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Board of Governors Professor of Chemistry and Chemical Biology
Research Synopsis: structural biology; single-molecule biophysics; RNA polymerases; antibacterial agents; antituberculosis agents
(848) 445-5179
laboratory webpage: https://www.waksman.rutgers.edu/ebright
Research Summary
Transcription--the synthesis of an RNA copy of genetic information in DNA--is the first step in gene expression and is the step at which most regulation of gene expression occurs. Richard H. Ebright's laboratory seeks to understand structures, mechanisms, and regulation of bacterial transcription complexes and to identify, characterize, and develop small-molecule inhibitors of bacterial transcription for application as antituberculosis agents and broad-spectrum antibacterial agents.
Structures of Transcription Complexes
Transcription initiation in bacteria requires RNA polymerase (RNAP) and the transcription initiation factor sigma. The bacterial transcription initiation complex contains six polypeptides (five in RNAP, one in sigma) and promoter DNA, and has a molecular mass of 0.5 MDa.
Understanding bacterial transcription initiation requires understanding the structures of polypeptides in bacterial transcription initiation complexes and the arrangements of these polypeptides relative to each other and relative to promoter DNA.
The Ebright lab uses x-ray crystallography to determine high-resolution structures of transcription initiation complexes, fluorescence resonance energy transfer (FRET) to define distances between pairs of site specifically incorporated fluorescent probes, photocrosslinking to define polypeptides near site-specifically incorporated photocrosslinking probes, and protein footprinting and residue scanning to define residues involved in contacts. In support of these activities, the lab develops procedures to incorporate fluorescent probes, photocrosslinking probes, and other biophysical and biochemical probes at specific sites within large multisubunit nucleoprotein complexes and develops automated docking algorithms to integrate structural, biophysical, biochemical, and genetic data in order to construct models for structures of complexes.
Crystal structure of the bacterial transcription initiation complex. (A) Summary of protein-nucleic-acid interactions. Black residue numbers and lines, interactions by RNA polymerase (RNAP); green residue numbers and lines; interactions by the transcription initiation factor σ, blue, -10 element of DNA nontemplate strand; light blue, discriminator element of DNA nontemplate strand; pink, rest of DNA nontemplate strand; red, DNA template strand; magenta, ribodinucleotide primer GpA; violet, active-center Mg2+; asterisks, water-mediated interactions; cyan boxes, bases unstacked and inserted into pockets. Residues are numbered as in E coli RNAP and σ70. (B) Overall structure (RNAP β' non conserved domain omitted for clarity). RNAP, gray; σ, yellow. Other colors as in A. (C) Interactions of RNAP and σ with the transcription-bubble nontemplate strand, the transcription bubble template strand, and downstream dsDNA (RNAP β subunit and β' non conserved domain omitted for clarity). Colors as in B.
[See Zhang, Y., Feng, Y., Chatterjee, S., Tuske, S., Ho, M., Arnold, E., and Ebright, R.H. (2012) Structural basis of transcription initiation. Science 338:1076-1080.]
Mechanism of Transcription
Transcription complexes are molecular machines that carry out complex, multistep reactions in transcription initiation and elongation:
- RNA polymerase (RNAP) binds to promoter DNA, to yield an RNAP-promoter closed complex.
- RNAP unwinds ~14 base pairs of promoter DNA surrounding the transcription start site, rendering accessible the genetic information in the template strand of DNA, and yielding an RNAP-promoter open complex.
- RNAP begins synthesis of RNA as an RNAP-promoter initial transcribing complex. During initial transcription, RNAP uses a "scrunching" mechanism, in which RNAP remains stationary on promoter DNA and unwinds and pulls downstream DNA into itself and past its active center in each nucleotide-addition cycle, resulting in generation of a stressed intermediate.
- After RNAP synthesizes an RNA product ~10-15 nucleotides in length, RNAP breaks its interactions with promoter DNA, breaks at least some of its interactions with sigma, escapes the promoter, and begins transcription elongation as a transcription elongation complex. Energy stored in the stressed intermediate generated by scrunching during initial transcription is used to drive breakage of interactions with promoter DNA and interactions with sigma during promoter escape.
During transcription elongation, RNAP uses a "stepping" mechanism, in which RNAP translocates relative to DNA in each nucleotide-addition step. Each nucleotide-addition cycle during initial transcription and transcription elongation can be subdivided into four sub-steps: (1) translocation of the RNAP active center relative to DNA (by scrunching in initial transcription; by stepping in transcription elongation); (2) binding of the incoming nucleotide; (3) formation of the phosphodiester bond; and (4) release of pyrophosphate.
Crystal structures have been reported for transcription elongation complexes without incoming nucleotides and for transcription elongation complexes with incoming nucleotides. Based on these crystal structures, it has been proposed that each nucleotide-addition cycle is coupled to an RNAP active-center conformational cycle, involving closing of the RNAP active center upon binding of the incoming nucleotide, followed by opening of the RNAP active center upon formation of the phosphodiester bond. According to this proposal, the closing and opening of the RNAP active center is mediated by the folding and the unfolding of an RNAP active-center structural element, the "trigger loop."
To understand transcription initiation, transcription elongation, and transcriptional regulation, it will be necessary to leverage the available crystallographic structural information, in order to define the structural transitions in RNAP and nucleic acid in each reaction, to define the kinetics of each reaction, and to define mechanisms of regulation of each reaction.
The Ebright lab is using FRET and photocrosslinking methods to define distances and contacts within trapped intermediates in transcription initiation and transcription elongation. In addition, the lab is using single-molecule FRET, single-molecule DNA nanomanipulation, and combined single-molecule FRET and single-molecule DNA nanomanipulation, to carry out single-molecule, millisecond-to-second timescale analysis of structural transitions.
Determination of RNAP clamp conformation in solution. (A) Measurement of single-molecule FRET between fluorescent probes incorporated at the tips of the RNAP β' pincer (clamp) and the RNAP β pincer. Open (red), partly closed (yellow), and closed (green) RNAP clamp conformational states are as observed in crystal structures. (B) Incorporation of fluorescent probes at the tips of the RNAP β' pincer (clamp) and the RNAP β pincer, by unnatural amino acid mutagenesis to incorporate 4 azidophenylalanine at sites of interest in β' and β subunits, followed by Staudinger ligation to incorporate fluorescent probes at 4 azidophenylalanines in β' and β subunits, followed by in vitro reconstitution of RNAP from labelled β' and β subunits and unlabelled α and ω subunits. (C) Relationship between single-molecule FRET efficiencies, E, and RNAP clamp conformational states. The red boxes denote the open (red), closed (green), and collapsed (blue) clamp states observed in this work for RNAP in solution.
[See Chakraborty, A., Wang, D., Ebright, Y., Korlann, Y., Kortkhonjia, E., Kim, T., Chowdhury, S., Wigneshweraraj, S., Irschik, H., Jansen, R., Nixon, B.T., Knight, J., Weiss, S., and Ebright, R. (2012) Opening and closing of the bacterial RNA polymerase clamp. Science 337, 591-595.]
Regulation of Transcription
Crystal structure of a transcriptional activator (catabolite activator protein, CAP; cyan) in complex with its target in the transcriptional machinery (RNA polymerase α-subunit C-terminal domain,αCTD; green) and DNA (red). There are no large-scale conformational changes in the activator and target, and the interface between the activator and target is small (residues highlighted in navy and yellow)—consistent with the proposal that transcriptional activation involves a simple "recruitment" mechanism.
[See Benoff, B., Yang, H., Lawson, C.L., Parkinson, G., Liu, J., Blatter, E., Ebright, Y.W., Berman, H.M., and Ebright, R.H. 2002. Science 297:1562-1566.]
The activities of bacterial transcription initiation complexes are regulated in response to environmental, cell-type, and developmental signals. In most cases, regulation is mediated by factors that bind to specific DNA sites in or near a promoter and inhibit (repressors) or stimulate (activators) one or more of the steps on the transcription initiation pathway. To provide the first complete structural and mechanistic descriptions of activation, the Ebright lab studies two of the simplest examples of activation in bacteria: (1) activation of the lac //promoter by catabolite activator protein (CAP) and (2) activation of the gal promoter by CAP. These model systems each involve only a single activator molecule and a single activator DNA site and, as such, are more tractable than typical examples of activation in bacteria and substantially more tractable than typical examples of activation in eukaryotes (which can involve tens of activator molecules and activator DNA sites).
The lab has established that activation at lac involves an interaction between CAP and the RNA polymerase (RNAP) alpha-subunit C-terminal domain that facilitates closed-complex formation. Activation at gal involves this same interaction and also interactions between CAP and the RNAP alpha-subunit N-terminal domain, and between CAP and sigma, that facilitate isomerization of closed complex to open complex.
Together with collaborators, the lab is using electron microscopy, x-ray crystallography, and NMR to determine the structures of the interfaces between CAP and its targets on RNAP. In addition, the lab is using FRET, photocrosslinking, and single-molecule FRET and single-molecule DNA nanomanipulation methods to define when each CAP-RNAP interaction is made as RNAP enters the promoter and when each interaction is broken as RNAP leaves the promoter.
Inhibitors of Transcription; Antibacterial Drug Discovery
Bacterial RNA polymerase (RNAP) is a proven target for broad-spectrum antibacterial therapy. The suitability of bacterial RNAP as a target for broad-spectrum antibacterial therapy follows from the fact that bacterial RNAP is an essential enzyme (permitting efficacy), the fact that bacterial RNAP-subunit sequences are highly conserved (providing a basis for broad-spectrum activity), and the fact that bacterial RNAP-subunit sequences are not highly conserved in human RNAPI, RNAPII, and RNAPIII (providing a basis for therapeutic selectivity). The rifamycin antibacterial agents--rifampin, rifapentine, rifabutin, and rifamixin--bind to and inhibit bacterial RNAP. The rifamycins bind to a site on bacterial RNAP adjacent to the RNAP active center and prevent extension of RNA chains beyond a length of 2–3 nucleotides. The rifamycins are in current clinical use in treatment of Gram-positive and Gram-negative bacterial infections. The rifamycins are of particular importance in treatment of tuberculosis; the rifamycins are first-line antituberculosis agents and are among the only antituberculosis agents able to clear infection and prevent relapse. The clinical utility of the rifamycin antibacterial agents is threatened by the existence of bacterial strains resistant to rifamycins. Resistance to rifamycins typically involves substitution of residues in or adjacent to the rifamycin-binding site on bacterial RNAP--i.e., substitutions that directly interfere with rifamycin binding.
In view of the public health threat posed by drug-resistant and multidrug-resistant bacterial infections, there is an urgent need for new classes of broad-spectrum antibacterial agents that (1) target bacterial RNAP (and thus have the same biochemical effects as rifamycins), but that (2) target sites within bacterial RNAP that do not overlap the rifamycin-binding site (and thus do not show cross-resistance with rifamycins).
