bluuebunny/crossref_metadata_2025 huggingface dataset:
A one dimensional, electrostatic Vlasov model for the generation of suprathermal electron tails in solar wind conditions
Authors: Califano F. , Mangeney A.
Published: June 2008

Space and laboratory collisionless plasmas are most often out of local thermodynamic equilibrium. In particular, their charged particle velocity distributions usually differ from simple Maxwellian distributions and exhibit a great variety of anisotropies and components such as suprathermal beams and tails. Here we propose a new model responsible for a “local” origin of electron suprathermal tails. The model is based on adding a high and a low frequency external forcing to the Vlasov‐Poisson system of equations. The first one represents mainly the thermal noise electric field generated by charge separation effects. The second one represents the energy injection resulting from the energy cascade generated by the large scale fluid (MHD) turbulence. We find that in typical solar wind conditions, our model could be the base of a full three dimensional, electromagnetic model capable of explaining the local generation of the electron halo population observed on the electron distribution function.
Addendum to “Late Cenozoic magnetochronology and paleoenvironmental changes in the northern foreland basin of the Tian Shan Mountains” by Jimin Sun, Qinghai Xu, and Baochun Huang
Authors: Charreau Julien , Sun Jimin , Chen Yan , Gilder Stuart , Huang Baochun , Wang Qingchen
Published: June 2008

Sun et al. (2007) constructed a magnetostratigraphic record of the Kuitun River section (Xinjiang Province, China) and reinterpreted a magnetostratigraphic record from the same section previously published by Charreau et al. (2005). In this paper, we show that Sun et al. miscorrelated their column with respect to that of Charreau et al. A compatible correlation, recognized by both sides, is presented.
Low‐energy electron current in the Martian tail due to reconnection of draped interplanetary magnetic field and crustal magnetic fields
Authors: Uluşen Demet , Linscott Ivan
Published: June 2008

We observe seasonal, nighttime clustering of significant enhancements in the Mars Global Surveyor electron omnidirectional flux data at low‐energy levels over a specific geographical region at the west edge of the crustal fields (at around 70°S and between 30°E and 150°E). We propose that photoelectrons generated over the crustal sources on the Martian dayside are transported along lines of the reconnected interplanetary magnetic field to the nightside and populate currents formed in the magnetotail. Comparison of the draping direction (estimated from the dayside data between 50° and 60°N latitude band over the northern hemisphere) at the closest time of the enhancements with the crustal fields at ∼150°E and ∼65°S shows the existence of favorable conditions for the reconnection. Seasonal variation observed in the draping direction accounts for the seasonal nature of the phenomenon. Moreover, a nearly 25 d periodic variation of the draping direction, due to solar rotation, strictly coincides with the periodic variation observed in the strength of the enhancements. We also demonstrate the effect of the Sun on the electron flux variations over two regions: (1) closed crustal fields and (2) the enhancement clustering region. Finally, we propose a model for the distribution of current sources on the nightside that accounts for the perturbations observed in the magnetic field data.
Urey ratio and the structure and evolution of Earth's mantle
Authors: Korenaga Jun
Published: June 2008

The Urey ratio describes the contribution of internal heat production to planetary‐scale energy balance, and knowing this thermal budget for Earth is essential to understand its long‐term evolution. Internal heat production is provided by the decay of radiogenic elements, whose budget is constrained by geochemical models of Earth. Understanding the thermal budget thus requires contributions from both geophysics and geochemistry. The purpose of this review is to elucidate various geochemical and geophysical arguments and to delineate the most likely thermal budget of Earth. While the bulk Earth Urey ratio is probably ∼0.35, the convective Urey ratio is estimated to be ∼0.2. That is, only ∼20% of convective heat flux seems to originate from radiogenic elements at present, so the rest should be supported by secular cooling. A likely scenario for Earth's thermal history indicates that the peculiarity of today's significant imbalance between heat production and heat loss may result from the initiation of plate tectonics in the early Earth.
Transfer RNA genes in pieces
Authors: Randau Lennart , Söll Dieter
Published: June 2008

The short genes encoding transfer RNA (tRNA) molecules are highly conserved in both sequence and structure, reflecting the central role of tRNA in protein biosynthesis. The frequent occurrence of fragmented intron‐containing tRNAs that require processing to form contiguous molecules is therefore surprising. Recent discoveries of permuted and split tRNA genes have added to the apparent creativity of nature regarding the organization of these fragmented genes. Here, we provide an overview of the various types of fragmented tRNA genes and examine the hypothesis that the integration of mobile genetic elements—including viruses and plasmids—established such genes in pieces.
Bringing order to translation: the contributions of transfer RNA anticodon‐domain modifications
Authors: Agris Paul F
Published: June 2008

The biosynthesis of RNA includes its post‐transcriptional modifications, and the crucial functions of these modifications have supported their conservation within all three kingdoms. For example, the modifications located within or adjacent to the anticodon of the transfer RNA (tRNA) enhance the accuracy of codon binding, maintain the translational reading frame and enable translocation of the tRNA from the A‐site to the P‐site of the ribosome. Although composed of different chemistries, the more than 70 known modifications of tRNA have in common their ability to reduce conformational dynamics, and to bring order to the internal loops and hairpin structures of RNA. The modified nucleosides of the anticodon domain of tRNA restrict its dynamics and shape its architecture; therefore, the need of the ribosome to constrain or remodel each tRNA to fit the decoding site is diminished. This concept reduces an entropic penalty for translation and provides a physicochemical basis for the conservation of RNA modifications in general.
Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy‐terminal tail
Authors: Wang Likun , Wang Lei , Vavassori Stefano , Li Shengjian , Ke Huimin , Anelli Tiziana , Degano Massimo , Ronzoni Riccardo , Sitia Roberto , Sun Fei , Wang Chih‐chen
Published: June 2008

