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Biologische Hochschulschriften (Goethe-Universität)
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- Cell-free expression and molecular modeling of the γ-secretase complex and G-protein-coupled receptors (2013)
- Alzheimer's disease (AD), which was first reported more than a century ago by Alhzeimer, is one of the commonest forms of dementia which affects >30 million people globally (>8 million in Europe). The origin and pathogenesis of AD is poorly understood and there is no cure available for the disease. AD is characterized by the accumulation of senile plaques composed of amyloid beta peptides (Ab 37-43) which is formed by the gamma secretase (GS) complex by cleaving amyloid precursor protein. Therefore GS can be an attractive drug target. Since GS processes several other substrates like Notch, CD44 and Cadherins, nonspecific inhibition of GS has many side effects. Due to the lack of crystal structure of GS, which is attributed to the extreme difficulties in purifying it, molecular modeling can be useful to understand its architecture. So far only low resolution cryoEM structures of the complex has been solved which only provides a rough structure of the complex at low 12-15 A resolution Furthermore the activity of GS in vitro can be achieved by means of cell-free (CF) expression. GS comprises catalytic subunits namely presenilins and supporting elements containing Pen-2, Aph-1 and Nicastrin. The origin of AD is hidden in the regulated intramembrnae proteolysis (RIP) which is involved in various physiological processes and also in leukemia. So far growth factors, cytokines, receptors, viral proteins, cell adhesion proteins, signal peptides and GS has been shown to undergo RIP. During RIP, the target proteins undergo extracellular shredding and intramembrane proteolysis. This thesis is based on molecular modeling, molecular dynamics (MD) simulations, cell-free (CF) expression, mass spectrometry, NMR, crystallization, activity assay etc of the components of GS complex and G-protein coupled receptors (GPCRs). First I validated the NMR structure of PS1 CTF in detergent micelles and lipid bilayers using coarse-grained MD simulations using MARTINI forcefield implemented in Gromacs. CTF was simulated in DPC micelles, DPPC and DLPC lipid bilayer. Starting from random configuration of detergent and lipids, micelle and lipid bilyer were formed respectively in presence of CTF and it was oriented properly to the micelle and bilyer during the simulation. Around DPC molecules formed micelle around CTF in agreement of the experimental results in which 80-85 DPC molecules are required to form micelles. The structure obtained in DPC was similar to that of NMR structure but differed in bilayer simulations showed the possibility of substrate docking in the conserved PAL motif. Simulations of CTF in implicit membrane (IMM1) in CHAMM yielded similar structure to that from coarse grained MD. I performed cell-free expression optimization, crystallization and NMR spectroscopy of Pen-2 in various detergent micelles. Additionally Pen-2 was modeled by a combination of rosetta membrane ab-initio method, HHPred distant homology modeling and incorporating NMR constraints. The models were validated by all atom and coarse grained MD simulations both in detergent micelles and POPC/DPPC lipid bilayers using MARTINI forcefield. GS operon consisting of all four subunits was co-expressed in CF and purified. The presence of of GS subunits after pull-down with Aph-1 was determined by western blotting (Pen-2) and mass spectrometry (Presenilin-1 and Aph-1). I also studied interactions of especially PS1 CTF, APP and NTF by docking and MD. I also made models and interfaces of Pen-2 with PS1 NTF and checked their stability by MD simulations and compared with experimental results. The goal is to model the interfaces between GS subunits using molecular modeling approaches based on available experimental data like cross-linking, mutations and NMR structure of C-terminal fragment of PS1 and transmembrane part of APP. The obtained interfaces of GS subunits may explain its catalysis mechanism which can be exploited for novel lead design. Due to lack of crystal/NMR structure of the GS subunits except the PS1 CTF, it is not possible to predict the effect of mutations in terms of APP cleavage. So I also developed a sequence based approach based on machine learning using support vector machine to predict the effect of PS1 CTF L383 mutations in terms of Aβ40/Aβ42 ratio with 88% accuracy. Mutational data derived from the Molgen database of Presenilin 1 mutations was using for training. GPCRs (also called 7TM receptors) form a large superfamily of membrane proteins, which can be activated by small molecules, lipids, hormones, peptides, light, pain, taste and smell etc. Although 50% of the drugs in market target GPCRs , only few are targeted therapeutically. Such wide range of targets is due to involvement of GPCRs in signaling pathways related to many diseases i.e. dementia (like Alzheimer's disease), metabolic (like diabetes) including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, pain and cancer. Cannabinoid and adrenergic receptors belong to the class A (similar to rhodopsin) GPCRs. Docking of agonists and antagonists to CB1 and CB2 cannabinoid receptors revealed the importance of a centrally located rotamer toggle switch, and its possible role in the mechanism of agonist/antagonist recognition. The switch is composed of two residues, F3.36 and W6.48, located on opposite transmembrane helices TM3 and TM6 in the central part of the membranous domain of cannabinoid receptors. The CB1 and CB2 receptor models were constructed based on the adenosine A2A receptor template. The two best scored conformations of each receptor were used for the docking procedure. In all poses (ligand-receptor conformations) characterized by the lowest ligand-receptor intermolecular energy and free energy of binding the ligand type matched the state of the rotamer toggle switch: antagonists maintained an inactive state of the switch, whereas agonists changed it. In case of agonists of β2AR, the (R,R) and (S,S) stereoisomers of fenoterol, the molecular dynamics simulations provided evidence of different binding modes while preserving the same average position of ligands in the binding site. The (S,S) isomer was much more labile in the binding site and only one stable hydrogen bond was created. Such dynamical binding modes may also be valid for ligands of cannabinoid receptors because of the hydrophobic nature of their ligand-receptor interactions. However, only very long molecular dynamics simulations could verify the validity of such binding modes and how they affect the process of activation. Human N-formyl peptide receptors (FPRs) are G protein-coupled receptors (GPCRs) involved in many physiological processes, including host defense against bacterial infection and resolving inflammation. The three human FPRs (FPR1, FPR2 and FPR3) share significant sequence homology and perform their action via coupling to Gi protein. Activation of FPRs induces a variety of responses, which are dependent on the agonist, cell type, receptor subtype, and also species involved. FPRs are expressed mainly by phagocytic leukocytes. Together, these receptors bind a large number of structurally diverse groups of agonistic ligands, including N-formyl and nonformyl peptides of different composition, that chemoattract and activate phagocytes. For example, N-formyl-Met-Leu-Phe (fMLF), an FPR1 agonist, activates human phagocyte inflammatory responses, such as intracellular calcium mobilization, production of cytokines, generation of reactive oxygen species, and chemotaxis. This ligand can efficiently activate the major bactericidal neutrophil functions and it was one of the first characterized bacterial chemotactic peptides. Whereas fMLF is by far the most frequently used chemotactic peptide in studies of neutrophil functions, atomistic descriptions for fMLF-FPR1 binding mode are still scarce mainly because of the absence of a crystal structure of this receptor. Elucidating the binding modes may contribute to designing novel and more efficient non-peptide FPR1 drug candidates. Molecular modeling of FPR1, on the other hand, can provide an efficient way to reveal details of ligand binding and activation of the receptor. However, recent modelings of FPRs were confined only to bovine rhodopsin as a template. To locate specific ligand-receptor interactions based on a more appropriate template than rhodopsin we generated the homology models of FPR1 using the crystal structure of the chemokine receptor CXCR4, which shares over 30% sequence identity with FPR1 and is located in the same γ branch of phylogenetic tree of GPCRs (rhodopsin is located in α branch). Docking and model refinement procedures were pursued afterward. Finally, 40 ns full-atom MD simulations were conducted for the Apo form as well as for complexes of fMLF (agonist) and tBocMLF (antagonist) with FPR1 in the membrane. Based on locations of the N- and C-termini of the ligand the FPR1 extracellular pocket can be divided into two zones, namely, the anchor and activation regions. The formylated M1 residue of fMLF bound to the activation region led to a series of conformational changes of conserved residues. Internal water molecules participating in extended hydrogen bond networks were found to play a crucial role in transmitting the agonist-receptor interactions. A mechanism of initial steps of the activation concurrent with ligand binding is proposed. I accurately predicted the structure and ligand binding pose of dopamine receptor 3 (RMSD to the crystal structure: 2.13 Å) and chemokine receptor 4 (CXCR4, RMSD to the crystal structure 3.21 Å) in GPCR-Dock 2010 competition. The homology model of the dopamine receptor 3 was 8 th best overall in the competition.
- Taxonomic revision, molecular phylogeny and zoogeography of the huntsman spider genus Eusparassus (Araneae: Sparassidae) (2013)
- The spider genus Eusparassus Simon, 1903 (Araneae: Sparassidae: Eusparassinae; stone huntsman spider) is revised worldwide to include 30 valid species distributed exclusively in Africa and Eurasia. The type species E. dufouri Simon, 1932 is redescribed and a neotype is designated from Portugal. An extended diagnosis for the genus is presented. Eight new species are described: Eusparassus arabicus Moradmand, 2013 (male, female) from Arabian Peninsula, E. educatus Moradmand, 2013 (male, female) from Namibia, E. reverentia Moradmand, 2013 (male, female) from Burkina Faso and Nigeria, E. jaegeri Moradmand, 2013 (male, female) from South Africa and Botswana, E. jocquei Moradmand, 2013 (male, female) from Zimbabwe, E. borakalalo Moradmand, 2013 (female) from South Africa, E. schoemanae Moradmand, 2013 (male, female) from South Africa and Namibia and E. mesopotamicus Moradmand and Jäger, 2012 (male and female) from Iraq, Iran and Turkey. 22 species are re-described six of them are transferred from the genus Olios Walckenaer, 1837. Six species-groups are proposed: the dufouri-group [8 species: E. dufouri, E. levantinus Urones, 2006, E. barbarus (Lucas, 1846), E. atlanticus Simon, 1909, E. syrticus Simon, 1909, E. oraniensis (Lucas, 1846), E. letourneuxi (Simon, 1874), E. fritschi (Koch, 1873); Iberian Peninsula to parts of north-western Africa], walckenaeri-group [3 species: E. walckenaeri (Audouin, 1826), E. laevatus (Simon, 1897), E. arabicus; eastern Mediterranean to Arabia and parts of north-eastern Africa], doriae-group [7 species: E. doriae (Simon, 1874), E. kronebergi Denis, 1958, E. maynardi (Pocock, 1901), E. potanini (Simon, 1895), E. fuscimanus Denis, 1958, E. oculatus (Kroneberg, 1846) and E. mesopotamicus; Middle East to Central and South Asia], vestigator-group (3 species: E. vestigator (Simon, 1897), E. reverentia, E. pearsoni (Pocock, 1901); central to eastern Africa and an isolated area in NW India], jaegeri-group [4 species: E. jaegeri, E. jocquei, E. borakalalo, E. schoemanae; southern and south-eastern Africa], tuckeri-group [2 species: E. tuckeri (Lawrence, 1927), E. educatus; south-western Africa). Two species, E. pontii Caporiacco, 1935 and E. xerxes (Pocock, 1901) cannot be placed in any of the above groups. Two species are transferred from Eusparassus to Olios: O. flavovittatus (Caporiacco, 1935) and O. quesitio Moradmand, 2013. 14 species are recognized as misplaced in Eusparassus, thus nearly half of the described species prior to this revision were placed mistakenly in this genus. Neotypes are designated for E. walckenaeri from Egypt, E. barbarus, E. oraniensis and E. letourneuxi (all three from Algeria) to establish their identity. The male and female of Cercetius perezi Simon, 1902, which was known only from the immature holotype, are described for the first time. It is recognized that the monotypic and little used generic name Cercetius Simon, 1902 — a species, which had been known only from the immature holotype — as a synonym of the widely used name Eusparassus. The case proposal 3596 (conservation of name Eusparassus) is under consideration by ICZN. The first comprehensive molecular phylogeny of the family Sparassidae with focus on the genus Eusparassus is investigated using four molecular markers (mitochondrial COI and 16S; nuclear H3 and 28S). The monophyly of Eusparassus and the dufouri, walckenaeri and doriae species-groups are recovered with the latter two groups more closely related. The monophyly of the tuckeri-group is not supported and the position of E. jaegeri as the only available member of the jaegeri-group is not resolved within the Eusparassus clade. DNA samples of the vestigator-group were not accessible for this study. The origination of the genus Eusparassus around 70 million years ago (MA) is estimated according to molecular clock analyses. Using this recent result in combination with some biogeographic and geological data, the Namib Desert is proposed as the place of ancestral origin for Eusparassus and putative Eusparassinae genera. Further analyses are done on the phylogenetic relationships of Sparassidae and its subfamilies. The Eusparassinae are not confirmed as monophyletic, with the two original genera Eusparassus and Pseudomicrommata in separate clades and only the latter clusters with most other assumed Eusparassinae, here termed the "African clade". Monophyly of the subfamilies Sparianthinae, Heteropodinae sensu stricto, Palystinae and Deleninae is recovered. The Sparianthinae are supported as the most basal clade, diverging considerably early (143 MA) from all other Sparassidae. The Sparassinae and genus Olios are found to be polyphyletic. The Sparassidae are confirmed as monophyletic and as most basal group within the RTA-clade. The divergence time of Sparassidae from the RTA-clade is estimated with 186 MA in the Jurassic. No affiliation of Sparassidae to other members of the "Laterigradae" (Philodromidae, Selenopidae and Thomisidae) is observed, thus the crab-like posture of this group was proposed a result of convergent evolution. Only the families Philodromidae and Selenopidae are found members of a supported clade. Including a considerable amount of RTA-clade representatives, the higher-level clade Dionycha is not but monophyly of the RTA-clade itself is supported.
- Investigation of the biosynthesis of bacterial natural products (2014)
- Natural products (NPs) have been a rich source for pharmaceutically used anti-infectives and other drugs. However, the application of anti-infectives inevitably causes the development of resistant and multiresistant pathogens, which have to be treated with novel anti-infectives. The industrial research for novel anti-infectives has been concentrating on members of the bacterial Actinomycetales for a long time. Due to several reasons, e.g. the rediscovery of already known NPs, pharmaceutical companies abandoned their NP-research and focused on drug development based on combinatorial chemistry. However, the limited structural diversity of merely synthetic compound libraries has not been a fruitful source for bioactive compounds. Hence the discovery of novel bioactive NPs as a source for anti-infectives is still of economical and humanitarian interest and will remain to be an important branch of research in the future. One strategy to circumvent the rediscovery of bioactive NPs is the analysis of yet unexplored bacterial taxa. Based on this assumption, this work aimed at the discovery of novel NPs from the entomopathogenic bacterial genera Xenorhabdus and Photorhabdus and other promising taxa, as well as the investigation of their biosynthesis. ...
- Substrate-dependent effects on the conformational equilibrium of the Na +, K +-ATPase monitored by VCF (2008)
- The Na+,K+-ATPase was discovered more than 50 years ago, but even today the pumpcycle and its partial reactions are still not completely understood. In this thesis, Voltage Clamp Fluorometry was used to monitor the conformational changes that are associated with several electrogenic partial reactions of the Na+,K+-ATPase. The conformational dynamics of the ion pump were analyzed at different concentrations of internal Na+ or of external K+ and the influences on the conformational equilibrium were determined. To probe the effect of the internal Na+ concentration on the Na+ branch of the ion pump, oocytes were first depleted of internal Na+ and then loaded with Na+ using the epithelial sodium channel which can be blocked by amiloride. The conformational dynamics of the K+ branch were studied using different external K+ concentrations in the presence and in the absence of external Na+ to yield additional information on the apparent affinity of K+. The results of our Voltage Clamp Fluorometry experiments demonstrate that lowering the intracellular concentration of Na+ has a comparable effect on the conformational equilibrium as increasing the amount of K+ in the external solution. Both of these changes shift the equilibrium towards the E1/E1(P) conformation. Furthermore, it can be shown that the ratio between external Na+ and K+ ions is also a determinant for the position of the conformational equilibrium: in the absence of external Na+, the K+ dependent shift of the equilibrium towards E1 was observed at a much lower K+ concentration than in the presence of Na+. In addition, indications were found that both external K+ and internal Na+ bind within an ion well. Finally, the crucial role of negatively charged glutamate residues in the 2nd extracellular loop for the control of ion-access to the binding sites could be verified.
- Biochemical characterisation of photosystem I complexes in diatoms (2009)