The Ebright lab has identified new drug targets within the structure of bacterial RNAP. Each of these new targets can serve as a potential binding site for compounds that inhibit bacterial RNAP and thereby kill bacteria. Each of these new targets is present in most or all bacterial species, and thus compounds that bind to these new targets are active against a broad spectrum of bacterial species. Each of these new targets is different from targets of current antibiotics, and thus compounds that bind to these new targets are not cross-resistant with current antibiotics. For each of these new targets, the lab has identified at least one lead compound that binds to the target, and the lab has synthesized analogs of the lead compound comprising optimized lead compounds. Several of the lead compounds and optimized lead compounds are extremely promising: they exhibit potent activity against a broad spectrum of bacterial pathogens (including Staphylococcus aureus MSSA, Staphylococcus aureus MRSA, Enterococcus faecalis, Enterococcus faecium, Clostridium difficile, Mycobacterium tuberculosis, Bacillus anthracis, Francisella tularensis, Burkholderia mallei, and Burkholderia pseudomallei) and exhibit no cross-resistance with current antibiotics.
In support of this work, the lab is identifying new small-molecule inhibitors of bacterial RNAP by analysis of microbial and plant natural products, by high-throughput screening, and by virtual screening. The lab also is using genetic, biochemical, biophysical, and crystallographic approaches to define the mechanism of action of each known, and each newly identified, small-molecule inhibitor of bacterial RNAP, and the lab is using microbiological approaches to define antibacterial efficacies, resistance spectra, and spontaneous resistance frequencies of known and new small-molecule inhibitors of bacterial RNAP.
The lab seeks to address the following objectives: to develop new classes of antituberculosis agents and broad-spectrum antibacterial agents, to develop antibacterial agents effective against pathogens resistant to current antibiotics, to develop antibacterial agents effective against pathogens of high relevance to public health, and to develop antibacterial agents effective against pathogens of high relevance to biodefense.
Structural basis of transcription inhibition by myxopyronin: contacts between RNA polymerase and myxopyronin.
- Binding pocket for myxopyronin. Cyan, surface representation of the binding pocket and adjacent hydrophobic pocket. Gray, ribbon representation of RNA polymerase backbone. Green, myxopyronin carbon atoms; red, myxopyronin oxygen atoms. RNA polymerase residues are numbered both as in T thermophilus RNA polymerase and as in E. coli RNA polymerase (in parentheses).
- Contacts between RNA polymerase and myxopyronin (stereoview). Gray, RNA polymerase backbone (ribbon representation) and RNA polymerase sidechain carbon atoms (stick representation); green, myxopyronin carbon atoms; red, oxygen atoms; blue, nitrogen atoms. "W," ordered bound water molecule. Dashed lines, H-bonds.
- Schematic summary of contacts between RNA polymerase and myxopyronin. "W", ordered bound water molecule. Red dashed lines, H-bonds. Blue arcs, van der Waals interactions.
[See Mukhopadhyay, J., Das, ., Ismail, S., Koppstein, D., Jang, M., Hudson, B., Sarafianos, S., Tuske, S., Patel, J., Jansen, R., Irschik, H., Arnold, E., and Ebright, R. (2008) The RNA polymerase "switch region" is a target of inhibitors Cell 135, 295-307.]
Heyduk, T., Lee, J., Ebright, Y., Blatter, E., Zhou, Y., and Ebright, R. (1993) CAP interacts with RNA polymerase in solution in the absence of promoter DNA. Nature 364, 548-549.
Chen, Y., Ebright, Y., and Ebright, R. (1994) Identification of the target of a transcription activator protein by protein-protein photocrosslinking. Science 265, 90-92.
Pendergrast, P.S., Ebright, Y., and Ebright, R. (1994) High-specificity DNA cleavage agent: design and application to kilobase and megabase DNA substrates. Science 265, 959-961.
Blatter, E., Ross, W., Tang, H., Gourse, R., and Ebright, R. (1994) Domain organization of RNA polymerase α subunit: C-terminal 85 amino acids constitute a domain capable of dimerization and DNA binding. Cell 78, 889-896.
Busby, S. and Ebright, R. (1994) Promoter structure, promoter recognition, and transcription activation in prokaryotes. Cell 79, 743-746.
Tang, H., Sun, X., Reinberg, D., and Ebright, R. (1996) Protein-protein interactions in eukaryotic transcription initiation: structure of the pre-initiation complex. Proc. Natl. Acad. Sci. USA 93, 1119-1124.
Pellegrini, M. and Ebright, R. (1996) Artificial DNA binding peptides. J. Amer. Chem. Soc. 118, 5831-5835.
Niu, W., Kim, Y., Tau, G., Heyduk, and Ebright, R. (1996) Transcription activation at Class II CAP-dependent promoters: two interactions between CAP and RNA polymerase. Cell 87, 1123-1134.
Miller, A., Wood, D., Ebright, R., and Rothman-Denes, L. (1997) RNA polymerase β: a target for DNA-binding-independent activation. Science 275, 1655-1657.
Kim, T.-K., Lagrange, T., Reinberg, D., and Ebright, R. (1997) Trajectory of DNA in the RNA polymerase II transcription preinitiation complex Proc. Natl. Acad. Sci. USA 94, 12268-12273.
Lagrange, T., Kapanidis, A., Tang, H., Reinberg, D., and Ebright, R. (1998) New core promoter element in RNA polymerase II-dependent transcription: sequence-specific DNA binding by transcription factor IIB. Genes & Development, 12, 34-44.
Estrem, S., Ross, W., Gaal., Chen, Z.W.S., Niu, W., Ebright, R., and Gourse, R. (1999) Bacterial promoter architecture: subsite structure of UP elements and interactions with the carboxyl-terminal domain of RNA polymerase alpha subunit. Genes & Development 13, 2134-2147.
Tan, Q., Linask, K.L., Ebright, R. and Woychik, N. (2000) Activation mutants in yeast RNA polymerase subunit RPB3 provide evidence for a structurally conserved surface required for activation in eukaryotes and bacteria. Genes & Development 14, 339-348.
Kim, T.-K., Ebright, R., and Reinberg, D. (2000) Mechanism of ATP-dependent promoter melting by transcription factor IIH. Science 288, 1418-1421.
Naryshkin, N., Revyakin, A., Kim, Y., Mekler, V., and Ebright, R. (2000) Structural organization of the RNA polymerase-promoter open complex. Cell 101, 601-611.
Minakhin, L., Bhagat, S. Brunning, A., Campbell, E., Darst, S., Ebright, R. and Severinov, K. (2001) Bacterial RNA polymerase subunit omega and eukaryotic RNA polymerase subunit RPB6 are sequence, structural, and functional homologs and promote RNA polymerase assembly Proc. Natl. Acad. Sci. USA 98, 892-897.
Mukhopadhyay, J., Kapanidis, A., Mekler, V., Kortkhonjia, E., Ebright, Y., and Ebright, R. (2001) Translocation of sigma70 with RNA polymerase during transcription: fluorescence resonance energy transfer assay for movement relative to DNA. Cell 106, 453-463.
Kapanidis, A., Ebright, Y., and Ebright, R. (2001) Site-specific incorporation of fluorescent probes into protein: hexahistidine-tag-mediated fluorescent labeling using (Ni2+:nitrilotriacetic acid)n-fluorochrome conjugates. J. Amer. Chem. Soc. 123, 12123-12125.
Mekler, V., Kortkhonjia, E., Mukhopadhyay, J., Knight, J., Revyakin, A., Kapanidis, A., Niu, W., Ebright, Y., Levy, R., and Ebright, R. (2002) Structural organization of RNA polymerase holoenzyme and the RNA polymerase-promoter open complex. Cell 108, 599-614.
Benoff, B., Yang, H., Lawson, C., Parkinson, G., Liu, J., Blatter, E., Ebright, Y., Berman, H., and Ebright, R. (2002) Structural basis of transcription activation: structure of the CAP-aCTD-DNA complex. Science 297, 1562-1566.
Lloyd, G., Niu, W., Trebbutt, J., Ebright, R., and Busby, S. (2002) Requirement for two copies of RNA polymerase α subunit C-terminal domain for synergistic transcription activation at complex bacterial promoters. Genes & Development 16, 2557-2565.
Mekler, V., Kortkhonjia, E., Mukhopadhyay, J., Knight, J., Revyakin, A., Kapanidis, A., Niu, W., Ebright, Y., Levy, R., and Ebright, R. (2002) Structural organization of RNA polymerase holoenzyme and the RNA polymerase-promoter open complex. Cell 108, 599-614.
Benoff, B., Yang, H., Lawson, C., Parkinson, G., Liu, J., Blatter, E., Ebright, Y., Berman, H., and Ebright, R. (2002) Structural basis of transcription activation: structure of the CAP-αCTD-DNA complex. Science 297, 1562-1566.
Chen, H., Tang, H., and Ebright, R.H. (2003) Functional interaction between RNA polymerase a subunit C-terminal domain and δ70 in UP-element- and activator-dependent transcription. Mol. Cell 11, 1621-1623.
Bayro, M., Mukhopadhyay, J., Swapna, G.V.T., Huang, J., Ma, L.-C., Sineva, E., Dawson, P., Montelione, G., and Ebright, R. (2003) Structure of antibacterial peptide microcin J25: a 21-residue lariat protoknot. J. Amer. Chem. Soc. 125, 12382-12383.
Revyakin, A., Ebright, R., and Strick, T. (2004) Promoter unwinding and promoter clearance by RNA polymerase: Detection by single-molecule DNA nanomanipulation. Proc. Natl. Acad. Sci. USA 101, 4776-4780.
Nickels, B., Mukhopadhyay, J., Garrity, S., Ebright, R., and Hochschild, A. (2004) δ70 mediates a promoter-proximal pause at the lac promoter. Nature Structl. Mol. Biol. 11, 544-550.
Mukhopadhyay, J., Sineva, E., Knight, J., Levy, R., and Ebright, R. (2004) Antibacterial peptide microcin J25 (MccJ25) inhibits transcription by binding within and obstructing the RNA polymerase secondary channel. Mol. Cell. 14, 739-751.
Knight, J., Mekler, V., Mukhopadhyay, J., Ebright, R., Levy, R. (2005) Distance-restrained docking of rifampicin and rifamycin SV to RNA polymerase using systematic FRET measurements: developing benchmarks of model quality and reliability. Biophys J. 88, 925-938.
Revyakin, A., Ebright, R., and Strick, T. (2005) Single-molecule DNA nanomanipulation: improved resolution through use of shorter DNA fragments. Nature Meths. 2, 127-138.
Lee, N.K., Kapanidis, A., Wang, Y., Michalet, X., Mukhopadhyay, J., Ebright, R.H., and Weiss, S. (2005) Accurate FRET measurements within diffusing single biomolecules using alternating-laser excitation. Biophys. J. 88, 2939 2953.
Nickels, B. Garrity, S., Mekler, V., Minakhin, L., Severinov, K., Ebright, R.H., and Hochschild, A. (2005) Altering the interaction between δ70 and the β-flap of Escherichia coli RNA polymerase provides evidence for a barrier to the extension of the nascent RNA during early elongation. Proc. Natl. Acad. Sci USA 102, 4488 4493.
Ebright, R. and Ebright, Y. (2005) Bis-transition-metal-chelate probes. US Patent #6,919,333.
Tuske, S., Sarafianos, S., Wang, X., Hudson, B., Sineva, E., Mukhopadhyay, J., Birktoft, J, Leroy, O., Ismail, S., Clark, A., Dharia, C., Napoli, A., Laptenko, O., Lee, J., Borukhov, S., Ebright, R., and Arnold, E., (2005) Inhibition of bacterial RNA polymerase by streptolydigin: stabilization of a straight-bridge-helix active-center conformation. Cell 122, 541-552.
Vrentas, C., Gaal, T., Ross, W., Ebright, R., and Gourse, R. (2005) Response of RNA polymerase to ppGpp: requirement for the w subunit and relief of this requirement by DksA. Genes Dev. 19, 2378-2387.
Kapanidis, A., Margeat, E., Laurence, T., Doose, S., Ho, S.O., Mukhopadhyay, J., Kortkhonjia, E., Mekler, V., Ebright, R., and Weiss, S. (2005) Retention of transcription initiation factor δ70 in transcription elongation: single molecule analysis. Mol. Cell 20, 347-356.
Margeat, E., Kapanidis, A., Tinnefield, P., Wang, Y., Mukhopadhyay, J., Ebright, R., and Weiss, S. (2006) Direct observation of abortive initiation and promoter escape within immobilized single transcription complexes. Biophys. J. 20, 347-356.
Tadigotla, V., O'Maoileidigh, D., Sengupta, A., Epshtein, V., Ebright, R., Nudler, E., and Ruckenstein, A. (2006) Thermodynamic and kinetic modeling of transcriptional pausing. Proc. Natl. Acad. Sci. USA 103, 4439-4444.
Seul, M. and Ebright, R. (2006) Color-encoding and in-situ interrogation of matrix-coupled chemical compounds. US Patent #7,083,914.
Popovych, N., Sun, S., Ebright, R., and Kalodimos, C. (2006) Dynamically driven protein allostery. Nature Structl. Mol. Biol. 13, 831-838.
Revyakin, A., Liu, C., Ebright, R.H. and Strick, T. (2006) Abortive initiation and productive initiation by RNA polymerase involve DNA scrunching. Science 314, 1139-1143.
Kapanidis, A., Margeat, E., Ho, S.O., Kortkhonjia, E., Weiss, S. and Ebright, R.H. (2006) Initial transcription by RNA polymerase proceeds through a DNA-scrunching mechanism. Science 314, 1144-1147.
Ebright, R. and Ebright, Y. (2006) Reagents and procedures for high-specificity labelling. US Patent #7,141,655.
Cellai, S., Vannini, N., Naryshkin, N., Kortkhonjia, E., Ebright, R., and Rivetti, C. (2007) Upstream promoter sequences and aCTD mediate stable DNA wrapping within the RNA polymerase open promoter complex. EMBO Reports 8, 271-278.
Ebright, R. and Ebright, Y. (2007) Ultra-high-specificity fluorescent labelling. US Patent #7,282,373.
Ebright, R. and Ebright, Y. (2008) Bis-transition-metal-chelate probes. US Patent #7,371,745.
Ebright, R. and Ebright, Y. (2008) Reagents and procedures for multi-label high-specificity labelling. US Patent #7,381,572.
Severinov, K., Pavlova, O., Sineva, E., Zakeyeva, I., and Ebright, R. (2008) Mutational derivatives of peptide antibiotic microcin J25 with increased antibacterial action. US Patent #7,442,762.
