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Summary: Ras family
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Ras subfamily Edit Wikipedia article
Ras is a family of related proteins which is expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction). Ras is the prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and regulate diverse cell behaviours.
When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation and survival. Mutations in ras genes can lead to the production of permanently activated Ras proteins. As a result, this can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals.
Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer.[1] The 3 Ras genes in humans (HRas, KRas, and NRas) are the most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20% to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer).[2] For this reason, Ras inhibitors are being studied as a treatment for cancer and other diseases with Ras overexpression.
The first two ras genes, HRAS and KRAS, were identified[3] from studies of two cancer-causing viruses, the Harvey sarcoma virus and Kirsten sarcoma virus, by Edward M. Scolnick and colleagues at the National Institutes of Health (NIH).[4] These viruses were discovered originally in rats during the 1960s by Jennifer Harvey[5] and Werner Kirsten,[6] respectively, hence the name Rat sarcoma.[3] In 1982, activated and transforming human ras genes were discovered in human cancer cells by Geoffrey M. Cooper at Harvard,[7] Mariano Barbacid and Stuart A. Aaronson at the NIH,[8] Robert Weinberg at MIT,[9] and Michael Wigler at Cold Spring Harbor Laboratory.[10] A third ras gene was subsequently discovered by researchers in the group of Robin Weiss at the Institute of Cancer Research,[11][12] and Michael Wigler at Cold Spring Harbor Laboratory,[13] named NRAS, for its initial identification in human neuroblastoma cells.
The three human ras genes encode extremely similar proteins made up of chains of 188 to 189 amino acids. Their gene symbols are HRAS, NRAS and KRAS, the latter of which produces the K-Ras4A and K-Ras4B isoforms from alternative splicing.
Ras contains six beta strands and five alpha helices.[14] It consists of two domains, a G domain of 166 amino acids, about 20kDa, that binds guanosine nucleotides, and a C-terminal membrane targeting region (CAAX-COOH, also known as CAAX box), which is lipid-modified by farnesyl transferase, RCE1 and ICMT.
The G domain contains five G motifs that bind GDP/GTP directly. The G1 motif, or the P-loop, binds the beta phosphate of GDP and GTP. The G2 motif, also called Switch I, contains threonine35, which binds the terminal phosphate (γ-phosphate) of GTP and the divalent magnesium ion bound in the active site. The G3 motif, also called Switch II, has a DXXGQ motif. The D is aspartate57, which is specific for guanine versus adenine binding, and Q is glutamine61, the crucial residue that activates a catalytic water molecule for hydrolysis of GTP to GDP. The G4 motif contains a LVGNKxDL motif, and provides specific interaction to guanine. The G5 motif contains a SAK consensus sequence. The A is alanine146, which provides specificity for guanine rather than adenine.
The two switch motifs, G2 and G3, are the main parts of the protein that move upon activation by GTP. This conformational change by the two switch motifs is what mediates the basic functionality as a molecular switch protein. This GTP-bound state of Ras is the "on" state, and the GDP-bound state is the "off" state.
Ras also binds a magnesium ion which helps to coordinate nucleotide binding.
Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, cell proliferation, cell differentiation, cell adhesion, apoptosis, and cell migration. Ras and Ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis.
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Ras activates several pathways, of which the mitogen-activated protein (MAP) kinase cascade has been well-studied. This cascade transmits signals downstream and results in the transcription of genes involved in cell growth and division.[15] Another Ras-activated signaling pathway is the PI3K/AKT/mTOR pathway, which stimulates protein synthesis and cellular growth, and inhibits apoptosis.
Activation and deactivation
Ras is a G protein, or a guanosine-nucleotide-binding protein. Specifically, it is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases). G proteins function as binary signaling switches with "on" and "off" states. In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP), while in the "on" state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP. This extra phosphate holds the two switch regions in a "loaded-spring" configuration (specifically the Thr-35 and Gly-60). When released, the switch regions relax which causes a conformational change into the inactive state. Hence, activation and deactivation of Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive GDP-bound forms.