- Photosystem (PS) I is a huge membrane protein complex which coordinates around 200 co-factors. Upon light excitation a charge separation at the PS I reaction centre is induced which leads to an electron transport across the thylakoid membrane and the generation of redox equivalents needed for several biochemical reactions, e.g. the synthesis of sugars. For higher plants and cyanobacteria the crystal structure of PS I complexes were resolved to resolutions of 4.4 Å and 2.5 Å. Furthermore, supramolecular structures of PS I of eukaryotic algae, mainly of the green line, were obtained recently. However, up to now, no structure of diatoms is available yet. Diatoms are key players in global primary production and derived from a secondary endosymbiosis event. Their chloroplasts are surrounded by four envelope membranes and their thylakoids are evenly arranged in bands of three, i.e. no separation in grana and stroma regions is apparent. In this thesis a protocol was developed to isolate a functional PS I complex of diatoms which can be used for structural analysis by transmissional electron microscopy (TEM). A photosystem I-fucoxanthin chlorophyll protein (PS I-FCP) complex was isolated from the pennate diatom Phaeodactylum tricornutum by ion exchange chromatography. Spectroscopic analysis proved that bound Fcp polypeptides function as a light-harvesting complex. An active light energy transfer from Fcp associated pigments, Chl c and fucoxanthin, towards the PS I core was proven by fluorescence spectroscopy. Oxidised minus reduced difference spectroscopy evidenced the activity of the PS I reaction centre P700 and yielded a chlorophyll a/P700 ratio of approximately 200:1. These data indicate that the isolated PS I-FCP complex exceeds the PS I cores from cyanobacteria and higher plants in the numbers of chlorophyll a molecules. Because of the strict conservation of PS I cores among organisms the additional 100 chlorophyll a molecules must either be coordinated by Fcps or function as linker molecules between the Fcp antenna and the PS I core as shown for the PS I-LHC I complex of higher plants. To tell something about the structural organisation, the PS I-FCP complex was compared with its cyanobacterial and higher plant counterparts. Whereas cyanobacterial PS I cores aggregate to trimers, usually without associated antennae, higher plant PS I is a monomer and binds additionally two LHC I heterodimers. BN-PAGE and gel filtration experiments showed that also diatoms contain PS I monomers associated with Fcps as light-harvesting antenna. First TEM studies evidenced these observations. Negatively stained PS I-FCP particles had an increased size compared to PS I cores of other organisms. No PS I trimers or higher oligomers have been found. The calculated diameter and shape of the particles correspond to PS I-LHC I particles obtained from green algae, which also comprise of a higher number of LHC I polypeptides compared to the higher plant x-ray structure. Additionally, the analysis of polypeptides indicates that the PS I associated Fcps differ from the free Fcp pool and also from Fcps of a PS II enriched fraction. The assumption that diatoms harbour just one Fcp antenna that serve both Photosystems equally seems to be wrong. To further study the association of Fcps with the two Photosystems, both complexes plus the free FCP complexes were isolated from the centric diatom Cyclotella meneghiniana. Because of the availability of antibodies directed against specific Fcp polypeptides of Cyclotella the PS I-FCP complex of Phaeodactylum could not be used. A trimeric FCP complex, FCPa, and a higher FCP oligomer, FCPb, have already been described for C. meneghiniana. The latter is assumed to be composed of only Fcp5, whereas the FCPa contains Fcp2 and Fcp6. Biochemical and spectroscopical evidences revealed a different subset of associated Fcp polypeptides within the isolated photosystem complexes. Whereas the PS II associated Fcp antenna resembles FCPa, at least three different Fcp polypeptides are associated with PS I. By re-solubilisation of the PS I complex and a further purification step Fcp polypeptides were partially removed from PS I and both fractions were analysed again by biochemical and spectroscopical means, as well as by HPLC. Thereby Fcp4 and a so far undescribed 17 kDa Fcp were found to be strongly coupled to PS I, whereas another Fcp, presumably Fcp5, is only loosely bound to the PS I core. Thus an association of FCPb and PS I is assumed.
- Structural analysis of the enzyme N-formylmethanofuran:tetrahydromethanopterin formyltransferase (2008)
- Archaea represent a third domain of life and some archaea exhibit a high degree of tolerance to extreme environmental conditions. Several members are methanogens and present in many anaerobic environments. Most methanogens are able to maintain growth simply on H2 and CO2 via the enzymatically catalyzed reaction 4H2 + CO2 > CH4 + 2 H2O. The archaeon Methanopyrus kandleri grows optimally at temperatures of 84°C to 110°C, pH values of 5.5 to 7.0 and NaCl concentrations 0.2% to 4%. The enzyme N-formylmethanofuran tetrahydromethanopterin formyltransferase (MkFTR) catalyzes the transfer of a formyl group from the cofactor N-formylmethanofuran (FMF) to the cofactor tetrahydromethanopterin (H4MPT), the second step of the above reaction. X-ray crystallographic analysis yielded insights into the structure and function of MkFTR, (1) the MkFTR monomer exhibits a pseudo-two fold structure suggestive of an evolutionary gene duplication. (2) The structure is a D2 homo-tetramer with prominent cleft-like surface features. Analysis of the interface contacts showed that the tetramer is best described as a dimer of dimers. The clefts were associated with the monomer:monomer interface and were weakly occupied by extra electron density which might be attributed to the H4MPT analog folate. (3) This suggested that the clefts are active sites and their association with oligomer interfaces suggested a basis for the dependence of activity on oligomerization. (4) The thermal stability of MkFTR most likely arises from the greater number of H- and ionic-bonds within the monomer and between monomers with respect to mesophilic protein structures. (5) The structure showed a large number of surface exposed negatively charged, glutamate and aspartate residues. These residues explain the salt dependent oligomerization, as only at high enough salt concentration is the electrostatic charge compensated by cation binding and neutralized allowing oligomerization. (6) These residues also improve the solubility of MkFTR at high salt concentration by increased charge repulsion. (7) Comparison of MkFTR structures from low and hight salt conditions showed that surface glutamate residues bind slightly more water molecules at high salt conditions further contributing to MkFTR solubility at high salt concentration.
- The non-apoptotic function of Caspase-8 in enothelial precursor cells (2009)
- Vasculogenesis as well as angiogenesis are important for postnatal development of blood vessels. Peripheral blood or bone marrow-derived endothelial precursor cells are used in clinical trials for therapeutic enhancement of postnatal neovascularization in patients suffering from coronary artery diseases. The vasculogenic potential of the precursor cell population depends on the appropriate retention of the infused cells to the ischemic tissue. However, cell-autonomous mechanisms regulating the attraction and retention of circulating cells in inflammatory tissue are not well understood. Caspases belong to a family of pro-apoptotic enzymes. Beyond cell death signals, caspase proteases additionally regulate non-apoptotic processes like cell morphology and migration in many cell types. The isoform Caspase-8 is essential for embryonal vasculogenesis in conditional knockout mice. In this study, we identified a novel apoptosis-unrelated role of Caspase-8 in circulating and bone marrow-derived cells for vascular repair. Caspase-8-specific inhibition abrogated the ex vivo formation of EPC from human peripheral blood. Moreover, Caspase-8 inhibition disables EPC migration and adhesion to different matrices and decreases the cell surface expression of the fibronectin receptor subunit integrin alpha 5 and the chemokine receptor CXCR4. In vitro and in vivo studies using bone marrow mononuclear cells derived from inducible Caspase-8- deficient mice revealed an essential role of Caspase-8 for EPC formation and neovascularization enhancing capacities of progenitor cells. Caspase-8 activity appears to be required for maintaining responses to matrix interaction and chemoattractants of EPC. Additional studies showed that the E3 ubiquitin ligase Cbl-b, a negative regulator of cell adhesion molecules including integrin alpha 5, is present in EPC at low protein levels under basal conditions, but markedly increases upon Caspase-8 inhibition. In vitro assays and overexpression studies in intact cells confirmed Caspase-8-dependent degradation of Cbl-b, providing a potential requirement for Caspase-8-regulated adhesion. Indeed, neovascularization of matrigel plugs was enhanced in mice lacking Cbl-b. Moreover, Cbl-b degradation in the presence of active Caspase-8 prevents the down-regulation of integrin alpha 5 and is associated with an enhanced vasculogenic activity of progenitor cells in hind limb ischemia. The identified upstream regulation of caspase-8 by cytokine IL-6 is only one possibility for fine-tuning the non-apoptotic enzymatic activity. In summary, this study shows a novel essential role of Caspase-8 for proper EPC adhesion-related signaling. Caspase-8 is involved in the function of adhesion molecules by regulation the E3 ubiquitin ligase Cbl-b. Strategies to improve survival of therapeutic injected progenitor cells by using caspase inhibitors should be addressed with caution. Because of the broad spectrum of activity of caspase-8, downstream targets of this caspase isoform and Cbl-b should be in more focus for therapeutic pretreatment to improve neovascularization of myocardial and ischemic tissue.
- Strukturelle und funktionelle Untersuchung der p53-Familie, im Besonderen p63 (2009)
- The transcription factor p63 is part of the p53 protein family, which consists of three members, p53, p63 and p73. P63 shares structural similarity with all family members, but is associated to different biological functions than p53 or p73. While p53 is mainly linked to tumor suppression and p73 is connected with neuronal development, p63 has been connected to critical biological roles within ectodermal development and skin stem cell biology as well as supervision of the genetic stability of oocytes. Due to its gene structure p63 is expressed as at least six different isoforms, three of them containing a N-terminal transactivation domain. The isoforms that are of biological relevance both have a C-terminal inhibitory domain that negatively regulates the transcriptional activity. This inhibitory domain is supposed to contain two individual components of which one is internally binding and masking the transactivation domain while the other one can be sumoylated. To further investigate this domain a mutational analysis with the help of transactivation assays in SAOS2 cells was carried out to identify the critical amino acids within the inhibitory domain and the impact on transcriptional activity of TAp63alpha, the p63-isoform which is essential for the integrity of the female germline. The results of these experiments show that a stretch of approximately 13 amino acids seems to be important for the regulation of transcriptional activity in TAp63alpha, due to the increased transcriptional activity occurring in this region after mutation. Additional experiments showed that this mechanism is distinct from sumoylation, which seems to have only implications for the intracellular level of TAp63alpha. As a conclusion, the C-terminus of the Tap63alpha is essential for two different mechanisms, which control the transcriptional activity of the protein. Both regulatory elements are independent from each other and can now be restricted to certain amino acids. Activation of the wild type protein might take place in the identified region via post-translational modification. Furthermore an inhibition assay was carried out to test if the same region might have implications on the second biological relevant isoform deltaNp63alpha. The results show that the same amino acids which show an impact on transcriptional activity in Tap63alpha lead to a significant change in functional behaviour of deltaNp63alpha. There is a possibility that both proteins are regulated with opposite effects via the same mechanisms, based at the C-terminus of the p63alpha-isoforms. In both cases a modification of these residues could lead to a more opened conformation of the protein with consequences on promoter binding, which can be even important for deltaNp63alpha with respect to promoter squelching. Both alpha-isoforms seem to be regulated via the C-terminus and to elucidate if that is also the case for TAp63gamma a deletion analysis was carried out. The results show that there are also amino acids within the C-terminus of TAp63gamma, which have implications on the transcriptional activity of the protein. Therefore the C-terminus seems to play a major role for regulation of diverse p63 isoforms.
- Three-dimensional structure of the Na +/H + antiporter from Methanococcus jannaschii (2009)
- Na+/H+ antiporters are ubiquitous membrane proteins involved in ion homeostasis and pH sensing. The amino acid sequence of one such antiporter, MjNhaP1, from Methanococcus jannaschii, shows a significant homology to eukaryotic sodium proton exchangers like NHE1 from Homo sapiens and SOS1 of Arabidopsis thaliana than to the well-characterized Escherichia coli NhaA or NhaB. MjNhaP1 shows activity at acidic pH unlike NhaA, which is active at basic pH. 13 transmembrane helices have been predicted to be present in NhaP1. A projection map, calculated by Cryo-EM of 2D crystals of MjNhaP1 grown at pH 4, showed it to be a dimer containing elongated densities in the centre of the dimer and a cluster of density peaks on either side of the dimer core (Vinothkumar et al., 2005). Incubation of 2D crystals at pH 8 on the EM grid resulted in well-defined conformational changes, clearly evident in a difference map as a major change in density distribution within the helix bundle (Vinothkumar et al., 2005). The aim of this dissertation is to understand the working mechanism of MjNhaP1 by determining its three-dimensional structure. The aim was initially approached by structure determination by X-ray crystallography. The limitation for this method was the low expression yield, which was 0.5–0.7mg/ml (Vinothkumar et al., 2005). After various optimization trials, the expression yield of the recombinant protein could be elevated to 2-2.5mg of pure protein per litre of culture by the method of autoinduction (Studier et al., 2005). To obtain well diffracting 3D crystals, purification conditions (Vinothkumar et al., 2005) were modified. 3D crystals were obtained under various conditions, which has so far not diffracted X-Ray beyond 8Å. Parallely, optimization of parameters (Vinothkumar et al., 2005) for 2D crystals formation was carried out. A combination of 1% DDM used for lipid solubilization, and 1% OG in the buffer of the purified protein produced 1-2 μm wide tubular 2D crystals of NhaP1. This batch of crystal proved to be the optimal for data collection at higher tilt angle with the electron microscope. A 3D map showed p22121 symmetry and revealed a tight dimer with an oval shape. The region in the central part of the dimer is composed of several tilted helices forming an interface between both monomers. On either side of the dimer interface, a group of six tightly packed helices form a bundle. This bundle contains three straight helices in the centre of the monomer and three helices in the periphery. Comparison of the structures of E.coli NhaA and M. jannaschii NhaP1 show substantial differences in length and slope of corresponding helices between both antiporters. A 3D model of NhaP1 based on the 3D map revealed 13 helices, which has been named as A-M to distinguish it from the NhaA helices. Overlaying the X-ray structure onto the 3D map revealed that the disrupted helices IV and XI of NhaA superimpose two central helices at similar position in the 3D map of NhaP1. The disrupted helices IV and XI in the X-ray structure of NhaA have been proposed as the putative ion-binding and translocation site (Hunte C et al, 2005; Arkin IT et al, 2007; Screpanti & Hunte (2007). This motif appears to be present also in NhaP1, as suggested by the close fit of NhaA helices IV and XI on the putative helices E and L of the NhaP1 model. These two putative helices E and L in NhaP1 contain the highly conserved TDP and GPRVVP motif, which are crucial for antiporter activity (Hellmer et al., 2002, Hellmer et al., 2003). In the overlay, helix V of NhaA containing the two essential, conserved aspartates D163 and D164 fits the density of the putative helix F of NhaP1, which contains the conserved motif FNDP. The homologous D161 in the FNDP motif of NhaP1 is essential for transport activity as show by mutagenesis (Hellmer at al., 2003). Significant differences are visible in the region of the dimer interface of the 3D map of NhaP1 occupied by helices VI, VII, and VIII in NhaA. This region shows an extra helical density (A) in the 3D map of NhaP1. By alignment of MjNhaP1 sequence with the amino acid sequences of several Na+/H+ exchangers, it was evident that the additional helix (A) is located in the N terminus of NhaP1. In our sequence alignment, a putative hydrophobic segment corresponding to this additional helix A is present in other archaeal and eukaryotic antiporters but not in any of the bacterial ones. The N-terminus of the human Na+/H+ exchanger NHE1 has been predicted to contain a highly hydrophobic signal peptide. This indicates the probability of the N-terminal helix A of NhaP1 to be an uncleaved signal peptide. Besides being a signal sequence targeting NhaP1 to the membrane, the map suggests that this helix might be involved in the formation of dimer contacts between both monomers. A gene duplication event is evident in the 3D map of NhaP1, as not only the helices D, E, F and K, L, M are related by an inverted repeat but also the helices B, C and I, J are related. We present here the three-dimensional architecture of a Na+/H+ antiporter from archaea. The presence of the 13th helix suggests the location of the N-terminus to be located in the cytosol and the C-terminus in the periplasm. This would orient NhaP1 in an inverted manner in the membrane in comparison to NhaA. Further structural information at higher resolution and biochemical and biophysical investigations are required to confirm the topology.
- Cell migration and organization (2009)
- Information sent to and received by cells is essential for a homeostatic development of tissues and organs. These same signals are responsible for the good functioning of lymphatic organs and therefore govern the immune response. Dysfunctioning of the signaling networks is related to pathological situations, among which one can find cancer and auto-immune diseases. Intercellular communication involves the synthesis and the adjustment of signals by the secreting/emitting cell in order to reach the needed threshold. Diffusion of the signal to the target cell in addition to its interpretation lead to functional changes like cell migration and aggregation. Individual cells such as bacteria find food or increase their virulence through taxis (directional stimulus) and/or kinesis (speed stimulus). Immune cells appear to use the same processes to find bacteria and cellular debris, as well as to perform the cellular dance observed in germinal centers. This behavior is a result of an up or down regulation of specific signals that suggest to B and T-cells the paths to follow. Furthermore, cell segregation in the white pulp of the spleen, was also shown to be a result of a tight adjustment of T-cell kinesis. Restriction to cellular tracks and other experimentally provided measurements does not ensure a full comprehension of the observed cellular behavior. Thus, the study of patterns opens new gates to our understanding of the immune system. With the help of the agent-based modeling technique, cellular migration and aggregation are investigated in response to various cell-cell interactions. This work aims to explore different mechanisms that lead to cellular migration and aggregation, by defining the emergent properties of interest and that will help distinguish between interactions, starting by a simple look at the emergent patterns, followed by an analysis of their size, their degree of aggregation and the effective communication distances. Finally, the results obtained from the in silico experiments provided a guideline to differentiate between many cell-cell interactions under specific circumstances. Chemotaxis and phototaxis with and without diffusive cellular motion were shown to be distinguishable through an analysis of the emerging aggregation profiles.