Feklistov, A., Mekler, V., Jiang, Q., Westblade, L., Irschik, H., Jansen, R., Mustaev, A., Darst, S., and Ebright, R.H. (2008) Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center. Proc. Natl. Acad. Sci. USA 105, 14820-14825.
Mukhopadhyay, J., Das, K., Ismail, S., Koppstein, D., Jang, M., Hudson, B., Sarafianos, S., Tuske, S., Patel, J., Jansen, R., Irschik, H., Arnold, E., and Ebright, R. (2008) The RNA polymerase "switch region" is a target of inhibitors Cell 135, 295-307.
Pavlova, O., Mukhopadhyay, J., Sineva, E., Ebright, R., and Severinov, K. (2008) Systematic structure-activity analysis of microcin J25 (MccJ25). J. Biol. Chem. 283, 25589-25595.
Kim, Y., Ebright, Y., Goodman, A., Reinberg, D., and Ebright, R. (2008) Non-radioactive, ultrasensitive site-specific protein-protein photocrosslinking: interactions of a-helix 2 of TATA-binding protein with general transcription factor TFIIA and with transcriptional repressor NC2. Nucl. Acids Res. 36, 6143-6154.
Naryshkin, N., Druzhinin S., Revyakin, A., Kim, Y., Mekler, V., and Ebright, R. (2009) Static and kinetic site-specific protein-DNA photocrosslinking: analysis of bacterial transcription initiation complexes. Meths. Mol. Biol. 543, 403-437.
Popovych, N., Tzeng, S.-R., Tonelli, M., Ebright¬, R., and Kalodimos, C. (2009) Structural basis of cAMP-mediated allosteric control of the catabolite activator protein, Proc. Natl. Acad. Sci. USA 106, 6927-6932.
Goldman, S., Ebright, R., and Nickels, B. (2009) Direct detection of abortive RNA transcripts in vivo. Science 324, 927-928.
Hudson, B., Quispe, J., Lara, S., Kim, Y., Berman, H., Arnold, E., Ebright, R., and Lawson, C. (2009) Three-dimensional structure of an intact activator-dependent transcription initiation complex. Proc. Natl. Acad. Sci. USA 106, 19830-19835.
Ho, M., Hudson, B., Das, K., Arnold, E., and Ebright, R. (2009) Structures of RNA polymerase-antibiotic complexes. Curr. Opin. Structl. Biol. 19, 715-723.
Chakraborty, A., Wang, D., Ebright, Y., and Ebright, R. (2010) Azide-specific labelling of biomolecules by Staudinger-Bertozzi ligation: phosphine derivatives of fluorescent probes suitable for single-molecule fluorescence spectroscopy. Meths. Enzymol. 472, 19-30.
Grohmann, D., Nagy, J., Chakraborty, A., Klose, D., Fielden, D., Ebright, R., Michaelis, J., and Werner, F. (2011) The initiation factor TFE and the elongation factor Spt4/5 compete for binding to the RNAP clamp during transcription initiation and elongation. Mol. Cell 43, 263-274.
Xiao, Y., Wei, X., Ebright, R., and Wall, D. (2011) Antibiotic production by myxobacteria plays a role in predation. J. Bacteriol. 193, 4626-4633.
Kuznedelov, K., Semenova, E., Knappe, T., Mukahmedjarov, D., Srivastava, A., Chatterjee, S., Ebright, R., Marahiel, M., and Severinov, K. (2011) The antibacterial threaded-lasso peptide capistruin inhibits bacterial RNA polymerase. J. Mol. Biol. 412, 842-848.
Srivastava, A., Talaue, M., Liu, S., Degen, D., Ebright, R.Y., Sineva, E., Chakraborty, A., Druzhinin, S., Chatterjee, S., Mukhopadhyay, J., Ebright, Y., Zozula, A., Shen, J., Sengupta, S., Niedfeldt, R., Xin, C., Kaneko, T., Irschik, H., Jansen, R., Donadio, S., Connell, N., and Ebright, R. (2011) New target for inhibition of bacterial RNA polymerase: "switch region." Curr. Opin. Microbiol. 14, 532-543.
Ebright, R. Switch region: target and method for inhibition of bacterial RNA polymerase. US Patent #8,114,583.
Ebright, R. (2012) Target and method for inhibition of bacterial RNA polymerase. US Patent #8,198,021.
Ebright, R. (2012) RNA exit channel: target and method for inhibition of bacterial RNA polymerase. US Patent #8,206,898.
Chakraborty, A., Wang, D., Ebright, Y., Korlann, Y., Kortkhonjia, E., Kim, T., Chowdhury, S., Wigneshweraraj, S., Irschik, H., Jansen, R., Nixon, B.T., Knight, J., Weiss, S., and Ebright, R. (2012) Opening and closing of the bacterial RNA polymerase clamp. Science 337, 591-595.
Srivastava, A., Degen, D., Ebright, Y., and Ebright, R. (2012) Frequency, spectrum, and nonzero fitness costs of resistance to myxopyronin in Staphylococcus aureus. Antimicrob. Agents Chemother. 56, 6250-6255.
Zhang, Y., Feng, Y., Chatterjee, S., Tuske, S., Ho, M., Arnold, E., and Ebright, R. (2012) Structural basis of transcription initiation. Science 338, 1076-1080.
Seul, M. and Ebright, R. (2013) Color-encoding and in-situ interrogation of matrix-coupled chemical compounds. Canadian Patent CA2291853.
Ebright, R., Mukhopadhyay, J., Severinov, K., and Semenova, E. (2013) Non-MccJ25-related lariat-peptide inhibitors of bacterial RNA polymerase. US Patent US8354246.
Ebright, R. and Wang, D. (2013) Bipartite inhibitors of bacterial RNA polymerase. US Patent 8372839.
Robb, N., Cordes, T., Hwang, L., Gryte, K., Duchi, D., Craggs, T., Santoso, Y., Weiss, S., Ebright, R., and Kapanidis, A. (2013) The transcription bubble of the RNA polymerase-promoter open complex exhibits conformational heterogeneity and millisecond-scale dynamics: implications for transcription start-site selection. J. Mol. Biol. 425, 875–885.
Ebright, R. and Severinov, K., (2013) Nucleic acid sequences for biosynthesis of non-MccJ25-related lariat peptides. US Patent 8461314.
Ebright, R. (2013) Target and method for inhibition of bacterial RNA polymerase. US Patent 8575306.
Vorobiev, S., Kramer, Y., Vahedian-Movahed, H., Seetharaman, J., Sua, M., Huang., J., Xiao, R., Kornhaber, G., Montelione, G., Tong, L., Ebright, R., and Nickels, B. (2014) Structure of the DNA binding and RNA polymerase binding region of transcription antitermination factor Q. Structure 22, 488 495.
Ebright, R. (2014) RNA exit channel: target and method for inhibition of bacterial RNA polymerase. US Patent 8697354.
Zhang, Y., Degen, D., Ho, M., Sineva, E., Ebright, K., Ebright, Y., Mekler, V., Vahedian-Movahed, H., Feng, Y., Yin, R., Tuske, S., Irschik, H., Jansen, R., Maffioli, S., Donadio, S., Arnold, E., and Ebright, R. (2014) GE23077 binds to the RNA polymerase "i" and "i+1" sites and prevents the binding of initiating nucleotides. eLife, e02450.
Degen, D., Feng, Y., Zhang, Y., Ebright, K., Ebright, Y., Gigliotti, M., Vahedian-Movahed, H., Mandal, S., Talaue, M., Connell, N., Arnold, E., Fenical, W., and Ebright, R. (2014) Transcription inhibition by the depsipeptide antibiotic salinamide A. eLife, e02451.
Vvedenskaya, I., Vahedian-Movahed, H., Bird, J., Knoblauch, J., Goldman, S., Zhang, Y., Ebright, R., and Nickels, B. (2014) Interactions between RNA polymerase and the "core recognition element" counteract pausing. Science 344, 1285-1289.
Tang, W., Liu, S., Degen, D., Ebright, R., Prusov, E. (2014) Synthesis and evalutaion of novel analogues of ripostatins. Chemistry 20, 12310-12309.
Chakraborty, A., Mazumder, A., Lin, M., Hasemeyer, A., Xu, Q., Wang, D., Ebright, Y., and Ebright, R. (2015) Site‑specific incorporation of probes into RNA polymerase by unnatural-amino-acid mutagenesis and Staudinger-Bertozzi ligation. Meths. Mol. Biol.1276, 101-131.
Hassan,H., Degen, D., JangK., Ebright, R., and Fenical, W. (2015) Salinamide F, New depsipeptide antibiotic and inhibitor of bacterial RNA polymerase from a marine-derived Streptomyces sp. J. Antibiot. 68, 206-209.
Feng, Y., Degen, D., Wang, X., Gigliotti, M., Liu, S., Zhang, Y., Das, D., Michalchuk, T., Ebright, Y.W., Talaue, M., Connell, N., and Ebright, R.H. (2015) Structural basis of transcription inhibition by CBR hydroxamidines and CBR pyrazoles. Structure, 23, 1470-1481.
Vvedenskaya, I., Zhang, Y., Goldman, S., Valenti, A., Visone, V., Taylor, D., Ebright, R., and Nickels, B. (2015) Massively systematic transcript end readout (MASTER): transcription start site selection and transcriptional slippage. Mol. Cell 60, 953-965.
Winkelman, J., Vvedenskaya, I., Zhang, Y., Zhang, Y., Bird, J., Taylor, D., Gourse, R., Ebright, R., and Nickels, B. (2016) Multiplexed protein-DNA cross-linking: Scrunching in transcription start site selection. Science 351, 1090-1093.
Vvedenskaya, I., Vahedian-Movahed, H., Zhang, Y., Taylor, D., Ebright, R., and Nickels, B. (2016) Interactions between RNA polymerase and the core recognition element are a determinant of transcription start site selection. Proc. Natl. Acad. Sci. USA 113, E2899-E290.
Feng, Y., Zhang, Y., and Ebright, R. (2016) Structural basis of transcription activation. Science 352, 1330‑1333.
Bird, J., Zhang, Y., Tian, Y., Panova, N., Barvík, I., Greene, L., Liu, M., Buckley, B., Krásný, L., Lee, J.K., Kaplan, C., Ebright, R., and Nickels, B. (2016) The mechanism of RNA 5′ capping with NAD+, NADH, and desphospho-CoA. Nature 535, 444-447.
Walker, S, Degen, D., Nickbarg, E., Carr, D., Soriano, A., Mandal, M., Painter, R., Sheth, P., Xiao, Li., Sher, X., Murgolo, N., Su, J., Olsen, D., Ebright, R., Young, K. (2017) Affinity selection-mass spectrometry identifies a novel antibacterial RNA polymerase inhibitor. ACS Chem. Biol. 12, 1346-1352.
Lin, W., Mandal, S., Degen, D., Liu, Y., Ebright, Y., Li, S., Feng, Y., Zhang, Y., Mandal, S., Jiang, Y., Liu, S., Gigliotti, M., Talaue, M., Connell, N., Das, K., Arnold, E., and Ebright, R. (2017) Structural basis of Mycobacterium tuberculosis transcription and transcription inhibition.. Mol. Cell 166, 169-179.
Maffioli, S., Zhang, Y., Degen, D., Carzaniga, T., Del Gatto, G., Serina, S., Monciardini, P., Mazzetti, C., Guglierame, P., Candiani, G., Chiriac, A.I., Facchetti, G., Kaltofen, P., Sahl, H.-G., Dehò, G., Donadio, S., and Ebright, R.H. (2017) Antibacterial nucleoside-analog inhibitor of bacterial RNA polymerase. Cell 169, 1240-1248.
Bird, J., Nickels, B., Ebright, R.H. (2017) RNA capping by transcription initiation with non-canonical initiating nucleotides (NCINs): determination of relative efficiencies of transcription initiation with NCINs and NTPs. Bio-Protocol 7, e2336.
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Yu, L., Winkelman, J., Pukhrambam, C., Strick, T., Nickels, B., and Ebright, R. (2017) The mechanism of variability in transcription start site selection. eLife 6, e32038.
Lin, W., Das, K., Degen, D., Mazumder, A., Duchi, D., Wang, D., Ebright, Y.W., Ebright, R.Y., Sineva, E., Gigliotti, M., Srivastava, A., Mandal, S., Jiang, Y., Liu, Y., Yin, R., Zhang, Z., Eng, E.T., Thomas, D., Donadio, S., Zhang, H., Zhang, C., Kapanidis, A.N., and Ebright, R.H. (2018) Structural basis of transcription inhibition by fidaxomicin (lipiarmycin A3). Mol. Cell 70, 60-71.
Vvedenskaya, I., Bird, J., Zhang, Y., Zhang, Y., Jiao, X., Barvík, I., Krásný, L., Kiledjian, M., Taylor, D., Ebright. R.H., and Nickels, B. (2018) CapZyme-Seq comprehensively defines promoter-sequence determinants for RNA 5' capping with NAD. Mol. Cell 70, 553-564.
Sosio, M., Gaspari, E., Iorio, M., Pessina, S., Medema, M., Bernasconi, A., Simone, M., Maffioli, S., Ebright, R.H., Donadio, S. (2018) Analysis of the pseudouridimycin biosynthetic pathway provides insights into the formation of C-nucleoside antibiotics.. Cell Chem. Biol. 25, 540-549.
Gabizon, R., Lee, A., Vahedian-Movahed, H., Ebright, R.H., and Bustamante, C. (2018) Pause sequences facilitate entry into long-lived paused states by reducing RNA polymerase transcription rates. Nature Comm., 9, 2930.
Duchi, D., Mazumder, A., Malinen, A., Ebright, R., and Kapanidis, A. (2018) The RNA polymerase clamp interconverts dynamically among three states and is stabilized in a partly closed state by ppGpp. Nucl. Acids Res. 14, 7284-7295.
Bird, J., Basu, U., Kuster, D., Ramachandran, A., Grudzien-Nogalska, E., Kiledjian, M., Temiakov, D., Patel, S., Ebright, R.H. and Nickels, B. (2018) Mitochondrial RNA capping: highly efficient 5'-RNA capping with NAD+ and NADH by yeast and human mitochondrial RNA polymerase. eLife, 7, e42179.
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Lin, W., Mandal, S., Degen, D., Cho, M., Feng, Y., Das, K., and Ebright, R.H. (2019) Structural basis of ECF-sigma-factor-dependent transcription initiation. Nature Commun. 10, 710.
Panduwawala, T., Iqbal, S., Thompson, A., Christensen, K., Genov, M., Pretsch, A., Pretsch, D., Liu, S., Ebright, R.H., Howells, A., Maxwell, A., and Moloney, M. (2019) Functionalised bicyclic tetramates derived from cysteine as antibacterial agents. Org. Biomol. Chem. 17, 5615-5632.
Talbot, G., Jezek, A., Murray, B., Jones, R., Ebright, R.H., Nau, G., Rodvold, K., Newland, J., and Boucher, H. (2019) The Infectious Diseases Society of America's 10 × '20 Initiative (Ten New Systemic Antibacterial Agents FDA-approved by 2020). Clin. Infect. Dis. 69, 1-11.
Yin, Z., Kaelber, J., and Ebright, R.H. (2019) Structural basis of Q-dependent antitermination. Proc. Natl. Acad. Sci. USA 116, 18384-18390.
Ebright, R.H., Werner, F., and Zhang, (2019).RNA polymerase reaches 60: transcription initiation, elongation, termination, and regulation in prokaryotes. J. Mol. Biol. 431, 3946-3946.
Li, L., Molodtsov, V., Lin, W., Ebright, R.H., and Zhang, Y. (2020) RNA extension drives a stepwise displacement of an initiation-factor structural module in initial transcription. Proc. Natl. Acad. Sci. USA 117, 5801-5809.