The process of exchanging the bound nucleotide is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). As per its classification, Ras has an intrinsic GTPase activity, which means that the protein on its own will hydrolyze a bound GTP molecule into GDP. However this process is too slow for efficient function, and hence the GAP for Ras, RasGAP, may bind to and stabilize the catalytic machinery of Ras, supplying additional catalytic residues ("arginine finger") such that a water molecule is optimally positioned for nucleophilic attack on the gamma-phosphate of GTP. An inorganic phosphate is released and the Ras molecule is now bound to a GDP. Since the GDP-bound form is "off" or "inactive" for signaling, GTPase Activating Protein inactivates Ras by activating its GTPase activity. Thus, GAPs accelerate Ras inactivation.
GEFs catalyze a "push and pull" reaction which releases GDP from Ras. They insert close to the P-loop and magnesium cation binding site and inhibit the interaction of these with the gamma phosphate anion. Acidic (negative) residues in switch II "pull" a lysine in the P-loop away from the GDP which "pushes" switch I away from the guanine. The contacts holding GDP in place are broken and it is released into the cytoplasm. Because intracellular GTP is abundant relative to GDP (approximately 10 fold more)[15] GTP predominantly re-enters the nucleotide binding pocket of Ras and reloads the spring. Thus GEFs facilitate Ras activation.[14] Well known GEFs include Son of Sevenless (Sos) and cdc25 which include the RasGEF domain.
The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity.
In the GTP-bound conformation, Ras has a high affinity for numerous effectors which allow it to carry out its functions. These include PI3K. Other small GTPases may bind adaptors such as arfaptin or second messenger systems such as adenylyl cyclase. The Ras binding domain is found in many effectors and invariably binds to one of the switch regions, because these change conformation between the active and inactive forms. However, they may also bind to the rest of the protein surface.
Other proteins exist may change the activity of Ras family proteins. One example is GDI (GDP Disassociation Inhibitor); These function by slowing the exchange of GDP for GTP and thus, prolonging the inactive state of Ras family members. Other proteins that augment this cycle may exist.
Membrane attachment
Ras is attached to the cell membrane owing to its prenylation and palmitoylation (HRAS and NRAS) or the combination of prenylation and a polybasic sequence adjacent to the prenylation site (KRAS). The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol, allowing Ras to loosely insert into the membrane of the endoplasmatic reticulum and other cellular membranes. The Tripeptide (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease and the new C-terminus is methylated by a methyltransferase. KRas processing is completed at this stage. Dynamic electrostatic interactions between its positively charged basic sequence with negative charges at the inner leaflet of the plasma membrane account for its predominant localization at the cell surface at steady-state. NRAS and HRAS are further processed on the surface of the Golgi apparatus by palmitoylation of one or two Cys residues, respectively, adjacent to the CaaX box. The proteins thereby become stably membrane anchored (lipid-rafts) and are transported to the plasma membrane on vesicles of the secretory pathway. Depalmitoylation by acyl-protein thioesterases eventually releases the proteins from the membrane, allowing them to enter another cycle of palmitoylation and depalmitoylation.[16] This cycle is believed to prevent the leakage of NRAS and HRAS to other membranes over time and to maintain their steady-state localization along the Golgi apparatus, secretory pathway, plasma membrane and inter-linked endocytosis pathway.
The clinically most notable members of the Ras subfamily are HRAS, KRAS and NRAS, mainly for being implicated in many types of cancer.[17]
However, there are many other members of this subfamily as well:[18] DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2
Ras in cancer
Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumors.[17] it is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain cancer types. Ras point mutations are the single most common abnormality of human proto-oncogenes.[19] Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib) exhibits profound anti-oncogenic effects in many cancer cell lines.[20][21]
Inappropriate activation
Inappropriate activation of the gene has been shown to play a key role in improper signal transduction, proliferation and malignant transformation.[15]
Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively activated their signals will transduce through Ras.