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Oxford Solid Mechanics is an initiative to promote
interaction between researchers in Mathematics, Materials
Science, Engineering and Physics in the University of Oxford
who work on the mechanics of solids across the full range of
spatial and temporal scales. This website collects together information
about people and events in Oxford that are of interest
to the Oxford Solid Mechanics community.
If you would like to get involved please send us an
This workshop is being held 2-4 June 2014 in Cesme-Izmir, Turkey, and is being organised
and attended by members of Oxford Solid Mechanics. For further information, see the
Events page.


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While husband and Bollywood actor Saif Ali Khan is busy promoting his upcoming film, 'Humshakals' Kareena who is enjoying some free time threw a private bash for her close friends at her residence. A selfie was posted by designer and close friend of the actress Tanya Ghavri with the host of the p
14th Annual Star Screen Awards 2008 - Part 1
14th Annual Star Screen Awards 2008 ... diya mirza and amrita arora performance
amrita arora
Motherhood is a beautiful thing but motherhood before marriage can be difficult to handle in our society as it has some stigma attached with it. In Hollywood, celebs often give birth to children before marri
On day 3 of the on-going Lakme Fashion week, Karisma Kapoor walked the ramp for ace designer Vikram Phadnis. Karisma who took a break from acting after getting married is back again with a bang. Mother of two, the actress looked absolutely stunning. She maintained her fitness and she upped t