text:
My respect for the 'Drax 29'
by Shaun Chamberlin on July 3rd, 2009
A week after NASA's leading climate scientist Dr. James Hansen, actress Darryl Hannah and others crossed the line into illegal direct action in a desperate attempt to prevent coal mining and burning from ending our hopes of retaining a hospitable climate, twenty-nine protesters are standing trial here in England for a similar action last year.
The 'Drax 29' admit stopping (safely) a coal train two miles outside the Drax power station in an attempt to prevent the deaths already being caused by climate change. Nonetheless they have entered a "Not Guilty" plea against the charge of 'Obstructing the Railway' (which carries a maximum two year prison sentence). They are defending themselves in court, and after reading their inspiring closing statement justifying this position to the jury, I felt moved to create the pledge above. You can read their defence yourself in The Guardian here, or it is reproduced in full below: Read more »

subset: commoncrawl


text:
problem with embryo carcinoma cell line , p19 , - (Sep/01/2011 )
problem with embryo carcinoma cell line , p19 ,
30 August 2011 - 12:39 PM
i am phd student
i am working on p19 cell lines
in the beginning of my first year the p19 cell line was supper confluent nearly 80-90% within 24hr and they were in a good condition
however, nowadays i have problem growing them. they start growing very slowly and they detached from the flask easily.
i have not change the medium alphaMEM with boven calf serum 7.5% and FBS 2.5%
i do not know why they start behave this way
any recommendation or opinion about what may go wrong with p19 cell line
thank you in advance
have you done a recent check for mycoplasma???


