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Cs go betting faze de ras

Chung I. Spatial control of EGF receptor activation by reversible dimerization on living cells. Bessman N. Cell Rep. Mechanisms for kinase-mediated dimerization of the epidermal growth factor receptor. Receptor tyrosine kinase transmembrane domains: Function, dimer structure and dimerization energetics. Sato K. Hunter T. Protein kinase C phosphorylation of the EGF receptor at a threonine residue close to the cytoplasmic face of the plasma membrane.

Pawson T. Morrison D. MAP Kinase Pathways. Cold Spring Harb. Lewis T. Lowenstein E. Buday L. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Jiang X. Grb2 regulates internalization of EGF receptors through clathrin-coated pits. Batzer A. Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Pelicci G. Okabayashi Y. Tyrosines and of activated human epidermal growth factor receptors are binding sites of Shc in intact cells.

Sakaguchi K. Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells. Salcini A. Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins. Van der Geer P. A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides. Chardin P. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling.

Egan S. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Rozakis-Adcock M. Simon J. Boriack-Sjodin P. The structural basis of the activation of Ras by Sos. Brtva T. Two distinct Raf domains mediate interaction with Ras.

Xiang X. Zang M. Characterization of Ser phosphorylation for Raf-1 activation. Diaz B. Phosphorylation of Raf-1 serine serine is an essential regulatory event for Ras-dependent activation and biological signaling. Fabian J. Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. Bondzi C. A novel assay for the measurement of Raf-1 kinase activity. Dhanasekaran N.

Signaling by dual specificity kinases. Sasaoka T. Lanzerstorfer P. Lee C. Zhao C. Soubeyran P. A mutant EGF-receptor defective in ubiquitylation and endocytosis unveils a role for Grb2 in negative signaling. Fukazawa T. Tyrosine phosphorylation of Cbl upon epidermal growth factor EGF stimulation and its association with EGF receptor and downstream signaling proteins.

Threshold-controlled ubiquitination of the EGFR directs receptor fate. Gureasko J. Membrane-dependent signal integration by the Ras activator Son of sevenless. Kim M. Maertens O. Bunda S. Src promotes GTPase activity of Ras via tyrosine 32 phosphorylation.

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Rodriguez-Viciana P. PhosphatidylinositolOH kinase as a direct target of Ras. Ras in cancer and developmental diseases. Genes Cancer. Hallberg B. Interaction of Ras and Raf in intact mammalian cells upon extracellular stimulation. Garcia-Rendueles M. Cancer Discov. Cysteine-rich region of Raf-1 interacts with activator domain of post-translationally modified Ha-Ras. Luo Z. An intact Raf zinc finger is required for optimal binding to processed Ras and for ras-dependent Raf activation in situ.

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Serine and tyrosine phosphorylations cooperate in Raf-1, but not B-Raf activation. King A. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine Chiloeches A. S phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3. Frost J. Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. Slack-Davis J. Chaudhary A. Phosphatidylinositol 3-kinase regulates Raf1 through Pak phosphorylation of serine Zhu J.

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Quantin B. Epidermal growth factor stimulates transcription of the c-jun proto-oncogene in rat fibroblasts. Hollenhorst P. Genomic and biochemical insights into the specificity of ETS transcription factors. Buchwalter G.

Ets ternary complex transcription factors. Herber B. Inducible regulatory elements in the human Cyclin D1 promoter. Albanese C. Transforming p21 ras mutants and c-Ets-2 activate the Cyclin D1 promoter through distinguishable regions. Okazaki K. Morton S. A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun.

Jin Y. Berry F. Regulation of FOXC1 stability and transcriptional activity by an epidermal growth factor-activated mitogen-activated protein kinase signaling cascade. Chambard J. ERK implication in cell cycle regulation. Acta Mol. Cell Res. Dibble C. Whitman M. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositolphosphate.

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Kim H. Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product. Mattoon D. BMC Biol. Lock L. Identification of an atypical Grb2 carboxyl-terminal SH3 domain binding site in Gab docking proteins reveals Grb2-dependent and -independent recruitment of Gab1 to receptor tyorosine kinases.

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Stephens L. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5- trisphosphate-dependent activation of protein kinase B. Casamayor A. Phosphorylation of Ser is essential for the activity of 3-phosphoinositide-dependent protein kinase Identification of five sites of phosphorylation in vivo. Sarbassov D. Gao T. Brognard J. Santi S. The Akt isoforms are present at distinct subcellular locations. Cell Physiol.

Yang Z. Zinda M. AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Cariaga-Martinez A. Cho H. Dummler B. Life with a single isoform of Akt: Mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Garofalo R. Arboleda M. Irie H. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial—mesenchymal transition. Cell Boil. Akt1 governs breast cancer progression in vivo.

Lee M. Cancer Sci. Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Linnerth-Petrik N. Opposing functions of Akt isoforms in lung tumor initiation and progression. Akt kinases in breast cancer and the results of adjuvant therapy. Breast Cancer Res. Staal S. Carpten J. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.

Chen M. Genes Dev. Cheng J. Roy H. AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Akt2 expression correlates with prognosis of human hepatocellular carcinoma. Altomare D. Perturbations of the AKT signaling pathway in human cancer. Parsons D. Colorectal cancer: Mutations in a signalling pathway. Okano J. Zhou B. Datta S. Akt phosphorylation of BAD couples survival signals to the cell- intrinsic death machinery.

Cardone M. Tang E. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Ogawara Y. Akt enhances Mdm2-mediated ubiquitination and degradation of p Feng J. Peterson T. Shaw R. Huang J. Inoki K. Manning B. Phosphorylation and functional inactivation of TSC2 by Erk: Implications for tuberous sclerosis and cancer pathogenesis.

Tee A. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin mTOR -mediated downstream signaling. Scott P. Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Dan H. Acosta-Jaquez H. Abraham R. Grewe M. Averous J. Vander Heiden M. Understanding the Warburg effect: The metabolic requirements of cell proliferation.

Elstrom R. Akt stimulates aerobic glycolysis in cancer cells. Courtnay R. Lien E. Recent Res. Nakamura Y. Roles of phospholipase C isozymes in organogenesis and embryonic development. Liao H. Absence of erythrogenesis and vasculogenesis in Plcg1-deficient mice. Sala G. Phospholipase Cgamma1 is required for metastasis development and progression.

Lattanzio R. Role of phospholipase C in cell invasion and metastasis. Rotin D. SH2 domains prevent tyrosine dephosphorylation of the EGF receptor: Identification of Tyr as the high-affinity binding site for SH2 domains of phospholipase C gamma. Anderson D. Chattopadhyay A. Falasca M. Nishibe S. Increase of the catalytic activity of phospholipase C-gamma 1 by tyrosine phosphorylation.

Serrano C. Gresset A. Mechanism of phosphorylation-induced activation of phospholipase C-gamma isozymes. Kang J. Protein kinase C PKC isozyme-specific substrates and their design. Cazaubon S. Threonine is a critical site for permissive activation of protein kinase C alpha. Identification of the phosphorylated region responsible for the permissive activation of protein kinase C.

Lund K. Phosphorylation of the epidermal growth factor receptor at threonine inhibits ligand-induced internalization and down-regulation. Kim Y. Phosphorylation and activation of phospholipase D1 by protein kinase C in vivo: Determination of multiple phosphorylation sites. Song J. Epidermal growth factor induces the production of biologically distinguishable diglyceride species from phosphatidylinositol and phosphatidylcholine via the independent activation of type C and type D phospholipases.

Cell Growth Differ. Phospholipase D and RalA cooperate with the epidermal growth factor receptor to transform 3Y1 rat fibroblasts. Joseph T. Transformation of cells overexpressing a tyrosine kinase by phospholipase D1 and D2. Park J. Phospholipase signalling networks in cancer.

Rous P. Three-dimensional structure of the tyrosine kinase c-Src. Williams J. The 2. Cooper J. Tyr is phosphorylated in pp60c-src: Implications for regulation. Okada M. CSK: A protein-tyrosine kinase involved in regulation of src family kinases. Regulation of the Src family kinases by Csk. Somani A.

Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase. Peng Z. Regulation of the Src tyrosine kinase and Syp tyrosine phosphatase by their cellular association. Fang K. Comparative study of three protein-tyrosine phosphatases. Chicken protein-tyrosine phosphatase lambda dephosphorylates c- Src tyrosine Charbonneau H. Human placenta protein-tyrosine-phosphatase: Amino acid sequence and relationship to a family of receptor-like proteins. Biscardi J.

Transforming gene product of Rous sarcoma virus phosphorylates tyrosine. Collett M. Levinson A. The purified product of the transforming gene of avian sarcoma virus phosphorylates tyrosine. Sen B. Signal Transduct. Thomas S. Cellular functions regulated by Src family kinases. Bao J. Src promotes destruction of c-Cbl: Implications for oncogenic synergy between Src and growth factor receptors.

Tice D. Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Goi T. Maa M. Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: Implications for the etiology of multiple human cancers. Poole E. ErbB receptor-induced activation of Stat transcription factors is mediated by Src tyrosine kinases.

Shan Y. Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization. Endoh H. Immunohistochemical analysis of phosphorylated epidermal growth factor receptor might provide a surrogate marker of EGFR mutation. Lung Cancer. Chung B. The role of cooperativity with Src in oncogenic transformation mediated by non-small cell lung cancer-associated EGF receptor mutants.

Mattila E. Baumdick M. Koppikar P. Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma. Gargalionis A. The molecular rationale of Src inhibition in colorectal carcinomas. Lin S.

Nuclear localization of EGF receptor and its potential new role as a transcription factor. Cao H. Functional nuclear epidermal growth factor receptors in human choriocarcinoma JEG-3 cells and normal human placenta. Wang Y. Nuclear trafficking of the epidermal growth factor receptor family membrane proteins.

Lee H. Kamio T. Immunohistochemical expression of epidermal growth factor receptors in human adrenocortical carcinoma. Novel prognostic value of nuclear epidermal growth factor receptor in breast cancer. Marti U. Nuclear localization of epidermal growth factor and epidermal growth factor receptors in human thyroid tissues. Psyrri A. Quantitative determination of nuclear and cytoplasmic epidermal growth factor receptor expression in oropharyngeal squamous cell cancer by using automated quantitative analysis.

Dittmann K. Nuclear EGFR shuttling induced by ionizing radiation is regulated by phosphorylation at residue Thr Liccardi G. Hsu S. De Angelis Campos A. Epidermal growth factor receptors destined for the nucleus are internalized via a clathrin-dependent pathway. Jaganathan S. A functional nuclear epidermal growth factor receptor, Src and Stat3 heteromeric complex in pancreatic cancer cells. Huo L. Bitler B.

Martinelli E. Anti-epidermal growth factor receptor monoclonal antibodies in cancer therapy. Ciardiello F. Modjtahedi H. Epidermal growth factor receptor inhibitors in cancer treatment: Advances, challenges and opportunities. Anticancer Drugs. Shukuya T. Efficacy of gefitinib for non-adenocarcinoma non-small-cell lung cancer patients harboring epidermal growth factor receptor mutations: A pooled analysis of published reports.

Harandi A. Clinical efficacy and toxicity of anti-EGFR therapy in common cancers. Lynch T. Bertotti A. The genomic landscape of response to EGFR blockade in colorectal cancer. Krasinskas A. Chung K. Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. Cunningham D. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. Laurent-Puig P. Cleary J. A phase 1 study of ABT in subjects with advanced solid tumors.

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The characterization of these pathways has taken centre stage, in hoping that these discoveries will lead to effective combination therapies. Being able to form homo- and heterodimers with one another, these family members can form a total of 28 different combinations with each other [ 22 ]. ERBB2 does not contain a ligand-binding domain, and no direct ligand for it has ever been identified, yet ERBB2 appears to be the preferred binding partner to its family members [ 23 , 24 , 25 ], as its dimerization arm is constitutively exposed [ 26 ].

ERBB3 does not contain a kinase domain, therefore ERBB3 homodimers possess little autophosphorylation activity, albeit some is present [ 27 ]. However, ERBB3 can still be phosphorylated and induce potent downstream signaling [ 25 ]. In Caenorhabditis elegans , the ErbB gene is a single receptor, with a single ligand [ 28 ].

In Drosophila , ErbB is made up of one receptor and four ligands [ 29 ]. EGFR pathways signaling studies in Drosophila have yielded tremendous information, especially regarding embryogenesis [ 30 ]. In normal cells, the expression of EGFR is estimated to be from 40,—, receptors per cell [ 33 ], whereas overexpression of more than 10 6 receptors per cell is observed in cancer cells [ 34 ].

Almost all cell types possess ErbB family members, with the exception of hematopoietic cells [ 41 ]. EGFR family genes are critical to the normal embryogenesis of vertebrates [ 42 ]. Null mutations of any of the ErbB genes in mice cause embryonic or perinatal lethality [ 43 , 44 ]. The specific phenotype depends on the genetic background of the mouse, but also on the ErbB family member that is knocked out. The lethality of EGFR null mice have been shown to be due to abnormalities in organs including in the brain, skin, lung, and gastrointestinal tract, as well as to the renewal of stem cells [ 45 , 46 ].

ERBB2 null mice die from cardiac trabeculae dysfunctions, but also exhibit malformations in motor nerves and sensory ganglia [ 47 , 48 , 49 ]. ERBB3 null mice suffer from defective cardiac formation [ 50 ] and severe neuropathies [ 51 ]. ERRB4 knockout mice die from defective trabeculation in the heart, similar to ERBB2 knockout mice, and also exhibit improper hindbrain-derived cranial neural crest cell migration [ 52 , 53 , 54 ].

EGFR also plays roles in rat embryonic skin maturation, hair follicle development, hair cycling [ 55 ], and corneal development [ 56 ]. In adolescence, EGFR family genes play key roles in mammary ductal development. Female mice with a TG substitution that impairs tyrosine kinase activity fail to develop proper mammary glands, due to defective ductal growth, causing their pups to die from malnutrition [ 57 , 58 , 59 ].

However, in mouse and rat astrocytes, EGFR is present in high levels in developing astrocytes, but becomes absent in mature astrocytes [ 61 , 62 ]. Interestingly, CNS disorders including ischemia, tumor development, and neurodegenerative diseases can re-upregulate EGFR in astrocytes, in a response termed reactive astrogliosis [ 63 , 64 ]. From N-terminal to C-terminal, the EGFR consists of 1 an extracellular ligand binding and dimerization arm exons 1—16 , 2 a hydrophobic transmembrane domain exon 17 , and 3 the intracellular tyrosine kinase and C-terminal tail domains exons 18—28 [ 43 ].

Here, we will describe the structure and function of each domain in the EGFR. The extracellular region of the EGFR is composed of amino acids and is subdivided into four domains, I amino acids 1—, exons 1—4 , II amino acids —, exons 5—7 , III amino acids —, exons 8—12 , IV amino acids —, exons 13— Domains I and III are leucine-rich fragments that participate in ligand binding.

Domain II forms homo- or hetero-dimers with the analogous domain of family members. Domains II and IV do not make contacts with the ligand, and are cysteine-rich regions. The TM domain is a 23 amino acid long hydrophobic single pass membrane structure, that anchors the receptor to the membrane [ 65 ].

It is 23 amino acids long, from Ile to Met [ 66 ]. The EGFR TM domain has been suggested to play a role in dimerization, as the N-terminal region of the TM helices have been hypothesized to contact during dimerization [ 67 ]. Furthermore, the ERBB2 TM may also be involved in aligning the intracellular domains through rotational twisting [ 69 ]. Transautophosphorylation relies on the interaction of the N-lobe of one receptor to the C-lobe of the other [ 72 ]. The kinase domain also contains lysine residues that are the primary sites of receptor ubiquitination.

The C-terminal tail includes various tyrosine residues, which when phosphorylated, allow the anchoring of a variety of intracellular proteins to the activated receptor. These proteins then participate in the signal transduction relay.

Certain types of cancers appear to favor certain locations for their mutations. For example, most glioblastomas appear to harbour aberrations to the ectodomain, whereas non-small cell lung cancers NSCLCs almost exclusively harbour kinase domain mutations [ 1 , 73 ]. Colorectal cancers less commonly harbour EGFR gene mutations [ 74 ]. Furthermore, some mutations allow the receptor to escape downregulation by endocytosis [ 79 ].

Mutations in the EGFR transmembrane region are rarely seen. EGFR ectodomain oncogenic alterations often cause the loss of the inhibitory regulatory domains for dimerization. The low constitutive activity is enough to impart cancer cells with increased signaling, however its growth advantage is due to the fact that these receptors are not downregulated by endocytosis [ 79 , 80 ].

While the mechanism of resistance of TM is not yet known, the bulkier methionine side chain may provide steric hindrance to TKI binding [ 89 ]. TM is located in exon 20, and other insertions in exon 20 have also been found to confer resistance to TKIs [ 86 ]. The first studies on the EGF in animals showed that it stimulated epidermal proliferation and keratinization [ 5 ]. We now know that the EGF can stimulate cell proliferation, cell differentiation, cell growth, migration, and inhibit apoptosis.

Furthermore, it was shown that EGF stimulation causes significant differences in expression of genes and proteins in human mammary epithelial cells HMEC [ 91 ]. Another study showed that the ERBB signaling network is estimated to encompass proteins and interaction [ 92 ]. Even without factoring in other types of post-translational modifications, it is clear that the effects of the EGF on the cell are profound and wide-ranging. The signal transduction mediated by the EGFR is extremely complex.

It begins with the EGFR being activated by one of its ligands, leading to receptor dimerization, the transphosphorylation of the C-terminal tail, and finally the propagation of the signal through various intricate signaling pathways to induce the expression of new genes. EGFR mutations and truncations can impart the EGFR with ligand-independent signaling, which lead to the upregulation of various pro-oncogenic processes, including chronic cell cycle proliferation.

Human EGF is a 6 kDa protein made up of 53 amino acids. Physiologically in humans, various organs regulate their innate EGF concentrations [ 93 ]. The sources of EGF from the human body have been documented previously [ 95 ]. EGF is implicated in the morphogenesis of teeth, brain, reproductive tracts, skin, gastrointestinal tracts, in cardiovascular differentiation and function, epithelial regeneration, and corneal epithelia reviewed in [ 96 ].