text:
When I loved myself enough, I began leaving whatever wasn't healthy. This meant people, jobs, my own beliefs and habits - anything that kept me small.
My judgement called it disloyal. Now I see it as self-loving.
Kim McMillen (via veg-pits)
(via evolve-now)
Source: yagazieemezi
He who does not understand your silence, will probably not understand your words.
Elbert Hubbard (via psychedelic-tea)
(via strange-bloom)
Source: rerylikes
(via brainfeather)
Source: cutestofthecute
My heart wants roots. My mind wants wings. I cannot bear their bickerings.
E. Y. Harburg (via wanderlunds)
(via synestheticpsych)
Source: king-atlas
(via ganjaqueen2013)
Source: aeonzool
Cobalt Blue Magic (Chalcopyrite crystals) by cobalt123 on Flickr.
(via thefirstchoice)
Source: paulaziz19
(via synestheticpsych)
Source: gifthescreen
(via crownisntsafe)
Source: wild-tropics
Page 1 of 454
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Book your room at Railway House - Apartments
Darlington serviced apartment with a fitness center
Situated in Darlington, this serviced apartment is close to Darlington Railway Centre and Museum, St Cuthbert Church, and Darlington Arena. Local attractions also include Blackwell Grange Golf Club.
Property Features
In addition to complimentary wireless Internet access, Railway House - Apartments provides dry cleaning/laundry services, free self parking, and a 24-hour front desk.
Room Amenities
Televisions come with digital channels. Guestrooms also feature kitchens, complimentary wireless Internet access, and refrigerators.Information missing or incorrect? Tell us!
At your hotel
At your hotel
Railway House - Apartments features a fitness center and dry cleaning/laundry services. High-speed wireless Internet access is complimentary. Onsite self parking is complimentary.
Railway House - Apartments is a smoke-free property.
- 24-hour front desk
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Stay connected
Available in all rooms: Free Wi-Fi
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Free self parking
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Check-in time starts at 4 PM
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Check-out time is 10 AM
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Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
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We specialize in making custom artistic cakes for any occasion. Located in the heart of San Diego in La Jolla, we offer exciting flavors and extraordinary designs. What makes us unique is that we
We are open Monday - Saturday from 10 am - 7 pm, please call ahead to schedule an appointment. Our phone is (858) 480-9790. Thank you very much!
We specialize in flavors and fillings that are savory and lightly moist.
We offer cakes for virtually any occasion!
Dear Elina,
I just wanted to take a moment to thank you sooooo much for the incredible giraffe birthday cake. It was a piece of art! Our daughter (31yrs) Was floored. :) You are amazing!!!! And the fact that it tasted as good as it looked made it even better. I cannot say enough. You are truly gifted and I will only ever use you for our special occasions in the future.
Thanks again Elina, Much success to you.
Jackie & Terry
Thanks Elina, you are super!!!
Got the cake for my friend's daughter's 4 years old birthday.
Everyone loved the look of the cake,
the chocolate mini mouse is a piece of art! The cake is super cute & beautiful!!!!!!