ERp44 mediates thiol‐dependent retention in the early secretory pathway, forming mixed disulphides with substrate proteins through its conserved CRFS motif. Here, we present its crystal structure at a resolution of 2.6 Å. Three thioredoxin domains—a, b and b′—are arranged in a clover‐like structure. A flexible carboxy‐terminal tail turns back to the b′ and a domains, shielding a hydrophobic pocket in domain b′ and a hydrophobic patch around the CRFS motif in domain a. Mutational and functional studies indicate that the C‐terminal tail gates the CRFS area and the adjacent hydrophobic pocket, dynamically regulating protein quality control.
Single‐headed mode of kinesin‐5
Authors: Kaseda Kuniyoshi , Crevel Isabelle , Hirose Keiko , Cross Robert A
Published: June 2008

In most organisms, kinesin‐5 motors are essential for mitosis and meiosis, where they crosslink and slide apart the antiparallel microtubule half‐spindles. Recently, it was shown using single‐molecule optical trapping that a truncated, double‐headed human kinesin‐5 dimer can step processively along microtubules. However, processivity is limited (∼8 steps) with little coordination between the heads, raising the possibility that kinesin‐5 motors might also be able to move by a nonprocessive mechanism. To investigate this, we engineered single‐headed kinesin‐5 dimers. We show that a set of these single‐headed Eg5 dimers drive microtubule sliding at about 90% of wild‐type velocity, indicating that Eg5 can slide microtubules by a mechanism in which one head of each Eg5 head‐pair is effectively redundant. On the basis of this, we propose a muscle‐like model for Eg5‐driven microtubule sliding in spindles in which most force‐generating events are single‐headed interactions and alternate‐heads processivity is rare.
Potential use of Oxygen as a Metabolic Biosensor in Combination with T2*-Weighted MRI to Define the Ischemic Penumbra
Authors: Santosh Celestine , Brennan David , McCabe Christopher , Macrae I Mhairi , Holmes William M , Graham David I , Gallagher Lindsay , Condon Barrie , Hadley Donald M , Muir Keith W , Gsell Willy
Published: June 2008

We describe a novel magnetic resonance imaging technique for detecting metabolism indirectly through changes in oxyhemoglobin:deoxyhemoglobin ratios and T2* signal change during ‘oxygen challenge’ (OC, 5 mins 100% O2). During OC, T2* increase reflects O2 binding to deoxyhemoglobin, which is formed when metabolizing tissues take up oxygen. Here OC has been applied to identify tissue metabolism within the ischemic brain. Permanent middle cerebral artery occlusion was induced in rats. In series 1 scanning ( n = 5), diffusion-weighted imaging (DWI) was performed, followed by echo-planar T2* acquired during OC and perfusion-weighted imaging (PWI, arterial spin labeling). Oxygen challenge induced a T2* signal increase of 1.8%, 3.7%, and 0.24% in the contralateral cortex, ipsilateral cortex within the PWI/DWI mismatch zone, and ischemic core, respectively. T2* and apparent diffusion coefficient (ADC) map coregistration revealed that the T2* signal increase extended into the ADC lesion (3.4%). In series 2 ( n = 5), FLASH T2* and ADC maps coregistered with histology revealed a T2* signal increase of 4.9% in the histologically defined border zone (55% normal neuronal morphology, located within the ADC lesion boundary) compared with a 0.7% increase in the cortical ischemic core (92% neuronal ischemic cell change, core ADC lesion). Oxygen challenge has potential clinical utility and, by distinguishing metabolically active and inactive tissues within hypoperfused regions, could provide a more precise assessment of penumbra.
Sequential Release of Nitric Oxide, Zinc, and Superoxide in Hypoglycemic Neuronal Death
Authors: Suh Sang Won , Hamby Aaron M , Gum Elizabeth T , Shin Byung Seop , Won Seok Joon , Sheline Christian T , Chan Pak H , Swanson Raymond A
Published: June 2008

Oxidative stress and zinc release are both known to contribute to neuronal death after hypoglycemia; however, the cause—effect relationships between these events are not established. Here we found, using a rat model of profound hypoglycemia, that the neuronal zinc release and translocation that occur immediately after hypoglycemia are prevented by the nitric oxide synthase inhibitor 7-nitroindazole but not by overexpression of superoxide dismutase-1 (SOD-1). However, overexpression of SOD-1 prevented activation of poly(ADP-ribose) polymerase-1 (PARP-1) and neuronal death, suggesting that zinc release is upstream of superoxide production. Accordingly, zinc-induced superoxide production was blocked in neuronal cultures by the NADPH oxidase inhibitor apocynin and by genetic deficiency in the p47phox subunit of NADPH oxidase. A key role for the vesicular zinc pool in this process was suggested by reduced superoxide formation and neuronal death in mice deficient in zinc transporter 3. Together, these findings suggest a series of events in which nitric oxide production triggers vesicular zinc release, which in turn activates NADPH oxidase and PARP-1. This sequence may also occur in other central nervous system disorders in which zinc, nitric oxide, and oxidative stress have been linked.
Angiotensin‐converting enzyme inhibitory and antioxidant activities of enzymatically synthesized phenolic and vitamin glycosides
Authors: Charles Rajachristu Einstein , Ponrasu Thangavel , Sivakumar Ramaiah , Divakar Soundar
Published: June 2008