The tumour suppressor gene NF1 encodes a Ras-GAP – its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated. Ras can also be amplified, although this only occurs occasionally in tumours.
Finally, Ras oncogenes can be activated by point mutations so that the GTPase reaction can no longer be stimulated by GAP – this increases the half life of active Ras-GTP mutants.[22]
Constitutively active Ras
Constitutively active Ras (RasD) is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state.
The most common mutations are found at residue G12 in the P-loop and the catalytic residue Q61.
- The glycine to valine mutation at residue 12 renders the GTPase domain of Ras insensitive to inactivation by GAP and thus stuck in the "on state". Ras requires a GAP for inactivation as it is a relatively poor catalyst on its own, as opposed to other G-domain-containing proteins such as the alpha subunit of heterotrimeric G proteins.
- Residue 61[23] is responsible for stabilizing the transition state for GTP hydrolysis. Because enzyme catalysis in general is achieved by lowering the energy barrier between substrate and product, mutation of Q61 to K necessarily reduces the rate of intrinsic Ras GTP hydrolysis to physiologically meaningless levels.
See also "dominant negative" mutants such as S17N and D119N.
Ras-targeted cancer treatments
Reovirus was noted to be a potential cancer therapeutic when studies suggested it reproduces well in certain cancer cell lines. It replicates specifically in cells that have an activated Ras pathway (a cellular signaling pathway that is involved in cell growth and differentiation).[24] Reovirus replicates in and eventually kills Ras-activated tumour cells and as cell death occurs, progeny virus particles are free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until all tumour cells carrying an activated Ras pathway are destroyed.
Another tumor-lysing virus that specifically targets tumor cells with an activated Ras pathway is a type II herpes simplex virus (HSV-2) based agent, designated FusOn-H2.[25] Activating mutations of the Ras protein and upstream elements of the Ras protein may play a role in more than two-thirds of all human cancers, including most metastatic disease. Reolysin, a formulation of reovirus, and FusOn-H2 are currently in clinical trials or under development for the treatment of various cancers.[26] In addition, a treatment based on siRNA anti-mutated K-RAS (G12D) called siG12D LODER is currently in clinical trials for the treatment of locally advanced pancreatic cancer (NCT01188785, NCT01676259).[27]
In glioblastoma mouse models SHP2 levels were heightened in cancerous brain cells. Inhibiting SHP2 in turn inhibited Ras dephosphorylation. This reduced tumor sizes and accompanying rise in survival rates.[28][29]
Other strategies have attempted to manipulate the regulation of the above-mentioned localization of Ras. Farnesyltransferase inhibitors have been developed to stop the farnesylation of Ras and therefore weaken its affinity to membranes.[2] Other inhibitors are targeting the palmitoylation cycle of Ras through inhibiting depalmitoylation by acyl-protein thioesterases, potentially leading to a destabilization of the Ras cycle.[30]
- ^ Goodsell DS (1999). "The molecular perspective: the ras oncogene". Oncologist. 4 (3): 263–4. PMID 10394594.
- ^ a b Downward J (January 2003). "Targeting RAS signalling pathways in cancer therapy". Nat. Rev. Cancer. 3 (1): 11–22. doi:10.1038/nrc969. PMID 12509763.
- ^ a b Malumbres M, Barbacid M (June 2003). "RAS oncogenes: the first 30 years". Nat. Rev. Cancer. 3 (6): 459–65. doi:10.1038/nrc1097. PMID 12778136.
- ^ Chang EH, Gonda MA, Ellis RW, Scolnick EM, Lowy DR (August 1982). "Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses". Proc. Natl. Acad. Sci. U.S.A. 79 (16): 4848–52. doi:10.1073/pnas.79.16.4848. PMC 346782 . PMID 6289320.