text:
Art Competition: Upload Art
| Gallery
Alexandra has worked at a number of major London galleries including White Cube and Marlborough Fine Art.
She combines her experience in top-class galleries with work for an arts consultant and freelance art advisory work for various property developers in London.
She has a BA degree from the University of Bristol, a Masters degree from University College, London and a GDL Law degree from BPP, London.
Alexandra Warder founded the contemporary art platform, Bosse & Baum, in 2013, with Lana Bount
Lana graduated with a BA History of Art before completing an MA in Curating the Art Museum at the Courtauld Institute of Art, London.
She has worked at several blue-chip galleries in London and organisations like Contemporary Art Society. She is currently working part-time as Research Curator at Calvert 22, UK's only non-profit organisation dedicated to supporting the cultural production of Russia and Eastern Europe.
Lana Bountakidou founded the contemporary art platform, Bosse & Baum, in 2013, with Alexandra Warder. They curate site-specific exhibitions and public art projects across a range of unusual spaces in London, supporting emergent practitioners of art.
For more information about Bosse & Baum and upcoming exhibitions please visit Bosse and Baum


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Originally written on Razzball | Last updated 10/25/14
Organizational Talent Rankings via Baseball America 2012 (18) | 2011 (15) | 2010 (26) | 2009 (25) | 2008 (11) 2012 Affiliate Records MLB: [89-73] AL West AAA: [73-71] Pacific Coast League – Salt Lake AA: [62-78] Texas League — Arkansas A+: [66-74] California League – Inland Empire A: [53-86] Midwest League – Cedar Rapids (Burlington beginning 2013) Arizona Fall League Players — Scottsdale Scorpions Buddy Boshers (LHP); Bobby Cassevah (RHP); Ryan Chaffee (RHP); Carlos Ramirez (C); Caleb Cowart (3B); Slade Heathcott (OF); Travis Witherspoon (OF) Graduated Prospects Mike Trout (OF); Jean Segura (SS); Garret Richards (RHP) The Run Down Of the Angels' top four prospects a year ago, zero remain. Mike Trout and Garret Richards are now with the big club, and Jean Segura and Johnny Hellweg were traded to Milwaukee. This system is in poor shape heading into the 2013 season -- Kaleb Cowart represents the only high-impact talent, and the farm is not deep with upside guys. Frankly, th...
Original Story: http://razzball.com/2013-minor-league...
PLAYERS: Ryan Chaffee, Carlos Ramirez, Travis Witherspoon, Mike Trout, Jean Segura, Kaleb Cowart
TEAMS: Los Angeles Angels, Milwaukee Brewers
TEAMS: Los Angeles Angels, Milwaukee Brewers
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text:
2014 Fed 100
Name: Naomi Lefkovitz
Title: Senior Privacy Policy Adviser, National Institute of Standards and Technology
Agency: Department of Commerce
Privacy advocate. Lefkovitz is quiet, but when she speaks, people pay attention. An expert in privacy and identity management, she expanded her role in 2013 to serve as the privacy lead for the National Strategy for Trusted Identities in Cyberspace. Identity management initiatives in the public and private sectors face the challenge of safeguarding individuals' privacy when creating directories and databases that link personal information to credentials. Lefkovitz made sure that NSTIC and its steering committees kept privacy at the heart of all their efforts -- and that the resulting standards could actually make the credential exchange work.
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Nominations are now open for the 2015 Federal 100 awards. Get the details and submit your picks!
Make a nomination today
A key contributor to Clinger-Cohen argues that federal IT has failed to take advantage of the tools that law provided.
A new report surveys the many different approaches to launching a dedicated innovation shop in government.
Nominations for 2015 are being accepted now through Dec. 23.
The flip side of default data encryption on mobile devices is that a lost or stolen device won't yield up its secrets -- an important feature for many federal employees.
A decade after the 9/11 Commission identified agencies' reluctance to share information as a dangerous shortcoming, the government is moving in the right direction.
The latest offering is intended to help agencies speed the process of deploying authorized cloud solutions.
Cartoonist John Klossner on the telltale indicators that not everything is running through the CIO.
SBA's innovation office invests in solutions to problems that don't yet exist – like the 2007 seed funding for research into an effective Ebola treatment.
The government-wide IT contract's final awards were put off a month as NASA waded through 233 proposals.
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text:
Photographers' Blog
On further reflection
Back on the subject of successful uses of reflection taken from the everyday pictures file I offer these images, the result of a by no means exhaustive trawl through our online archive.
This image by Jean-Paul Pelissier shows the car of Formula One driver Fernando Alonso in the pit lane reflected in a fireman's visor. It is not until you have looked at this picture for a few moments that you remember that there is somebody behind the visor looking back us.
Still on Formula One drivers, Claro Cortes IV's picture of Lewis Hamilton requires a second look to fully understand what is happening. Almost symetrical but not quite, the white line reinforces a first impression that this is some sort of technical malfunction which has given us two halves of consecutive frames.
Eddie Keogh's interesting action shot from this year's Wimbledon of Marat Safin reflected in a window looks like motion blur but is just a result of imperfection in the glass.
One of my favourites referred to in a previous blog is this image by Dylan Martinez of Filippo Inzhagi after his team won the Champions League final. Of course he's kissing the cup but the way Dylan sees it makes it hard to tell whether the real object of Inzaghi's affections is the trophy or the image of himself.
A real masterpiece is getting a hi res reflection from someone' eyes.
Very difficult to do – but very haunting
Superb images – Champions League one is very stiking.