Each ligand appears to activate the EGFR in the same way: through ligand binding, receptor dimerization, receptor transautophosphorylation, and the recruitment of signaling proteins or adaptors. Despite these similarities, the activation of the EGFR by different ligands has been shown to cause distinct downstream biological activities [ 24 , 97 ]. The exact mechanism by which each ligand brings about distinct biological effects is unclear, however some theories have been put forward.

One theory is that each ligand induces preferred dimer pairs within the EGFR family, which leads to a distinct signal. Another theory examines the contribution of the type of ligand to the fate of the receptor. The differential sorting may be due to the different pH sensitivities of each ligand-receptor combinations. Therefore, since the ligand affects the location of the EGFR within the cell, each ligand is likely able to create distinct signaling patterns that tunes the biological response respectively.

Lastly, it is hypothesized that each ligand may cause different conformations of dimerized receptors, resulting in differential accessibilities of substrates to the C-terminal tail [ ]. The exact mechanism of the differential signaling is still a subject of research.

Most growth factors act in a paracrine fashion, where the growth factor produced from a cell targets a neighboring cell. However, examples of autocrine mechanisms have been documented. Originally elaborated by Sporn and Roberts [ ], this dangerous situation puts the cell in charge of its own cell division. For example, the EGFR is the target of sarcoma virus-transformed mouse fibroblasts, which encodes EGF-like molecules to stimulate its own growth [ ].

However, it was a matter of controversy which process occurred first. Dimerization of domain II is followed by rearrangements in the transmembrane domain that also leads to rearrangements in the juxtamembrane segment. The intracellular juxtamembrane segment then forms interactions with the kinase domain that are important for the formation and stability of the EGFR dimer [ ].

The EGFR dimer is an asymmetric EGFR dimer pair, in that the C-terminus of the activating kinase inserts into the active site of the receiving kinase, so that this allosteric interaction can activate the receiving kinase, resulting in transautophosphorylation [ 72 ]. This is different to other RTKs, where dimerization induces a conformational change that induces each receptor monomer to activate itself.

There is evidence that preformed unliganded EGFR dimers do exist [ , , ], however their precise structure and function are still controversial. Using quantum dot-based optical tracking of single molecules, researchers found that these preformed temporally-transient dimers were observed to be stabilized together at the dimerization arms, and were enriched at the cell periphery in regions of high actin and EGFR expression [ ].

However, others have argued against this, showing that preformed extracellular dimers of the EGFR are structurally heterogeneous [ , ]. Moreover, isothermal titration calorimetry measurements showed that pre-dimerized EGFRs did not have enhanced ligand binding, whereas ligand binding could promote dimerization [ ]. However, these studies were conducted using only the extracellular region of the EGFR that was engineered to self-dimerize with the addition of a dimerizing F c domain or of a dimeric leucine zipper.

The characterization of the interactions between EGFR domains remains difficult since many experiments are carried out predominantly with isolated domains, either extracellular, TM, or intracellular. As such, it is difficult to understand the synergy between each domain throughout ligand activation [ ]. This is in stark contrast to other RTKs that use the ligand as a bridge between receptors to form the dimer.

For example, two nerve growth factor molecules bridge together two TrkA receptors without the receptors ever making contact. Two intermediatory forms of dimerization have also been described. The first is the formation of a ligand-mediated dimer that includes receptor contacts, such as for c-KIT and stem cell factor.

The second, such as in the FGFR, includes a combination of bivalent ligand binding, direct receptor-receptor contacts, but also requires an accessory molecule [ 22 ]. These subtle differences lead to approaches by which pharmaceutical targeting of the EGFR could take advantage of these facts.

Large strides have been accomplished in elucidating the pathways involved in mediating EGFR activity. Current research largely focuses on the crosstalk and compensation between pathways, so to elucidate how cancer cells develop resistance to pharmacological inhibition of pathways and how to properly intervene.

The metabolic alterations mediated by these pathways are also of focus. We will focus on the important domains and amino acids that help propagate the signaling pathways. As these pathways are inter-linked, the activation of the EGFR actually stimulates an entire signaling network associated with a wide number of outcomes, such as cell proliferation, growth, differentiation, migration, and inhibition of apoptosis. In addition to these autophosphorylated sites, there are also residues that are phosphorylated by other kinases, which interestingly appear downstream in the EGFR-activation cascade.

Regardless, the newly phosphorylated tyrosine residues serve as docking sites for proteins harboring phosphor-tyrosine-binding residues, such as those with Src Homology 2 SH2 and phosphotyrosine binding PTB domains [ ]. A major target of cancer therapy is MEK.

ERK MAPK mitogen-activated protein kinase interacts with over a hundred substrates to initiate a wide array of physiological and pathological responses, including growth, proliferation, differentiation, migration, and inhibition of apoptosis [ , ]. Substantial bodies of evidence have supported the pharmacological targeting of this pathway for cancer treatment. Here, we will first briefly outline the domains and amino acid residues that mediate the binding of a protein to the next protein in the signaling cascade.

Then we will explore each protein in more details. Regardless, these two adaptors link the ligand-activated EGFR to complex intracellular biochemical pathways. For example, GRB2 can bind phospholipase D, which hydrolyzes phosphatidylcholine to form the important secondary messenger phosphatidic acid PA and choline [ ]. Therefore, the latest model for the RAS activation cycle is as follows [ ].

Activated RAS then engages with its downstream effectors. Active RAS has the ability to activate three major downstream effectors. The ability of RAS to activate these major pathways indicates why RAS-activating mutations or mutations within the RAS pathways are among the most common causative genetic alterations in cancer.

However, despite over 30 years of research, RAS has been described as undruggable. Typically, to inhibit the activity of kinases, the ATP-binding pocket usually represents a target of pharmacological blocking with relatively high specificity.

However, in the case of RAS, a functional GTP-catalyzing pocket is required to shut off its activity, precluding the site from pharmacological inhibition. Therefore, specifically targeting RAS is a difficult endeavor. Rather, RAS initiates RAF activation by translocating it to the plasma membrane, where additional membrane-localized activation events occur.

In addition to this site, the RAS cysteine-rich domain CRD, amino acids — has been shown to be important for the efficient activation of RAF-1 [ , , , ]. RAF is a serine-threonine protein kinase with complex regulation [ ]. RAF is composed of an N-terminus regulatory domain and a C-terminus kinase domain. Only a small pool of RAF-1 is activated in ligand-stimulated cells [ ]. Activated RAF-1 is phosphorylated at S and Y, which are about 20 amino acids upstream of the ATP-binding domain in the regulatory region [ ].

RAF S phosphorylation is induced by the addition of growth factor, however the molecular mechanism is unclear. It has been proposed that RAF S phosphorylation occurs by auto-phosphorylation [ ]. In addition, PAK1 has been shown to phosphorylate S, but likely in a growth factor-independent context [ , , ]. In addition to S and Y, the phosphorylation of S in the catalytic loop, and of T and S, have been reported to stimulate RAF-1 activity [ , ].

Both pS and pS are bound by , which keeps RAF-1 in an inactivate conformation [ , ]. The phosphorylation of S is catalyzed by AKT [ ]. The significance of the pS site is controversial, although it appears RAS-binding to the site is necessary for RAF-1 kinase activity [ ].

The requirement of the site has been difficult to study however, as mutations to S cause the mutant RAF-1 to lose kinase activity [ ]. Although appears to inhibit RAF-1 activity, its reversible association with RAF-1 appear necessary for its activation via RAS-dependent interactions [ , ].

Furthermore, serine residues 29, 43, , , , and have been reported as ERK-catalyzed phosphorylation sites, which are associated with feedback inhibition [ ]. In the cytosol, it can activate RSK1 p90 ribosomal S6 kinase 1 by phosphorylation at T, a site located in the C-terminal kinase domain activation loop of RSK1 [ ]. Activated ERK itself also translocates to the nucleus to activate ternary complex factor TCF transcription factors, which play a major role in the induction of immediate early genes IEGs [ ].

ERK is also known to regulate pyrimidine synthesis, chromatin remodeling, ribosome synthesis, and protein translation reviewed in [ ]. PI3K was discovered in the s by the Cantley group [ ]. It was shortly found to be activated by EGF stimulation [ ]. PI3K is comprised of a regulatory p85 subunit that mediates binding to the receptor, and a catalytic p domain that phosphorylates the 3-OH group of the membrane lipid phosphatidylinositol-4,5-bisphosphate PIP 2 to generate phosphatidylinositol-3,4,5-triphosphate PIP 3 [ , , ].

It is activated by a dual regulatory mechanism, requiring its translocation to the PM and phosphorylation at two conserved residues. T phosphorylation is necessary and sufficient for AKT activation, however maximal activation is achieved by phosphorylation at S [ , ].

Active PDK1 is autophosphorylated at S [ ]. There is no consensus on the role of each isoform in cells, due to the controversial pool of data regarding their function. AKT1 has been found localized to the cytoplasm and nucleus, AKT2 to mitochondria, and AKT3 to the nucleus and nuclear membrane [ ], although their localization may differ based on the cell type [ ].

AKT2 appears to be the main AKT responsible for glucose metabolism and the induction of apoptosis, which supports its mitochondrial role. In fact, Akt2 null mice seem unable to maintain glucose metabolism whereas Akt1 null mice maintain normal metabolism, but are smaller compared to normal mice [ , , ].

Many Akt1 null mice suffer embryonic lethality, suggesting Akt2 and Akt3 cannot fully compensate for Akt1 activity [ ]. In fact, it has indeed been observed that an Akt isoform will not compensate for the loss of another isoform, as Santi and colleagues found that siRNA ablation of one or two Akt isoforms did not significantly alter the subcellular localization of the remaining Akt isoform [ ]. Interestingly, some studies suggest opposing roles for the two isoforms.

Similarly, Arboleda and colleagues showed that AKT2 overexpression promoted adhesion and invasion in human breast cancer cell lines, whereas AKT1 overexpression did not [ ]. Another study found that AKT1 was important for lung tumor growth, whereas AKT2 inhibited this growth in mice [ ]. Overexpression of AKT1 has been reported in gastric and breast cancers [ , ]. Furthermore, the gain-of-function E17K somatic mutation of AKT1 occurs in breast, colorectal, and ovarian cancers [ ].

AKT1 also appears to mediate tumour development in Pten haplodeficient mice [ ]. On the other hand, AKT2 overexpression has been reported in ovarian, pancreatic, and colorectal cancers, and in hepatocellular carcinomas [ , , , ].

Genetic amplification of AKT2 is prominently observed [ , , ]. However, depending on the cell line, the AKT isoforms are differentially activated in a little understood RAS-dependant manner. In the absence of serum or growth factors, EGFR overexpression does not appear to constitutively activate AKT, however ERBB2 overexpression has been shown to do so in breast cancer cells [ , ].

AKT mediates its wide range of physiological responses through the activation or deactivation of several downstream proteins. Here, we discuss its role in mediating cell survival, in activating mTOR, and in metabolism. In terms of cell survival, AKT functions in an anti-apoptotic manner by directly phosphorylating components of the cell death machinery.

AKT also phosphorylates MDM2 at S and facilitates its translocation to the nucleus, where it ubiquitinates and downregulates p53, the well-known tumour suppressor [ , , ]. The mTOR receives stimulatory signals from growth factors through RAS and PI3K, as well as from nutrient inputs through amino acids, glucose, and oxygen availability [ ].

These two effectors of mTORC1 have tremendous impacts on protein synthesis and cell growth, as 4E-BP is an inhibitor of translational inhibition and S6K is an activator of translation [ ]. In normal cells, high oxygen levels favor the use of oxidative phosphorylation over glycolysis, as it is a more efficient mechanism for generating ATP.

Tumour cells however continuously use glycolysis even at high oxygen levels, a term coined aerobic glycolysis and also the principle behind the phenomenon known as the Warburg effect [ ]. Although aerobic glycolysis is less efficient than oxidative phosphorylation at generating ATP, cancer cells continue using it, as it also synthesizes macromolecules that support cancer growth, such as ribosephosphate, acetyl-CoA, and NADPH [ ].

AKT is one of the main drivers of the Warburg effect, as it increases glucose uptake through the upregulation of glucose transporters [ , ]. In addition, various components of the PI3K-AKT-mTOR pathway also coordinate the uptake of nutrients, including glucose, glutamine, nucleotides, and lipids, to better support the enhanced proliferation and growth needs of cancer cells [ ].

Thirteen PLC isozymes have been described so far, and they are grouped within six classes based on their function and regulatory activation mechanisms [ ]. Notably, the Plcg1 null knockout mouse is embryonic lethal at E9. IP 3 binds to IP 3 -receptors at the endoplasmic reticulum to induce intracellular calcium release. Phosphorylation at the activation loop of the kinase domain of PKC by PDK1 is necessary for its activation, and the specific residues that are phosphorylated have been characterized [ ].

Another substrate is phospholipase D PLD. The first virus ever identified to cause cancer encoded a viral isoform of c-SRC also known as pp60src. CSK c-Src kinase has been implicated as the kinase for Y [ , ]. Furthermore, auto-phosphorylation at Y Y in human c-SRC displaces the pYcontaining activation loop from the catalytic cleft, thereby allowing SRC to gain access to substrates [ ].

Phosphorylation of Y has been suggested as a diagnostic marker for various cancer treatments, including for NSCLCs [ , ]. However, as mentioned in Section 2. High levels of nuclear EGFR have been found in various types of cancers [ , , ], and nuclear EGFR signaling has been reported to mediate radio-resistance and chemo-resistance, such as to ionizing radiation and cisplatin [ , , ]. Nuclear EGFR appears to be the full-length receptor [ ].

The mechanism by which the EGFR translocates to the nucleus has been studied, but is still far from clear. Furthermore, similar to the majority of clathrin-mediated and non-clathrin-mediated forms of EGFR endocytosis, following internalization, the EGFR that is destined to the nucleus appears to first sort into endosomes, as nuclear EGFR has been shown to co-localize with endosomal markers [ ]. However, there is no established mechanism for the translocation of endosomal EGFR to nucleus.

In the nucleus, the EGFR supports gene regulation by acting as a transcriptional co-activator. The EGFR and its signaling pathways play key roles in oncogenesis. Two major classes of EGFR-targeted therapies have been developed. The first class of therapy developed includes humanized monoclonal antibodies against the EGFR extracellular domain, designed to block ligand binding or to mediate its downregulation [ ]. The second class includes tyrosine kinase inhibitors TKIs. These drugs have been approved for the treatment of non-small-cell lung cancer gefitinib and erlotinib , metastatic colorectal cancer cetuximab and panitumumab , head and neck cetuximab , pancreatic cancer erlotinib , and breast lapatinib cancer [ ].

Typically, EGFR inhibitors are used as monotherapy or in combination with cytotoxic chemotherapy or high-dose radiation. However, certain challenges still remain for the effective use of EGFR inhibitors. However, whether tumours with these different factors benefit from anti-EGFR therapy is still confusing and uncertain [ ]. For example, increased EGFR expression, typically determined by immunohistochemistry, was shown to not correlate with response to EGFR inhibitors [ , ], whereas another studied showed a positive correlation [ ].

It has been speculated that these controversial results are due to the variation in EGFR antibodies used in immunohistochemistry, and that a standardized testing method be established [ ]. Rindopepimut did not pass Phase III clinical trials and was discontinued in In addition to the challenge of implementing bio-markers for predicting response or resistance to anti-EGFR therapy, another challenge faced by the use of EGFR inhibitors is that the duration of the response is often limited and many tumours invariably develop resistance [ ].

Also, epithelial to mesenchymal transition EMT has also been shown to frequently accompany the acquisition of resistance to TKIs, although the mechanism of the transition is still under investigation [ , , , , ]. Lastly, skin toxicity remains a common side effect that frequently causes the discontinuation of the drug [ , ]. Other common side effects to EGFR inhibitors also include perturbations to the colon and cornea [ , , ].

The G1 arrest appears to be due to the upregulation of p27 KIP1 activity [ , , , , , , , , ]. Pharmacological inhibition of EGFR is highly beneficial to radiotherapy, as ionizing radiation can actually stimulate EGFR and activate its cryoprotective signaling cascades. Other mechanisms of action by which EGFR inhibition decrease tumour growth include the inhibition of angiogenic activity by reducing the secretion of vascular endothelial growth factor VEGF , decreasing cell invasion and metastasis by inhibiting the production of matrix metalloproteinase, and through the promotion of apoptosis in EGFR-addicted cancer cells reviewed in [ ].

For example, colorectal cancers often acquire resistance to cetuximab and panitumumab treatment [ , ]. Two direct inhibitors of MEK, trametinib and cobimetinib, have been approved by the FDA for melanoma treatment [ , ]. These mechanisms of RTK upregulation when challenged with PI3K pathway inhibition maintains receptor activity, which produce more PIP 3 to compensate for a loss of downstream signaling.

Furthermore, another mechanism underlying tumour resistance to mTOR inhibition is the upregulation of autophagy [ ]. The biological response of EGFR signaling is mediated by the activation of transcription factors. A pulse of EGF stimulation during early G1 and another at late G1 are sufficient to drive cells past the restriction point R point , the instant at which the cell commits to the completion of the cell cycle [ , , ]. These types of cancers also have lower patient prognostic values.

Constitutively active oncogenic EGFR uses these pathways to continuously drive cells past the R point to promote hyperplasia. Sustained ERK activation is required for progression of G1 into S, as transient ERK activation due to insufficient doses of growth factor does not lead to S-phase progression [ ].

This has been proposed to be due to a poorly understood APdependant manner [ ]. These include the oral drugs palbociclib, abemaciclib, and LEE, with both palbociclib and LEE having been recently approved for breast cancer in combination with letrozole, an aromatase inhibitor.

However, this combination would need to effectively eliminate cancer cells before they demonstrate classical signs of resistance to EGFR inhibitors, including the de novo upregulation of EGFR signaling pathways Section 2. The EGFR is at the head of one of the most important signaling pathways to mammalian cell physiology, and to oncogenesis.

As this review has shown, tremendous amounts of research has been conducted on each of the many components of the EGFR. The sum of our knowledge from this vast array of research is allowing us to create even more effective drugs or drug combinations to target cancers with EGFR aberrations. In addition to understanding these signaling pathways in cancer, the spatial and temporal regulation of the EGFR remain understudied. For example, spatially, EGFR internalization by endocytosis results in EGFR signal attenuation, and has been studied by many groups [ 93 , , , , ].