text:
Speedlite 90EX
A compact, high performance flash that delivers superbly lit everyday shots such as portraits and indoor scenes plus creative lighting effects. The ideal companion for the EOS M.
- Slim, pocketable design
- Shoot superbly lit portraits and indoor scenes
- High power in a compact body
- Explore creative lighting effects
- Quick, discreet and fully automatic flash shooting
- Powered by readily available AAA batteries
Detailed Features
Take a look at a more detailed look into the Canon Speedlite 90EX
Slim, pocketable design – ideal for the EOS M
The compact flash of choice for the EOS M users, the Canon Speedlite 90EX weighs just 50g (without batteries) and its space-saving design means it will fit into even the smallest of kit bags.
Shoot superbly lit portraits and indoor scenes
Ideal for shooting with ultra wide-angle lenses, the Speedlite 90EX delivers exactly the right illumination for great portraits as well as superb indoor and group shots.
High power in a compact body
Despite its diminutive size, the Speedlite 90EX has plenty of power and with a maximum guide number of 9 (m, ISO100) it's ideal for illuminating dark and night time scenes such as a party or an evening barbeque. It's also perfect as a fill-in flash for subjects shot outdoors with the sun behind you.
Explore creative lighting effects
The Speedlite 90EX opens up countless creative lighting opportunities, thanks to its built-in Wireless master function. As a master flash unit it can wirelessly trigger up to three groups of other flashes, which have a built-in slave function such as the Speedlite 270EX II, from up to 7 meters away indoors.
Quick, discreet and fully automatic flash shooting
When you want to take continuous shots quickly and discreetly the Speedlite 90EX is always ready for action. Power recycling is silent and fast - it takes only 5.5 seconds before its ready for the next shot. It's also compatible with the autoflash metering systems found in the EOS M and other EOS DSLR cameras, ensuring fully automatic accurate flash exposure in all situations.
Powered by readily available AAA batteries
To keep the size and weight of the working flash unit down to a minimum and for maximum convenience the Speedlite 90EX is powered by two readily available AAA/LR03 batteries (either Ni-MH or lithium).
Product Specification
Find out more about the Canon Speedlite 90EX, its features and what it can do.


text:
Get free shipping if you spend another .
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The perfect way to protect and prolong the life of your garments.
*With Any Purchase. Maximum 1 per order.
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text:
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FootJoy Thermal Quilted Vestview other products
Sometimes a full jacket is just too cumbersome and a little unnecessary, which is when a body warmer like this quilted vest becomes the ideal choice.
Easy care fabric makes this layering piece easy to maintain whilst ensuring long-term durability. The stand-up collar gives extra protection from the elements and helps retain the flexibility required for on-course action.
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What more can we say other than why not order yours today?


text:
Important update April 18 - 10:17 UTC
Pakistani sources report that the earthquake destroyed 3,000 houses in Mashkeel, Pakistan's border province with Iran.
Officials said a total of 19,000 people were reported to be in need of shelter and wait for help.
Aid materials can only be sent by military helicopters, as relief trucks are hindered by the blocked roads and desert terrain. Civil aid organizations have not reached the region yet.
Military sent a large scale of search & rescue team and a field hospital was established in the region.
A total of 36 people got killed, 150 others were injured in Pakistan alone.
Islamabad administration hasn't replied to the offers of international agencies yet.
This Mashkeel, Pakistan image says it all (courtesy and copyright The Nation, Pakistan)
Understanding the Massive M7.8 Iran - Pakistan earthquake
The April 16, 2013 M 7.8 earthquake east of Khash, Iran, occurred as a result of normal faulting at an intermediate depth in the Arabian plate lithosphere, approximately 80 km beneath the Earth's surface.
Regional tectonics are dominated by the collisions of the Arabian and India plates with Eurasia; at the longitude of this event, the Arabian plate is converging towards the north-northeast at a rate of approximately 37 mm/yr with respect to the Eurasian plate.
Arabian plate lithosphere is subducted beneath the Eurasian plate at the Makran coast of Pakistan and Iran, and becomes progressively deeper to the north.
The subducted Arabian plate is known to be seismically active to depths of about 160 km. The frequency of moderate and large earthquakes within the subducted Arabian plate is not high compared with similar events in some other subducted plates worldwide, but several earthquakes have occurred within this slab in the region of today's event over the past 40 years, including a magnitude 6.7 shock 50 km to the south in 1983.
In January of 2011, a M 7.2 earthquake occurred approximately 200 km to the east, in a similar tectonic environment to the April 16 earthquake.
Important update 02:48 UTC :
- The death toll currently stands at somewhere between 30 and 35 in Pakistan and 0 in Iran. Over 150 have been injured in Pakistan.
27 people are now confirmed injured in Iran. We have decreased the earlier number of 1 to O for Iran as we could not find a reconfirmation of the Iranian fatality.
- 1000+ houses have been damaged to some extent in Pakistan.
- 25 villages (15 in Khash, 10 in Saravan) have been reviewed by Red Crescent. Only 3 destroyed houses have been found at this point in the village Qadrabad in Khash, however there has been major damage in Pakistan across the border in Soran.
- It is interesting to see why there has been significant damage across the border in Pakistan. There could be "directivity" at play in terms of a stronger direction of earthquake energy in one direction along the fault break causing higher ground motion over the border.
- Another reason could be for more vulnerable building typologies being used across the border in Pakistan.
- In Iran, there are many houses with cracks and moderate damage therefore given the warm temperatures it has been advised that residents of some of these houses stay outside for a while for fear of aftershocks.
- 2,000 tents, 5,000 blankets and 500 food packages are part of the expedition sent by the Red Crescent in South Khorasan province.
Update 21:33 UTC :
The United States offered to provide humanitarian assistance to the victims of the Tuesday's massive earthquake that severely jolted parts of Pakistan's Balochistan province bordering Iran. We offer our condolences to the families who lost loved ones during the earthquake," a State Department spokesman said.
"The United States does stand ready to assist either Iran or Pakistan at this point," Patrick Ventrell said in response to a question at the daily briefing.
Update 21:15 UTC :
As you can see below, we have listed only 4 aftershocks of M3.5 or more since the mainshock. These were reported by the international agencies. Also the Iranian seismological agency has counted only 4 which is very few for such a massive earthquake.
Update 18:23 UTC :
The death toll in Pakistan has further increased to 34 according to Pakistan TV. 150 have been reported injured in Mashkeel Tehsil.
Over 1'000 houses have been damaged in the area.
Update 17:18 UTC :
Iranian media now reports the first fatality inside Iran. No specifics where it happened or the conditions. This is however not confirmed by any other Iranian source.
Update 16:39 UTC :
We, at ER are somewhat puzzled why the main devastation and fatalities are being reported from a relatively big distance in Pakistan. The image below shows probably why ! The Mashkeel area looks like a dry lake on Google Earth and the surrounding cities are showing soft soil and farming fields, this contrary to a rocky soil in Iran (Rocks are decreasing the shaking impact).
The many images below so show what we are trying to explain. The image just below this text shows a satellite Google map and one can see clearly the many rivers arriving in the Mashkeel lake. These rivers may have transported huge amounts of sediment, sediment who will be propagating the earthquake waves at full force ( Remember the Mexico City liquefaction earthquake).
Science will have a huge work in defining what triggered the devastation in Pakistan.
Update 16:24 UTC :
President Asif Ali Zardari and Prime Minister Mir Hazar Khan Khoso have expressed grief and sorrow over the loss of precious lives and damage to property caused by the earthquake.In Iran at least forty people have been killed and hundreds were injured.
Update 16:17 UTC :
German TV has just released a number of 30 fatalities in Pakistan. Pakistan TV however mentions 26 deaths (21 in Mashkeel and 5 in Panjgur). Sad numbers.
Update 15:35 UTC :
Iran update : Iranian sources now report 27 injuries from which 3 have been hospitalized.
Update 15:20 UTC :
The quake death toll keeps climbing and has reached 21 people so far. About 100 people have been reported injured so far. Pakistani troops started rescue and relief operations in the earthquake-stricken areas. According to authorities, the rescuers will distribute tents, food and supplies to the earthquake-stricken areas.
Update 14:56 UTC :
- Fardanews Iran is stating that so far, inside Iran, only 27 people were reported injured
- Reuters reports now 13 fatalities inside Baluchistan, Pakistan (among the deaths, 3 children).
- A lot of damage based on this report but as saif earlier, no confirmation as yet.
Important update 14:24 UTC :
- Indian media quoting Radio Pakistan are now talking about 12 deaths and a lot of injured in inside western Pakistan. No Pakistan media are confirming this news. Panjgur and Kharan districts of Balochistan, the quted districs where some buildings presumably collapsed, are indeed neighboring areas to Iran. The following hours will make sure if this news is correct. We keep searching for confirmation in to be trusted sources.
Very Important update 13:44 UTC :
- IRAN, by means of the Governor of the hit province has OFFICIALLY DENIED that there were 40 fatalities. He said that communications and infrastructure has been affected.
- As further assessment is underway in Iran, we expect that it will take several more hours before a serious report will be published
Earthquake-Report.com is happy with the outcome of this earthquake.
Important update 13:18 UTC :
- There is a total confusion about the damage and possible fatalities / injured. The earthquake occurred in a remote sparsely populated area in Iran. Assessment teams and 3 helicopters and rescue teams have been send to the epicenter area, but so far NO news from them.
- Some sources in India are taking about 5 fatalities inside Pakistan (Baluchistan). In Mashkel area of Kharan, 3 children and 2 adults would have been killed and many injured have been brought to a nearby military hospital. We cannot confirm this news based on a second independent source.
Important update 12:51 UTC :
- We are irritated by the world press who is looking for ghost fatalities. In their search and copy/paste work they are mixing 2 earthquakes, the one from last week who led to the death of 41 people and today's one. Reports that are appearing here and there that also some people have been killed in Pakistan could not be confirmed inside Pakistan.
Important update 12:35 UTC :
- UGS Pager has again changed the expected impact stating now that the Max shaking would be very strong (MMI VII) near the epicenter. This is the third map we publish, not to blemish USGS but to proof that seismology is not an exact science and needs a lot of recalculation.
- The shaking intensity is now expected to be (theoretical) :
MMI VI (strong shaking) Khash 70,000 inhabitants
MMI V (moderate shaking) : Iranshahr, Zahedan, Panjgur, 'Alaqahdari Dishu and Turbat
MMI IV (light shaking) : Mirabad, Rudbar, Khan Neshin and Dalbandin
Important update 12:27 UTC :
- We have now confirmed reports of 3 injured people in Saravan (Iran) and 5 injured people in Pakistan (various locations) (probably shock related).
- Some cracks are reported in houses closer to the epicenter.
- 100 rescuers are on their way to the epicenter area and will probably need approx. 5 hours to reach the epicenter area.
Important update 12:19 UTC :
At the moment of writing we have NO REASON and NO REPORT of any deaths.
The 40 fatalities reported in many sites (and copied, copied, copied) are probably taken from the fatalities of last week earthquake. You should NOT believe this at this moment.
We are proud to say that this site is probably one of the most reliable in the world, due to our experience in the field.
Update 12:15 UTC :
Population statistics of people living within a certain radius near the epicenter :
100 km 290000 people, 75 km 50000 people, 50 km 17000 people, 20 km <1000 people, 10 km <1000 people, 5 km <1000 people and 2 km no people
We have to be careful with these data as extracting the exact epicenter location is very tricky. An error margin of 10 to 20 km is normal.
- A similar depth earthquake (our viewers would remember) happened in January 2011 in Pakistan - This was Mw7.2 and a bit shallower, and caused 1 direct death and 2 indirect deaths with around 200 houses damaged.
- We expect that there will be damage however, we hope the fatalities will be kept to a minimum.
- According to the last census, the population of Saravan is 173000, khash 290000 and suran 69000 - Probably another several thousand in the nearby villages...
Update 12:08 UTC :
- Historic Fault depths are often right and also in this case, James Daniell, our CATDAT Damage specialist had a hard time to believe the shallow depths reported at the beginning (confusing data are nothing special for seismology). A massive earthquakes in the past showed a depth of 64 km. At this moment depths are varying from 51 to 82 km, a world of difference for damage prediction.
- Lets hope that the assessment and Rescue teams will find only material damage (we are sure that there will be damage).
- This is the second major earthquake to be felt in the Emirates region in less than a week !, however both quakes are not necessarily related.
Very important Update 11:57 UTC :
- USGS has also changed the depth of the hypocenter from 17 km to 82 and changed the color of his pager to GREEN = they expect NO fatalities.
- We are giving a lot of credit to this change as also the close by 1983 earthquake had no fatalities and was deep too.
Update 11:53 UTC :
- Iran has send 12 assessment teams to the earthquake epicenter area.
- we have still no confidence in the various seismological reports. They are still conflicting on the depth of the hypocenter. The depth of an earthquake is a main trigger for damage estimates.
- Some newspapers are publishing deaths but we have to stress that this is too soon. The numbers may be derived of earlier earthquakes. As soon as we have official data or to be trusted numbers, we will publish them immediately.
Important update 11:44 UTC : Iran seismological Institute is also reporting a depth of 95 km at this moment (earlier shallower). We like this extremely.
- Red Crescent Iran is sending 3 helicopters to the epicenter area and at least the 7 villages closest to the epicenter
We can finally write again.
Our server was blocked due to too high demand too many readers at the same time).
Most seismological agencies (even Iran) are reporting a depth of approx. 100 km, which is far better than a shallow depth.
- EMSC has changed to M7.7 and 50km : not good at all
- GEOFON, Mw7.7 and 95km
- WAPMERR switches to 10-600 deaths, and 100-2000 injuries using the USGS data.... thus they show the range
- No accurate information on damage on hand at the moment, but according to some local sources 40 deaths are estimated
- this could also be mixed up with the previous earthquake
- Fars news (persian) quotes the geophysical institute of tehran universuty: depth of 18km
- 15 seconds of shaking in the UAE
Most important Earthquake Data:
Magnitude : 7.8
Local Time (conversion only below land) : 2013-04-16 15:14:25
GMT/UTC Time : 2013-04-16 10:44:25
Depth (Hypocenter) : 87 km
Depth and Magnitude updates in the list below.
Share your earthquake experience (I Have Felt It) with our readers.
Click on the "I Felt It" button behind the corresponding earthquake. Your earthquake experience is not only important for science, but also for people in the area as well as our global readership.
|Refresh this list
|UTC Date/time
|Iran-pakistan Border Region
|Apr 16 21:32
|MAP I Felt It INFO
|Iran-pakistan Border Region
|Apr 16 21:02
|Southern Iran
|Apr 16 20:43
|Southeastern Iran
|Apr 16 20:43
|MAP I Felt It INFO
|Southeastern Iran
|Apr 16 20:43
|Southeastern Iran
|Apr 16 19:14
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|Southeastern Iran
|Apr 16 19:14
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|Iran-pakistan Border Region
|Apr 16 16:26
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|Apr 16 13:54
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|Apr 16 13:54
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|Iran-pakistan Border Region
|Apr 16 10:44
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|Southwestern Pakistan
|Apr 16 10:44
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|Apr 16 10:44
|Fast EARTHQUAKE and TSUNAMI TWEETS @ your MAGNITUDE choice
Other earlier earthquakes in the greater epicenter area (since 2012)
Strongest earthquakes Magnitude 3.5 or more within a 150 km radius from this earthquake (max. 60)