text:
Roychowdhury, Raju (2010) Select Topics in Quantum Gravity : A Maiden Voyage. [Tesi di dottorato] (Unpublished)
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|Tesi di dottorato
|Uncontrolled Keywords:
|Black Holes, Attractors, Special Geometry, Gravitino Propagator.
|Date Deposited:
|08 Dec 2010 12:41
|Last Modified:
|30 Apr 2014 19:43
We study selected aspects of Theoretical Physics confronting some key issues related to the fundamental interactions along the line of Black Holes (BHs) and Attractors and its thread may be found in the concepts of Supersymmetry, Supergravity and Holography which encompass all of String theory and Quantum gravity. Then we also had an encounter with maximally symmetric spaces in General Relativity such as de Sitter and we did some significant computation in this backdrop which is tempting to pursue keeping in mind the recent observational data in favor of inflationary picture of the Universe.
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Posts by Alistair Wall
51 posts • joined 23 Oct 2007
Boffins pump hot, vivid fluid into squidgy robostarfish
Re: Hat
To hide the results of a previous experiment with squishy robot cephalopods.
Molesworth and the New Latin
Re: Anyway
While I was looking that up, I found a bit I hadn't read before:
"... neither the author(s) nor Apress shall have any liability to any person or entity with respect to any loss or damage caused or alleged to be caused directly or indirectly by the information contained in this work."
What's in the box, Windows sysadmin?
Yes - use Powershell.
Word and Excel creator: How Gates, Jobs and HAL shaped Office
"today, people confuse the homonyms"
"Simonyi was a programming protege "
Steve Jobs had 'personal moral failures', was no role model
Proverbs 29:18
is in the Old Testament.
Irish woman doesn't go down after scrotum ripping assault
These things come in threes
Also, why did it take four years to come to trial?
It's in the book - page 50.
Apple shares drop after Jobs resignation
new CEO
Bill Gates has a lot of time on his hands nowadays.
Brit men descend from mammoth hunters, not farmers
It is not just British men who are descended from mammoth hunters. Any women who have fathers will also have a male line of ancestry from this source.
Latest Hubble Snaptastic goodness: Centaurus A
The scaled photo shows 8000 light years square, and the dimensions are 1000x1000 pixels, so each pixel covers an area of about 10^23 Wales.
Entire London 2012 Olympics' cultural events database held on Excel
experience of managing a large and complex database
and no mention of backup and recovery.
Brit expats aghast as Denmark bans Marmite
Excess vitamins
Excess water-soluble vitamins are excreted. Vitamins A and D accumulate in the liver, which is why you can get vitamin A poisoning from eating polar bear liver.
BOFH: Attack of the Global Corporate Overlords
how long's the PFY ...
Anyone twentyfive years younger than you is a child and always will be.
Fired-up eco-boffin gives it '180 per cent'
O level arithmetic (1973)
180% is 70 percentage points more than 110%, but only 64% more.
Moderate boozing good for your heart: Official
We should do this for the next G20 summit
or perhaps not.
Hansard to pulp paper processes
"The spokesperson said the system is complicated, as each parliamentary question has a unique identity number and the answer has to be linked to this."
Foreign keys are complicated?
Paris Hilton meets bikers, opens up... wallet
Is this a new Reg unit?
Buyer's Guide: all-in-one inkjet printers
Linux drivers
How can you do a review of printers without saying whether they work in Linux?
Daily Mail breaks iPhone 4 recall scoop
not just the mail
Copyright wally of the week
fair use
The copyright notice on the Wind-Watch website does say "This site contains copyrighted material, the use of which has not always been specifically authorized by the copyright owner. ", followed by the EFF fair use policy.
Tom Stacy's proposal would fit a careful reading of this policy.
Utah Attorney General tweets execution go-ahead
given a death penalty it's probably pretty obvious
The lawyers have argued that a case of meningitis at the age of four may have caused Gardner considerable brain damage, debilitating his capacity for empathy and impulse control. He was also sexually abused, used drugs between the ages of six and 11 and had a troubled childhood, with two parents who were both alcoholics and physically abusive.
Boffins snare swollen 'excited giant' in forcefield prison
a "ponderomotive force" field
Named after the wizard Ponder Stibbins.
Austrian takes pickaxe to Street View spymobile
Kangaroos in Austria
Secret documents: The Truth about MoD's UFO files
Dr David Clarke of Sheffield Hallam
distinguishes him from Dr David Clarke of Glasgow, and from a bunch of Americans.
BOFH: The PFY Chronicles
spoiler alert
May I be the first to ask whether the BOFH really dead, or whether the PFY has persuaded his LUG to stage a fake funeral while the BOFH is on his annual pilgrimage?
Gas mask bra secures Ig Nobel prize
This, Chris Packham (http://www.theregister.co.uk/2009/09/22/panda_death/) is why we need to save the giant panda.
Cosmic flashbulb effect caused by 'black-hole invaders'
ccentripetal force battling with the hole's pull?
The centripetal force IS the hole's pull
Cats mix baby 'cry' with purr to score dinner
Call youself a sub?
Didn't Death say "CATS. CATS ARE NICE".
@Andrew Culpeck
PG Wodehouse: Cats as a class, have never completely got over the snootiness caused by that fact that in Ancient Egypt they were worshipped as gods.
It's from one of the Mulliner stories.
Orange UK exiles Firefox from call centres
Plug in
Aren't there any plugins for IE to emulate Firefox?
Rogue Atlantis knob removed by hand
@Doug Glass
Bloke uses nail clippers to go roundhead
He is demonstrating his genetic fitness by his ability to endure pain and recover from injury - nowadays, drinking a lot of beer is not enough to set him apart from the competition.
The girls will be queuing up when he comes out of hospital.
German old timers torture financial adviser
@Andy Barber
In German, these are very different: Rufen Sie Polizei/Rufen Sie Grundsatz, so the advisor must have been writing in French, Italian or English, where the captors might have missed a message that was subtle enough for the Swiss bank to miss it.
We need a zimmer frame icon.
OpenOfficers pitch Oracle on life after Sun
Collaboration Suite
has been replaced with Beehive. I thought you would know that.
Worm burrows into Church of England email system
c) Call the Microsoft helpdesk - Science 0, Medieval superstitious bullshit 1
Secret emails reveal sexing-up of Iraq dossier
The joke was about a claim that Hussein had assembled experts for his nuclear programme.
Google's MapReduce suddenly not so backward
select min(id) keep (dense rank first order by ((x-p_x)*(x-p_x) + (y-p_y)*(y-p_y) + (z-p_z)*(z-p_z)) ) from points
(Oracle syntax)
Bear prints found on Georgian cyber-attacks
Nino Doijashvili is probably an ex-patriat rather than an ex-patriot.
Obama bloats Vista by 11MB
This affects Linux as well - I have just tested it on OpenOffice/PCLinuxOS.
Al-Qaeda targets net-connected coffee machine
not the first
It is not the first networked coffee maker: http://www.ddj.com/architect/184409827
American auto dealer offers free handguns
@Chad H
Jean de Menezes did not skip paying for the tube.
30 years of Spam - and we ain't finished yet
11% of people?
If 20% of the population is online (1.3 billion/6.5 billion) and 11% of people admit to buying from spam, then more than 50% of internet users buy from spam. This seems rather high.
It is more likely that the universe of Sophos' survey was not "people".
McAfee 'Hacker Safe' cert sheds more cred
screen readers
The alt text says alt="HACKER SAFE certified sites prevent over 99.9% of hacker crime." even if the image is not displayed (eg http://www.haworthpressinc.com/default.asp).
Does this mean that blind users will be told that the site has passed the test when it hasn't?
Bolluxed router configuration? Click here for help
@ Ash
flashback table "Users" to before drop;
or if you are using a cheapo version of Oracle,
create table "Users" as select * from "Users" as of timestamp (systimestamp-1/24);
Quake rocks Britain
Global Warming
It was due to global warming - the north of Britain is still bouncing back after the weight of ice pushed it down in the last ice age.
English language succumbs to Symbiotic Ephemeralization
Be fair
According to the revision history, it is only a draft.
Daring Register raid snatches key government URL
Plan B
I thought perhaps they mistyped http://www.ictmarketingstrategy.gov.uk/, but that domain is free as well.
VMware clobbers the world, while big, solid disks rise
BOFH: Friday madness
The solution
Ensure all the clocks in the office are synchronised to UTC, then install your own time server.
Security minister defends ID cards, longer detention
Did he actually say "giga-terror" , "giga/tera" or "giga ... tera"?
Most read
- Crawling from the Wreckage Want a more fuel efficient car? Then redesign it – here's how
- Human spaceships dodge ALIEN BODY skimming Mars
- Review Xperia Z3: Crikey, Sony – ANOTHER flagship phondleslab?
- Downrange Are you a gun owner? Let us in OR ELSE, say Blighty's top cops
- Origins of SEXUAL INTERCOURSE fished out of SCOTTISH LAKE