Amyloglucosidase from Rhizopus mould and β‐glucosidase from sweet almond were employed for the preparation of phenolic and vitamin glycosides of vanillin, N‐vanillylnonanamide, DL‐dopa, dopamine, curcumin, α‐tocopherol (vitamin E), pyridoxine (vitamin B6), ergocalciferol (vitamin D2), thiamin (vitamin B1) and riboflavin (vitamin B2). Approx. 20 enzymatically prepared phenolic and vitamin glycosides were subjected to ACE (angiotensin‐converting enzyme) inhibition activity measurements, and 14 glycosides were tested for antioxidant activities. Both phenolic and vitamin glycosides exhibited IC50 values for ACE inhibition in the 0.52±0.03–3.33±0.17 mM range and antioxidant activities ranging from 0.8±0.04 to 1.18±0.06 mM. Comparable ACE inhibition values were observed between free phenols and vitamin glycosides. However, antioxidant activities of glycosides were, in general, lesser than those of free phenols. Best IC50 value for ACE inhibition were observed for 11‐O‐(D‐fructofuranosyl)thiamin (0.52±0.03 mM), 3‐hydroxy‐4‐O‐(6‐D‐sorbitol)phenylalanine (0.56±0.03 mM), 4‐O‐(β‐D‐glucopyranosyl)vanillin (0.61±0.03 mM), 4‐O‐(D‐galactopyranosyl)vanillin (0.61±0.03 mM) and pyridoxine‐D‐glucoside (0.84±0.04 mM). Similarly, best IC50 values for antioxidant activity were observed for 1,7‐O‐(bis‐β‐D‐glucopyranosyl)curcumin (0.8±0.04 mM), 4‐O‐(β‐D‐glucopyranosyl)vanillin (0.9±0.05 mM), 3‐hydroxy‐4‐O‐(β‐D‐galactopyranosyl‐(1′→4)β‐D‐glucopyranosyl)phenylalanine (0.9±0.05 mM), 20‐O‐(D‐glucopyranosyl)ergocalciferol (0.9±0.05 mM) and dopamine‐D‐galactoside (0.93±0.05 mM).
Dissecting isoform selectivity of PI3K inhibitors: the role of non-conserved residues in the catalytic pocket
Authors: Frazzetto Mark , Suphioglu Cenk , Zhu Jiuxiang , Schmidt-Kittler Oleg , Jennings Ian G. , Cranmer Susan L. , Jackson Shaun P. , Kinzler Kenneth W. , Vogelstein Bert , Thompson Philip E.
Published: June 2008

The last few years have seen the identification of numerous small molecules that selectively inhibit specific class I isoforms of PI3K (phosphoinositide 3-kinase), yet little has been revealed about the molecular basis for the observed selectivities. Using site-directed mutagenesis, we have investigated one of the areas postulated as being critical to the observed selectivity. The residues Thr886 and Lys890 of the PI3Kγ isoform project towards the ATP-binding pocket at the entrance to the catalytic site, but are not conserved. We have made reciprocal mutations between those residues in the β isoform (Glu858 and Asp862) and those in the α isoform (His855 and Gln859) and evaluated the potency of a range of reported PI3K inhibitors. The results show that the potencies of β-selective inhibitors TGX221 and TGX286 are unaffected by this change. In contrast, close analogues of these compounds, particularly the α-isoform-selective compound (III), are markedly influenced by the point mutations. The collected data suggests two distinct binding poses for these inhibitor classes, one of which is associated with potent PI3Kβ activity and is not associated with the mutated residues, and a second that, in accord with earlier hypotheses, does involve this pair of non-conserved amino acids at the catalytic site entrance and contributes to the α-isoform-selectivity of the compounds studied.
Ins(1,4,5)P3 3-kinase-A overexpression induces cytoskeletal reorganization via a kinase-independent mechanism
Authors: Windhorst Sabine , Blechner Christine , Lin Hong-Ying , Elling Christian , Nalaskowski Marcus , Kirchberger Tanja , Guse Andreas H. , Mayr Georg W.
Published: June 2008

In the present study, effects of increased IP3K-A [Ins(1,4,5)P3 3-kinase-A] expression were analysed. H1299 cells overexpressing IP3K-A formed branching protrusions, and under three-dimensional culture conditions, they exhibited a motile fibroblast-like morphology. They lost the ability to form actin stress fibres and showed increased invasive migration in vitro. Furthermore, expression levels of the mesenchymal marker proteins vimentin and N-cadherin were increased. The enzymatic function of IP3K-A is to phosphorylate the calcium-mobilizing second messenger Ins(1,4,5)P3 to (Ins(1,3,4,5)P4. Accordingly, cells overexpressing IP3K-A showed reduced calcium release and altered concentrations of InsPs, with decreasing concentrations of Ins(1,4,5)P3, InsP6 and Ins(1,2,3,4,5)P5, and increasing concentrations of Ins(1,3,4,5)P4. However, IP3K-A-induced effects on cell morphology do not seem to be dependent on enzyme activity, since a protein devoid of enzyme activity also induced the formation of branching protrusions. Therefore we propose that the morphological changes induced by IP3K-A are mediated by non-enzymatic activities of the protein.
Evolving improved Synechococcus Rubisco functional expression in Escherichia coli
Authors: Mueller-Cajar Oliver , Whitney Spencer M.
Published: June 2008