text:
What's the best way to dispose of an old cell phone? If you're attending the FOSE trade show, you can drop it off at the show for recycling and help support U.S. troops overseas in the process.
FOSE, being held April 3-5 at the Washington Convention Center, aligned last year with Operation Gratitude to support its cell-phone recycling program to help raise funds for care packages sent to service members.
Operation Gratitude, based in California and now in its ninth year, collects donations through a variety of channels and to date has delivered more than 750,000 care packages to troops. The cell-phone recycling program, which also lets people ship used phones, sends them to GRC Wireless Recycling, which pays up to $30 for each phone.
The cell-phone program has raised more than $100,000 since it was started in 2005, Carolyn Blashek, Operation Gratitude's founder, said in an e-mail.
Blashek said the organization's goal is twofold: lift military morale and give people an opportunity to say thanks to the troops. Taking an old phone to FOSE makes it easy, not to mention green.
FOSE isn't entirely about new technologies — even some old tech can do some good.
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text:
Art as Life
Work No. 12 (Lunar)
0:30 Added Nov 07, 2011
Created By:
Mr. & Mrs. Hahn
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Created By:
Mr. & Mrs. Hahn
Schmooru.com devotes resources towards the encouragement of creative producers to do what they do best: take chances, create, and feel free in doing so.
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Cory Booker dominates a poll of likely voters with less than a week to go before New Jersey's special U.S. Senate race primary on Tuesday.
The Quinnipiac University survey released Wednesday shows 54 percent of likely Democratic primary voters support the Newark mayor.
U.S. Rep. Frank Pallone gets 17 percent, Rep. Rush Holt receives 15 percent and Assembly Speaker Shelia Oliver is backed by 5 percent.
U.S. & World
The day's top national and international news.
Steve Lonegan trumps Alieta Eck 74 to 10 percent among likely Republican primary voters.
Booker leads Lonegan 54 to 29 percent among registered voters surveyed in the race to fill the vacancy caused by the death of Sen. Frank Lautenberg.
"Unless the sky falls, Newark Mayor Cory Booker can start looking for a Washington apartment. He dominates both the Democratic primary and a general election against Steve Lonegan," said Maurice Carroll, director of the Quinnipiac University Polling Institute.
The poll of 2,042 New Jersey voters has a higher sampling error among the smaller subsets of Democratic and Republic voters.


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Whether it is a low-key Friendsgiving or an elaborate Thanksgiving celebration with family, two things are certain: A big meal is imminent, and a festive outfit is in order. No need to fret about what to wear though—don one of these outfits and you'll be raved about almost as much as the pumpkin pie.
Laid-Back and Ladylike
Kate Upton, donned the perfect Thanksgiving-ready outfit. The simple-yet-stylish dark denim. The relaxed-yet-refined tweed blazer. The icing on the cake: her chunky black bracelets—such great conversation starters!
Get the Look
Studio M jacket, $70, macys.com Notify stretch-denim jeans, $99, bluefly.com Black lace stretch bangle, $65, betseyjohnson.com
Pajama Power
Let's face it: We all want to lounge around and be as chill as possible on Thanksgiving, so why not just follow designer Rachel Roy's lead and wear matching pajamas? Dress them up by accessorizing with glimmering chains and a luxurious clutch.
Get the Look
Ralph Lauren stripe knit pajamas, $68, nordstrom.com Juicy Couture pavé toggle necklace, $86, amazon.com Deux Lux fold-over spiked clutch, $95, lastcall.com
Comfortably Glam
Choose your Thanksgiving fashion wisely by picking a loose, easygoing sweater—if you plan to go for seconds, that is. Keep things stylish by pairing with a metallic miniskirt and, like Kate Bosworth, an orangey red lip.
Get the Look
Knitted angora cable jumper, $92, topshop.com Magaschoni shimmer skirt, $55, amazon.com Nars limited-edition cinematic lipstick, $26, neimanmarcus.com
A Little Faux Fur
Leave it to stylish Sienna Miller to take an oversize blouse and make it look fab—not drab—courtesy of a furry scarf. The whole look gives off a festive yet easygoing vibe.
Get the Look
Mongolian dip-dye lapel collar, $69, asos.com Worthington pleather-trim blouse, $16, jcpenney.com Stella ankle-zip jean leggings, $56, express.com
Cozy Pattern Play
This cool sweater-pants combo that Blake Lively wore, is intriguing and cozy. Not only do the patterns play well, she wisely chose patent flats to keep things comfy—a must-do when it comes to Thanksgiving Day dressing.
Get the Look
Splendid bouclé active sweater, $98, shopbop.com Street-chic houndstooth leggings, $9, forever21.com Kelsi Sagger Suzara loafers, $95, lorisshoes.com
Festive Red Trousers
Julianne Hough chose a sweet embroidered top, bright red trousers, and clear clutch combination. It's a wonderful ensemble for Friendsgiving—just bring the dessert and you'll be a strong contender for best guest.
Get the Look
Nude pearl-embellished top, $29, dorothyperkins.com Pleated baggy trousers $60, mango.com Crystal glimmer clutch, $50, nastygal.com
Have a Happy Thanksgiving!
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Sunday, December 15, 2013
Holiday baking: Sliced Almond Christmas Cookies
From the recipe archives!
It's the time to bake various Christmas cookies again. While I'll certainly be making and baking and decorating a batch of these favourite Estonian piparkoogid ("pepper cakes"), then this year I have another recipe in mind as well. These sliced Christmas cookies with almonds found their way into my heart in the midst of the summer heatwave, as I was choosing and testing recipes for my Christmas cookbook. I had seen a recipe for "French gingebread cookies" in a Swedish food magazine that I liked, and that reminded me of Jules Destrooper's wonderful almond thins that I used to love. After some tweaking here and there (less sugar and less cloves, more almonds), I ended up with this great recipe.
I usually divide the dough into four equal portions and roll and wrap them individually. Then I bake one and place three in the freezer - I can then bake fresh and aromatic Christmas cookies whenever I feel like :)
Almond Gingerbread Cookies
Makes a lot - about 4 large sheets
250 g butter
200 g caster sugar
140 g light baking syrup (about 100 ml)
420 g plain flour (700 ml)
1 Tbsp ground cinnamon
0.5 Tbsp ground cloves
0.5 Tbsp baking soda
100 g sliced almonds
Melt the butter in a saucepan. Add sugar and syrup, stir until combined. Remove from the heat and let cool completely.
Combine flour, cinnamon, cloves, baking soda and almonds in a bowl, then fold into the cool butter-sugar-syrup mixture. Stir until combined.
Divide the cookie dough into four equal parts, then form each one into a cylinder/sausage, about 4 cm in diameter. Wrap in clingfilm or baking paper and place into the fridge to rest. (Ideally for 24 hours).
To bake the cookies, cut each "sausage" into 3-4 mm (1/8th inch) slices, and place onto a parchment covered cookie sheet.
Bake in the middle of a preheated 200 C oven for 6 to 8 minutes, until golden brown.
Remove from the oven, let rest for a few minutes, then transfer onto a metal rack to cool completely.
Jõulud kodus ("Christmas at Home"), published in Estonian in November 2011.
9 comments:
- Alanna Kellogg said...
This looks just like a recipe that called to me yesterday! : - ) What is "light syrup" - do you know if it's what we have in the States, clear corn syrup? (Clear in color, vs dark syrup, dark in color there is a "light" version too but it has Splenda or something.)
- 7:19 pm, December 10, 2011
- Pille said...
Alanna, it's a simple caramelized sugar syrup (you'd need about 250 g sugar and 200 ml water), but you could use Lyle's Golden Syrup or corn syrup. Here in Estonia I use DanSukker's light syrup (they've also got dark syrup - same thing, stronger caramelisation). You can actually buy it in the US as well: http://www.swedensbest.com/ljussirap.html (light one) or http://www.swedensbest.com/dabasy.html (dark one).
Both can be used for making both of my gingerbread recipes, just I prefer the lighter one.
- 7:35 pm, December 10, 2011
- Katarina said...
Delicious cookies and the flavors are great!
- 5:33 am, December 11, 2011
- Rebecca Mackay said...
I'm starting on Tuesday. Cookies, puddings, plenty treats; treacly things and marzipan sweets :D enjoy!
- 7:40 am, December 11, 2011
- Jackie at mulledwinerecipe said...
I wonder if this would work with gluten-free flour.
- 1:50 pm, December 13, 2011
- Gitte said...
Your cookies look and sound wonderful. Nothing better than Christmas cookies with traditional seasonal spices.
- 1:58 pm, December 14, 2011
- juliemarg said...
All of the above you posted are all delicious.Thanks for sharing this to us!
- 8:44 pm, August 16, 2012
- tanita✿davis said...
I like a thin almond cookie, and adding ginger this time of year seems a good plan. I'm going to try these with almond flour to see how it goes...
- 12:18 am, December 17, 2013
- Jeff @ Cheese-burger.net said...
This cookies goes to my list for Christmas and New Year.
- 9:40 am, December 19, 2013


