SiOx (x < 0.75) films based on silicon dangling bonds percolation model
Authors: Wang Yuefei , Qian Xinye , Chen Kunji , Fang Zhonghui , Li Wei , Xu Jun
Published: January 2013

The unipolar resistive switches are investigated in silicon highly rich SiOx (x < 0.75) films. The as-deposited SiO0.73 films contain high concentration (1.0 × 1019 cm−3) of silicon dangling bonds (Si-DBs) and are rich in SiO2≡Si–Si and O3≡Si–Si configurations. Unlike the currently reported normal silicon-rich SiOx (x > 1.8) based devices, our Pt/SiO0.73/Pt devices operate at lower voltage regime (<2.0 V) and exhibit much lower resistance (∼30 Ω). The reset voltage (∼0.7 V) is lower than set voltage (∼1.7 V) and the performance is reduced in the vacuum environment. We propose a Si-DBs percolation model to explain the above characteristics. The experimental evidences for supporting our model are presented and discussed.
Anharmonic zero point vibrational energies: Tipping the scales in accurate thermochemistry calculations?
Authors: Pfeiffer Florian , Rauhut Guntram , Feller David , Peterson Kirk A.
Published: January 2013

Anharmonic zero point vibrational energies (ZPVEs) calculated using both conventional CCSD(T) and MP2 in combination with vibrational second-order perturbation theory (VPT2) are compared to explicitly correlated CCSD(T)-F12 and MP2-F12 results that utilize vibrational configuration interaction (VCI) theory for 26 molecules of varying size. Sequences of correlation consistent basis sets are used throughout. It is found that the explicitly correlated methods yield results close to the basis set limit even with double-zeta quality basis sets. In particular, the anharmonic contributions to the ZPVE are accurately recovered at just the MP2 (or MP2-F12) level of theory. Somewhat surprisingly, the best vibrational CI results agreed with the VPT2 values with a mean unsigned deviation of just 0.09 kJ/mol and a standard deviation of just 0.11 kJ/mol. The largest difference was observed for C4H4O (0.34 kJ/mol). A simplified version of the vibrational CI procedure that limited the modal expansion to at most 2-mode coupling yielded anharmonic corrections generally within about 0.1 kJ/mol of the full 3- or 4-mode results, except in the cases of C3H8 and C4H4O where the contributions were underestimated by 1.3 and 0.8 kJ/mol, respectively (34% and 40%, respectively). For the molecules considered in this work, accurate anharmonic ZPVEs are most economically obtained by combining CCSD(T)-F12a/cc-pVDZ-F12 harmonic frequencies with either MP2/aug-cc-pVTZ/VPT2 or MP2-F12/cc-pVDZ-F12/VCI anharmonic corrections.
Manipulation of the electron transport through a mesoscopic island by surface acoustic wave
Authors: Chen S. W. , Yang Z. B. , Song L. , Gao J.
Published: January 2013

We have studied the surface acoustic waves (SAWs) transport electrons through a multiple constrictions where a mesoscopic island is placed between the adjacent ones. The electrochemical potential of the island can be modulated by changing the adjacent gate voltages. Then, with the help of the accumulated charge in the island, some peculiar quantized events are observed in the experiments. And a physical model is proposed to explain this quantization, which could help us to understand the mechanism of the acousto-electric current further. In addition, if the SAW dots drive electrons through a static impurity dot which placed at the transport channel, then due to the regulating action by the static impurity dot, the current display fractional plateaus.
Comparison of thermomigration behaviors between Pb-free flip chip solder joints and microbumps in three dimensional integrated circuits: Bump height effect
Authors: Ouyang Fan-Yi , Jhu Wei-Cheng
Published: January 2013

Packaging technology is currently transition from flip chip technology to three dimensional integrated circuits (3D ICs) to meet the requirements of consumer electronic products. Compared to flip chip technology, the dimension of microbumps in 3D ICs is shrunk by a factor of 10. In this study, the behaviors of thermomigration in Pb-free solders of flip chip and 3D ICs are presented. When the bump height is 100 μm in the flip chip samples, the Sn protrusion was observed at the hot end and voids formation at the cold end. However, when the bump height is reduced to 5.8 μm in the 3D IC samples, no significant microstructural evolution of Sn was found; instead, the dissolution of Ni under-bump metallization at hot end was observed. We propose that discrepancy between flip chip solder joints and 3D IC microbumps is mainly attributed to the effect of back stress and the presence of thicker Ni under-bump metallization in the 3D IC packaging. Moreover, the critical temperature gradient in terms of different bump heights is discussed, showing below which there will be no net effect of thermomigration of Sn.
A stochastic optimization approach to coarse-graining using a relative-entropy framework
Authors: Bilionis Ilias , Zabaras Nicholas
Published: January 2013

Relative entropy has been shown to provide a principled framework for the selection of coarse-grained potentials. Despite the intellectual appeal of it, its application has been limited by the fact that it requires the solution of an optimization problem with noisy gradients. When using deterministic optimization schemes, one is forced to either decrease the noise by adequate sampling or to resolve to ad hoc modifications in order to avoid instabilities. The former increases the computational demand of the method while the latter is of questionable validity. In order to address these issues and make relative entropy widely applicable, we propose alternative schemes for the solution of the optimization problem using stochastic algorithms.
Implementation of focal zooming on the Nike KrF laser
Authors: Kehne D. M. , Karasik M. , Aglitsky Y. , Smyth Z. , Terrell S. , Weaver J. L. , Chan Y. , Lehmberg R. H. , Obenschain S. P.
Published: January 2013

In direct drive inertial confinement laser fusion, a pellet containing D-T fuel is imploded by ablation arising from absorption of laser energy at its outer surface. For optimal coupling, the focal spot of the laser would continuously decrease to match the reduction in the pellet's diameter, thereby minimizing wasted energy. A krypton-fluoride laser (λ = 248 nm) that incorporates beam smoothing by induced spatial incoherence has the ability to produce a high quality focal profile whose diameter varies with time, a property known as focal zooming. A two-stage focal zoom has been demonstrated on the Nike laser at the Naval Research Laboratory. In the experiment, a 4.4 ns laser pulse was created in which the on-target focal spot diameter was 1.3 mm (full width at half maximum) for the first 2.4 ns and 0.28 mm for the final 2 ns. These two diameters appear in time-integrated focal plane equivalent images taken at several locations in the amplification chain. Eight of the zoomed output beams were overlapped on a 60 μm thick planar polystyrene target. Time resolved images of self-emission from the rear of the target show the separate shocks launched by the two corresponding laser focal diameters.