The photosynthetic CO2-fixing enzyme Rubisco [ribulose-P2 (D-ribulose-1,5-bisphosphate) carboxylase/oxygenase] has long been a target for engineering kinetic improvements. Towards this goal we used an RDE (Rubisco-dependent Escherichia coli) selection system to evolve Synechococcus PCC6301 Form I Rubisco under different selection pressures. In the fastest growing colonies, the Rubisco L (large) subunit substitutions I174V, Q212L, M262T, F345L or F345I were repeatedly selected and shown to increase functional Rubisco expression 4- to 7-fold in the RDE and 5- to 17-fold when expressed in XL1-Blue E. coli. Introducing the F345I L-subunit substitution into Synechococcus PCC7002 Rubisco improved its functional expression 11-fold in XL1-Blue cells but could not elicit functional Arabidopsis Rubisco expression in the bacterium. The L subunit substitutions L161M and M169L were complementary in improving Rubisco yield 11-fold, whereas individually they improved yield ∼5-fold. In XL1-Blue cells, additional GroE chaperonin enhanced expression of the I174V, Q212L and M262T mutant Rubiscos but engendered little change in the yield of the more assembly-competent F345I or F345L mutants. In contrast, the Rubisco chaperone RbcX stimulated functional assembly of wild-type and mutant Rubiscos. The kinetic properties of the mutated Rubiscos varied with noticeable reductions in carboxylation and oxygenation efficiency accompanying the Q212L mutation and a 2-fold increase in Kribulose-P2 (KM for the substrate ribulose-P2) for the F345L mutant, which was contrary to the ∼30% reductions in Kribulose-P2 for the other mutants. These results confirm the RDE systems versatility for identifying mutations that improve functional Rubisco expression in E. coli and provide an impetus for developing the system to screen for kinetic improvements.
Characterization, expression and localization ofS-adenosylhomocysteine hydrolase from amphioxusBranchiostoma belcheri tsingtaunese
Authors: Wang Yuan , Zhao Bosheng , Zhang Shicui , Qu Xiaojuan
Published: June 2008

A cDNA clone encoding AmphiSAHH [amphioxus SAHH (S-adenosylhomocysteine hydrolase)] protein was isolated from a cDNA library from the gut of Branchiostoma belcheri tsingtaunese. It contained a 1305 bp open reading frame corresponding to a deduced protein of 434 amino acid residues, with a predicted molecular mass of approx. 47.8 kDa. Phylogenetic analysis showed that AmphiSAHH and sea-urchin SAHH joined together and positioned at the base of the vertebrate SAHH clade, suggesting that both AmphiSAHH and sea-urchin SAHH might share some characteristics of the archetype of vertebrate SAHH proteins. The genomic DNA sequence of AmphiSAHH contained eight exons and seven introns, which was similar to B. floridae and sea-urchin SAHH exon/intron organization. Sequence comparison suggested the evolutionary appearance of the ten exon/nine intron organization of SAHH genes after the split of invertebrates and vertebrates, after which it has been highly conserved. AmphiSAHH has been successfully expressed in Escherichia coli and purified. Western blotting confirmed that the enzyme has a native molecular mass of approx. 48 kDa, and the catalytic activities and NAD+/NADH binding affinity of recombinant AmphiSAHH were measured. Immunohistochemistry analysis showed that SAHH was strongly expressed in hepatic caecum, gill, spermary and ovary of amphioxus.
Definitive endoderm: a key step in coaxing human embryonic stem cells into transplantable β-cells
Authors: Semb Henrik
Published: June 2008

Using the Edmonton protocol, a number of patients with Type 1 diabetes mellitus have remained insulin-independent for prolonged periods of time. In spite of this success, transplantation of islets from cadaver donors will remain a therapy for very few patients owing to a lack of donors. Thus, if cell therapy should be widely available, it will require an unlimited source of cells to serve as a ‘biological’ insulin pump. At this time, the development of β-cells from hESCs (human embryonic stem cells) has emerged as the most attractive alternative. It is envisioned that ultimate success of an in vitro approach to programme hESCs into β-cells will depend on the ability, at least to a certain degree, to sequentially reproduce the individual steps that characterizes normal β-cell ontogenesis during fetal pancreatic development, including definitive endoderm from which all gastrointestinal organs, including the pancreas, originate. In the present article, differentiation of hESCs into putative definitive endodermal cell types is reviewed.
Control of pancreatic development by intercellular signals
Authors: Duvillié Bertrand , Stetsyuk Volodymyr , Filhoulaud Gaëlle , Guillemain Ghislaine , Scharfmann Raphaël
Published: June 2008

Understanding pancreatic development is important for at least three reasons: first, from a cognitive point of view, to understand the development of a complex organ, the pancreas; next, because it is now clear that abnormal pancreatic development can give rise to specific forms of diabetes in humans; and finally, because, if we want to define new treatments for diabetes based on cell therapy or regenerative medicine, we will have to understand in detail how β-cells develop. In the present paper, we summarize what we currently know concerning pancreatic development and concentrate on some intercellular and environmental signals controlling pancreatic development.
Insulin signalling in islets
Authors: Persaud Shanta J. , Muller Dany , Jones Peter M.
Published: June 2008

Studies in transgenic animals, rodent insulin-secreting cell lines and rodent islets suggest that insulin acts in an autocrine manner to regulate β-cell mass and gene expression. Very little is known about the in vitro roles played by insulin in human islets, and the regulatory role of insulin in protecting against β-cell apoptosis. We have identified mRNAs encoding IRs (insulin receptors) and downstream signalling elements in dissociated human islet β-cells by single-cell RT (reverse transcription)–PCR, and perifusion studies have indicated that insulin does not have an autocrine role to regulate insulin secretion from human islets, but activation of the closely related IGF-1 (insulin-like growth factor 1) receptors is linked to inhibition of insulin secretion. Knockdown of IR mRNA by siRNAs (small interfering RNAs) decreased IR protein expression without affecting IGF-1 receptor levels, and blocked glucose stimulation of preproinsulin gene expression. Similar results were obtained when human islet IRS (IR substrate)-2 was knocked down, whereas depletion of IRS-1 caused an increase in preproinsulin mRNA levels. Studies using the mouse MIN6 β-cell line indicated that glucose protected β-cells from undergoing apoptosis and that this was a consequence, at least in part, of insulin release in response to elevated glucose. IGF-1 also exerted anti-apoptotic effects. These data indicate that insulin can exert autocrine effects in human islets through receptors on β-cells. It protects β-cells against apoptosis and increases preproinsulin mRNA synthesis, but does not affect insulin secretion.
Granule docking and cargo release in pancreatic β-cells
Authors: Barg Sebastian , Lindqvist Anders , Obermüller Stefanie
Published: June 2008