In addition to endocytosis, although the EGFR has been well-studied temporally for its role in G1, its function throughout the rest of the cell cycle—S, G2, and mitosis—remains rarely studied. For example, the EGFR has been seldom studied during mitosis, yet a differential regulation of its signaling and endocytosis is apparent [ , , , ].

Further investigations of EGFR function throughout the rest of the cell cycle are warranted. National Center for Biotechnology Information , U. Journal List Cancers Basel v. Cancers Basel. Published online May Samuel C. Mok, Academic Editor. Author information Article notes Copyright and License information Disclaimer.

Received Apr 7; Accepted May This article has been cited by other articles in PMC. Abstract The epidermal growth factor receptor EGFR is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Signal Transduction The first studies on the EGF in animals showed that it stimulated epidermal proliferation and keratinization [ 5 ].

Open in a separate window. Figure 1. Conclusions The EGFR is at the head of one of the most important signaling pathways to mammalian cell physiology, and to oncogenesis. Acknowledgments P. Conflicts of Interest There are no conflicts of interest to report. References 1. Pines G. FEBS Lett. Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal.

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Okabayashi Y. Tyrosines and of activated human epidermal growth factor receptors are binding sites of Shc in intact cells. Sakaguchi K. Shc phosphotyrosine-binding domain dominantly interacts with epidermal growth factor receptors and mediates Ras activation in intact cells. Salcini A. Formation of Shc-Grb2 complexes is necessary to induce neoplastic transformation by overexpression of Shc proteins.

Van der Geer P. A conserved amino-terminal Shc domain binds to phosphotyrosine motifs in activated receptors and phosphopeptides. Chardin P. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling.

Egan S. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Rozakis-Adcock M. Simon J. Boriack-Sjodin P. The structural basis of the activation of Ras by Sos. Brtva T. Two distinct Raf domains mediate interaction with Ras. Xiang X. Zang M. Characterization of Ser phosphorylation for Raf-1 activation. Subject: Adequacy of reform of data security and implementation of the recommendations in the Echelon report.

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Subject: Upper rate of VAT for goods or services not in the environmental, public health and food safety domain. Subject: Follow up to written question on alleged forced sterilisations in India. Subject: Redevelopment of former sugar factory in Finale Emilia. Hence, is it not time for the Commission to make structural changes to ongoing adjustment programmes?

All economic adjustment programmes are designed to address the severe problems and imbalances at the root of the crisis in the respective countries and are agreed between the Government and its creditors. The Commission's role in these programmes is to act on behalf of the euro area Member States, including when negotiating a memorandum of understanding. Programme reviews that take place every three months allow checking both the implementation of reforms and their effect of the economy.

As warranted, changes are decided by the euro area Member States, including the country concerned. In — , it financed the creation of networks to promote preventative measures in amateur sport, sport for all and physical exercise.

An assessment of these measures would seem premature at this stage. However, these projects have already contributed to the development of joint EU initiatives in the field of sport. The Commission has supported this work logistically and financially and the draft recommendations of the Experts will be ready for adoption by the Council before the end of Funds will be spent according to rules and procedures still to be adopted for the programme in general.

For historical and cultural reasons and because of ethnic and political affinities, shared values and common civilisation references, Canada is an important and reliable partner of the European Union. There are obstacles in this relationship, specifically in fishing, security and immigration.

However, compared to other countries, EU-Canada relations are stable and fruitful for both partners. When concluded, these two agreements will take our relations with Canada to another level and promote a deepening of ties across the board. The CETA will be a ground-breaking agreement, which seeks an ambitious liberalisation of trade and investment relations.

The aim of the SPA is to advance EU-Canada foreign policy and sectoral cooperation beyond the Framework Agreement and the Partnership Agenda, and to provide a platform for joint action in the international arena. The EU and Canada have shared interests and cooperate, inter alia , in foreign and security policy, in the field of justice and home affairs, in reinvigorating global economic growth, and in tackling global challenges including climate change and poverty in developing countries.

The next EU-Canada summit, to be hosted by Canada, has not yet been scheduled. The conflict between Russia and Georgia, a country which has stated its desire to join the European Union and to adhere to its values, has underlined the urgency for a European strategy for the South Caucasus. Under the Eastern Partnership, the European Union offers political association and economic integration to the countries of the South Caucasus.

This sets out the roadmap for achieving the Protocol's aims, including the establishment of regional and national strategies. It is too early to make any sort of assessment about the implementation of the Protocol. The action plan will be subject to a mid-term review and evaluation in De que modo? Has its application brought about a collective response that is stronger and more capable of facing the challenges that terrorism and cross-border crime place on our legal systems and police forces?

In what way has it done this? The Commission is not aware of activities in the two countries regarding the preparation of the implementation of the provisions of the Agreement. Which ones? The participation of the Swiss Confederation and the Principality of Liechtenstein in the work of the Frontex Agency is based on specific Arrangements concluded to that effect between each of the Schengen Associated Countries Iceland, Norway, Switzerland, and Liechtenstein and the European Union.

The Commission values the level of participation of the four Schengen Associated Countries in the work of the Frontex Agency, and expects the Associated Countries to continue to support the coordination work undertaken by the Agency at the external borders of the European Union. The European Union cooperates in many fields with Switzerland and Liechtenstein respectively.

Any cooperation going beyond the existing policy fields would need to be assessed on a needs basis taking into account the general relations between the European Union and these two countries. Que perspetivas futuras oferece? What future prospects does it offer? Has the bilateral protection clause been applied? EU exports to Korea are up by The prospects are therefore bright and EU exporters are also making increasing use of the preferential tariffs. The creation of a European public sphere was met with indifference by the people of Europe and disinterest by national public opinion.

This does not seem to justify the massive investment made in information and promotion by the institutions, which previously distanced themselves from the European project in a worrying manner. The European Commission's communication activities are driven by the desire to involve citizens and listen to their concerns — and thereby strengthen a European Public Space as highlighted in last year's State of the European Union speech by President Barroso.

One of the central aims is to discuss European affairs from European point of view. This is work in progress, nor something which is already created as the question implies. The European Year of Citizens which will be evaluated at the end of the project has been designed, together with the European Parliament, as the vehicle for stronger engagement. Members of the Commission, Members of the European Parliament as well as national and regional politicians take part. The dialogues with citizens will continue in the run-up to the European elections in The Commission's Recommendation for the next election of the European Parliament also supports a European Public Space by suggesting European candidates for the post of President of the Commission, by highlighting the role of European party families and advocating to vote on a single day in all Member States.

Of course the Commission will also support the European Parliament's communication campaign. In a report conducted by the European Transport Safety Council, it is emphasised that fatigue can be exacerbated by three key elements:. Sleep-related component the amount and quality of sleep, time since the last period of sleep and sleep inertia ;.

Task-related component time-on-task, i. Each of these needs has to be considered as part of a fatigue management process. How will the Commission ensure that its proposal will take all these three elements into account when proposing new FTLs? The same report underlines that sleep taken when on standby is always for shorter periods and of poorer quality.

Moreover, there have been no studies into the effects of standby with regard to fatigue. How will the Commission take the issue of standby into account when evaluating the new FTLs, and will standby if it interferes with normal sleep patterns be counted towards flight duty periods? The Commission's intention is to put in place even stricter safety rules with a view to implement those principles. It has therefore launched a corresponding amendment. This concerns for example stricter more protective rules concernig nigh duties or the rules on in-flight rest or standby duties.

The Honourable Member is right in pointing out that there are no studies concerning the effects of standby with regard to aircrew fatigue. For this reason, the Commission has based itself on best national practices, on operational experience and on aircrew fatigue principles. According to the Commission, standby periods interfering with normal sleep patterns should be counted as duty periods under certain circumstances.

Pur stabilendo norme comuni sulle condizioni e procedure di concessione dello status di rifugiato, il diritto dell'UE in materia di asilo attualmente non prevede il mutuo riconoscimento, da parte degli Stati membri, dello status di rifugiato concesso da altri Stati membri. The normal practice in such cases is for people to be kept in the detention centre for some months prior to expulsion and for scheduled flights or special flights arranged by the Frontex agency to be used for that purpose.

In its latest report, Amnesty International states that the Kazakh police and security forces regularly use torture against political opponents and dissidents. The issues set out by the Honourable Member raise questions as regards the compatibility of the actions taken by the Italian authorities with the EU's return and asylum acquis.

The Commission, in close contact with the European External Action Service, will examine carefully the reply from the Italian authorities and closely monitor any further developments. Although EU asylum law establishes common rules concerning the conditions and procedure for granting refugee status, it does not currently provide for mutual recognition by Member States of refugee status granted by other Member States.

The recently approved general guidelines on transport in Europe stress the Atlantic corridor as an investment priority with a view to constructing infrastructure with European added value. This would mean a project to resolve one of the long-standing bottlenecks hindering rail transport Spain and France. The report states that the high-speed link between Bordeaux and Toulouse is a priority and that the construction of the new line between Bordeaux and Hendaye — part of the Atlantic corridor and a source of bottlenecks — is to be postponed until after These criteria encourage the development of infrastructure projects providing cross-border connections, promoting intermodality, providing links to at least one main sea port and increasing the capacity of saturated routes.

Does the Commission think that the new plans are consistent with the commitments made by France during the negotiation and approval of the trans-European transport routes? As the Honourable Member pointed out, some of the conclusions of this report may appear not to be fully in line with the objectives of the proposed Trans-European Transport Network TEN-T such as the completion of a new high speed line between Bordeaux and Hendaye after , whereas the Bordeaux — Toulouse high speed line is proposed to be completed by Both sections are part of the Core Network and could receive funding from the Connecting Europe Facility, with higher co-funding rates for the cross-border sections than for the national ones.

Ist die Kommission der Auffassung, dass Gebiete, die der Kommission als EU-Vogelschutzgebiete gemeldet, aber noch nicht nach nationalem Recht ausgewiesen wurden, als faktische Vogelschutzgebiete anzusehen sind? The German army is planning to construct a new mock town covering an area of around 6.

The project will have a considerable negative impact on the conservation objectives of the FFH area and the registered bird protection area. What stage has the complaint reached, and how long is the procedure expected to take? Does the Commission think that areas which have been registered with it as EU bird protection areas but which have not yet been designated as such under national law do in fact constitute bird protection areas?

The Commission will endeavour to take a decision on the substance either to open infringement proceedings or to close the case within twelve months of registration of the complaint. The Commission decides from case to case which steps are to be taken.

Wann wird die EU-Kommission konkrete Leitlinien bzw. Many local authorities in Germany — particularly in Bavaria — also have such models, under which local residents can purchase building land in their place of residence at a discount. The Commission has opened infringement proceedings against Germany on this matter, and these are currently pending.

The aim is for rural areas especially to remain attractive as places to live. When will the Commission publish specific guidelines or a detailed list of criteria for the permissibility of local models so that local authorities can be sure of legal certainty in this matter?

Is it true that local models are permitted if they take the following criteria into account, at least to a reasonable degree: residence locally; income level; number of children; employment in the district; voluntary activities; family members in the district in need of care? When does the Commission expect to complete the infringement proceedings against Germany? As mentioned by the Honourable Member, the Court of Justice has confirmed that the purpose of responding to the housing needs of low-income or other disadvantaged sections of the local population can constitute an overriding reason in the public interest justifying restrictions on fundamental freedoms, provided that the measures are appropriate and proportionate to the objective pursued.

The Commission does not intend to publish guidelines or detailed criteria for this assessment. Several hundred workers could be affected in this sector. The workers believe that they should be entitled to receive some financial compensation. Is the Commission considering taking appropriate measures e. Could supportive measures be implemented through the funding from the European Social Fund or by using any other available EU instrument that might contribute to the solution of this problem?

The Commission is fully aware of and takes into account the challenges that Croatia's labour market is going to face following the accession to the European Union and in view of global economic trends. Funding from the European Social Fund ESF is available to help undertake the necessary adaptation not only in the labour market but also in the education system, as well as to improve social inclusion and strengthen institutional capacities.

The Commission and Croatia are now commencing discussions for programming investments to be supported by the ESF in the period for The issue of the forwarding agents will also be tackled. There will be a possibility for persons employed as forwarding agents to use training and retraining measures offered through active employment measures by the Croatian Employment Service CES which will be co-financed by the ESF.

Through individual counselling the redundant workers have been offered several possibilities of support whose details can be obtained from the Ministry of Labour and Pension System which is the Managing Authority responsible for the ESF operational programme in Croatia. Regional CES offices will continue with visits to the employers and with mobile team activities in order to establish possible redundancies of forwarding agents and in order to provide services to workers based on established plans.

Angesichts dieses Urteils:. Welchen Standpunkt vertritt die Kommission in Bezug auf Systeme, die Dienstleistungserbringer verpflichten, sich vor der zeitweiligen Erbringung von Dienstleistungen in anderen Mitgliedstaaten zu melden? Belgien hat am Oggetto: Libera prestazione di servizi e obbligo di registrazione prima della prestazione di servizi.

Alla luce della sentenza:. Come valuta la Commissione la misura proposta dal governo belga per rispettare la decisione? Inoltre, ha stabilito che la legislazione belga in questione richiede informazioni di natura dettagliata dai prestatori dei servizi prima della prestazione, senza una giustificazione sufficiente per quanto riguarda sotto qual profilo la comunicazione di tali informazioni risulti necessaria per conseguire gli obiettivi di interesse generale da esso invocati e sotto qual profilo l'obbligo di previa comunicazione di tali informazioni non vada oltre i limiti di quanto necessario ai fini del conseguimento degli obiettivi medesimi.

Betreft: Vrijheid van dienstverlening, verplichte registratie voor het begin van de dienstverlening. In het licht van dit arrest wilde ik de Commissie het volgende vragen:. Wat is de mening van de Commissie over de maatregel die de Belgische regering heeft voorgesteld?

Wat denkt de Commissie over regelingen die dienstverleners verplichten zich te laten registreren voor het begin van het tijdelijk verrichten van diensten in een andere lidstaat? Het Hof oordeelde ook dat de in het geding zijnde Belgische wetgeving vereiste dat de dienstverleners voorafgaand aan de dienstverlening zeer gedetailleerde informatie verstrekken, zonder voldoende rechtvaardiging van het feit op welke wijze de verstrekking van die informatie noodzakelijk is om de doelstellingen van algemeen belang waarop de wetgeving berust te bereiken en op welke wijze de verplichting om die informatie vooraf te verstrekken niet verder gaat dan hetgeen noodzakelijk is om die doelstellingen te bereiken.

Die conclusies kunnen gelden voor andere soortgelijke systemen op grond waarvan zelfstandige dienstverleners in het algemeen verplicht zijn vooraf mededeling te doen van de aanvang van hun activiteiten. Jakie jest stanowisko Komisji nt. In view of this judgment:. Is the Commission aware of the existence of the similar systems in other Member States? It also found that the Belgian legislation at stake required very detailed information from service providers in advance of the service provision, without sufficient justification as to how the provision of that information is necessary in order to achieve the objectives of public interest on which it relies and how the obligation to give that information in advance does not go beyond what is necessary to achieve those objectives.

These conclusions could apply to other similar systems obliging self-employed service providers in general to notify the commencement of their activities in advance. The financial and economic crisis is, at the moment, spilling over to become a social crisis, too. Youth work, in particular detached youth work, is a very effective tool to enhance the skills, development and social inclusion of young people in times of high youth unemployment.

In addition, in the context of the crisis, the Commission has proposed the Youth Opportunities Initiative in an effort to enhance the employability of young people. However, youth work is very developed in certain Member States, but under-developed in others. In times of financial crisis, it is very important that youth work does not lose ground, and it should focus particularly on marginalised and disadvantaged young people with fewer opportunities.

In line with this, is the Commission planning on launching any initiatives to address this imbalance between different Member States? The Commission shares the opinion expressed by the Member as to the effectiveness of youth work in the development of skills and competences of young people; the non-formal learning approach implemented by youth work is a useful way to enhance the employability of young people as well as their active participation in society, thus contributing to their social inclusion.

The Commission promotes youth work in various ways, all of which should help, over time, to encourage more balanced progress across the European Union:. Objet: Le bon fonctionnement de la libre circulation des capitaux. Restitution of property is considered a capital movement.

Any restriction also have to observe the principle of proportionality, requiring that the measures are appropriate to attain the objectives which they pursue and do not go beyond what is necessary in order to attain them, and have to be non-discriminatory. Based on the limited amount of information available to the Commission, it is not possible to give a more detailed answer regarding the situation referred to by the Honourable Member.

They have been responsible for crushing dissent inside Iran, and are accused of funding numerous terrorist activities outside the country. In particular, they have allegedly funded and armed the Taliban, Hamas and Hezbollah, assassinated Iranian dissidents abroad, and assisted the planning of multiple plots to commit atrocities, particularly in Israel, a country which the IRG have stated they wish to destroy.

The United States and Canada have already proscribed Quds as a terrorist organisation. In addition, a number of members of IRGC and other entities owned or controlled by IRGC are also listed under the nuclear sanctions regime because of their involvement in the Iranian nuclear programme.

Il meccanismo di assistenza tecnica JASPERS stabilito per i nuovi paesi che hanno aderito all'UE nel e nel fornisce agli Stati membri interessati un sostegno e una competenza specializzata mirata relativamente ai principali progetti finanziati dall'UE.

Non ritiene la Commissione che, date le persistenti avverse condizioni economiche, l'accesso a detto meccanismo debba essere consentito a ogni Stato membro che lo richieda? Prevede la Commissione di estendere a nuovi paesi la partecipazione a detto meccanismo? In caso contrario, per quali motivi? Does the Commission not take the view that, owing to the persistent adverse economic conditions, access to this facility should be granted to any requesting Member State?

Is the Commission considering including more countries in the list of eligible participants? Is the Commission planning to extend participation in this tool to new countries? If so, which ones? If not, why not? What are the conditions that need to be met in order for a country to be included? This was justified by the need to ensure support to those Member States in the preparation of large infrastructure projects for financing under the European Regional Development Fund and the Cohesion Fund, particularly in areas where those Member States lacked the necessary knowledge and experience.