- ^ Harvey JJ (December 1964). "An unidentified virus which causes the rapid production of tumours in mice". Nature. 204 (4963): 1104–5. doi:10.1038/2041104b0. PMID 14243400.
- ^ Kirsten WH, Schauf V, McCoy J (1970). "Properties of a murine sarcoma virus". Bibl Haematol (36): 246–9. PMID 5538357.
- ^ Cooper GM (August 1982). "Cellular transforming genes". Science. 217 (4562): 801–6. doi:10.1126/science.6285471. PMID 6285471.
- ^ Santos E, Tronick SR, Aaronson SA, Pulciani S, Barbacid M (July 1982). "T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes". Nature. 298 (5872): 343–7. doi:10.1038/298343a0. PMID 6283384.
- ^ Parada LF, Tabin CJ, Shih C, Weinberg RA (June 1982). "Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene". Nature. 297 (5866): 474–8. doi:10.1038/297474a0. PMID 6283357.
- ^ Taparowsky E, Suard Y, Fasano O, Shimizu K, Goldfarb M, Wigler M (December 1982). "Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change". Nature. 300 (5894): 762–5. doi:10.1038/300762a0. PMID 7177195.
- ^ Marshall CJ, Hall A, Weiss RA (September 1982). "A transforming gene present in human sarcoma cell lines". Nature. 299 (5879): 171–3. doi:10.1038/299171a0. PMID 6287287.
- ^ Hall A, Marshall CJ, Spurr NK, Weiss RA (1983). "Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1". Nature. 303 (5916): 396–400. doi:10.1038/303396a0. PMID 6304521.
- ^ Shimizu K, Goldfarb M, Perucho M, Wigler M (January 1983). "Isolation and preliminary characterization of the transforming gene of a human neuroblastoma cell line". PNAS. 80 (2): 383–7. doi:10.1073/pnas.80.2.383. PMC 393381 . PMID 6300838.
- ^ a b Vetter IR, Wittinghofer A (November 2001). "The guanine nucleotide-binding switch in three dimensions". Science. 294 (5545): 1299–304. doi:10.1126/science.1062023. PMID 11701921.
- ^ a b c Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D, Darnell J (2000). "Chapter 25, Cancer". Molecular cell biology (4th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-3706-X.
- ^ Rocks O, Peyker A, Bastiaens PI (2006). "Spatio-temporal segregation of Ras signals: one ship, three anchors, many harbors". Current Opinion in Cell Biology. 18 (4): 351–7. doi:10.1016/j.ceb.2006.06.007. PMID 16781855.
- ^ a b Bos J (1989). "ras oncogenes in human cancer: a review". Cancer Res. 49 (17): 4682–9. PMID 2547513.
- ^ Wennerberg K, Rossman KL, Der CJ (March 2005). "The Ras superfamily at a glance". J. Cell Sci. 118 (Pt 5): 843–6. doi:10.1242/jcs.01660. PMID 15731001.
- ^ Robbins and Cotran (2010). Pathologic Basis of Disease 8th ed. p. 282.
- ^ Rotblat B, Ehrlich M, Haklai R, Kloog Y (2008). "The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer". Methods Enzymol. 439: 467–89. doi:10.1016/S0076-6879(07)00432-6. PMID 18374183.
- ^ Roy Blum; yoel kloog (2005). "Ras Inhibition in Glioblastoma Down-regulates Hypoxia-Inducible Factor-1, Causing Glycolysis Shutdown and Cell Death". Cancer Research. 65 (3): 999–1006. PMID 15705901.
- ^ Reuter C, Morgan M, Bergmann L (2000). "Targeting the Ras signaling pathway: a rational, mechanism-based treatment for hematologic malignancies?". Blood. 96 (5): 1655–69. PMID 10961860.
- ^ Omim - Neuroblastoma Ras Viral Oncogene Homolog; Nras
- ^ Lal R, Harris D, Postel-Vinay S, de Bono J (October 2009). "Reovirus: Rationale and clinical trial update". Curr. Opin. Mol. Ther. 11 (5): 532–9. PMID 19806501.