Biphasic insulin secretion is required for proper insulin action and is observed not only in vivo, but also in isolated pancreatic islets and even single β-cells. Late events in the granule life cycle are thought to underlie this temporal pattern. In the last few years, we have therefore combined live cell imaging and electrophysiology to study insulin secretion at the level of individual granules, as they approach the plasma membrane, undergo exocytosis and finally release their insulin cargo. In the present paper, we review evidence for two emerging concepts that affect insulin secretion at the level of individual granules: (i) the existence of specialized sites where granules dock in preparation for exocytosis; and (ii) post-exocytotic regulation of cargo release by the fusion pore.
Why expression of some genes is disallowed in β-cells
Authors: Quintens Roel , Hendrickx Nico , Lemaire Katleen , Schuit Frans
Published: June 2008

A differentiated β-cell results not only from cell-specific gene expression, but also from cell-selective repression of certain housekeeping genes. Indeed, to prevent insulin toxicity, β-cells should handle insulin stores carefully, preventing exocytosis under conditions when circulating insulin is unwanted. Some ubiquitously expressed proteins would significantly jeopardize this safeguard, when allowed to function in β-cells. This is illustrated by two studied examples. First, low-Km hexokinases are disallowed as their high affinity for glucose would, when expressed, significantly lower the threshold for glucose-induced β-cell function and cause hypoglycaemia, as happens in patients with β-cell tumours. Thus the β-cell phenotype means not only expression of glucokinase but also absence of low-Km hexokinases. Secondly, the absence of MCTs (monocarboxylic acid transporters) in β-cells explains the pyruvate paradox (pyruvate being an excellent substrate for mitochondrial ATP production, yet not stimulating insulin release when added to β-cells). The relevance of this disallowance is underlined in patients with exercise-induced inappropriate insulin release: these have gain-of-function MCT1 promoter mutations and loss of the pyruvate paradox. By genome-wide ex vivo mRNA expression studies using mouse islets and an extensive panel of other tissues, we have started to identify in a systematic manner other specifically disallowed genes. For each of those, the future challenge is to explore the physiological/pathological relevance and study conditions under which the phenotypically disallowed state in the β-cell is breached.
TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic β-cells
Authors: Loder Merewyn K. , Xavier Gabriela da Silva , McDonald Angela , Rutter Guy A.
Published: June 2008

Genetic studies have linked the risk of Type 2 diabetes with SNPs (single nucleotide polymorphisms) in the gene encoding the Wnt signalling-associated transcription factor, TCF7L2 (T-cell factor 7-like 2). The risk alleles have been associated with reduced glucose and GLP-1 (glucagon-like peptide 1)-stimulated insulin secretion. Recent evidence has suggested that inheritance of the at-risk T allele at SNP rs7903146 may increase the expression of TCF7L2 in adult human islets. However, the cellular mechanisms by which changes in TCF7L2 levels may affect insulin secretion are unclear. In the present paper, we describe the use of RNA silencing to investigate the role of TCF7L2 on insulin secretion and gene expression in rodent islets. We find that reduced TCF7L2 expression reduces glucose-simulated insulin secretion and insulin gene expression while slightly potentiating glucose stimulated changes in intracellular free Ca2+ concentrations.
Regulation of the GPR40 locus: towards a molecular understanding
Authors: Ridner Gabriela , Bartoov-Shifman Reut , Zalogin Tatyana , Avnit-Sagi Tali , Bahar Keren , Sharivkin Revital , Kantorovich Lia , Weiss Sara , Walker Michael D.
Published: June 2008

GPR40 {FFAR1 [non-esterified (‘free’) fatty acid receptor 1]} is a G-protein-coupled receptor expressed preferentially in pancreatic β-cells. GPR40 functions as a receptor for medium and long-chain fatty acids, and has been implicated in mediating both physiological and pathological effects of fatty acids on β-cells. The GPR40 gene is encoded at an interesting chromosomal locus that contains several genes: at the 5′-end of the locus, located ∼4 kb upstream of GPR40, is CD22, a gene encoding a receptor expressed selectively in lymphocytes and involved in B-lymphocyte maturation and function. At the 3′-end of the locus are the GPR41 (FFAR3) and GPR43 (FFAR2) genes encoding receptors activated by short-chain fatty acids. The intergenic region between CD22 and GPR40 contains several evolutionarily conserved sequence blocks, among them HR2 and HR3. β-Cell-specific expression of GPR40 is controlled at the transcriptional level through HR2, a potent β-cell-specific enhancer. The mechanisms controlling cell-specific expression of the remaining genes in the cluster are unknown. Given the divergent modes of expression of the genes within the locus and their demonstrated physiological significance, it is important to analyse further the locus with a view to fully understanding the basis for transcriptional regulation of the encoded genes.
Cytokinesis and the establishment of early embryonic cell polarity
Authors: Burgess David R.
Published: June 2008