More recently, the Commission agreed to extend some support under JASPERS to Greece, to boost the capacity of the Greek authorities to prepare sound projects for urgent implementation in the context of the current economic crisis. Die Tabakerzeugung wird dabei neutral behandelt. It will probably again be possible during the forthcoming aid period to apply for European aid funds for growing and processing raw tobacco as an agricultural product.

What interactions does the Commission anticipate from the interplay of these two approaches? Does the Commission consider that subsidising tobacco farming, while at the same time applying trade restrictions in a bid to limit tobacco consumption, adds up to a coherent policy? What grounds can the Commission cite for the need for uniform pan-European regulation of tobacco products? Why is this a task for the European Union? Special financial support for the raw tobacco production was phased out in according to the reform of the common agricultural policy CAP of The production of raw tobacco is fully integrated into the general agricultural policy instruments.

Tobacco production is treated in a neutral way. However, the tobacco sector is not included in the list of products eligible to the voluntary coupled support scheme applicable from onwards. The aim of this new scheme is to grant a support in regions or sectors undergoing certain difficulties.

The aid to the Canary Islands for several products is guided by the same objective. Furthermore, the Rural Development RD programmes of the CAP, offer numerous possibilities to help farmers who decide structural changes in production.

Oggetto: Aumenti tariffari ingiustificati dei prodotti omeopatici. La Commissione non ha potere per intervenire nella definizione di tali tariffe a livello nazionale. These measures clearly stand at odds with the procedures in various other EU Member States e. France and Germany and irreversibly damage the competitiveness of Italian businesses, which are forced to withdraw products from the market because of high registration fees, as well as that of foreign companies operating in Italy, the third biggest market in Europe after France and Germany.

Does the Commission believe that such an increase dramatically alters the balance of the market? Does it have the authority to encourage Italy, the third biggest market in Europe in terms of turnover, to bring itself in line with the legislation in force in Germany and France for homoeopathic medicines? Rules, such as those of the Italian Decree-Law mentioned by the Honourable Members in their question, setting fees for the national registration of homeopathic medicines are the exclusive responsibility of Member State authorities.

The Commission is not empowered to intervene in the setting of these fees at national level. L'organizzazione di elezioni rientra nelle competenze degli Stati membri. Compared with countries with a perfect or almost perfect gender balance in their representations in Parliament — such as Finland, Slovenia, Estonia, the Netherlands and Denmark — women are greatly under-represented in the delegations of most Member States in Parliament.

Organisation of elections falls within the remit of Member States. However, encouraging the participation of EU citizens in the democratic life is a high priority on the Commission's agenda. The Commission took measures to address the gender imbalance in the European Parliament with the adoption in of the specific programme Fundamental Rights and Citizenship.

More specifically, one of the annual thematic priorities for was dedicated to improving the gender balance in the European Parliament. Thus, the Commission has been funding several projects of NGOs and other organisations awarded under this priority. Le garanzie fondamentali in materia di protezione dei diritti umani previste dalla Costituzione del Pakistan non sono in vigore nelle aree tribali, dove vige il regolamento sui crimini di frontiera risalente all'era coloniale.

Nel , inoltre, i regolamenti di azione a sostegno del potere civile hanno dato all'esercito ulteriori poteri arbitrari d'arresto e imprigionamento. I modesti tentativi del governo pakistano di modificare il regolamento sui crimini di frontiera non sono stati all'altezza delle norme e degli standard internazionali sui diritti umani e sono stati ulteriormente compromessi dall'entrata in vigore dei regolamenti del Quali azioni intende dunque promuovere l'Alto Rappresentante per sollecitare il governo pakistano a una riforma del proprio sistema legale, profondamente difettoso e causa del perpetuarsi del ciclo di violenze nelle aree tribali?

According to statements by United Nations representatives on the ground, many men detained by the armed forces have alleged torture, and others have never been seen again after being transferred to secret detention centres. The Taliban and other armed groups also continue to pose a deadly threat to Pakistani society, often carrying out brutal, unlawful killings of captured soldiers or suspected spies, sometimes following quasi-judicial proceedings that fail to meet even the most basic international fair trial standards.

Although the armed forces have regained control of most of the tribal areas over the past three years, they have arbitrarily arrested thousands of people, imprisoning them for long periods with virtually no due-process safeguards. Moreover, in the armed forces were granted further sweeping powers of arrest and detention under the Actions in Aid of Civil Power Regulations. Although the courts have nevertheless heard cases challenging the lawfulness of some detentions, there have been no prosecutions of armed forces personnel for alleged torture, enforced disappearance or deaths in custody.

Limited attempts by the Pakistani Government to reform the FCR have fallen far short of international human rights law and standards, and have been further undermined by the entry into force of the regulations. What action will the High Representative therefore take to urge the Pakistani Government to reform its legal system, which is deeply flawed and the cause of the constant violence in the tribal areas? This issue will be raised with the new government of Pakistan in the next EU-Pakistan human rights dialogue which is expected to take place in the autumn of Oggetto: Anomala moria di delfini nel Mar Tirreno.

Il Ministero dell'Ambiente ha deciso di monitorare la situazione e di allertare il reparto ambientale marino. Secondo i primi accertamenti sarebbe possibile escludere, quale causa dell'insolita moria, eventi eccezionali causati dall'uomo, come versamenti in mare di petrolio o di sostanze inquinanti. Sembra essere invece probabile una causa di natura infettiva a causa delle tracce del batterio Photobacterium Damselae rinvenute su 6 carcasse esaminate. Per avvalorare tale ipotesi gli esperti sono alla ricerca dell'eventuale presenza di virus o fioritura di alghe anomale.

Since the start of the year an environmental crisis has been affecting the seas off Italy: since January, dozens of striped dolphin carcasses have been found along the Tyrrhenian coast. This represents an abnormally high mortality rate compared with the historical average of about four corpses found per year.

The Ministry of the Environment has decided to monitor the situation and to alert the marine environment department. According to initial findings, any exceptional man-made events, such as oil spills or pollution, can be ruled out as the cause of these unusual deaths. The probable cause actually seems to be an infection, as shown by the traces of the Photobacterium Damselae bacterium found in six of the carcasses examined. In order to confirm this hypothesis, experts are looking for the presence of viruses or abnormal algae blooms.

Pending concrete data comparing theoretical knowledge of sea currents with marine weather data from the last few months, the Italian Ministry of the Environment has requested information about any animals washed up on the beaches of France and Spain in order to obtain a more accurate picture of the situation. Is the Commission aware of the unusual dolphin deaths in the Tyrrhenian Sea over the last few months?

If so, has it launched an investigation to establish the cause? Molte delle aziende in cui sono occupati producono abbigliamento per marchi internazionali o applicano illegalmente etichette di marchi internazionali. Altre piccole fabbriche della zona lavorano in subappalto.

Molte sfruttano il lavoro in nero dei birmani e producono prodotti con marchi falsi. I lavoratori birmani clandestini vivono spesso nelle fabbriche dove lavorano, dormono e mangiano e vengono nascosti ogni qualvolta vengano compiute ispezioni da parte della polizia tailandese. Solo gli immigrati regolari sono assunti con contratto.

Gli orari di lavoro sono estremamente lunghi e non di rado i lavoratori effettuano gli straordinari sino alle 11 di sera. Secondo quanto riportato da fonti locali, in alcune aziende sarebbero impiegati anche i bambini delle lavoratrici migranti adibiti alla pulizia nelle fabbriche tessili.

Many of the companies in which they work produce clothes for international brands or illegally use international brand labels. Some of the work is subcontracted to other small factories in the region. Only legal immigrants are given an employment contract. The dormitories are too small and overcrowded, there is a total lack of hygiene and, to make an already complicated situation even worse, there are no procedures in place to resolve any disputes that arise with their employers. According to local sources, even the children of some migrant workers are employed to clean the textile factories.

The EU pursues this matter in several ways, both in bilateral dialogues with the Thai authorities, and within the relevant international bodies. The EU supports the ratification and effective implementation of the Conventions of the International Labour Organisation ILO , in particular with regard to the core labour standards, and cooperates with the ILO in this respect.

Such instruments also address health, safety and labour conditions along companies' supply chain. When finally concluded, the EU-Thailand Partnership and Cooperation Agreement will provide for an additional framework for discussion and engagement with Thailand on these topics.

A circa tre anni e mezzo di distanza la situazione abitativa nel paese resta sconcertante, con circa Qualche mese prima, nell'agosto , grazie al sostegno dei donatori internazionali, il governo haitiano aveva lanciato un programma per trasferire i residenti di 50 tendopoli in 16 nuove strutture residenziali, attraverso un incentivo per famiglia di dollari per 12 mesi e 25 dollari per i trasporti.

Il progetto ha aiutato alcune famiglie, ma gli incentivi troppo bassi hanno impedito a molte altre di trasferirsi e accedere a una soluzione abitativa a lungo termine. La catastrofe del ha peggiorato seriamente la situazione a Port-au-Prince costringendo 1,5 milioni di persone a rifugiarsi nei campi per gli sfollati interni.

Living conditions in the tent cities are worsening by the day and there is little access to water, sanitation and waste disposal. This has contributed to the spread of cholera and other infectious diseases.

Furthermore, women and girls, as already highlighted in a previous written question, are at constant risk of rape or sexual assault. Although the project has helped some families, the incentives are too low, preventing many others from moving and gaining access to long-term housing. The withdrawal of the main humanitarian operators from Haiti and the resulting funding cuts are making the situation even worse. In view of the above, what measures will the High Representative take to try to resolve the difficult issue of housing in Haiti?

Is she aware that resolving this problem would secure more rights for the Haitian population? Housing is a chronic problem in Haiti that predates the earthquake. The disaster severely aggravated the housing shortage in Port-au-Prince and forced 1. The EU responded immediately to this humanitarian challenge. To complement the humanitarian response, the national authorities and international donors have launched several initiatives aimed at the provision of sustainable housing.

The EU has also made urban reconstruction one of its priority areas of intervention. A sustainable, long-term solution to the issue of housing in Haiti requires addressing deep-rooted structural causes, including widespread poverty and the absence of a national housing policy.

Welche Leistungen werden erbracht? Wenn ja, welche und warum? Wie stellt die Kommission sicher, dass derartige Interessenkonflikte bekannt werden? What benefits are obtained? Were contracts awarded without a public invitation to tender? If so, which ones and why? Can the Commission state whether any former IMG employees are now working in its services as local members of staff? Can it state whether any family members of IMG employees are working in its services as local members of staff?

Can the High Representative state whether any former IMG employees are now working in her services as local members of staff? Can she state whether any family members of IMG employees are working in her services as local members of staff? The countries concerned benefit from the transfer of public expertise in post-conflict zones. IMG has undergone an assessment which concluded that IMG applies accounting, audit, internal control and procurement procedures equivalent to internationally accepted standards.

The Commission may entrust implementation to such an organisation through joint management. The selection has to be justified in an objective and transparent manner. Eight of the 11 ongoing contracts were awarded in this manner, while three through negotiated procedure in accordance with the provisions for flexible contract award procedures in crisis situations defined in the Financial Regulation.

The Commission is not in a position to know about activities of family members of its partners. All staff members are obliged to declare any conflict of interest they could incur during the accomplishment of tasks. Non-disclosure of any potential conflict of interest would expose staff members to disciplinary sanctions. Members of an evaluation committee have to sign a confidentiality and impartiality declaration.

Rules concerning ethical and organisational values are regularly brought to the attention of Delegation staff including local agents. Asunto: Litigios comerciales entre la UE y China. What measures is the Commission taking to protect wine growers and distributors from this trade dispute?

Does the Commission have an action plan to protect European interests, given that the number of trade disputes continues to multiply in direct relation to commercial ties? In this context, it has been providing the Member States and wine industry stakeholders with relevant assistance and has been also in contact with the Chinese authorities to ensure a good level of bilateral cooperation and compliance of the pending proceedings with the WTO rules.

As a result of these pre-consultations, China narrowed down the number of alleged subsidy schemes it is investigating. The Commission is of the opinion that China has the right to initiate AS and AD investigations and to impose trade defence measures provided that the relevant WTO rules are respected. The Commission always carefully analyses the merits and development of such investigations and in this context actively cooperates with relevant stakeholders.

Should that not be the case, the Commission would not hesitate to duly intervene. There are still barriers to the digital sale and distribution of audiovisual content. Making digital audiovisual content available to potential users, regardless of their geographical location and no matter where the content has been licensed, will benefit consumers and rights holders as a result of competition and broader exposure.

Does the Commission have in place any concrete measures to ensure the completion of the digital single market? In spite of this agreement, however, Israel continues to violate the rights of Palestinians throughout occupied territories. Among these rights abuses are policies aimed directly at ridding the city of Jerusalem of its Palestinian population. Nonetheless, Israel continues with its strategy to purge the city of Palestinians which, since , has included the revocation of over 14 IDs from Palestinians in Jerusalem, thereby stripping them of their right to live in the city in which they were born.

The concrete effects that the use of each of these instruments has had on Israeli policies over the past twenty years? What will be the main measures? What steps will be taken to facilitate disability vetting procedures? Under the EU's Lifelong Learning Programme LLP , mobile learners with special needs may benefit from specific measures, including subsistence and travel costs of an accompanying person.

LLP National Agencies make all information and offices accessible to disabled people. All activities described above take into account the guidance and expertise provided by the European Agency for Development in Special Needs Education. Esos pasajeros tienen derecho a asistencia gratuita en los aeropuertos, puertos, estaciones de ferrocarril y de autocar y a bordo de los distintos medios de transporte. The purchase of goods and services and relevant and accessible information on them should include appropriate commercial solutions, as well as goods and services designed to be accessible in the long term.

The European Design for All e-Accessibility Network EDeAN is a network that provides support and resources in the field of universal design, and this centre of excellence and the associated organisations in each of the Member States are responsible for drafting reports, conducting studies and promoting the exchange of knowledge, information and good practice. Are these data taken into account in the European institutions? Does the Commission think it should take legislative and practical measures to support these associations, requiring manufacturers to market their products with disabled people in mind?

Are disabled consumers informed of their rights with regard to products and services that do not take account of their needs? EU passenger rights legislation ensures that disabled persons and persons with reduced mobility have the same rights to travel as other passengers and cannot be discriminated upon booking or boarding on the ground of their disability.

These passengers have the right to free of charge assistance at airports, ports, railway stations and bus terminals and on-board. En la respuesta conjunta de la Sra. The Commission will follow closely this matter. The Commission also understands that the Spanish Constitutional Court will examine the amended provisions on court fees. De hecho, en el caso de los taxis, hay muy pocas unidades adaptadas a pesar de que, por insuficiencias de otros medios de transporte, se han convertido en la forma de desplazamiento preferida de este colectivo pese al elevado coste de sus tarifas.

En el caso del metro, hay ciudades en que hay muchas estaciones sin adaptar, especialmente conforme se alejan del centro urbano. El cumplimiento de estos reglamentos se ha delegado en autoridades nacionales de cada Estado miembro. Las normas aplicables al transporte en taxi o en metro de pasajeros con discapacidad se desarrollan principalmente a nivel nacional o regional, lo que permite tener adecuadamente en cuenta las circunstancias y preferencias locales.

It is important to bear in mind the number of citizens in the European Union who have disabilities or reduced mobility, as well as the fact that members of this group are often unable to drive a private vehicle and, as a result, depend on other people or on urban transport to move about and to be able to lead their lives normally. Does the Commission not take the view that these services should be regulated as well?

HOW CAN I PUT A BET ON THE GRAND NATIONAL

Background and aims Marketing inducements for addictive products, such as wagering, can prompt impulse purchasing by triggering consumption reminders, urges, and cravings. Wagering inducements incentivize betting by providing bonus bets , money-back guarantees, deposits into betting accounts, and discounts. Their promotion during sporting events, push marketing efforts directed at consumers, and ease of uptake at the point-of-sale, may trigger betting on impulse.

This study examined whether the uptake of wagering inducements predicted impulse betting on sport. Results More frequent users of wagering inducements had a greater tendency to place impulse in-play bets , which were also predicted by problem gambling, higher buying impulsiveness, higher frequency of watching sports, younger age, and higher educational status.

Sports bettors with a greater tendency to place impulse bets before match commencement also tended to have higher buying impulsiveness and to be younger, but they used inducements less frequently, and tended to be female, less-educated and non-problem, moderate risk, or problem gamblers.

Discussion and conclusions Uptake of wagering inducements appeared to be particularly effective in stimulating impulse in-play betting among problem gamblers and frequent sports viewers. These results suggest that a more cautious approach to the regulation of both in-play bets and wagering inducements may be required to better protect young adults from gambling problems and harm.

Strain TD 1 was Gram positive, rod-shaped, aerobic, motile, and endospore forming. The cell was 2. The cellular fatty acid content was mainly C, which comprised Bayesian tree analysis strongly supported the idea that strain TD 1 is affiliated with genus Aeribacillus, as Aeribacillus pallidus strain TD 1. The cellular fatty acid content was mainly C , which comprised A number of diazepines are known to inhibit bromo- and extra-terminal domain BET proteins. Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework.

Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c- MYC expression.

These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors. Time-dependent anisotropic distributed source capability in transient 3-d transport code tort- TD. The transient 3-D discrete ordinates transport code TORT- TD has been extended to account for time-dependent anisotropic distributed external sources. Since feedback effects are not relevant in this zero-power configuration, this offers a unique opportunity to validate the time-dependent neutron kinetics of TORT- TD with experimental data.

The steady state of the YALINA-Thermal assembly and its response to an artificial square-wave source pulse sequence have been analysed with TORT- TD using pin-wise homogenised cross sections in 18 prompt energy groups with P 1 scattering order and 8 delayed neutron groups. The TD 50 concept was introduced by Peto R. Using TD 50 values available for substances, the procedure presented here allows one to determine OLVs corresponding to a fixed excess risk.

It is based on a mathematical high-to-low doses extrapolation of the TD OLVs obtained with this procedure are compared with currently available TLVs and other occupational guidelines. Editorial Scott Ergonomics SA. Username, Password, Remember me, or Register. Here we show effect of the polyamine polymer chain length to BET isotherms.