- ^ Fu, Xinping; Prigge-J, Cai-R; Xiaoliu Zhang. "A mutant type 2 herpes simplex virus deleted for the protein kinase domain of the ICP10 gene is a potent oncolytic virus". Molecular Therapy. 13 (5): 882–890. doi:10.1016/j.ymthe.2006.08.180.
- ^ Thirukkumaran C, Morris DG (2009). "Oncolytic viral therapy using reovirus". Methods Mol. Biol. 542: 607–34. doi:10.1007/978-1-59745-561-9_31. PMID 19565924.
- ^ "ClinicalTrials.gov".
- ^ Bunda, Severa; Burrell, Kelly; Heir, Pardeep; Zeng, Lifan; Alamsahebpour, Amir; Kano, Yoshihito; Raught, Brian; Zhang, Zhong-Yin; Zadeh, Gelareh (2015-11-30). "Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis". Nature Communications. 6: 8859. doi:10.1038/ncomms9859. PMC 4674766 . PMID 26617336.
- ^ Taub, Ben (2015-12-03). "Scientists Find Way To Deactivate Most Common Cancer-Causing Protein". IFLScience. Retrieved 2016-02-20.
- ^ Chavda, Burzin; Arnott, John A.; Planey, Sonia Lobo (September 2014). "Targeting protein palmitoylation: selective inhibitors and implications in disease". Expert Opinion on Drug Discovery. 9 (9): 1005–1019. doi:10.1517/17460441.2014.933802. ISSN 1746-045X. PMID 24967607.
Further reading
- Agrawal AG, Somani RR (June 2009). "Farnesyltransferase inhibitor as anticancer agent". Mini Rev Med Chem. 9 (6): 638–52. doi:10.2174/138955709788452702. PMID 19519490.
- Agrawal G, Somani RR (2011). "Farnesyltransferase Inhibitor in Cancer Treatment, Current Cancer Treatment". In Özdemir Ö. Current Cancer Treatment - Novel Beyond Conventional Approaches. InTech. ISBN 978-953-307-397-2.
External links
- "Brain tumour findings offer hope of new strategy Canadian Cancer Society says" at ncic.cancer.ca
- "Novel cancer treatment gets NCI support" at arstechnica.com
- ras Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
- ras Genes at the US National Library of Medicine Medical Subject Headings (MeSH)
- Drosophila Ras oncogene at 85D - The Interactive Fly
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Ras superfamily Edit Wikipedia article
|OPM protein
The Ras superfamily is a protein superfamily of small GTPases.[1] Members of the superfamily are divided into families and subfamilies based on their structure, sequence and function. The five main families are Ras, Rho, Ran, Rab and Arf GTPases.[2] The Ras family itself is further divided into 6 subfamilies: Ras, Ral, Rap, Rheb, Rad and Rit. Miro is a recent contributor to the superfamily. Each subfamily shares the common core G domain, which provides essential GTPase and nucleotide exchange activity.
The surrounding sequence helps determine the functional specificity of the small GTPase, for example the 'Insert Loop', common to the Rho subfamily, specifically contributes to binding to effector proteins such as WASP.
In general, the Ras family is responsible for cell proliferation: Rho for cell morphology, Ran for nuclear transport, and Rab and Arf for vesicle transport.[3]
Subfamilies and members
The following is a list of human proteins belonging to the Ras superfamily:[1]
See also
- ^ a b Wennerberg K, Rossman KL, Der CJ (March 2005). "The Ras superfamily at a glance". J. Cell Sci. 118 (Pt 5): 843–6. doi:10.1242/jcs.01660. PMID 15731001.
- ^ Goitre, L; Trapani, E; Trabalzini, L; Retta, SF (26 December 2013). "The Ras superfamily of small GTPases: the unlocked secrets". 1120: 1–18. doi:10.1007/978-1-62703-791-4_1. PMID 24470015. Retrieved 2 January 2015.