Cleavage divisions in many animals form a blastula made up of a simple polarized epithelium. This simple embryonic epithelium possesses an apical surface covered with microvilli and primary cilia separated from the basolateral surfaces by cell–cell junctions. The apical membrane proteins and lipids differ from those of the basolateral on these embryonic epithelial cells, as is found in adult epithelial cells. Formation of cell polarity in embryos at fertilization, including those from both protostomes and deuterostomes, uses the same molecules and signalling machinery as do polarizing epithelial cells that polarize upon cell–cell contact. In addition, the actin–myosin cytoskeleton plays an integral role in establishment and maintenance of this early cell polarity. However, early cleaving blastomeres from higher organisms including echinoderms and vertebrates have not been considered to exhibit cell polarity until formation of junctions at the third through to the fifth cleavage divisions. The role of new membrane addition into the late cleavage furrow during the early rounds of cytokinesis may play a key role in the early establishment of cell polarity in all animal embryos.
Insights from vaccinia virus into Toll-like receptor signalling proteins and their regulation by ubiquitin: role of IRAK-2
Authors: Bowie Andrew G.
Published: June 2008

TLRs (Toll-like receptors) are an important class of pathogen-sensing proteins, which signal the presence of a pathogen by activating transcription factors, such as NF-κB (nuclear factor κB). The TLR pathway to NF-κB activation involves multiple phosphorylation and ubiquitination events. Notably, TRAF-6 [TNF (tumour necrosis factor)-receptor-associated factor-6] Lys63 polyubiquitination is a critical step in the formation of signalling complexes, which turn on NF-κB. Here, the relative role of different IRAKs [IL-1 (interleukin 1)-receptor-associated kinases] in NF-κB activation is discussed. Further, I demonstrate how understanding one molecular mechanism whereby vaccinia virus inhibits NF-κB activation has led to a revealing of a key role for IRAK-2 in TRAF-6-mediated NF-κB activation.
Role of theVHL(von Hippel–Lindau) gene in renal cancer: a multifunctional tumour suppressor
Authors: Nyhan Michelle J. , O'Sullivan Gerald C. , McKenna Sharon L.
Published: June 2008

The VHL (von Hippel–Lindau) tumour-suppressor gene is inactivated in VHL disease and in sporadic cases of CCRCC [clear-cell RCC (renal cell carcinoma)]. pVHL (VHL protein) functions as part of an E3 ubiquitin ligase complex that targets proteins for proteasomal degradation. The best-characterized substrate is HIF-α (hypoxia-inducible factor-α). Loss of pVHL and subsequent up-regulation of HIF target genes has been attributed to the highly vascular nature of these neoplasms. However, pVHL does not just function as the executioner of HIF-α. Additional functions of pVHL that may be important in preventing CCRCC tumorigenesis have been identified, including primary cilium maintenance, assembly of the extracellular matrix and roles in the stabilization of p53 and Jade-1 (gene for apoptosis and differentiation in epithelia). Current evidence indicates that pVHL probably requires additional co-operating signalling pathways for CCRCC initiation and tumorigenesis.
Control of mRNA degradation in trypanosomes
Authors: Clayton Christine , Schwede Angela , Stewart Mhairi , Robles Ana , Benz Corinna , Po June , Wurst Martin , Quieroz Rafael , Archer Stuart
Published: June 2008

Control of gene expression in trypanosomes relies almost exclusively on post-transcriptional mechanisms. Trypanosomes have the normal enzymes for mRNA decay: both the exosome and a 5′–3′-exoribonuclease are important in the degradation of very unstable transcripts, whereas the CAF1/NOT complex plays a major role in the degradation of all mRNAs tested. Targeted RNA interference screening was used to identify RNA-binding proteins that regulate mRNA degradation, and it revealed roles for proteins with RNA recognition motifs or pumilio domains.
Function and regulation of the mammalian Musashi mRNA translational regulator
Authors: MacNicol Angus M. , Wilczynska Anna , MacNicol Melanie C.
Published: June 2008

The evolutionarily conserved RNA-binding protein, Musashi, regulates neural stem cell self-renewal. Musashi expression is also indicative of stem cell populations in breast and intestinal tissues and is linked to cell overproliferation in cancers of these tissues. Musashi has been primarily implicated as a repressor of target mRNAs in stem cell populations. However, little is known about the mechanism by which Musashi exerts mRNA translational control or how Musashi function is regulated. Recent findings in oocytes of the frog, Xenopus, indicate an unexpected role for Musashi as an activator of a number of maternal mRNAs during meiotic cell cycle progression. Given the importance of Musashi function in stem cell biology and the implications of aberrant Musashi expression in cancer, it is critical that we understand the molecular processes that regulate Musashi function.
Comet and cup genes in Drosophila spermatogenesis: the first demonstration of post-meiotic transcription
Authors: Barreau Carine , Benson Elizabeth , White-Cooper Helen
Published: June 2008

Post-meiotic transcription is widespread in mammalian spermatogenesis, but is generally believed to be absent from Drosophila spermatogenesis. Genes required during meiosis, in early spermatids or later in spermiogenesis are typically transcribed in primary spermatocytes in Drosophila. Their mRNAs are then stored in the cytoplasm until the protein product is needed. Recently, using in situ hybridization, we identified 17 Drosophila genes, collectively named ‘comets’ and ‘cups’, whose mRNAs are most abundant in, and localize to the distal ends of, elongating spermatids. Using a single-cyst quantitative RT–PCR (reverse transcription–PCR) assay, we confirmed this unusual expression pattern and conclusively demonstrate the existence of post-meiotic transcription in Drosophila spermatids. We found that transcription of comets and cups occurs just before protamines can be detected in spermatid nuclei.
The role of Snu114p during pre-mRNA splicing
Authors: Frazer Lily Novak , Nancollis Verity , O'Keefe Raymond T.
Published: June 2008