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Update to the update: According to Israel Hayom, Islamic Jihad has now called for the resignation of Essam al-Erian and the death of returning Jews. (with thanks: Lily)
Final update: Essam el-Arian has resigned.
A Muslim Brotherhood official's call on Egyptian TV for Egyptian Jews to return to Egypt - even though they supported the 'occupation' (of Palestine) - has met with a barrage of criticism from within Israel and Egypt. (With thanks: Lily)
(JTA) -– A Cairo-born Israeli* has grabbed headlines in leading Arab media with a letter mocking a top Egyptian official's call for the return of Egypt's Jews from Israel.
Azi Nagar's letter, which received coverage in Al-Hayat and Al Ahram, ridicules the call made last week by Essam al-Erian, deputy head of the Muslim Brotherhood's Freedom and Justice Party and an adviser to Egyptian President Mohamed Morsi.
"I basically asked al-Erian a few questions about my impending return," Nagar told JTA, "like whether he would compensate me for my family's house, which the government confiscated when we left for Israel, or whether I would have to join the destitute homeless and jobless who live in Cairo's cemeteries."
In a televised speech last week, al-Erian urged Jews to leave Israel in order to "make room for the Palestinians" and said Israel will cease to exist in the next decade.
Read article in full
Here is the transcript of the MEMRI TV clip:
Issam Al-'Aryan: Most of the Egyptian people are Muslims. Our Arab Islamic culture was shared by the Christians, the Muslims, and even the Jews who used to live here. I wish the Jews would return to Egypt in order to make room for the Palestinians. The Palestinians would return to their country, and the Arab Jews would return to their countries.
Interviewer: Are you welcoming the Egyptian Jews...
Issam Al-'Aryan: The Jews deported by Abd Al-Nasser should return. Why did he deport them?!
Interviewer: So they should get their property back?
Issam Al-'Aryan: They supported the occupation. Every Egyptian has the right to return, especially if he would be making room for a Palestinian. I want to enable the Palestinians to return to their land. The Right of Return cannot be ignored or relinquished.
Interviewer: But the right to return is unconditional, right? An Egyptian who left his country has the right to return to it.
Issam Al-'Aryan: I am calling upon them: Egypt is worthier of you than Israel. Why do you live in a racist, occupying entity? Why do you allow yourselves to be soiled with war crimes, for which the occupation leaders will be punished? They will not escape punishment.
ABC News carries the Associated Press report alleging that Al-Aryan's remarks met with criticism inside Egypt:
"The criticism ran an unusual gamut of Egyptians' attitudes toward Jews, Israel and the Brotherhood itself.
Some denounced the Brotherhood for trying to put up a veneer of tolerance by inviting Jews to return while Egypt's other religious minorities, particularly Christians, are increasingly worried about persecution under the new Islamist rulers and an Islamist-slanted constitution.
"Others saw the comments as a sort of outreach to Zionists, considered the enemy, and as a new example of how the Brotherhood has had a hard time melding its longtime anti-Israeli and anti-Jewish rhetoric with its new responsibilities since coming to power. Under Morsi — who hails from the Brotherhood — the government has continued cooperation with Israel, upheld the two countries' peace deal and Morsi last month helped mediate a cease-fire between Hamas and Israel.
The restoration of the Maimonides synagogue in Cairo (Photo: AP)
And there were a few voices calling for Egypt to sincerely look at past treatment of its Jewish community — including why they left or were expelled — and whether they should have the right to return.
"Speaking on private ONTV, historian Khaled Fahmy suggested taking el-Erian's comments at face value. "I am taking the call seriously. I would like to see it in part as respectable, as addressing morals and high principles." He said Egyptians should talk about the past "harm to Egyptian Jews" and consider them as still having Egyptian nationality.
"I wish this was put to a public discussion," he said."
Read article in full
*Nagar reportedly heads an Association for the Promotion of Compensation for Jews from Arab Lands
Et tu Morsi? In 2010 TV interview the Egyptian president said: Jews are apes, piugs and bloodsuckers (World Jewish Daily)


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- Foundation – http://www.zurb.com
- See – Credits in Docs/


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Coronavirus Updates: The latest information on the global pandemic and campus operations. COVID-19 Website
Coronavirus Updates: The latest information on the global pandemic and campus operations. COVID-19 Website
All on-campus admissions visit activities are suspended. Visit gotu.us/forwardtugether for ways to connect with us and experience campus virtually.
Could Trinity be right for you? Trinity University seeks to enroll a diverse class of bright, energetic, and engaged students that will take advantage of Trinity's expert faculty, beautiful campus, first-rate resources and opportunities, and a community focused on their undergraduate education.
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Submit your financial aid forms by your corresponding application deadline
One of the best ways to determine if Trinity is the right school for you is to come and see for yourself. We look forward to welcoming you to our skyline campus and sunny San Antonio. Whether you're visiting for a few hours or a few days, we want to acquaint you with our dynamic students, engaging faculty, state-of-the-art facilities, and fantastic city.Read About Campus Visits & Programs
You can apply to the University as an undergraduate by submitting the Common Application, the Apply Texas application, or the Coalition application and submitting all of the required documents. They are available for online submission and free of charge.
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Most Trinity students receive financial support, and we offer a comprehensive aid program designed to address the concerns of families at all income levels. The Office of Financial Aid is willing and ready to help you whether you are embarking on your Trinity experience, are in the middle of your journey, or nearing the completion of your degree.Learn about Aid, Scholarships, and Grants


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Yet again it is mid-September, and hopefully some of you will know what that means, if not, check here out: MCC I, MCC II, MCC III. But that aside, it is time for the...
The Mini Castle Contest IV
Create a smaller than minifig scale castle MOC.
Now with a special category, Mini Movement!
For Mini Moc inspiration and examples, check out Bruce's Microbricks.
1. The creation must be castle based. By this I mean pretty much anything that was around in medieval times.
2. The creation can be Ninja and/or Ancient times and/or Viking.
3. The creation's base size cannot exceed 32x32 studs.
4. There is no piece or height restriction.
5. You may use customized pieces, but not pieces from any clone brands.
6. You may enter as many entries as you want, but try to go for quality as opposed to quantity.
7. You may not enter creations entered in any other contest, past or present.
Mini Movement:
This year I have decided to do something a bit different and made a special category, complete with its own prize(TBA). Build a miniature creation that moves, it can be anything, a Dragon, a ship, a wagon, a mine cart, whatever you want, so long as it is a model of something that moves. Note: The actual creation does not have to have any moving parts or such, it just needs to be a model of something that would move. Same rules apply here as with the main contest.
The deadline for entries is midnight (CC server time), October 31st. This contest ends just as the CCC VI starts.
1st: 7979 LEGO® Castle Advent Calendar
2nd: 5618 Troll Warrior
3rd: 852194 Dwarf Key Chain
Mini Movement: 5614 The Good Wizard
I, and an as yet unnamed CC member will be judging.
You may submit as many pictures for your entry as you want. But please, keep them under 1024x768 pixels. And if you post a picture in this thread, please keep them under 400x300.
*You may submit entries by replying to this thread.
If you have questions, please ask and I will try to answer ASAP.
Best of luck to everybody this year.