- ^ a b c d Munemitsu S, Innis M, Clark R, McCormick F, Ullrich A, Polakis P (1990). "Molecular cloning and expression of a G25K cDNA, the human homolog of the yeast cell cycle gene CDC42". Mol Cell Biol. 10 (11): 5977–82. ISSN 0270-7306. PMC 361395 . PMID 2122236.
This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Ras family Provide feedback
Includes sub-families Ras, Rab, Rac, Ral, Ran, Rap Ypt1 and more. Shares P-loop motif with GTP_EFTU, arf and myosin_head. See PF00009 PF00025 PF00063. As regards Rab GTPases, these are important regulators of vesicle formation, motility and fusion. They share a fold in common with all Ras GTPases: this is a six-stranded beta-sheet surrounded by five alpha-helices [1].
Literature references
Stenmark H, Olkkonen VM; , Genome Biol 2001;2:REVIEWS3007.: The Rab GTPase family. PUBMED:11387043 EPMC:11387043
Internal database links
|AAA AAA_15 AAA_16 AAA_18 AAA_22 AAA_23 AAA_24 AAA_5 AAA_7 ABC_tran AIG1 Arf ATP_bind_1 ATPase_2 cobW DLIC Dynamin_N FeoB_N G-alpha GTP_EFTU Gtr1_RagA IIGP MeaB MMR_HSR1 MMR_HSR1_Xtn MnmE_helical NACHT NOG1 PduV-EutP PET117 RNA_helicase Roc RsgA_GTPase Septin SRPRB TniB
|Similarity to PfamA using HHSearch:
|GTP_EFTU Arf Septin MMR_HSR1 FeoB_N ATP_bind_1 RsgA_GTPase RsgA_GTPase Gtr1_RagA Roc SRPRB PduV-EutP MnmE_helical
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001806
Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain [PUBMED:2122258, PUBMED:1898771]. Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity [PUBMED:2029511].
Crystallographic analysis of various small G proteins revealed the presence of a 20 kDa catalytic domain that is unique for the whole superfamily [PUBMED:1898771, PUBMED:2196171]. The domain is built of five alpha helices (A1-A5), six beta-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound form, allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg(2+) and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg(2+) binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base [PUBMED:11995995].
The small GTPase superfamily can be divided into at least 8 different families, including:
- Arf small GTPases. GTP-binding proteins involved in protein trafficking by modulating vesicle budding and uncoating within the Golgi apparatus.
- Ran small GTPases. GTP-binding proteins involved in nucleocytoplasmic transport. Required for the import of proteins into the nucleus and also for RNA export.
- Rab small GTPases. GTP-binding proteins involved in vesicular traffic.
- Rho small GTPases. GTP-binding proteins that control cytoskeleton reorganisation.
- Ras small GTPases. GTP-binding proteins involved in signalling pathways.
- Sar1 small GTPases. Small GTPase component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).
- Mitochondrial Rho (Miro). Small GTPase domain found in mitochondrial proteins involved in mitochondrial trafficking.
- Roc small GTPases domain. Small GTPase domain always found associated with the COR domain.
Gene Ontology
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function
|GTP binding (GO:0005525)
|GTPase activity (GO:0003924)
Domain organisation
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
Pfam Clan
This family is a member of clan P-loop_NTPase (CL0023), which has the following description:
AAA family proteins often perform chaperone-like functions that assist in the assembly, operation, or disassembly of protein complexes [2].