Pre-mRNA splicing is an essential step in gene expression where intron regions are removed and coding exon sequences are joined to form an mRNA for translation. Splicing is catalysed by an RNA–protein complex called the spliceosome. A number of spliceosome proteins are required for assembly and remodelling of the spliceosome with pre-mRNA to orient the splice sites correctly and catalyse the two steps of splicing. The spliceosome protein Snu114p is a GTPase that is related to the translation elongation factor EF-2. Snu114p plays a key role in spliceosome remodelling. In the present review, we briefly summarize the current knowledge of the function of Snu114p in pre-mRNA splicing and the role it plays in spliceosome dynamics.
Association between both lipid and protein oxidation and the risk of fatal or non-fatal coronary heart disease in a human population
Authors: Woodward Mark , Croft Kevin D. , Mori Trevor A. , Headlam Henrietta , Wang Xiao Suo , Suarna Cacang , Raftery Mark J. , MacMahon Stephen W. , Stocker Roland
Published: June 2008

The role of oxidative damage in the aetiology of coronary disease remains controversial, as clinical trials investigating the effect of antioxidants have not generally been positive. In the present study, 227 coronary cases, identified from a cohort study, were matched, by age and gender, with 420 controls in a nested case-control design. Stored plasma samples were analysed for F2-isoprostanes by stable isotope dilution MS, and specifically oxidized forms of apoA-I (apolipoprotein A-I) by HPLC of HDL (high-density lipoprotein). Median values of F2-isoprostanes were higher in plasma samples that contained oxidized apoA-I compared with samples with undetectable oxidized apoA-I (1542 compared with 1165 pmol/l). F2-Isoprostanes were significantly correlated with variants of non-oxidized apoA-II (r=−0.15) and were associated with HDL-cholesterol (P<0.0001). F2-Isoprostanes in cases (median, 1146 pmol/l) were not different from controls (1250 pmol/l); the odds ratio (95% confidence interval) for a 1 S.D. increase in F2-isoprostanes was 1.08 (0.91–1.29). Similarly, there was no independent association between the presence of oxidized apoA-I, detected in approx. 20% of the samples, and coronary risk. In conclusion, we found no evidence of associations between markers of lipid (F2-isoprostanes) and protein (oxidized apoA-I) oxidation and the risk of fatal or non-fatal coronary heart disease in a general population. This may be due to a true lack of association or insufficient power.
Nonadiabatic electron dynamics in the exit channel of Na-molecule optical collisions
Authors: Rebentrost F. , Figl C. , Goldstein R. , Hoffmannn O. , Spelsberg D. , Grosser J.
Published: June 2008

We study optical collisions of Na atoms with N2, CO, C2H2, and CO2 molecules in a crossed-beam experiment. Excited electronic states of the collision complex are selectively populated during the collision. We measure the relative population of the Na(3p) fine-structure levels after the collision and observe in this way the nonadiabatic transitions occuring in the final phase of the collision process. For the NaCO, NaC2H2, and NaCO2 systems new ab initio potential surfaces were generated. The theoretical analysis of the nonadiabatic electron dynamics on the excited potential surfaces is made within the classical-path formalism. The results are in good qualitative agreement with the experimental data and provide insight into the nonadiabatic mechanisms prevailing during the evolution in the upper 3p manifold. The differences between the different collisional systems are related to the presence and system-specific locations of conical intersections and avoided crossing seams in the excited potential surfaces.
Dielectric relaxation of polychlorinated biphenyl/toluene mixtures: Component dynamics
Authors: Cangialosi Daniele , Alegría Angel , Colmenero Juan
Published: June 2008

The dynamics of homogenous polychlorinated biphenyl (PCB54)/toluene mixtures have been investigated by means of broadband dielectric spectroscopy. The mixture presents dynamical heterogeneity, alike miscible polymer blends, which is manifested with the presence of two relaxational processes. The relatively slow one has been attributed to the motion of PCB54 in the mixture, whereas the relatively fast one was related to the toluene dynamics in the mixture. These results have been interpreted according to the self-concentration concept, first introduced to describe the dynamics of miscible polymer blends, which relies on the limited size of the cooperative length scale in glass-forming liquids. The self-concentration concept has been incorporated in the Adam–Gibbs theory of the glass transition relating the characteristic relaxation time and the length scale for structural relaxation to the configurational entropy. This allowed the determination of the cooperative length scale of PCB54 and toluene both in mixture and alone through the fitting of a single parameter, namely, that connecting the cooperative length scale to the configurational entropy. This length scale resulted to be in the range of 1–2nm for all systems. Finally, the out-of-equilibrium dynamics of toluene induced by the selective freezing in of PCB54 has been examined and its relation to the Johari–Goldstein relaxation of pure toluene was critically discussed.
Atomic motions in the αβ-merging region of 1,4-polybutadiene: A molecular dynamics simulation study
Authors: Narros A. , Arbe A. , Alvarez F. , Colmenero J. , Richter D.
Published: June 2008