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Discover & Explore Arts Award Adviser training - 24 February 2016
Develop young people's creativity and reward achievement with Arts Award. This course is for adults who want to become Discover and Explore Arts Award advisers.
Do you work with young people? Support their creative development with Arts Award. Train as an Arts Award Discover & Explore adviser and learn everything you need to deliver these two Arts Award levels, enabling you to support children and young people up to 25 to discover and explore the arts.
This course is suitable for anyone that meets the requirements outlined in the adviser person specification including: teachers and teaching assistants, youth workers and arts co-ordinators and arts & music professionals.
Arts Award is open to young people of all interests and backgrounds, and can be delivered within a variety of settings and timescales through any arts, cultural or media activity. Arts Award Explore is accredited on the Qualifications and Credit Framework at Entry Level 3. Arts Award Discover is an introductory level.
Note: The session taking place on the 6th May at Graeae theatre company is a SEN training which has the specific focus of delivering Arts Award with young people with learning difficulties. Examples and case studies will be drawn from projects involving young people with learning difficulties in schools and informal youth settings from across the region.
List of training dates run by A New Direction:
Full list of training dates with other providers can be found here


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Ugur Hasdemir
With a financial background combined with his passion for Information Technology, Uğur is a trusted advisor with experience in ERP implementation since 2010 in the area of Financial and Management accounting. Driven by his passion for new technologies, Uğur has focused on SAP S/4HANA since the introduction of Simple Finance in 2014. Read More: https://s4hanablog.com/about-me/
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It turns out that the Red Sox's medical staff has Crawford on a "four-day program", meaning he cannot play more than four consecutive days, to protect his left elbow from overuse. But what makes this so strange is that the Red Sox had an off day on Thursday.
Crawford looked good on Friday night, hitting a few line drives and slugging his first home run of the year. So Saturday was actually only his second consecutive game, not fifth. (Maybe his elbow not understand the concept of off days.)
Incredibly, the existence of this plan was news to Crawford:
I'm not really sure what's the program. ... I just found out about that today. Like I said, [Valentine] texted me this morning and told me that.Manager Bobby Valentine was told about the plan awhile ago, but he immediately went against it and played Crawford for six consecutive games before giving him last Sunday off. Valentine admitted that was a "no-no".
They told me before that game that he wasn't playing, and I kind of did the old veto power, "Who says he's not playing?" and I played him. Never to be done again. ...Valentine said he is getting these orders directly from the medical staff, not from GM Ben Cherington.
I don't think it's going to be four days and a day off all year. I hope not.
What a mess. The lack of communication between the training staff, the front office, Valentine, and Crawford is shocking.
I don't want to run from guys. It feels more like I'm hiding from somebody. Not playing against someone is more embarrassing than anything. My body is fine right now.Crawford also said that he was told in April that he would need Tommy John surgery on his left elbow, and the sooner he gets it done, the better.
I try not to even think about it, to be honest with you. ... I figure one day it will blow out and when that happens, time to go, you know?The front office has said repeatedly that surgery is not inevitable.
And before the game, there was a bizarre scene in the Red Sox clubhouse when former manager and current ESPN analyst Terry Francona chatted for about thirty minutes with Dustin Pedroia, David Ortiz, Clay Buchholz, Jarrod Saltalamacchia, Cody Ross, and others. One report said that Pedroia offered Francona a chair and the two started talking. The Herald's Michael Silverman wrote that Tito was soon "surrounded by an adoring, giggling and ever-growing circle" of players. According to all reports, Valentine remained in his office across the hall.


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SCENIC AND CINEMATIC: If you've been to Monterey and Carmel, and let's just assume that you have if you've been in the Golden State for any amount of time, you know that both towns, and the region they call home, is frankly nearly fake. We say this in a complimentary fashion, of course; one cannot believe that the cypress trees and otters and Cannery Row and the ruggedness of the beach-close rocks and the bucolic dells and ranches are not part of a movie studio backlot. This might come across as a mite travel-brochure-y, but, please, if you've spent time in the area, you're nodding and agreeing with us on this point. The whole area is really the cherry on top of the sundae that is California, meaning it has attracted the Hollywood set for exactly as long as there has been a Hollywood set. Not only did they come to lounge, play, and eat artichokes and crustaceans -- those are two staples of your Monterey menu, too, we hope -- but they came to make movies. Quite a few movies, too, and many of them capitalized upon that backlot-beautiful scenery the area is famous for. Ever wondered where "A Summer Place" or "Play Misty for Me" set up the cameras? Film guide Doug Lumsden leads a look-around at the settings of these films during his Monterey Movie Tour.
START IN MONTEREY: The tour coach starts in Monterey, a burg that's appeared in such films as "I Cover the Waterfront" and "Star Trek IV: The Voyage Home" (you'll remember the whales and the aquarium, Trekkers). The tour then visits the edge of Monterey Bay, Pebble Beach, and 17-Mile Drive, where "The Parent Trap" -- the original -- filmed. (Truth time: Was Brian Keith's ranch in that movie not the most gorgeous film house ever? Pretty much, save James Mason's house in "North by Northwest," which was not shot in the area, but, you know, we have to make mention.) The day wraps up 'round Carmel-by-the-Sea, where works like "Seems Like Old Times" will receive some love. It's an outing for film buffs and devotees of the area, which, we hope, constitutes most of us. Yep, Monterey and environs may seem almost too lovely to exist, but we think having a backlot-esque vibe is something rather great.


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That's how many Californians there were as of July 2010, according to the State Department of Finance.
That represents unusually slow growth for California -- 350,000 more Californians than in July 2009, or less than 1 percent growth. What happened? Most of that growth came from births, with foreign immigration accounting for the rest. Californians also lost 72,000 people to other states, which undercut the growth:
The state finance department explains:
Natural increase remains the primary source of the state's growth since 2002. The natural increase of 284,000 in the past year is composed of roughly 525,000 births minus 241,000 deaths. This accounted for 81 percent of the 2009-10 fiscal year growth. Net migration contributed over 66,000 new residents, around 19 percent of the growth. Net migration includes all legal and unauthorized foreign immigrants, residents who left the state to live abroad, and the balance of hundreds of thousands of people moving within the United States both to and from California. During the fiscal year, the state gained over 138,000 new foreign immigrants and, similar to the net domestic outmigration of the prior five years, experienced a modest loss of 72,000 persons to other states.
One caution: federal estimates of the California population are nearly 2 million less-- the feds calculate their population numbers based on different data.


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We've redesigned our new small and light Latitude family to remove obstacles and help you work faster than ever with game-changing features like Dell ExpressSign-in, ExpressCharge, and ExpressConnect.
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1 Based on internal analysis November 2018
2 Within Dell Power Manager software, selecting ExpressCharge can recharge system battery from 0% up to 80% within 60 minutes. After charging has reached 80% capacity, charging speed will return to normal speed. Recommended for use with the provided Dell power adapter; not recommended with a smaller capacity power adapter. Charging time may vary +/-10% due to system tolerance.
* Based on August 2019 internal analysis. Most sustainable based on EPEAT Points and use of sustainable materials and processes in product and packaging.
** Leasing and financing is provided to qualified commercial customers by Dell Bank International d.a.c., trading as Dell Financial Services (DFS) at Innovation House, Cherrywood Science & Technology Park, Cherrywood, Dublin 18, Ireland and is regulated by the Central Bank of Ireland. Offers may not be available or may vary by country. Not all customers may qualify for these rates. Offers may be changed without notice and are subject to product availability, eligibility, credit approval and execution of documentation provided by and acceptable to DFS. Dell EMC and the DELL EMC logo are trademarks of Dell Inc.


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Professor James Leamon explores the significance of a series of letters from William Bayley, a Revolutionary War soldier, to his mother in Falmouth (Portland).
Leamon, professor emeritus of Early American History at Bates College, is the author of The Revolution Downeast: The War for American Independence in Maine (The University of Massachusetts, 1993). He also is co-editor of Maine in the Early Republic (The University of New England Press, 1988) and a contributor to Maine: The Pine Tree State (The University of Maine Press, 1995).
Click on the play button to hear Professor's Leamon's introduction to this collection of documents:
Transcription of Leamon's comments:
The sixteen documents in the William Bayley collection offer insights into the military career of William Bayley of Falmouth, now Portland, Maine, a common soldier who served in the American army during most of the Revolution. Letters from William to his mother back home in Falmouth constitute the bulk of the collection, which includes only one from the many that Mrs. Jean Bayley wrote to her solider son. Nonetheless, these documents are as revealing of life on the home front as they are of life in the military, and collectively reveal much about the impact of the war on family relationships.
Item 1 of 13


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Customer can return his/her received good within three days after receiving. For returning any goods he/she can go in three ways:
- Replacement with other product: Customer can change his/her received product with any other product of amarshop24.com based on availability of his/her desired goods. In this case, he/she has pay additional amount (if any) and return-deliver fee.
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Podcast: Play in new window | Download
Blendover Episode Ninety Eight:
Blendover is looking for a new permanent co-host – let us know if you're interested!
Rick Laprade guests, & we turn to an outbreak of Ebola is spreading in Guinea, and is now in Canada. On the lighter side, we examine claims that North Korea issued a mandate that all males were to have Kim Jong Un hair. We turn to rant about Ninja Turtles, and the recently unveiled plans for Spider-Man.
Topics Discussed:
- Shout-Outs
- Netflix Viewing
- Ebola
- Kim Jong Un and North Korea
- Lime Cordiale
- Teenage Mutant Ninja Turtles
- Spider-Man
BlendoveR is a fun, hard-hitting podcast where rules are regularly thrown out the window in favor of honest, open commentating opinions. Presented by Greg Davies (cGt2099 from The-TrukstoP.com), and Terr Ciavarra (Media Nox from medianox.bandcamp.com), we stray on to any topic that presents itself or wanders off onto its own tangent.
Netflix Viewing
Ebola Death Toll in Guinea Rises to 70 as Senegal Closes Border
Ebola Outbreak in Guinea Spreads to Canada
Ebola virus outbreak in Guinea kills at least 59 people
Guinea orders ban on eating bat meat as West Africa's first Ebola outbreak spreads to capital
Map of the distribution of Fruit Bats across the world
Wikipedia: Ebola virus disease
Kim Jong Un and North Korea
Do people seriously believe this kind of shit?
Kim Jong Un haircut mandate debunked
Mandatory Kim Jong Un Haircuts For North Koreans Are No More Than An Unfounded Rumor
Lime Cordiale
Lime Cordiale @ Triple J Unearthed
Teenage Mutant Ninja Turtles
TEENAGE MUTANT NINJA TURTLES – Official Trailer (2014) [HD]
DAN SLOTT Teams 1000's of SPIDER-MEN vs. MORLUN in SPIDER-VERSE
SPIDER-VERSE's Spider-Men: We Name Them All!
Music Featured:
- "Bullshit Aside" by Lime Cordiale from the album Falling Up The Stairs