Bet -hedging response to environmental variability, an intraspecific comparison. A major challenge in ecology is to understand the impact of increased environmental variability on populations and ecosystems. To maximize their fitness in a variable environment, life history theory states that individuals should favor a bet -hedging strategy, involving a reduction of annual breeding performance and an increase in adult survival so that reproduction can be attempted over more years.

As a result, evolution toward longer life span is expected to reduce the deleterious effects of extra variability on population growth, and consequently on the trait contributing the most to it e. To investigate this, we compared the life histories of two Black-browed Albatross Thalassarche melanophrys populations breeding at South Georgia Atlantic Ocean and Kerguelen Indian Ocean , the former in an environment nearly three times more variable climatically e.

As predicted, individuals from South Georgia in the more variable environment showed significantly higher annual adult survival 0. In both populations, climatic conditions affected the breeding success and the survival of inexperienced breeders, whereas the survival of experienced breeders was unaffected. The strength of the climatic impact on survival of inexperienced breeders was very similar between the two populations, but the effect on breeding success was positively related to environmental variability.

These results provide rare and compelling evidence to support bet -hedging underlying changes in life history traits as an adaptive response to environmental variability. In natural and social science, many events happened at different space-times may be closely correlated.

The Ps Td invariant solution show that the event happened at A will happen also at B. These solutions, such as single soliton solutions, infinitely many singular soliton solutions, soliton-cnoidal wave interaction solutions, and symmetry reduction solutions etc. Full Text Available BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors of BET proteins exhibit potent anti-proliferative activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways.

However, little is currently known about the activity of BET inhibitors in solid tumor models, and whether down-regulation of MYC family genes contributes to sensitivity. Here we provide evidence for potent BET inhibitor activity in neuroblastoma, a pediatric solid tumor associated with a high frequency of MYCN amplifications. Oral administration of I- BET to mouse xenograft models of human neuroblastoma results in tumor growth inhibition and down-regulation MYCN and BCL2 expression, suggesting a potential role for these genes in tumor growth.

Taken together, our data highlight the potential of BET inhibitors as novel therapeutics for neuroblastoma, and suggest that sensitivity is driven by pleiotropic effects on cell growth and apoptotic pathways in a context-specific manner. CTF is a transient code based on a separated flow representation of the two-phase flow. The steady state cases are based on a quarter core model while the transient test case models a control rod ejection transient in a small PWR mini-core fuel assembly arrangement.

BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells. Transcription of inflammatory genes is tightly regulated by acetylation and deacetylation of histone tails. An inhibitor of the acetylated-lysine reader bromodomain and extra-terminal domain BET proteins, I- BET , is known to counteract the induction of expression of inflammatory genes in. Full Text Available A synthetic gene encoding bovine terminal deoxynucleotidyl transferase Td T was generated, cloned into an expression vector and expressed in E.

The effects of altering culture and induction conditions on the nature of recombinant protein production were investigated. This led to the expression of active recombinant bovine Td T in E. After purification and characterisation, the activity of the enzyme was assessed in a biological assay for apoptosis.

The process described in this report enables the economical production of Td T for high throughput applications. Ergonomics SA : Site Map. ISSN: Metallographic examination of TD -nickel base alloys. Techniques are evaluated for chemical, electrochemical, and thermal etching of thoria dispersed TD nickel alloys. An electrochemical etch is described which yielded good results only for large grain sizes of TD -nickel. Two types of thermal etches are assessed for TD -nickel: an oxidation etch and vacuum annealing of a polished specimen to produce an etch.

It is shown that the first etch was somewhat dependent on sample orientation with respect to the processing direction, the second technique was not sensitive to specimen orientation or grain size, and neither method appear to alter the innate grain structure when the materials were fully annealed prior to etching. An electrochemical etch is described which was used to observe the microstructures in TD -NiCr, and a thermal-oxidation etch is shown to produce better detail of grain boundaries and to have excellent etching behavior over the entire range of grain sizes of the sample.

Here, we generated a floxed STOP td Tomato rat that conditionally expresses a red fluorescent protein variant td Tomato in the presence of exogenous Cre recombinase. The td Tomato signal vividly visualizes neurons including their projection fibers and spines without any histological enhancement.

Our rat reporter system will facilitate connectome studies as well as the visualization of the fine structures of genetically identified cells for long periods both in vivo and ex vivo. This new phenomenon has not been revealed in the scie Til brug for sine overvejelser har kommissionen Bet OnMath azzardo e matematica a scuola.

Why do people gamble? A large body of research suggests that cognitive distortions play an important role in pathological gambling. Many of these distortions are specific cases of a more general misperception of randomness, specifically of an illusory perception of patterns in random sequences. In this article, we provide further evidence for the assumption that gamblers are particularly prone to perceiving illusory patterns. In particular, we compared habitual gamblers to a matched sample of community members with regard to how much they exhibit the choice anomaly 'probability matching'.

Probability matching describes the tendency to match response proportions to outcome probabilities when predicting binary outcomes. It leads to a lower expected accuracy than the maximizing strategy of predicting the most likely event on each trial. Previous research has shown that an illusory perception of patterns in random sequences fuels probability matching. So does impulsivity, which is also reported to be higher in gamblers.

We therefore hypothesized that gamblers will exhibit more probability matching than non-gamblers, which was confirmed in a controlled laboratory experiment. Additionally, gamblers scored much lower than community members on the cognitive reflection task, which indicates higher impulsivity.

This difference could account for the difference in probability matching between the samples. These results suggest that gamblers are more willing to bet impulsively on perceived illusory patterns. While couched in the framework of concentrating minds betting on natural hazards carries an ethical cost. When children dare each other to do risky things parents know that when such dares are taken harm frequently occurs.

Giving those who claim that there is no hazard financial reasons to avoid ameliorative actions or to double down in support of their public stance requires a moral calculation. Challenging the conclusions of those who accept such bets while denying danger will lead them to attempt to save face by increasing risk to themselves or others.

Thus such wagers, whether person to person or on betting markets, require balancing between alerting the opposing party and others to the risks of not taking action, the associated scientific consensus and the possible harmful outcomes of the bets themselves. This talk will describe strategies for minimizing potential harm while maximizing the instructive component of climate bets. Best practices include having the bet rest on a technical issue that can be authoritatively resolved in a short time.

Unfortunately the nature of natural hazard risks makes it difficult to meet all of these criteria, but those making such bets should be aware of the ethical double bind. Minimal research has been published about inducements for sports and race betting , despite their ready availability and aggressive advertising. This paper aimed to document the range and structural features of these inducements, and analyse their alignment with the harm minimisation and consumer protection goals of responsible gambling.

A scan of all inducements offered on the websites of 30 major race and sports betting brands located separate inducements which we categorised into 15 generic types, all offering financial incentives to purchase. All inducements were subject to numerous terms and conditions which were complex, difficult to find, and obscured by legalistic language.

Play-through conditions of bonus bets were particularly difficult to interpret and failed basic requirements for informed choice. Website advertisements for inducements were prominently promoted but few contained a responsible gambling message. The results were analysed to generate 12 research propositions considered worthy of empirical research to inform much needed regulatory reform in this area.

Kharenko, Olesya A. Bromodomains are epigenetic readers that specifically bind to the acetyl lysine residues of histones and transcription factors. Small molecule BET bromodomain inhibitors can disrupt this interaction which leads to potential modulation of several disease states. Here we describe the binding properties of a novel BET inhibitor RVX that is structurally related to the clinical compound RVX, currently undergoing phase III clinical trials for the treatment of cardiovascular diseases, but is distinctly different in its biological and pharmacokinetic profiles.

Betting odds are frequently found to outperform mathematical models in sports related forecasting tasks, however the factors contributing to betting odds are not fully traceable and in contrast to rating-based forecasts no straightforward measure of team-specific quality is deducible from the betting odds. The present study investigates the approach of combining the methods of mathematical models and the information included in betting odds. A soccer forecasting model based on the well-known ELO rating system and taking advantage of betting odds as a source of information is presented.

Data from almost The novel betting odds based ELO model is shown to outperform classic ELO models, thus demonstrating that betting odds prior to a match contain more relevant information than the result of the match itself. It is shown how the novel model can help to gain valuable insights into the quality of soccer teams and its development over time, thus having a practical benefit in performance analysis.

Moreover, it is argued that network based approaches might help in further improving rating and forecasting methods. Recome S. What do children observe and learn from televised sports betting advertisements? A qualitative study among Australian children. To explore children's awareness of sports betting advertising and how this advertising may influence children's attitudes, product knowledge and desire to try sports betting.

Semi-structured qualitative interviews were conducted with 48 children years from Melbourne, Victoria. The interview schedule explored children's recall and interpretations of sports betting advertising, strategies within advertisements that may appeal to children, children's product knowledge and understanding of betting terminology, and factors that may encourage gambling.

Interviews were transcribed and thematic analysis was conducted. Children recalled in detail sports betting advertisements that they had seen, with humour the most engaging appeal strategy. They were also able to describe other specific appeal strategies and link these strategies to betting brands. Many children described how advertisements demonstrated how someone would place a bet , with some children recalling the detailed technical language associated with betting.

Children had detailed recall of sports betting advertisements and an extensive knowledge of sports betting products and terminology. Implications for public health: To protect children from the potential harms associated with sports betting , governments should consider changing regulations and implementing evidence-based education campaigns to counter the positive messages children receive from the sports betting industry.

Finding the right alternative BET settings can be a difficult and time-con The Bet v 1 fold: an ancient, versatile scaffold for binding of large, hydrophobic ligands. Full Text Available Abstract Background The major birch pollen allergen, Bet v 1, is a member of the ubiquitous PR family of plant pathogenesis-related proteins.

In recent years, a number of diverse plant proteins with low sequence similarity to Bet v 1 was identified. In addition, determination of the Bet v 1 structure revealed the existence of a large superfamily of structurally related proteins. In this study, we aimed to identify and classify all Bet v 1-related structures from the Protein Data Bank and all Bet v 1-related sequences from the Uniprot database.

Results Structural comparisons of representative members of already known protein families structurally related to Bet v 1 with all entries of the Protein Data Bank yielded 47 structures with non-identical sequences.

They were classified into eleven families, five of which were newly identified and not included in the Structural Classification of Proteins database release 1. The taxonomic distribution of these families extracted from the Pfam protein family database showed that members of the polyketide cyclase family and the activator of Hsp90 ATPase homologue 1 family were distributed among all three superkingdoms, while members of some bacterial families were confined to a small number of species.

Comparison of ligand binding activities of Bet v 1-like superfamily members revealed that their functions were related to binding and metabolism of large, hydrophobic compounds such as lipids, hormones, and antibiotics. Phylogenetic relationships within the Bet v 1 family, defined as the group of proteins with significant sequence similarity to Bet v 1, were determined by aligning Bet v 1-related sequences.

A distance-based phylogenetic tree yielded a classification into 11 subfamilies, nine exclusively containing plant sequences and two subfamilies of bacterial proteins. Biosynthesis and characterization of polyhydroxyalkanoates copolymers produced by Pseudomonas putida Bet isolated from palm oil mill effluent. Full Text Available The biosynthesis and characterization of medium chain length polyhydroxyalkanoates mcl-PHA produced by Pseudomonas putida Bet isolated from palm oil mill effluent was studied.

The biosynthesis of mcl-PHA in this newly isolated microorganism follows a growth-associated trend. Mcl-PHA accumulation ranging from Molecular weight of the polymer was found to be ranging from No unsaturated monomer was detected. Thermo-chemical analyses showed the accumulated PHA to be semi-crystalline polymer with good thermal stability, having a thermal degradation temperature T d of The biosynthesis and characterization of medium chain length polyhydroxyalkanoates mcl-PHA produced by Pseudomonas putida Bet isolated from palm oil mill effluent was studied.

Bet Dwarka Island is situated on the extreme west of Indian territory in Jamnagar district of Gujarat. Underwater, the most preserved remains of ancient maritime activity could be the stone anchors of different types, as every boat requires Umadevi, P. Abdul; Kumar, J.

Krishna; Sreekumar, Sreejith; Basim, A. A new system was designed, realised and qualified meeting the mission requirements of RLV- TD , at the same time taking advantage of the flight heritage attained in INS through various Launch vehicle Missions of the country. The new system has additional redundancy in acceleration channel, in-built inclinometer based bias update scheme for acceleration channels and sign conventions as employed in an aircraft.

Data acquisition in micro cycle periodicity 10 ms was incorporated which was required to provide rate and attitude information at higher sampling rate for ascent phase control. Provision was incorporated for acquisition of rate and acceleration data with high resolution for aerodynamic characterisation and parameter estimation. GPS aided navigation scheme was incorporated to meet the stringent accuracy requirements of the mission.

Navigation system configuration for RLV- TD , specific features incorporated to meet the mission requirements, various tests carried out and performance during RLV- TD flight are highlighted. BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells. Full Text Available Neural stem cells and progenitor cells NPCs are increasingly appreciated to hold great promise for regenerative medicine to treat CNS injuries and neurodegenerative diseases.

However, evidence for effective stimulation of neuronal production from endogenous or transplanted NPCs for neuron replacement with small molecules remains limited. Through screening small molecule libraries with annotated targets, we identified BET bromodomain inhibition as a novel mechanism for enhancing neurogenesis.

Gene expression profiling analysis demonstrated that BET bromodomain inhibition induced a broad but specific transcription program enhancing directed differentiation of NPCs into neurons while suppressing cell cycle progression and gliogenesis. Together, these results highlight a crucial role of BET proteins as epigenetic regulators in NPC development and suggest a therapeutic potential of BET inhibitors in treating brain injuries and neurodegenerative diseases. BET inhibitors in metastatic prostate cancer: therapeutic implications and rational drug combinations.

The bromodomain and extra-terminal BET family of proteins are epigenetic readers of acetylated histones regulating a vast network of protein expression across many different cancers. Therapeutic targeting of BET is an attractive area of clinical development for metastatic castration-resistant prostate cancer mCRPC , particularly due to its putative effect on c-MYC expression and its interaction with the androgen receptor AR.

Areas covered: We speculate that a combination approach using inhibitors of BET proteins BETi with other targeted therapies may be required to improve the therapeutic index of BET inhibition in the management of prostate cancer. Preclinical data has identified several molecular targets that may enhance the effect of BET inhibition in the clinic. This review will summarize the known preclinical data implicating BET as an important therapeutic target in advanced prostate cancer, highlight the ongoing clinical trials targeting this protein family, and speculate on rationale combination strategies using BETi together with other agents in prostate cancer.

A literature search using Pubmed was performed for this review. Full Text Available Complexity in mainstream economics consists in high intermediary consumption of mathematics. A new approach to complexity economics dwells upon path-dependent global systems; their emergence and evolving organisation. The focus here is on the complexity of the real economic world due to globalisation.

On-line betting related match-fixing is a case in point about which the article presents non-exhaustive empirical evidence and shows how it is analysed with the standard model of the economics of crime. There is no room for complexity in such an individualistic approach to corrupt behaviour applied to bet -related fixes.

A more complex model is sketched based on interactions between a global though underground market for fixes and the actual partly legal, partly illegal global sport betting market. These interactions exhibit how complex is the issue of combating betting -related match fixing. The novelty in this approach is a variable increasing rate applied to increasing tranches of taxation gains which should dry up the worst cases of on-line bettingrelated match fixing.

Gambling is one of the favourite leisure activities. Over the last few years, however, the variety of opportunities to gamble has changed. Decreasing numbers of casino visitors can be seen against an ever-increasing number of people using slot machines, and taking part in national lotteries and sport betting. Comprehensive empirical research regarding consumer behaviour and addiction potential involved in sport betting has been non-existent and only a few studies have dealt with lottery.

In the present study, subjects were questioned in Austrian betting offices. Of the sport betting subjects who additionally play lottery, Based on the criteria of substance addiction, the data demonstrate that sport betting and lottery have addiction potential and can therefore be seen as non-substance-related addiction. This paper aims to update the information available on the lithic assemblage from the entire sequence of TD 6 now that the most recent excavations have been completed, and to explore possible changes in both occupational patterns and technological strategies evidenced in the unit.

This is the first study to analyse the entire TD 6 sequence, including subunits TD 6. We also present an analysis of several lithic refits found in TD 6, as well as certain technical features that may help characterise the hominin occupations. The archaeo-palaeontological record from TD 6 consists of 9, faunal remains, coprolites, 1, lithic pieces, hominin remains and 91 Celtis seeds. The characteristics of this record seem to indicate two main stages of occupation. In the oldest subunit, TD 6.

In contrast, the lithic assemblages from TD 6. Despite the occupational differences between the lowermost subunit and the rest of the deposit, technologically the TD 6 lithic assemblage is extremely homogeneous throughout. In addition, the composition and spatial distribution of the 12 groups of lithic refits found in unit TD 6, as well as the in situ nature of the assemblage demonstrate the high degree of preservation at the site.

This may help clarify the nature of the Early Pleistocene hominin occupations of TD 6, and raise reasonable doubt about the latest interpretations that support the ex situ character of the assemblage as a whole. Full Text Available In order to solve the security problem of transmission image across public networks, a new image encryption algorithm based on TD -ERCS system and wavelet neural network is proposed in this paper.

According to the permutation process and the binary XOR operation from the chaotic series by producing TD -ERCS system and wavelet neural network, it can achieve image encryption. This encryption algorithm is a reversible algorithm, and it can achieve original image in the rule inverse process of encryption algorithm.

Finally, through computer simulation, the experiment results show that the new chaotic encryption algorithm based on TD -ERCS system and wavelet neural network is valid and has higher security. This paper describes the implementation of a time-dependent distributed external source in TORT- TD by explicitly considering the external source in the ''fixed-source'' term of the implicitly time-discretised 3-D discrete ordinates transport equation.

Anisotropy of the external source is represented by a spherical harmonics series expansion similar to the angular fluxes. Good agreement is achieved concerning the multiplication factor. The response of the system to an artificial time-dependent source consisting of two square-wave pulses demonstrates the time-dependent external source capability of TORT- TD.

The result is physically plausible as judged from validation calculations. As a result, we experienced rolling outages for a few months in the Tokyo and Tohoku area. As a result, the Japanese Electricity System Reform policy was adopted. Knowledge of these elements has a strong impact on the unitarity triangle, of interest for studies of CP violation in the B system. During fieldwork conducted with workers and customers in betting shops in London research participants consistently conceptualized betting shops as masculine spaces in contrast to the femininity of other places including home and the bingo hall.