text:
11 active jobs |
Company Website
Since 1950, Volt has provided clients of all sizes with the talented people they need to be successful. Our flexible staffing services and workforce management expertise makes us the first call for many of America's most respected companies, which enables us to provide our employees with challenging, satisfying jobs in a wide range of industries and job classifications. Volt is an equal opportunity employer.
You deserve a job you love. Find yours at Volt.
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For your privacy and protection, when applying to a job online:Never give your social security number to a prospective employer, provide credit card or bank account information, or perform any sort of monetary transaction. Learn More >>
By applying to a job using CareerBuilder.com you are agreeing to comply with and be subject to the CareerBuilder.com Terms and Conditions for use of our website. To use our website, you must agree with the Terms and Conditions and both meet and comply with their provisions.
Embedded Systems Engineer
Volt has been serving some of the nation's strongest companies for over 60 years. We have a talented and upbeat staffing team focused on the quality...
Posted on
NC - Cary
Manufacturing Analyst
Volt is currently seeking a Manufacturing Analyst. 1) Help establish, manage all necessary hardware and software systems to properly record, collect,...
Posted on
NC - Morganton
Document Reviewer/SOP Editor
Volt Workforce Solutions offers full-service staffing and talent management consulting to help local, regional, national, and international companies...
NC - Durham
Staffing Business Development Manager
Volt Workforce Solutions is a Fortune 1000 Staffing Industry Leader with operations throughout four continents. As we expand our footprint nationally...
NC - Charlotte
IT Engineering Assistant (Manufacturing) - Fortune 500!
We are looking to add an IT Engineering Assistant to our Fortune 500 organization! Could YOU be that person? This is a rewarding career opportunity...
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NC - Wilmington
INVENTORY CLERKS NEEDED FOR ONE DAY ASSIGNMENT!!! Volt Workforce Solutions is currently recruiting Inventory Clerks for one of our customers located...
NC - Raleigh
Operations Reporting Specialist
This position is responsible for the processing of external data received in various formats and other operational tasks associated with required...
Sr. Business Development Manager (Remote)
The Senior Business Development Manager (SBDM) is responsible for the aggressive pursuit and sales of Strategic and Key Accounts, while communicating...
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Sr. Systems/Wintel Engineer
Carry out high to complex level tasks in administration of customer systems as assigned by team leader or manager. Provide leadership in the...
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Documentation Assistant
Volt has been a leader in the Staffing Industry for 60 years and currently has more than 350 branches nationwide to serve both our clients' and...
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Accounts Receivable Specialist
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text:
Taken with Instagram
Me with Joel David Moore, Steven Schub, and the Catfish. These guys are playing the Ramones in the upcoming CBGB's film with Alan Rickman. (Taken with Instagram)
Sidewalk chalk (Taken with Instagram)
I love being in character (Taken with Instagram)
Sarah and Janet take me to the beach #2 (Taken with Instagram)
Me as Father Seamus in the movie "The Firstling" (Taken with Instagram)
Janet and Sarah take me to the beach #1 (Taken with Instagram)
No matter where we come from or how rough a start we are given…we learn by living, loving, losing, trying, failing, fighting, flailing, repeating, regretting, reconciling, and then moving on to the next tragedy, tribulation, or triumph. If you try you might fail…but if you don't try you are guaranteed to. Those who hide behind the excuses that society will readily provide them and play the martyr need to remember something…YOU CAN NOT BE A MARTYR IF YOU NAILED YOURSELF TO THE DAMN CROSS.
Shane Gray's New and improved IMDB Page
The IMDB page of Actor/stand-up comedian/writer Shane Gray. Now including more photos, a full resume, film footage including the death scene from Abraham Lincoln Vs Zombies. Please check me out and hit the like button on my page (well if you like it that is.)


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Questo esercizio e un discreto riscaldamento o un fine-serie.? Per non sentire dolore basta NON forzare il collo, concentrandosi bene non sul risutato di voler toccare il piede, ma di muovere i muscoli giusti. Pu essere che all'inizio non arrivi al piede, quel che conta non e quello, ma stimolare il muscolo in modo che si "sfilacci" e venga irrobustito. Toccare il piede e un target approssimativo.
What is the direction of tornadoes, and their movements?.
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text:
- Includes FREE MP3 version of this album Here's how (restrictions apply)
- An Amazon.com Best of 2005 selection.
Product Details
Would you like to update product info or give feedback on images?.
|Disc: 1
|1. In Your Honor
|2. No Way Back
|3. Best of You
|5. Hell
|6. The Last Song
|7. Free Me
|8. Resolve
|9. The Deepest Blues Are Black
|10. End Over End
|Disc: 2
|1. Still
|2. What If I Do?
|3. Miracle
|4. Another Round
|5. Friend of a Friend
|6. Over and Out
|7. On the Mend
|8. Virginia Moon
|9. Cold Day in the Sun
|10. Razor
|From this Discussion
|Copy protection
Is this CD stilll copy-protected? I can't tell by looking at the reviews...even the recent ones suggest buying the vinyl edition if you want to avoid the bother of copy-protection.
Also, supposedly high end CD players can't play copy protected CDs either. And I don't have a stand-alone CD... Read More
Aug 6, 2013 by Jonathan Cardwell | See all 3 posts
|Want to burn this to your I-Pod???
|Be the first to reply


text:
Majority Whip Kevin McCarthy will replace Eric Cantor as House Majority Leader after a vote Thursday by House Republicans.
David Brat, a conservative economics professor, shocked the political world Tuesday night when he ousted House Majority Leader Eric Cantor in a GOP primary.
Vincent Parker, a 16-year-old honor student with no prior history of violence, plead guilty to killing his parents last year after they tried to make him do chores and took away his iPod when he misbehaved.
Watch what happens when a Bitcoin ATM shows up on Capitol Hill.
The Black Friday madness began Thursday evening.
Gus Deeds reportedly stabbed his father, State Senator Creigh Deeds from Virginia before shooting and killing himself.
The stabbing death of the high school football player shocked peers and parents in Prince William County, Virginia. Six people are charged in connection with the murder.
The college are warning students "out of an abundance of caution."
Johnny Pimentel, a 42-year-old Peruvian national, was sentenced to up to seven years in prison for slashing the asses of nine women in Virginia malls.
The Democrat from Virginia is being investigated for his relationship with a 17 year old girl.
The FBI are not giving up hope of finding missing teen Alexis Murphy alive.
Claiming that his interest is in protecting children, Virginia Attorney General Ken Cuccinelli is looking to ban the sex acts as he mounts a campaign for the governorship.
A woman handing out free pizza was shot and killed by Loudoun County Sheriff's deputies at a Costco store in Sterling, Virginia. One of the deputies was also wounded in the incident.
Four men have been charged with hazing after two Virginia State University freshman were swept away while trying to cross a river as part of an initiation rite.
Two women were shot and police have a suspect in custody.


text:
Interesting People
mailing list archives
From: Brett Glass [brett () lariat net]
Sent: Friday, August 01, 2008 3:48 PM
To: David Farber; ip
Subject: Re: [IP] FCC rules Comcast violated Internet access policy - NYTimes.com
The scary part of this is that the FCC did not just bypass its own
rulemaking process and take action that was against the law (as was
noted by Commissioner McDowell in his excellent and well supported
dissent; see
for the full text). It also made incorrect statements about the
ruling and about the proceeding in an attempt to justify its rash
action. For example, FCC Chairman Kevin Martin's public statement
regarding the ruling said, "The specific practice Comcast was
engaging in has been roundly criticized and not defended by a
single other broadband provider."
Did he somehow not hear my Stanford testimony -- which I delivered
while looking him in the eye after spending about $1,000 on a last
minute trip to the west coast?
At that meeting, I did defend and explain the reasons for Comcast's
network management practices and for P2P mitigation in general; see
my testimony at http://www.brettglass.com/FCC/remarks.html. I
furthermore defended it in my filings with the FCC at
And in the record, at the recent hearing in Philadelphia, AT&T
likewise said that it prohibits P2P traffic on its wireless
networks by contract.
We can only hope that the arbitrary, capricious, and illegal action
taken by the FCC today will be promptly overturned.
--Brett Glass
Archives: https://www.listbox.com/member/archive/247/=now
RSS Feed: https://www.listbox.com/member/archive/rss/247/
Powered by Listbox: http://www.listbox.com
By Date
By Thread


text:
The Strathspey Server
Your resource for Scottish country dance and music
Message 17951
· 16 Jul 1999 22:05:07
· Fixed-width font
· Whole thread
Ron enquired;
> Have any studies been done on the effects of learning Scottish Country
> Dancing at a young age?
One of our members who was a schoolteacher who started a children's
class at school found that there were some very real benefits.
She was lead into a false sense of security the first year as she
worked with a group of fairly high achievers.
The second year she had some problem children in the class, and
everything was a lot more difficult. However as the year progressed
the discipline and group skills of SCD produced an effect outside
the dance floor, and there was a noticable improvement in their
behaviour. She noticed this effect with other groups in subsequent
But why should this effect be limited to school children - my
spouse-in-law takes a group of adults with learning difficulties,
and they seem to benefit from the same enforced teamwork, (even
if the musician has to add on a couple of bars to enable them to
get back to place!).
Many companies spend large sums of money sending their employees
on courses to develop their teamwork skills - I often wonder whether
everyone would benefit if they just sent them along to the local
SCD class.
_ _
|_|_ |_| Malcolm & Helen Brown - York (UK) - email@example.com (Tir-Nan-Og)
_ |_|_
|_| _|_| Connecting via NETCOM Internet Ltd