The clan contains the following 229 members:6PF2K AAA AAA-ATPase_like AAA_10 AAA_11 AAA_12 AAA_13 AAA_14 AAA_15 AAA_16 AAA_17 AAA_18 AAA_19 AAA_2 AAA_21 AAA_22 AAA_23 AAA_24 AAA_25 AAA_26 AAA_27 AAA_28 AAA_29 AAA_3 AAA_30 AAA_31 AAA_32 AAA_33 AAA_34 AAA_35 AAA_5 AAA_6 AAA_7 AAA_8 AAA_9 AAA_PrkA ABC_ATPase ABC_tran ABC_tran_Xtn Adeno_IVa2 Adenylsucc_synt ADK AFG1_ATPase AIG1 APS_kinase Arf ArsA_ATPase ATP-synt_ab ATP_bind_1 ATP_bind_2 ATPase ATPase_2 Bac_DnaA BCA_ABC_TP_C Beta-Casp Cas_Csn2 Cas_St_Csn2 CbiA CBP_BcsQ CDC73_C CENP-M CFTR_R CLP1_P CMS1 CoaE CobA_CobO_BtuR CobU cobW CPT CSM2 CTP_synth_N Cytidylate_kin Cytidylate_kin2 DAP3 DBINO DEAD DEAD_2 DLIC DNA_pack_C DNA_pack_N DNA_pol3_delta DNA_pol3_delta2 DnaB_C dNK DUF1611 DUF1726 DUF2075 DUF2326 DUF2478 DUF257 DUF2791 DUF2813 DUF3584 DUF463 DUF815 DUF853 DUF87 DUF927 Dynamin_N Dynein_heavy Elong_Iki1 ELP6 ERCC3_RAD25_C Exonuc_V_gamma FeoB_N Fer4_NifH Flavi_DEAD FTHFS FtsK_SpoIIIE G-alpha Gal-3-0_sulfotr GBP GBP_C GTP_EFTU Gtr1_RagA Guanylate_kin GvpD HDA2-3 Helicase_C Helicase_C_2 Helicase_C_4 Helicase_RecD Herpes_Helicase Herpes_ori_bp Herpes_TK HSA HydF_dimer HydF_tetramer Hydin_ADK IIGP IPPT IPT IstB_IS21 KAP_NTPase KdpD Kinase-PPPase Kinesin KTI12 LAP1C Lon_2 LpxK MCM MeaB MEDS Mg_chelatase Microtub_bd MipZ MMR_HSR1 MMR_HSR1_C MobB MukB MutS_V Myosin_head NACHT NB-ARC NOG1 NTPase_1 NTPase_P4 ORC3_N ParA Parvo_NS1 PAXNEB PduV-EutP PhoH PIF1 Ploopntkinase1 Ploopntkinase2 Ploopntkinase3 Podovirus_Gp16 Polyoma_lg_T_C Pox_A32 PPK2 PPV_E1_C PRK PSY3 Rad17 Rad51 Ras RecA ResIII RHD3 RHSP RNA12 RNA_helicase Roc RsgA_GTPase RuvB_N SbcCD_C SecA_DEAD Septin Sigma54_activ_2 Sigma54_activat SKI SMC_N SNF2_N Spore_IV_A SRP54 SRPRB SulA Sulfotransfer_1 Sulfotransfer_2 Sulfotransfer_3 Sulfotransfer_4 Sulphotransf SWI2_SNF2 T2SSE T4SS-DNA_transf Terminase_1 Terminase_3 Terminase_6 Terminase_GpA Thymidylate_kin TIP49 TK TniB Torsin TraG-D_C tRNA_lig_kinase TrwB_AAD_bind TsaE UvrB UvrD-helicase UvrD_C UvrD_C_2 Viral_helicase1 VirC1 VirE Zeta_toxin Zot
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
Alignment types
We make a range of alignments for each Pfam-A family:
- seed
- the curated alignment from which the HMM for the family is built
- full
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- UniProt
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- meta
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- jalview
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- PP/Heatmap
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
- Selex
- Stockholm
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
View options
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
|Representative proteomes
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
Download options
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
|Representative proteomes
|Raw Stockholm
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logo
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:
|Previous IDs:
|Sequence Ontology:
|Sonnhammer ELL , Fenech M
|Number in seed:
|Number in full:
|Average length of the domain:
|152.00 aa
|Average identity of full alignment:
|28 %
|Average coverage of the sequence by the domain:
|59.14 %
HMM information
|HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Model details:
|Model length:
|Family (HMM) version:
|download the raw HMM for this family
Species distribution
Sunburst controlsHide
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Colour assignments
|Other sequences
|Unclassified sequence
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
- superkingdom
- kingdom
- phylum
- class
- order
- family
- genus
- species
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
Tree controlsHide
Download tree
- Save a text representation
Selected sequences
- (Uncheck all)
- graphically
- as an alignment
- sequence accessions
- sequences in FASTA format
The tree shows the occurrence of this domain across different species. More...