According to this argument, betting on horses and dogs was 'men's business' and betting shops were 'men's worlds'. Two explanations were offered to account for this situation. The first suggested that betting was traditionally a pastime enjoyed by men rather than women.

The second was that betting is intrinsically more appealing to men because it is based on calculation and measurement, and women prefer more intuitive, simpler challenges. I use interviews with older people to describe how the legalisation of betting in cash in changed the geography of betting. I then draw upon interviews with regular customers in order to show how knowledge about betting is shared within rather than between genders.

Finally, I use my experience of training and working as a cashier to describe how the particular hegemonic masculinity found in betting shops in London is maintained through myriad everyday practices which reward certain kinds of gendered performances while at the same time suppressing alternatives. The article shows how particular spaces may become gendered as an unanticipated consequence of legislation and how contingent gendered associations are both naturalized and, at the same time, subjected to intense attention.

Sports betting marketing during sporting events: a stadium and broadcast census of Australian Football League matches. Using Australian Football League AFL matches as a case study, we investigated the frequency, length and content of marketing strategies for sports betting during two specific settings: 1 at stadiums during four live matches; and 2 during eight televised broadcasts of matches.

Census of sports betting marketing during Round 12 of the AFL premiership season. Per match, there was an average of A diverse range of marketing techniques were used to: a embed sports betting within the game; b align sports betting with fans' overall experience of the game; and c encourage individuals to bet live during the game.

There were very few visible or audible messages such as responsible gambling or Gambler's Help messages to counter-frame the overwhelmingly positive messages that individuals received about sports betting during the match. This study raises important questions about the impacts of saturation, integrated and impulse gambling marketing strategies in sporting matches. Future research should explore: 1 how wagering industry marketing strategies may affect the attitudes and behaviours of community sub-groups e.

Full Text Available This article is about the design of controllers for magnetic levitation Maglev system in both simulation and real time. Local linearization around the equilibrium point has been done for the nonlinear Maglev system to obtain a linearized model transfer function.

In this study, the design of integral-tilted-derivative I- TD controller has been proposed for the Maglev system and its performance is compared with conventional tilted-integral-derivative TID controller.

In this study, TID controller parameters have been optimized through genetic algorithm GA and those set of values have been employed for the design of I- TD controller. The analysis shows the superiority of I- TD controller over TID controller in terms of maximum overshoot, gain margin and phase margin.

The settling time remains almost same in both the cases. In future, a detailed study of robustness in presence of model uncertainties will be incorporated as a scope of further research. Td PIR minisatellite fingerprinting as a useful new tool for Torulaspora delbrueckii molecular typing. Torulaspora delbrueckii yeast strains are being increasingly applied at the industrial level, such as in the winemaking process, and so their identification and characterisation require effective, fast, accurate, reproducible and reliable approaches.

Therefore, the development of typing techniques that allow discrimination at the strain level will provide an essential tool for those working with T. Here, 28 T. The aim was to determine and compare the efficacies, reproducibilities and discriminating powers of these molecular methods. Moreover, the Td PIR3 primers showed reproducible profiles when the stringency of the PCR protocol was varied, which highlighted the great robustness of this technique.

In contrast, variation of the stringency of the M13 PCR protocol resulted in modification of the amplified profiles, which suggested low reproducibility of this technique. Nonselective inhibition of the epigenetic transcriptional regulator BET induces marked lymphoid and hematopoietic toxicity in mice.

Lee, Dong U. Through their bromodomain, these proteins bind to acetylated lysine residues of histones and are recruited to transcriptionally active chromatin. Inhibition of the BET -histone interaction provides a tractable therapeutic strategy to treat diseases that may have epigenetic dysregulation.

JQ1 is a small molecule that blocks BET interaction with histones. It has been shown to decrease proliferation of patient-derived multiple myeloma in vitro and to decrease tumor burden in vivo in xenograft mouse models.

While targeting BET appears to be a viable and efficacious approach, the nonclinical safety profile of BET inhibition remains to be well-defined. We report that mice dosed with JQ1 at efficacious exposures demonstrate dose-dependent decreases in their lymphoid and immune cell compartments.

At higher doses, JQ1 was not tolerated and due to induction of significant body weight loss led to early euthanasia. Flow cytometry analysis of lymphoid tissues showed a decrease in both B- and T-lymphocytes with a concomitant decrease in peripheral white blood cells that was confirmed by hematology.

Further investigation with the inactive enantiomer of JQ1 showed that these in vivo effects were on-target mediated and not elicited through secondary pharmacology due to chemical structure. Bet hedging in yeast by heterogeneous, age-correlated expression of a stress protectant. Full Text Available Genetically identical cells grown in the same culture display striking cell-to-cell heterogeneity in gene expression and other traits.

A crucial challenge is to understand how much of this heterogeneity reflects the noise tolerance of a robust system and how much serves a biological function. In bacteria, stochastic gene expression results in cell-to-cell heterogeneity that might serve as a bet -hedging mechanism, allowing a few cells to survive through an antimicrobial treatment while others perish. Despite its clinical importance, the molecular mechanisms underlying bet hedging remain unclear.

Here, we investigate the mechanisms of bet hedging in Saccharomyces cerevisiae using a new high-throughput microscopy assay that monitors variable protein expression, morphology, growth rate, and survival outcomes of tens of thousands of yeast microcolonies simultaneously.

We find that clonal populations display broad distributions of growth rates and that slow growth predicts resistance to heat killing in a probabalistic manner. We identify several gene products that are likely to play a role in bet hedging and confirm that Tsl1, a trehalose-synthesis regulator, is an important component of this resistance.

Tsl1 abundance correlates with growth rate and replicative age and predicts survival. Our results suggest that yeast bet hedging results from multiple epigenetic growth states determined by a combination of stochastic and deterministic factors. Bet hedging via seed banking in desert evening primroses Oenothera, Onagraceae : demographic evidence from natural populations.

Bet hedging is one solution to the problem of an unpredictably variable environment: fitness in the average environment is sacrificed in favor of lower variation in fitness if this leads to higher long-run stochastic mean fitness. While bet hedging is an important concept in evolutionary ecology, empirical evidence that it occurs is scant. Here we evaluate whether bet hedging occurs via seed banking in natural populations of two species of desert evening primroses Oenothera, Onagraceae , one annual and one perennial.

Four years of data on plants and 3 years of data on seeds yielded two transitions for the entire life cycle. One year was exceptionally dry, leading to reproductive failure in the sample areas, and the other was above average in precipitation, leading to reproductive success in four of five populations. Stochastic simulations of population growth revealed patterns indicative of bet hedging via seed banking, particularly in the annual populations: variance in fitness and fitness in the average environment were lower with seed banking than without, whereas long-run stochastic mean fitness was higher with seed banking than without across a wide range of probabilities of the wet year.

This represents a novel, unusually rigorous demonstration of bet hedging from field data. Webster, R. We examine, in particular, the impact of basis set size and quality on the prediction of the optical gap and exciton binding energy. The formation of bound excitons by photoexcitation is observed in all the studied systems and this is shown to be correlated to specific features of the Hartree-Fock exchange component of the TD -DFT response kernel.

We attribute this reduced exciton binding to the incorrect asymptotics of the B3LYP exchange correlation ground state functional and of the TD -B3LYP response kernel, which lead to a large underestimation of the Coulomb interaction between the excited electron and hole wavefunctions. Cognitive bias is prevalent among gamblers, especially those with gambling problems.

Grounded in the heuristics theories, this study contributes to the literature by examining a cognitive bias triggered by the break streak pattern in the casino setting. We postulate that gamblers tend to bet on the latest outcome when there is a break-streak pattern. Moreover, three determinants of the betting decision under break-streak pattern, including the streak length of the alternative outcome, the frequency of the latest outcome, and gender, were identified and examined in this study.

A non-participatory observational study was conducted among the Cussec gamblers in a casino in Macao. An analysis of bets confirms our postulation, particularly when the streak of the alternative outcome is long, the latest outcome is frequent, and the gamblers are females.

The findings provide meaningful implications for casino management and public policymakers regarding the minimization of gambling harm. Full Text Available Displacement of Bromodomain and Extra-Terminal BET proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family Brd2, Brd3, Brd4, Brdt, making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes.

JQ1 increases insulin content in INS-1 cells, accounting for increased secretion, in both rat and human islets. Higher concentrations of JQ1 decrease intracellular triglyceride stores in INS-1 cells, a result of increased fatty acid oxidation. Specific inhibition of both Brd2 and Brd4 enhances insulin transcription, leading to increased insulin content. Inhibition of Brd2 alone increases fatty acid oxidation. Results imply that cancer and diseases of chronic inflammation or disordered metabolism are related through shared chromatin regulatory mechanisms.

Displacement of Bromodomain and Extra-Terminal BET proteins from chromatin has promise for cancer and inflammatory disease treatments, but roles of BET proteins in metabolic disease remain unexplored. Small molecule BET inhibitors, such as JQ1, block BET protein binding to acetylated lysines, but lack selectivity within the BET family Brd2, Brd3, Brd4, Brdt , making it difficult to disentangle contributions of each family member to transcriptional and cellular outcomes.

Genetic variants alter T- bet binding and gene expression in mucosal inflammatory disease. Genome-wide association studies have identified single nucleotide polymorphisms SNPs that may be causative for autoimmune diseases. The majority of these polymorphisms are located within non-coding distal regulatory elements. It is considered that these genetic variants contribute to disease by altering the binding of regulatory proteins and thus gene expression, but whether these variants alter the binding of lineage-specifying transcription factors has not been determined.

Here, we show that SNPs associated with the mucosal inflammatory diseases Crohn's disease, ulcerative colitis UC and celiac disease, but not rheumatoid arthritis or psoriasis, are enriched at T- bet binding sites. Furthermore, we identify disease-associated variants that alter T- bet binding in vitro and in vivo.

ChIP-seq for T- bet in individuals heterozygous for the celiac disease-associated SNPs rs and rs and the IBD-associated SNPs rs and rs, reveals decreased binding to the minor disease-associated alleles. Furthermore, we show that rs is an expression quantitative trait locus eQTL for the neighboring gene IL18RAP, with decreased T- bet binding associated with decreased expression of this gene.

These results suggest that genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T- bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner. A technique is described where an atmospheric pressure-thermal desorption AP- TD device and electrospray ionization ESI -mass spectrometry are coupled and used for the rapid analysis of Bacillus spores in complex matrices.

T- bet -mediated Tim-3 expression dampens monocyte function during chronic hepatitis C virus infection. Hepatitis C virus HCV induces a high rate of chronic infection via dysregulation of host immunity. Importantly, silencing T- bet gene expression decreases Tim-3 expression and enhances interleukin secretion as well as signal transducer and activator of transcription 1 phosphorylation.

These findings reveal a novel mechanism for Tim-3 regulation via T- bet during HCV infection, providing new targets to combat this global epidemic viral disease. Full Text Available The RNA-binding protein L1 TD 1 is one of the most specific and abundant proteins in pluripotent stem cells and is essential for the maintenance of pluripotency in human cells.

Here, we identify the protein interaction network of L1 TD 1 in human embryonic stem cells hESCs and provide insights into the interactome network constructed in human pluripotent cells. L1 TD 1 interacts with multiple stem-cell-specific proteins, many of which are still uncharacterized in the context of development. The pharmacology of TD , a potent and selective 5-HT4 receptor agonist with gastrointestinal prokinetic properties. Full Text Available This study evaluated the in vitro and in vivo pharmacological properties of TD , a potent and selective 5-HT4 receptor agonist.

TD had moderate intrinsic activity IA in the in vitro assays. In conscious guinea pigs, subcutaneous s. Following intraduodenal i. In a single ascending oral dose study in healthy human subjects, TD 0. It is concluded that TD is a potent and selective 5-HT4 receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal GI tract of guinea pigs, rats, dogs and humans.

TD may have clinical utility in patients with disorders of reduced GI motility. Hybrids between the indica and japonica subspecies of rice Oryza sativa are usually sterile, which hinders utilization of heterosis in the inter-subspecific hybrid breeding. The complex locus Sa comprises two adjacently located genes, Sa F and Sa M, which interact to cause abortion of pollen grains carrying the japonica allele in japonica-indica hybrids.

The resultant artificial neutral alleles did not affect pollen viability and other agricultural traits, but did break down the reproductive barrier in the hybrids. We found that some rice lines have natural neutral allele Sa -n, which was compatible with the typical japonica or indica Sa alleles in hybrids. Our results demonstrate that Sa F and Sa M are required for hybrid male sterility, but are not essential for pollen development.

This study provides effective approaches for the generation of hybrid-compatible lines by knocking out the Sa locus or using the natural Sa -n allele to overcome hybrid male sterility in rice breeding. Bioelectromagnetics published by Wiley Periodicals, Inc. The unknown electric field intensity, electric flux density, and polarization densities representing Kerr nonlinearity along with Lorentz dispersion relation, all of which are induced inside the scatterer upon excitation, are expanded using half and full Schaubert-Wilton-Glisson functions in space.

The TD -EFVIE and the constitutive relations between polarization, field, and flux terms are cast in the form of a first-order ordinary differential equation. The resulting matrix system is integrated in time using a predictor-corrector scheme to obtain the time dependent unknown expansion coefficients.

The resulting MOT scheme is explicit and accounts for nonlinearity by simple function evaluations. Due to the mass effect, muonic molecular ions are about times smaller than their electronic counterparts. The properties of this ion are central to understanding the phenomenon of muon catalysis. The method takes into account both the Coulomb interactions and the strong nuclear forces responsible for the fusion reaction.

The wave functions obtained from this method were used to predict very accurately branching ratios and transition rates relevant for various stages of the muon catalytic cycle. Knowledge of these quantities will guide the experiments and help to answer the question of feasibility of net energy production via muon catalysis. This paper describes the application of generalized equivalence theory to the time-dependent 3-D discrete ordinates neutron transport code TORT- TD.

The introduction of pin cell discontinuity factors into the discrete ordinates transport equation is described by assuming a linear dependence of the homogenized neutron angular flux within a pin cell which may be discontinuous at the interfaces to adjacent cells. The homogenized flux discontinuity at cell interfaces is expressed by pin cell discontinuity factors which in turn are determined from fuel assembly lattice calculations using HELIOS.

Oxidation behavior of TD -NiCr in a dynamic high temperature environment. The oxidation behavior of TD -NiCr has been studied in static and high-speed flowing air environments at and C. It has been found that the stable oxide morphologies formed on the specimens exposed to the static and dynamic environments were markedly different.

The faceted crystal morphology characteristic of static oxidation was found to be unstable under high-temperature, high-speed flow conditions and was quickly replaced by a porous NiO 'mushroom' type structure. Also, it was found that the rate of formation of CrO3 from Cr2O3 was greatly enhanced by high gas velocity conditions. The stability of Cr2-O3 was found to be greatly improved by the presence of an outer NiO layer, even though the NiO layer was very porous.

An oxidation model is proposed to explain the observed microstructures and overall oxidation behavior of TD -NiCr alloys. With the commencement of construction of the smart grid, the demand power business for reliability and security continues to improve, the reliability transmission of power TD -LTE Wireless Private Network are more and more attention. For TD -LTE power private network, it can provide different QoS services according to the user's business type, to protect the reliable transmission of business.

This article describes in detail the AF module of PCC in the EPC network, specifically introduces set up AF module station and QoS mechanisms in the EPS load, fully considers the business characteristics of the special power network, establishing a suitable architecture for mapping QoS parameters, ensuring the implementation of each QoS business. Through using radio bearer management, we can achieve the reliable transmission of each business on physical channel.

In the first major part of this chapter, in Sect. In the second major part of this chapter, Sect. In Section 5. This requires identifying promising candidate technologies and advancing them in technology readiness until they are acceptable. Researchers strongly disagree as to what are the best technology project selection methods, or even if there are any proven ones.

Technology development is risky and outstanding achievements are rare and unpredictable. There is no simple formula for success. Organizations that are satisfied with their project selection approach typically use a mix of financial, strategic, and scoring methods in an open, established, explicit, formal process.

This approach helps to build consensus and develop management insight. It encourages better project proposals by clarifying the desired project attributes. We propose a project scoring technique based on a method previously used in a federal laboratory and supported by recent research. Projects are ranked by their perceived relevance, risk, and return - a new 3 R's.

Risk is the estimated probability that the project will achieve its specific objective. Return is the reduction in mission life cycle cost obtained if the project is successful. If the project objective technology performs a new function with no current cost, its return is the estimated cash value of performing the new function.

The proposed project selection scoring method includes definitions of the criteria, a project evaluation. For the computational experiments the information from the web sources was used. The authors did not aim to pro- duce a final numerical results, which describe the possible operating conditions. It was expected only to get accurate qualita- tive results, which can adequately describe the behavior of the airplane IL TD VD when landing on the slippery runway.

So, the authors were able to obtain a typical turn of plane at the end of run and show that the pilot style in these conditions has little effect on the qualitative behavior of the aircraft. The most important factor leading to such maneuvers, lies in the special connection of longitudinal and lateral friction of gear wheels with runway. The results that agree qualitatively with the known situations indicate the possibility for MMS AFD to properly reproduce various cases of aircraft IL TD VD landing to Antarctica ice airfield and identify any inaccurately knownparameters.

Live cell imaging of KOPR- td T enables visualization of time course of agonist-induced internalization of KOPR in real time for 60 min, without photobleaching and apparent cell toxicity. Discussion td T is an alternative to, or even a better tool than, GFPs for fusing to GPCR for trafficking studies, because td T has higher brightness and thus better resolution and less photobleaching problems due to reduced laser power used.

It also has advantages associated with its longer-wavelength emission including spectral separation from autofluorescence and GFPs, reduced cell toxicity the laser may impose, and greater tissue penetration. This work presents the details of mission critical avionics hardware mainly Mission Management Computer MMC and sequencing hardware.

Digital autopilot execution in MMC with a periodicity of 10 ms in ascent phase is introduced for the first time and successfully demonstrated in the flight. SPS is designed as a high reliability system by incorporating various fault tolerance and fault detection features.