We present fully atomistic molecular dynamics simulations on 1,4-polybutadiene in a wide temperature range from 200to280K, i.e., in the region where the α- and β-relaxations merge and above. A big computational effort has been performed—especially for the lowest temperatures investigated—to extend the simulation runs to very long times (up to 1μs for 200K). The simulated sample has been carefully validated by using previous neutron scattering data on the real sample with similar microstructure. Inspecting the trajectories of the different hydrogens in real space, we have observed a heterogeneous dynamical behavior (each kind of hydrogen moves in a different way) with signatures of combined hopping and diffusive motions in the whole range investigated. The application of a previously proposed model [Colmenero et al., Europhys. Lett. 71, 262 (2005)] is successful and a characterization of the local motions and diffusion is possible. The comparison of our results to those reported in the literature provides a consistent scenario for polybutadiene dynamics and puts into a context the different experimental observations. We also discuss the impact of the hopping processes on the observation and interpretation of experimentally accessible magnitudes and the origin of the deviations from Gaussian behavior in this system.
Interdiffusion, phase formation, and stress development in Cu–Pd thin-film diffusion couples: Interface thermodynamics and mechanisms
Authors: Chakraborty J. , Welzel U. , Mittemeijer E. J.
Published: June 2008

Cu–Pd thin-film diffusion couples (individual layer thicknesses of 50nm) have been prepared by dc-magnetron sputtering on silicon substrates coated with a thin amorphous Si3N4 layer. Stress evolution, microstructural development, and phase formation during interdiffusion have been investigated employing Auger-electron spectroscopy (in combination with sputter-depth profiling), x-ray diffraction, wafer curvature measurements and transmission electron microscopy. Upon annealing at relatively low temperatures (175–250°C) for durations up to 10h, considerable diffusional intermixing occurs. Interdiffusion is accompanied by sequential formation of new phases. First, Cu3Pd forms; subsequently, CuPd forms and grows at the expense of Cu3Pd, which has been interpreted as a consequence of interface thermodynamics. Annealing leads to a slight sharpening of the pre-existing {111}-fiber textures and a little increase in the average grain size. A combination of ex situ (x-ray diffraction) and in situ (wafer curvature) stress measurements revealed that tensile stresses are generated during annealing. The obtained stress results have been discussed in the light of possible mechanisms of stress generation, and the dominant sources of stress buildup and relaxation have been identified.
Optimization of amorphous silicon thin film solar cells for flexible photovoltaics
Authors: Söderström T. , Haug F.-J. , Terrazzoni-Daudrix V. , Ballif C.
Published: June 2008

We investigate amorphous silicon (a-Si:H) thin film solar cells in the n-i-p or substrate configuration that allows the use of nontransparent and flexible substrates such as metal or plastic foils such as polyethylene-naphtalate (PEN). A substrate texture is used to scatter the light at each interface, which increases the light trapping in the active layer. In the first part, we investigate the relationship between the substrate morphology and the short circuit current, which can be increased by 20% compared to the case of flat substrate. In the second part, we investigate cell designs that avoid open-circuit voltage (Voc) and fill factor (FF) losses that are often observed on textured substrates. We introduce an amorphous silicon carbide n-layer (n-SiC), a buffer layer at the n/i interface, and show that the new cell design yields high Voc and FF on both flat and textured substrates. Furthermore, we investigate the relation between voids or nanocrack formations in the intrinsic layer and the textured substrate. It reveals that the initial growth of the amorphous layer is affected by the doped layer which itself is influenced by the textured substrate. Finally, the beneficial effect of our optical and electrical findings is used to fabricate a-Si:H solar cell on PEN substrate with an initial efficiency of 8.8% for an i-layer thickness of 270 nm.
Characteristic capacitance in an electric force microscope determined by using sample surface bias effect
Authors: Qi G. C. , Yan H. , Guan L. , Yang Y. L. , Qiu X. H. , Wang C. , Li Y. B. , Jiang Y. P.
Published: June 2008

A method to determine the dependence of characteristic capacitance of an electric force microscopy tip on tip-sample separation is presented. It is demonstrated that by introducing sufficient voltage to the sample surface, the first derivative of the characteristic capacitance for tip-sample complex could be obtained and, subsequently, the characteristic capacitance versus tip-sample separation could be determined. In addition, the effective charge position on the tip relative to sample surface could also be identified.
Postgrowth annealing of GaInAs∕GaAs and GaInAsN∕GaAs quantum well samples placed in a proximity GaAs box: A simple method to improve the crystalline quality
Authors: Pakarinen J. , Peng C. S. , Puustinen J. , Laukkanen P. , Korpijärvi V.-M. , Tukiainen A. , Pessa M.
Published: June 2008

The effects of thermal annealing on GaInAs∕GaAs and GaInAsN∕GaAs quantum wells, grown by molecular beam epitaxy, were investigated. Optical and structural properties were examined upon annealing when the samples had a 200nm thick SiO2 cap layer, or were placed in a so-called GaAs box or were left uncapped. The GaAs box gave rise to the strongest photoluminescence without significant blueshift or structural changes at moderate annealing temperature. Capping with SiO2 impaired the samples and caused a more pronounced blueshift for the GaInAs quantum wells than for the GaInAsN ones. These results consolidate our understanding of the blueshift mechanisms.
Subwavelength nondiffraction beam generated by a plasmonic lens
Authors: Lin Ding-Zheng , Chen Chih-Hao , Chang Chin-Kai , Cheng Tsung-Dar , Yeh Chau-Shioung , Lee Chih-Kung
Published: June 2008

We experimentally examined the near-field and far-field optical properties of a subwavelength annular aperture (SAA) made on silver film and undertook finite difference time domain simulations. In our near-field measurements, an interference pattern with a period very close to half of the surface plasmon (SP) wavelength (λSP∕2) was found on the surface of the silver film. Moreover, we observed that the transmitted light of the 442nm incident laser was focused at several micrometers behind the silver SAA structure at a tiny spot (354nm) and with a remarkable 31μm depth of focus. This implies that the silver SAA structure can generate a nondiffraction beam and can be used to fabricate high aspect ratio subwavelength structures.