text:
Image courtesy NASA/JPL
A computer model of Saturn's C ring shows the circular gap apparently created as the moon Titan's gravity tugs at ring particles, creating "tsunamis." Illustration courtesy NASA/JPL/Cornell.
Published October 6, 2010
The gravitational pull of Saturn's largest moon, Titan, causes giant, circling "tsunamis" of icy particles in one of the planet's rings, new data suggest. The discovery may solve the 30-year-old mystery of a gap in Saturn's faint, inner C ring.
NASA's Voyager 1 probe—observing Saturn's rings from a single, shallow angle—first recorded a rippling region within the C ring during a November 1980 flyby.
The otherwise regular ripple was interrupted by a gap that seemed to be almost 9.3 miles (15 kilometers) wide, based on radio data. Complicating the matter, later pictures of the C ring showed no large gap.
Now scientists working with NASA's Cassini orbiter have confirmed the gap exists.
Because the ripples and gaps are generally too subtle to discern in Cassini images, the researchers observed the gap largely indirectly, via light shining through the opening as stars passed behind the ring.
"A reasonable analogy is a person walking behind a picket fence and shining a flashlight through," astronomer Phil Nicholson of Cornell University said Monday. "Light from bright stars drifting behind the rings gets blocked by denser regions of particles but passes through the gaps."
The recent Cassini observations taken from several different angles show the opening to be much narrower than previously thought—a mere third of a mile (half a kilometer) wide. Voyager's slantwise perspective, it turns out, had resulted in the gap seeming much wider than it is, Nicholson said during a briefing at a meeting of the American Astronomical Society's Division of Planetary Sciences in Pasadena, California.
What's more, in about half of Cassini's readings the gap becomes a peak, as if something were blocking the view—"like a gap in the fence had been turned into a fence post," Nicholson said.
The new starlight data suggest that, at some angles, spiraling walls of icy particles on either side of the gap line up so that they block the gap from view, he said.
Based on the Cassini data, he added, each peak seems to be "like a tsunami propagating away from an earthquake fault," he said. "If you were standing next to this tsunami, it'd be pretty big"—with each peak just under a mile (1.6 kilometers tall)—"but it's moving pretty slowly, about 250 meters [820 feet] a day."
(See Saturn pictures.)
Titan-Tsunami Connection
Several known gaps elsewhere in Saturn's rings can be explained by tiny moons that orbit inside the rings, carving paths through the particles. But some gaps, like this one in the C ring, are associated with no known moons, making the gaps' origins a mystery. (Related: "'Pinball' Collisions Seen in Saturn Ring.")
As it turns out, the tsunamis' rotations matched the orbital rate of Titan, the researchers realized—circling Saturn once every 16 days. Because of that correlation, the scientists suspect the peaks are results of the C ring's gravitational relationship with the moon.
As Titan orbits Saturn, its gravity likely yanks the section of ring particles that are in resonance with the moon—or moving at the same speed as Titan's gravitational field, explained Larry Esposito, an astronomer at the University of Colorado at Boulder who was not involved in the new research.
"For decades people have said these resonances can [also] open gaps" in Saturn's rings, Esposito said. "This data confirms those predictions."
(Related: "Saturn's Rings as Old as Solar System, Study Says.")
Saturn Tsunami Shines
Although the tsunami feature is normally too small to see in Cassini's pictures, the craft saw it directly for the first time during Saturn's equinox, when the sun's rays hit the rings edge-on, Cornell's Nicholson added. The low angle of sunlight caused the tilted wall to shine like a bright arc in the otherwise dark ring.
(Find out how Saturn's equinox has helped astronomers find new moons, how it made Saturn temporarily "lose" its rings, and more.)
"Think of the sun illuminating gently undulating topography on Earth right after sunrise or just before sunset," he said. "On average there's not much illumination ... but a slope [facing the sun] can look quite bright."
In general, Nicholson said, the new find adds to evidence that Saturn's disk of rings is actually less two-dimensional than once believed.
According to the University of Colorado's Esposito, the finding may not have any major implications for studies of Saturn's rings, but there's no denying "it's an intriguing case."
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About Love Food
Love Food, the cookbook brand from Parragon Books, is dedicated to providing simple, delicious recipes for the home cook.
Links to Our Tumblrs
Meat-Free Monday: Vegetable Toad in the Hole
From Love Food book: The British Pub Cookbook
Serves 4-6
100 g/31/2 oz plain flour,
pinch of salt,
2 eggs, beaten,
200 ml/7 fl oz milk,
2 tbsp wholegrain mustard,
2 tbsp vegetable oil.
25 g/1 oz butter,
2 garlic cloves, crushed,
1 onion, cut into eight wedges,
75 g/23/4 oz baby carrots, halved lengthways,
50 g/13/4 oz French beans,
50 g/13/4 oz canned sweetcorn, drained,
2 tomatoes, deseeded and cut into chunks,
1 tsp wholegrain mustard,
1 tbsp chopped fresh mixed herbs
salt and pepper
1) Preheat the oven to 200°C/400°F/Gas Mark 6. To make the batter, sift the flour and salt into a bowl. Beat in the eggs and milk to make a batter. Stir in the mustard and leave to stand.
2) Pour the oil into a shallow ovenproof dish and place in the preheated oven for 10 minutes.
3) To make the filling, melt the butter in a frying pan and sauté the garlic and onion, stirring constantly, for 2 minutes. Cook the carrots and beans in a saucepan of boiling water for 7 minutes, or until tender. Drain well.
4) Add the sweetcorn and tomatoes to the frying pan with the mustard and chopped mixed herbs. Season with salt and pepper to taste and add the carrots and beans.
5) Remove the preheated dish from the oven and pour in the batter over the hot oil. Spoon the vegetables into the centre, return to the oven and cook for 30-35 minutes, or until the batter has risen and set. Serve immediately.


text:
Welcome to the contact and details page for B & Q in Hornchurch. StoreLocate.co.uk is a store finder for the UK and provides shopping location information for UK stores. Please see below for the B & Q Hornchurch opening and closing times, the B & Q Hornchurch phone number and a local map to help you find exactly where the B & Q in Hornchurch is located.
The B & Q in Hornchurch is one of a chain of B & Q stores that can be found across the UK. We provide information on shops throughout the UK – quickly find the store details you are looking for with StoreLocate.
Address for B & Q HornchurchRoneo Corner
Hornchurch Road
Telephone: 01708 734210
B & Q in Hornchurch Store Opening Times:
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Choose a store:Aldi


text:
Definición de toughie en inglés:
toughieSilabificación: tough·ie
Pronunciación: /ˈtəfē /
1A person who is tough, determined, and not easily daunted.
Más ejemplos en oraciones
- When the going gets tough, you toughies really do get up - so make the extra effort this week to help others not fortunate enough to have been born Capricorns with some of your true grit, fortitude and soul support.
- The toughies she encountered during her teaching career knew exactly where they stood with her and respected her for it.
- College students are held in low esteem, thanks to commercial movies that regularly feature youth as toughies amid free-flowing booze, drugs, and gals.
2A difficult problem or question: Whom do you admire most? That's a toughie
Más ejemplos en oraciones
- But some students cracked real toughies, too, without batting an eyelid.
- That's a toughie, because there's no way to get around it - if they're fat-free, the cookies aren't so great, and you end up eating more.
- That's a toughie, because they sometimes want detail.
Definición de toughie en:
- el diccionario Inglés británico e internacional
Obtener más de Oxford Dictionaries
Subscribirse para eliminar anuncios y acceder a los recursos premium
Palabra del día retroflex
Pronunciación: ˈrɛtrə(ʊ)flɛks
turned backwards


text:
Someone took it, and didn't even bother to take Xanthe's name off it. If you could do me a favor, guys? Go report the shit out of them. This is ridiculous.
Just click on the title above and it'll take you straight to it.
Oh, and it's a total copy paste job. She never posted this to ff.net, which is probably why they think they can get away with this.
If you don't read Suits fic, or slash, or whatever…. Please go report them anyways.
Have fun storming the castle!
#don't even try to convince me they're not a couple #not after this #this whole episode #guh
#Arent you Louis's BOY?!? #his BOY?! #Harvey you do realise you are using words that should come out of a dom's mouth? #right?
#'please harvey you have to get me back' #this show is so ridiculous i can't
he may not be allowed to fondle the vinyl, but he can fondle other things.
#no mike #see you are getting it wrong #it's not just that you were fondling the vinyl #it's that you were spending your time fondling the vinyl when you could have been fondling him #don't you understand? #harvey doesn't allow you to choose who you fondle #that's his decision #and mike is just begging at this point #god my OTP is flawless
#if Harvey's going to bet Mike I'd rather it be like this #where they're both taking it in good humor #married
#wow harvey #did you crate him when you got him home as well #bad dog
"No more fondling the vinyl." Is it what young people call it these days?
#turn to your left now to wonder at the majestic Harveticus Specticus while he engages in the mating ritual commonly known as 'eye-sexing' with his potential mate of the rather rare Micus Rossus species
#I could tag every single suits gif with MIKE YOUR GAY IS SHOWING and it would be accurate every time #MIKE YOUR GAY IS SHOWING #See?
#patrick's hair in this promos are a constant source of amusement for me
second give reminds me of sherlock in a way!
#eh… why is PJ stroking Gabriel? the WTF face is accurate #also HAIR
#hey guys do you remember suits? #because remember suits. #sweet baby jesus new season come to me now
#soon my pretties #so soon #the day of my last exam #i can love you for all of my time
#I forget if certain scenes are parts from D/s fics I read or actually canon
I have never confused fanfiction and canon this much before.