CEM is a relay based module for sequence command execution. The ban of animal testing has enhanced the development of new in vitro technologies for cosmetics safety assessment. Impedance metrics is one such technology which enables monitoring of cell viability in real time. However, analyzing real time data requires moving from static to dynamic toxicity assessment. These models account for the fate of the tested compounds during the assay. Only for one out of the three compounds, the models calibrated with a single exposure were able to predict repeated exposure data.

We therefore recommend the use of long-term exposure in vitro data in order to adequately account for chronic hepatotoxic effects. The models we propose here are capable of being coupled with human biokinetic models in order to relate dose exposure and human hepatotoxicity. Published by Elsevier Ireland Ltd..

Project BET Business and Education Together was initiated by the California Chamber of Commerce in January to assist local chambers of commerce in developing long-term school-business partnerships. We present a model with leverage and margin constraints that vary across investors and time. Full Text Available n this paper, we have made a brief analysis on how to make decisions in betting on European football with the help of data mining techniques.

Whether you refer to betting a few days in advance of the sporting event or live betting , both options have been taken into consideration. By using a clustering algorithm for analyzing both the database containing events from football matches and the odds given by bookmakers, we have obtained graphs indicating the probabilities associated with analyzed events.

Given the purely informative aspect of the current paper, we have only analyzed the number of corners from a match. Archaeology of Bet Dwarka Island. Artefacts of both Costs, biases and betting markets: new evidence. Established gambling operators have argued that betting exchanges should not be allowed on the grounds that they represent unfair competition.

In this paper, we argue that, in fact, betting exchanges have brought about reductions in traditional market biases and significant efficien BET measurements: Outgassing of minerals. Outgassing minerals at elevated temperatures prior to BET measurements can lead to phase changes, especially in the case of amorphous and poorly crystalline materials.

In order to evaluate the applicability of the BET method when low outgassing temperatures are required, selected aquifer minerals The results demonstrate that measured specific surface areas of iron oxides are strongly dependent on outgassing conditions Therefore low outgassing temperatures are preferable for minimizing phase changes.

As demonstrated in this study Low-Risk Investing without Industry Bets. The authors refute this notion by showing that a strategy of betting against beta has delivered positive returns both as an industry-neutral bet within each industry and as a pure bet across industries TD Waterhouse discount brokerage: a competitive strategy.

Discount brokerage in Canada is an increasingly lucrative industry and contributes significantly to the bottom lines of every major financial institution in the country. It is also a rapidly changing and intensely price-competitive industry in which an explicit, educated business strategy is of the utmost importance.

TDW currently employs a somewhat ambiguou Biggest bets in the universe unveiled. Betting on the greatest unsolved problems in the universe is no longer the preserve of academic superstars such as Stephen Hawking. From Thursday, anyone will be able to place bets on whether the biggest physics experiments in the world will come good before Bookmaker and pari-mutuel betting.

A widely documented empirical regularity in gambling markets is that bets on high probability events a race won by a "favourite" have higher expected returns than bets on low probability events a "longshot" wins. Such favourite-longshot FL biases however appear to be more severe and persist Such favourite-longshot FL biases however appear to be more severe Our results help understand these differences: the odds grid in bookmaker markets leads to a built-in FL bias, whereas that used in pari-mutuel betting pushes these markets toward a reverse Bet -hedging applications for conservation.

Bet hedging; Bitterroot wilderness; environmental correlation; grizzly bear; least tern; Sterna antillarum; Ursus arctos horribilis Asthma: T- bet --a master controller? Recent evidence suggests that these factors may affect airway immunopathology in asthma. The legalisation of online gambling in multiple territories has caused a growth in the exposure of consumers to online sports betting OSB advertising.

While some efforts have been made to understand the visible structure of betting promotional messages, little is known about the latent components of OSB advertisements. The present study sought to address this issue by examining the metaphorical conceptualisation of OSB advertising.

Following Lakoff and Johnson's conceptual metaphor theory, four main structural metaphors that shaped how OSB advertising can be understood were identified: betting as 1 an act of love, 2 a market, 3 a sport, and 4 a natural environment. In general, these metaphors, which were found widely across 29 different betting brands, facilitated the perception of bettors as active players, with an executive role in the sport events bet upon, and greater control over bet outcomes. The photophysical behaviour of N- 2-hydroxy benzylidene aniline or most commonly known as salicylideneaniline SA has been investigated using the ab initio and DFT levels of theory.

The quantum chemical calculations show that the optimized non planar enol 1 form of the SA molecule is the most stable conformer Based on the development experiences of mobile communication industry over the world, the development strategy of TD -LTE single market in the early stage is expounded, in the meantime, the TD -LTE spectrum planning is analyzed.

One of the early tenets of conservation biology is that population viability is enhanced by maintaining multiple populations of a species. The strength of this tenet is justified by principles of bet -hedging. Management strategies that reduce variance in population size will also reduce risk of extinction. Asynchrony in population Betting is loving and bettors are predators: a conceptual metaphor approach to online sports betting advertising.

Growth of Internet gambling has fuelled concerns about its contribution to gambling problems. However, most online gamblers also gamble on land-based forms, which may be the source of problems for some. Studies therefore need to identify the problematic mode of gambling online or offline to identify those with an online gambling problem. Identifying most problematic form of online gambling e.

This study pursued this approach, aiming to: 1 determine demographic, behavioral and psychological risk factors for gambling problems on online EGMs, online sports betting and online race betting ; 2 compare the characteristics of problematic online gamblers on each of these online forms.

An online survey of 4, Australian gamblers measured gambling behavior, most problematic mode and form of gambling, gambling attitudes, psychological distress, substance use, help-seeking, demographics and problem gambling status. Risk factors for online EGM gambling were: more frequent play on online EGMs, substance use when gambling, and higher psychological distress.

Risk factors for online sports betting were being male, younger, lower income, born outside of Australia, speaking a language other than English, more frequent sports betting , higher psychological distress, and more negative attitudes toward gambling. Risk factors for. Full Text Available Growth of Internet gambling has fuelled concerns about its contribution to gambling problems. Sports betting : can gamblers beat randomness?

Although skills are not considered relevant in chance-governed activities, only a few studies have assessed the extent to which sport expert skills in wagering are a manifestation of the illusion of control. This study examined a whether expert hockey bettors could make better predictions than chance, b whether expert hockey bettors could achieve greater monetary gains than chance, and c what kind of strategies hockey gamblers rely on when betting.

Accordingly, 30 participants were asked to report their state lottery hockey bets on 6 occasions. We suggest that the information used by bettors, along with near-misses, reinforces their perception of expertise. The results of this experiment suggest that the so-called "skills" of the sports bettors are cognitive distortions.

Effects of expertise on football betting. Full Text Available Abstract Background Football soccer is one of the most popular sports in the world, including Europe. It is associated with important betting activities. A common belief, widely spread among those who participate in gambling activities, is that knowledge and expertise on football lead to better prediction skills for match outcomes.

Methods Two hundred and fifty-eight persons took part in the study: Logistic regressions were carried out to assess the link between the accuracy of the forecasted scores and the expertise of the participants expert, amateur, layperson, controlling for age and gender. Conclusions Expertise, age, and gender did not appear to have an impact on the accuracy of the football match prognoses.

Public health policies may need to consider the phenomenon in order to prevent problem gambling related to football betting. Football soccer is one of the most popular sports in the world, including Europe. If unfounded, however, this belief should be considered as a form of "illusion of control. Two hundred and fifty-eight persons took part in the study: Logistic regressions were carried out to assess the link between the accuracy of the forecasted scores and the expertise of the participants expert, amateur, layperson , controlling for age and gender.

Expertise, age, and gender did not appear to have an impact on the accuracy of the football match prognoses. Therefore, the belief that football expertise improves betting skills is no more than a cognitive distortion called the "illusion of control. Scythopolis - Bet Shean-, city of the decapolis.

Ergonomics SA. Journal Homepage Image. Ergonomics SA esa provides a medium for publication of material relevant to occupational conditions and needs in Southern Africa at a time of change unparalleled in history.

To this end the journal accepts articles in the following categories: research papers, review articles, conceptual theories, SA Rugby. SA Rugby Youth Week players: a pilot study. J Brown,1, Consensus Statement for Concussion in Sport [1] and World. Laukhina, E. Fiziki Tverdogo Tela; Laukhin, V.

Here the synthesis, X-ray structure, and physical properties of two hydrated halides of BET -TTF that are isostructural and present stable metallic properties are described. Given these characteristics, it is possible that profitable wagering strategies could exist for informed bettors of the WNBA.

Using betting data on the WNBA from —, we find that simple betting strategies do not earn statistically significant returns. WNBA bettors are like NBA bettors; however, in that they strongly prefer the best teams, particularly when they are on the road. Despite this clear bias, betting against the most popular public wagers is not found to earn statistically significant profits.

The informational content of odds posted in sports betting market has been an ongoing topic of research. In this paper, I test whether fixed odds betting markets in soccer are informationally efficient. The contributions of the paper are threefold: first, I propose a simple yet flexible statistical.

See www. On the effect of taxation in the online sports betting market. We analyse the effect of taxation in the online sport betting market. This market is characterized by its negligible marginal costs. We model the two most popular online sport betting bets : fixed-odds and spread, as compared with another traditional sport betting : parimutuel. Rejection of attractive gambles is explained by loss aversion, while counterproductive risk seeking is attributed Introduction to the TD build project network.

TD build project network includes three layers. The second layer has m level and each level has horizontal subnetwork composed of n cluster bin NDn. The third layer is equipment. The number of the equipment of per cluster bin NDn is TD network is used for P project.

It has highest running reliability and long-term stability as well as powerful suitability and flexibility. It has many tie points, strong real-time ability and excellent interference suppression. Through testing, all kinds of characteristics are satisfactory. It is an ideal selection for industrial use. Asthma: T- bet — A Master Controller? Clinical trials for BET inhibitors run ahead of the science. Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated.

There is enthusiasm for the anti-proliferative effect of inhibiting BRD4, one of the targets of these inhibitors, which is thought to cooperate with MYC, a long-desired target for cancer therapeutics. Each BET protein controls distinct transcriptional pathways that are important for functions beyond cancer cell proliferation, including insulin production, cytokine gene transcription, T cell differentiation, adipogenesis and most seriously, active repression of dangerous latent viruses like HIV.

Failure to appreciate that at concentrations used, no available BET inhibitor is member-selective, or to develop a sound biological basis to understand the diverse functions of BET proteins before undertaking for these clinical trials is reckless and likely to lead to adverse events. More mechanistic information from new basic science studies should enable proper focus on the most relevant cancers and define the expected side effect profiles.

All rights reserved. Heuristic and analytic processing in online sports betting. This article presents the results of two studies that examine the occurrence of heuristic i. The first study was qualitative and was conducted with a convenience sample of 12 regular online sports gamblers who described the processes by which they arrive at a sports betting decision. The results of this study showed that betting online on sports events involves a mix of heuristic and analytic processes.

The second study consisted in a survey of online sports gamblers where performance in terms of monetary gains, experience in online sports betting , propensity to collect and analyze relevant information prior to betting , and use of bookmaker odds were measured. This study showed that heuristic and analytic processes act as mediators of the relationship between experience and performance.

The findings stemming of these two studies give some insights into gamblers' modes of thinking and behaviors in an online sports betting context and show the value of the dual mediation process model for research that looks at gambling activities from a judgment and decision making perspective. This paper collects the measurement results of MHZMHZ spectrum in the coastal areas, and analyzes the characteristics of TV broadcast spectrum occupancy in the measurement region. It is shown that the polinomial extrapolation of the wave function to the nonphysical region of the variable Q 2 turns not to be sure for determination of the coupling constants.

The CUT- TD code has been developed to find minimal cut sets for a given fault tree and to calculate the occurrence probability of its top event. This code uses an improved top-down algorithm which can enhance the efficiency in deriving minimal cut sets. As a result, this processing directly produces cut sets for the redefined single gate with each gate not being developed.

This option can reduce the number of minimal cut sets, save the computing time and assists the user in reviewing the result. A content analysis of how 'normal' sports betting behaviour is represented in gambling advertising. The pervasiveness of sports betting marketing and advertising is arguably normalising betting behaviour among increasingly larger groups of population.

In their adverts, bookmakers represent characters and situations that conventionalise betting and promote specific behaviours while ignoring others. Using content an Betting patterns for sports and races: a longitudinal analysis of online wagering in Australia. Online wagering is increasing in popularity as it is easily accessible through websites which market these services widely.

However, few studies have examined online betting based on actual behavioural data. This paper describes the results of an analysis of 2,, bets placed with an Australian online wagering operator over a 1-year period.

The majority of bets placed were for a win Sports betting was dominated by ball sports, reflecting popular interest in these events. More than three-quarters The most popular bets placed to win, had a relatively high rate of losses and lowest average returns, which may reflect less sophisticated betting behaviour. More specific handicap and total bets were placed by fewer customers, but were larger bets with the greatest returns. Similarly, bets placed on less popular sporting events had greater average returns potentially reflecting greater customer sophistication and knowledge raising the possibility of a proportion of bettors being more 'skilled'.

As the first paper to analyze the types of bets placed on events and outcomes the results support the notion that wagering is an entertainment activity, and the majority of customers are motivated by factors other than simply winning money. Extracting local information from crowds through betting markets. In this research, a set-up is considered in which users can bet against a forecasting agency to challenge their probabilistic forecasts. From an information theory standpoint, a reward structure is considered that either provides the forecasting agency with better information, paying the successful providers of information for their winning bets , or funds excellent forecasting agencies through users that think they know better.

Especially for local forecasts, the approach may help to diagnose model biases and to identify local predictive information that can be incorporated in the models. The challenges and opportunities for implementing such a system in practice are also discussed. Becker's side bet theory remaining in a job because of perceived costs of leaving was tested using data from working business students.

Three factors were most consistent with the theory: bureaucratic organization, nonwork-related concerns, and adjustment to social position. Attachment to the organization was significantly linked to tangible…. The double french nuclear bet was an ultimate political choice of an old nation which did not wanted to renounce its glamour.

Is it always possible to conceive a national energy policy, knowing that the french military nuclear strategy is opposed to the rules of the next International Penal Court? Delayed bet -hedging resilience strategies under environmental fluctuations.

Many biological populations, such as bacterial colonies, have developed through evolution a protection mechanism, called bet hedging, to increase their probability of survival under stressful environmental fluctuation. In this context, the concept of preadaptation refers to a common type of bet -hedging protection strategy in which a relatively small number of individuals in a population stochastically switch their phenotypes to a dormant metabolic state in which they increase their probability of survival against potential environmental shocks.

Hence, if an environmental shock took place at some point in time, preadapted organisms would be better adapted to survive and proliferate once the shock is over. In many biological populations, the mechanisms of preadaptation and proliferation present delays whose influence in the fitness of the population are not well understood.

In this paper, we propose a rigorous mathematical framework to analyze the role of delays in both preadaptation and proliferation mechanisms in the survival of biological populations, with an emphasis on bacterial colonies. Our theoretical framework allows us to analytically quantify the average growth rate of a bet -hedging bacterial colony with stochastically delayed reactions with arbitrary precision.

We verify the accuracy of the proposed method by numerical simulations and conclude that the growth rate of a bet -hedging population shows a nontrivial dependency on their preadaptation and proliferation delays. Contrary to the current belief, our results show that faster reactions do not, in general, increase the overall fitness of a biological population.

Operationens fokus forud for de udenlandske troppers exit er at udvikle sikkerhedsinstitutionerne og skabe arbejdspladser Hjemmesiden giver overblik In total, 80 participators 15 students, 20 workers, 20 civil servants, 15 handicraftsmen and 10 self employments participated to study and filled in the questionnaire that expert opinion was taken, validity and reliability were done, According to the results acquired, it was determined that participators take part in betting to enhance the quality of life, bring enjoy and attraction of their life, getting rid of stress and most importantly making money because of some reasons such as economic crisis and financial difficulty in their society, their low income level and their debts.

MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal BET bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model GEMM -derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN.

We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice. Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1.

SFI attenuated lung injury and regulated lung immune disorders. Betting on impulse, without thoughtful consideration, research or informed decision-making, may cause financial and other harms and lead to the development of gambling problems. Impulse betting undermines responsible consumption of gambling because it reflects self-regulatory failure, impaired control, unreflective decision-making and betting more than planned. In this paper we define impulse gambling and report on a study that aimed to understand more about the intrinsic characteristics of sports bettors who have a greater tendency to bet on impulse.

Specifically, the study aimed to identify behavioural, psychological and socio-demographic predictors of impulse sports betting. A sample of Australian sports bettors completed an online survey that measured the proportion of their bets placed on impulse both before and during sporting events, as well as bets that were researched and planned in advance. Impulse betting was common, accounting for nearly one-half of all past-year sports bets by respondents. Over three-quarters of respondents had placed one or more impulse bets in the last year and one in seven respondents had made all of their sports bets on impulse.

More impulsive sports bettors were characterised as having higher trait impulsiveness, higher problem gambling severity, more frequent sports betting and a shorter history of sports betting. They favoured betting on in-match contingencies instead of overall match outcomes. While health promotion strategies are needed to discourage impulse betting , research into contextual factors that arouse urges to bet would also provide direction for harm minimisation measures that help consumers to resist impulsive betting decisions.

Understanding persuasive attributes of sports betting advertisements: A conjoint analysis of selected elements. Background and aims Despite recent growth in sports betting advertising, minimal research has examined the influence of different advertising message attributes on betting attitudes and behaviors. This study aimed to identify which attributes of sports betting advertisements most engage attention, interest, desire and likelihood of betting among non-problem, low-risk, moderate-risk, and problem gamblers.

Methods A novel approach utilizing an experimental design incorporating conjoint analysis examined the effects of: three message formats commentary, on-screen display, and studio crossover ; four appeals neutral, jovial, ease of placing the bet , and sense of urgency ; three types of presenters match presenter, sports betting operator, and attractive non-expert female presenter ; and four bet types traditional, exotic key event, risk-free, and micro- bet.

A professional film company using paid actors produced 20 mock television advertisements simulating typical gambling messages based on the conjoint approach. These were embedded into an online survey of Australian adults. Results The most attention-grabbing attributes were type of presenter and type of bet.

The attractive non-expert female presenter gained more attention from all gambler groups than other presenters. The type of bet was most persuasive in converting attention into likely betting among all gambler groups, with the risk-free bet being much more persuasive than other bet types. Problem gamblers were distinct by their greater attraction to in-play micro- bets. Discussion and conclusion Given the potential for incentivized bets offering financial inducements and for in-play micro- bets to undermine harm minimization and consumer protection, regulators and wagering operators should reconsider whether these bet types are consistent with their responsible gambling objectives.

Manin has constructed quantum theta functions from the lattice embedding into vector space x finite group. We extend Manin's construction of quantum thetas to the case of general embedding of vector space x lattice x torus. It turns out that only for the vector space part of the embedding there exists the holomorphic theta vector, while for the lattice part there does not.

Furthermore, the so-c Internet-based structural characteristics of sports betting and problem gambling severity: is there a relationship? With the adoption and popularization of internet-based platforms, sports betting has introduced new functionalities that transform the design of its products and therefore the way bettors interact with them. This study aims to explore the association between the use of new structural characteristics of online betting and gambling severity.

Five characteristics are examined here: i live in-play betting ; ii cash out feature use as example of in-play betting in-built features ; iii fantas Archives: Water SA. Items 1 - 50 of Log in or Register to get access to full text downloads. Vol 44, No 1 Archives: Health SA Gesondheid. Items 1 - 42 of No risk, no fun-- betting on sports events costs the gamblers a lot of money and brings excellent profits to those who offer the bets.

Among the people who bet on a regular basis, the proportion of young adults is frighteningly high. We now suggest a concept as part of a basic mathematics course for acquiring the necessary mathematical knowledge…. A lot of people risk money with bets on sport events or other events. Bookkeepers that offer such bets earn a lot of money. We are making a proposal more exactly: a concept for a part of a basic mathematics course for learning mathematics behind the screen internet bets are very popular.

Learners should organize a "sports event"…. A strategic assessment of the sports betting industry in the United Kingdom. The dissertation focuses on the field of strategic management, through which it tries to identify the competitive advantage of three operators in the United Kingdom online sports betting market; Betfair Group plc, Bet and William Hill plc.

Even in the case of hydrated particles, for which vertical excitations are generally well described with all XC potentials, the use of TD -B3LYP appears to result in CT-problems for certain particles. Rejection of attractive gambles is explained by loss aversion, while counterproductive risk seeking is attributed to limited level of reasoning.

The current research highlights a shortcoming of this popular but often implicit "contradicting biases" assertion. Studies of "negative-sum betting games" reveal hig Full Text Available The present work has great importance for the economic and financial area due to the fact that targets the relevance of the financial indicators in anticipation of the stock variation. The aim is to measure the correlation, the type and intensity, between the variation of stock market profitability and the profitability of the securities traded by banks in Romania, listed on the BSE.

The research is approached transversely banks in Romania listed on the stock market as well as longitudinally from the date of listing on the Stock Exchange of each bank until Rovira, C. Khimicheskoj Fiziki; Doublet, M. The first example of a metallic charge-transfer salt derived from cis-bis ethylenethio -tetrathiafulvalene BET -TTF is reported. X-ray crystal structure of the mixed-valence salt revealed that trans-cis isomerization occurs upon one electron oxidation.

In spite of the structural disorder in both BET -TTF and the counterion, salt is metallic down to 60 K and then resistance increases slowly down to 4 K. When more than one TDD network operates in adjacent frequency bands, severe interference may happen due to adjacent channel interference ACI and unsynchronized operations.

In this paper, coexistence issues between TD -LTE and other systems are analyzed and coexistence requirements are provided. This paper has three research objectives. Second, an uplink scheduling algorithm is proposed to utilize a leakage pattern of ACI in synchronized operations. Third, minimum requirements for coexistence in unsynchronized operations are analyzed by introducing a concept of adjacent-channel coupling loss.

From the analysis and simulation results, we can see that coexistence of TD -LTE with other TDD systems is feasible if the two networks are synchronized. For the unsynchronized case, some special cell-site engineering techniques may be required to reduce the ACI.

SA Journal of Radiology. Health SA Gesondheid. Histone acetylation regulates activation and repression of multiple inflammatory genes known to play critical roles in chronic inflammatory diseases. However, proteins responsible for translating the histone acetylation code into an orchestrated pro-inflammatory cytokine response remain poorly characterized.

We hypothesize that members of the BET family of dual bromodomain-containing transcriptional regulators directly control inflammatory genes. We examined the genetic model of brd2 lo mice, a BET protein hypomorph, to show that Brd2 is essential for pro-inflammatory cytokine production in macrophages.

Furthermore, we show that Brd2 and Brd4 physically associate with the promoters of inflammatory cytokine genes in macrophages. We propose that targeting BET proteins with small molecule inhibitors will benefit hyper-inflammatory conditions associated with high levels of cytokine production. However, proteins responsible for translating the histone acetylation code into an orchestrated proinflammatory cytokine response remain poorly characterized.

Bromodomain and extraterminal BET proteins are "readers" of histone acetylation marks, with demonstrated roles in gene transcription, but the ability of BET proteins to coordinate the response of inflammatory cytokine genes through translation of histone marks is unknown.

We examined the genetic model of brd2 lo mice, a BET protein hypomorph, to show that Brd2 is essential for proinflammatory cytokine production in macrophages. We propose that targeting BET proteins with small-molecule inhibitors will benefit hyperinflammatory conditions associated with high levels of cytokine production. Comparison of TiC coating and TD coating in actual application.

Amount of deformation was measured and compared to find the process which gives the least deformation. Wear tests were carried out for specimens treated by each process. BET domain co-regulators in obesity, inflammation and cancer. Bromodomain proteins are chromatin 'readers'; they recruit chromatin-regulating enzymes, including 'writers' and 'erasers' of histone modification, to target promoters and to regulate gene expression.

Conventional wisdom held that complexes involved in chromatin dynamics are not 'druggable' targets. However, small molecules that inhibit bromodomain and extraterminal BET proteins have been described. We examine these developments and discuss the implications for small molecule epigenetic targeting of chromatin networks in cancer. BET bromo- domain inhibition gene expression response.

Down-, up- and non The x-axis shows position along the chromosome with gene. Correlations between TD annihilation and oxygen precipitation in Czochralski-grown silicon. The investigations show that 1 TD 's cannot act as nuclei for oxide precipitates and that 2 their annihilation, connected with the increased formation of Si I induced defects RLD's , proves TD 's to consist also of self-interstitials. Td T activity in acute myeloid leukemias defined by monoclonal antibodies.

Blast cells from eight out of 71 patients diagnosed with acute myeloid leukemia AML by morphological, cytochemical, and immunological criteria showed Td T activity. Full text of publication follows. The main objective of the Action is to increase the knowledge of imaging-guided drug delivery procedures and to apply this knowledge to the development of theranostic agents through an interdisciplinary approach that involves chemists, biologists, imaging and pharmaceutical technologists.

Investigations devoted to the design, synthesis, physico-chemical characterization and testing of imaging reporters tailored for theranostic applications are carried out. Some results appear particularly worth to be noted: novel chelator system for Sc radionuclides and for MRI, macrocyclic ligands containing bis phosphonate side arm s yielding excellent systems for the coordination of Ga, applications of this and other PET isotopes e.

In the MRI field, where the sensitivity is the key-issue, it has been shown that innovative systems, based on Gd, may allow the in vivo visualization of cellular targeting and may serve as multimodal probes. The results from the research activities carried out in the. The ultraviolet galactic background from TD -1 satellite observations. Using statistical tests those data contaminated by noise due to charged particles in the atmosphere have been discarded, and the remainder have been arranged to form ultraviolet profiles of the Galaxy.

These profiles have been constructed at and A. The zodiacal light components of the total radiation field have been separated from the galactic components to give the intensity of the zodiacal light at elongation 90 0 as function of ecliptic latitude. The spectrum of the zodiacal light in the near ultraviolet is found to be redder than that of the Sun. The intensity of the diffuse galactic light as a function of galactic latitude has been obtained by subtraction of the zodiacal light and contributions due to faint stars calculated using an axi-symmetric model of the Galaxy.

On comparison with predictions of the diffuse galactic light from a radiative transfer model it is found that the ratio of the albedos at and A is relatively insensitive to the model used, and is 0. The albedo at A is found to be 0. Lee is still very active at over 80, pursuing his theory work to this day. Lisa Randall's two initial papers have been quoted both more than times, making her the most cited theoretical physicist in the world in the last five years as of last autumn - a total of about 10, citations!

A mathematical analysis of an exchange-traded horse race betting fund with deterministic payoff betting strategy for institutional investment to challenge EMH. The primary hypothesis challenges the semi-strong efficient market hypothesis applied to horse race wagering. An optimal deterministic betting model DBM is derived from the existing stochastic model fundamentals, mathematical pooling principles, and new theorem.

The exchange-traded betting fund ETBF is derived from force of interest first principles. Alpha is excess return above financial benchmark, and invokes betting strategy alpha that is composed of model alpha and fund alpha. The results and analysis from statistical testing of a global stratified data sample of three hundred galloper horse races accepted at the ninety-five percent confidence-level positive betting strategy alpha, to endorse an exchange-traded horse race betting fund with deterministic payoff into financial market.

Does the uptake of wagering inducements predict impulse betting on sport? Background and aims Marketing inducements for addictive products, such as wagering, can prompt impulse purchasing by triggering consumption reminders, urges, and cravings.

Wagering inducements incentivize betting by providing bonus bets , money-back guarantees, deposits into betting accounts, and discounts. Their promotion during sporting events, push marketing efforts directed at consumers, and ease of uptake at the point-of-sale, may trigger betting on impulse. This study examined whether the uptake of wagering inducements predicted impulse betting on sport.

Results More frequent users of wagering inducements had a greater tendency to place impulse in-play bets , which were also predicted by problem gambling, higher buying impulsiveness, higher frequency of watching sports, younger age, and higher educational status. Sports bettors with a greater tendency to place impulse bets before match commencement also tended to have higher buying impulsiveness and to be younger, but they used inducements less frequently, and tended to be female, less-educated and non-problem, moderate risk, or problem gamblers.

Discussion and conclusions Uptake of wagering inducements appeared to be particularly effective in stimulating impulse in-play betting among problem gamblers and frequent sports viewers. These results suggest that a more cautious approach to the regulation of both in-play bets and wagering inducements may be required to better protect young adults from gambling problems and harm.

Strain TD 1 was Gram positive, rod-shaped, aerobic, motile, and endospore forming. The cell was 2. The cellular fatty acid content was mainly C, which comprised Bayesian tree analysis strongly supported the idea that strain TD 1 is affiliated with genus Aeribacillus, as Aeribacillus pallidus strain TD 1. The cellular fatty acid content was mainly C , which comprised A number of diazepines are known to inhibit bromo- and extra-terminal domain BET proteins.

Their BET inhibitory activity derives from the fusion of an acetyl-lysine mimetic heterocycle onto the diazepine framework. Herein we describe a straightforward, modular synthesis of novel 1,2,3-triazolobenzodiazepines and show that the 1,2,3-triazole acts as an effective acetyl-lysine mimetic heterocycle. Structure-based optimization of this series of compounds led to the development of potent BET bromodomain inhibitors with excellent activity against leukemic cells, concomitant with a reduction in c- MYC expression.

These novel benzodiazepines therefore represent a promising class of therapeutic BET inhibitors. Time-dependent anisotropic distributed source capability in transient 3-d transport code tort- TD. The transient 3-D discrete ordinates transport code TORT- TD has been extended to account for time-dependent anisotropic distributed external sources. Since feedback effects are not relevant in this zero-power configuration, this offers a unique opportunity to validate the time-dependent neutron kinetics of TORT- TD with experimental data.

The steady state of the YALINA-Thermal assembly and its response to an artificial square-wave source pulse sequence have been analysed with TORT- TD using pin-wise homogenised cross sections in 18 prompt energy groups with P 1 scattering order and 8 delayed neutron groups. The TD 50 concept was introduced by Peto R. Using TD 50 values available for substances, the procedure presented here allows one to determine OLVs corresponding to a fixed excess risk.

It is based on a mathematical high-to-low doses extrapolation of the TD OLVs obtained with this procedure are compared with currently available TLVs and other occupational guidelines. Editorial Scott Ergonomics SA.

Username, Password, Remember me, or Register. Here we show effect of the polyamine polymer chain length to BET isotherms. Bet -hedging response to environmental variability, an intraspecific comparison. A major challenge in ecology is to understand the impact of increased environmental variability on populations and ecosystems.

To maximize their fitness in a variable environment, life history theory states that individuals should favor a bet -hedging strategy, involving a reduction of annual breeding performance and an increase in adult survival so that reproduction can be attempted over more years. As a result, evolution toward longer life span is expected to reduce the deleterious effects of extra variability on population growth, and consequently on the trait contributing the most to it e.

To investigate this, we compared the life histories of two Black-browed Albatross Thalassarche melanophrys populations breeding at South Georgia Atlantic Ocean and Kerguelen Indian Ocean , the former in an environment nearly three times more variable climatically e.

As predicted, individuals from South Georgia in the more variable environment showed significantly higher annual adult survival 0. In both populations, climatic conditions affected the breeding success and the survival of inexperienced breeders, whereas the survival of experienced breeders was unaffected. The strength of the climatic impact on survival of inexperienced breeders was very similar between the two populations, but the effect on breeding success was positively related to environmental variability.

These results provide rare and compelling evidence to support bet -hedging underlying changes in life history traits as an adaptive response to environmental variability. In natural and social science, many events happened at different space-times may be closely correlated. The Ps Td invariant solution show that the event happened at A will happen also at B. These solutions, such as single soliton solutions, infinitely many singular soliton solutions, soliton-cnoidal wave interaction solutions, and symmetry reduction solutions etc.

Full Text Available BET family proteins are epigenetic regulators known to control expression of genes involved in cell growth and oncogenesis. Selective inhibitors of BET proteins exhibit potent anti-proliferative activity in a number of hematologic cancer models, in part through suppression of the MYC oncogene and downstream Myc-driven pathways.

However, little is currently known about the activity of BET inhibitors in solid tumor models, and whether down-regulation of MYC family genes contributes to sensitivity. Here we provide evidence for potent BET inhibitor activity in neuroblastoma, a pediatric solid tumor associated with a high frequency of MYCN amplifications.

Oral administration of I- BET to mouse xenograft models of human neuroblastoma results in tumor growth inhibition and down-regulation MYCN and BCL2 expression, suggesting a potential role for these genes in tumor growth. Taken together, our data highlight the potential of BET inhibitors as novel therapeutics for neuroblastoma, and suggest that sensitivity is driven by pleiotropic effects on cell growth and apoptotic pathways in a context-specific manner.

CTF is a transient code based on a separated flow representation of the two-phase flow. The steady state cases are based on a quarter core model while the transient test case models a control rod ejection transient in a small PWR mini-core fuel assembly arrangement. BET bromodomain inhibition reduces maturation and enhances tolerogenic properties of human and mouse dendritic cells. Transcription of inflammatory genes is tightly regulated by acetylation and deacetylation of histone tails.

An inhibitor of the acetylated-lysine reader bromodomain and extra-terminal domain BET proteins, I- BET , is known to counteract the induction of expression of inflammatory genes in. Full Text Available A synthetic gene encoding bovine terminal deoxynucleotidyl transferase Td T was generated, cloned into an expression vector and expressed in E.

The effects of altering culture and induction conditions on the nature of recombinant protein production were investigated. This led to the expression of active recombinant bovine Td T in E. After purification and characterisation, the activity of the enzyme was assessed in a biological assay for apoptosis.

The process described in this report enables the economical production of Td T for high throughput applications. Ergonomics SA : Site Map. ISSN: Metallographic examination of TD -nickel base alloys. Techniques are evaluated for chemical, electrochemical, and thermal etching of thoria dispersed TD nickel alloys.

An electrochemical etch is described which yielded good results only for large grain sizes of TD -nickel. Two types of thermal etches are assessed for TD -nickel: an oxidation etch and vacuum annealing of a polished specimen to produce an etch. It is shown that the first etch was somewhat dependent on sample orientation with respect to the processing direction, the second technique was not sensitive to specimen orientation or grain size, and neither method appear to alter the innate grain structure when the materials were fully annealed prior to etching.

An electrochemical etch is described which was used to observe the microstructures in TD -NiCr, and a thermal-oxidation etch is shown to produce better detail of grain boundaries and to have excellent etching behavior over the entire range of grain sizes of the sample. Here, we generated a floxed STOP td Tomato rat that conditionally expresses a red fluorescent protein variant td Tomato in the presence of exogenous Cre recombinase.

The td Tomato signal vividly visualizes neurons including their projection fibers and spines without any histological enhancement. Our rat reporter system will facilitate connectome studies as well as the visualization of the fine structures of genetically identified cells for long periods both in vivo and ex vivo. This new phenomenon has not been revealed in the scie Til brug for sine overvejelser har kommissionen Bet OnMath azzardo e matematica a scuola.

Why do people gamble? A large body of research suggests that cognitive distortions play an important role in pathological gambling. Many of these distortions are specific cases of a more general misperception of randomness, specifically of an illusory perception of patterns in random sequences. In this article, we provide further evidence for the assumption that gamblers are particularly prone to perceiving illusory patterns. In particular, we compared habitual gamblers to a matched sample of community members with regard to how much they exhibit the choice anomaly 'probability matching'.

Probability matching describes the tendency to match response proportions to outcome probabilities when predicting binary outcomes. It leads to a lower expected accuracy than the maximizing strategy of predicting the most likely event on each trial.

Previous research has shown that an illusory perception of patterns in random sequences fuels probability matching. So does impulsivity, which is also reported to be higher in gamblers. We therefore hypothesized that gamblers will exhibit more probability matching than non-gamblers, which was confirmed in a controlled laboratory experiment.

Additionally, gamblers scored much lower than community members on the cognitive reflection task, which indicates higher impulsivity. This difference could account for the difference in probability matching between the samples. These results suggest that gamblers are more willing to bet impulsively on perceived illusory patterns.

While couched in the framework of concentrating minds betting on natural hazards carries an ethical cost. When children dare each other to do risky things parents know that when such dares are taken harm frequently occurs. Giving those who claim that there is no hazard financial reasons to avoid ameliorative actions or to double down in support of their public stance requires a moral calculation.

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