Species trees
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
Interactive tree
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 83 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Ras domain has been found. There are 1238 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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Last year, we launched a new mobile Gmail experience for iPhone and Android-powered devices. Since then, those of us who use Gmail in English could go to gmail.com from our mobile browsers and get most of the same features we're used to in the desktop version of Gmail — including search, stars, labels, and threaded conversations.
Starting today, this updated version of Gmail for mobile is now available in 44 new languages. Check out the mobile blog for the complete list of languages and more info.

subset: commoncrawl


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NEW YORK, Feb. 21 (UPI) -- Actor, writer and producer Steve Coogan, who is half Irish and was raised Catholic, has said he felt a deep connection to the stirring true story at the heart of his Oscar-nominated, big-screen drama "Philomena."
Directed by Stephen Frears, the movie is about Philomena Lee, an unwed pregnant teen sent in the 1950s to the Sean Ross Abbey in Roscrea, Ireland, where she was forced to work in the convent laundry and give up her son for adoption when he was a toddler.
Former British Labor party aide-turned-journalist Martin Sixsmith first heard Lee's story in 2004 and traveled to Ireland and the United States to help her find out what happened to her child. Judi Dench and Coogan play Lee and Sixsmith in the film, while Sophie Kennedy Clark plays Lee as a younger woman.
"I'm creative. I write. I wanted to tell a story. I came across this story. It moved me. I felt connected to it. I felt connected to the subject matter. I'm half Irish. I'm Catholic. I was raised Catholic, so I feel like I have license to properly connect with the subject matter and not fall into cliches about how the Irish are rendered and religion is represented," Coogan told reporters at a roundtable interview in New York before the film's U.S. theatrical run began last fall.
The 48-year-old Greater Manchester, England, native said he relied heavily on Sixsmith's 2009 book, "The Lost Child of Philomena Lee," but also conducted his own extensive research as he penned the movie's screenplay with co-writer Jeff Pope.
"I retraced some of Martin's footsteps. I went and looked around the abbey and had a little hunt around as any good, self-respecting journalist would," Coogan recalled. "I did my own research as a writer and sometimes I was walking in the footsteps of Martin."
The actor-scribe went on to say he also spent time with the real Lee and Sixsmith in an effort to fully understand their incredible journey.
"In fact, one of the scenes of the film, just as an example, when I sat down with Philomena and Martin at his house... I did lots of interviews and recorded them, just like you are doing now, and used that as the basis for the script," Coogan explained. "I saw some video footage of [Lee's son] Anthony and I was sitting next Philomena and she hadn't seen this footage before. It was him when he was 3 years old. The footage was of her son the last time she saw him and she suddenly became overwhelmed and grabbed my hand and said, 'I did love him, you know.' And I put that line in the film as if it was happening to Martin, but, in reality, it happened to me. So, there was a lot of art imitating life in the way I went about this."
Co-starring Mare Winningham, Anna Maxwell Martin, Michelle Fairley and Ruth McCabe, "Philomena" is in theaters now. The film earned Oscar nominations for Best Picture and Best Adapted Screenplay, as well as a Best Actress nod for Dench.


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"After several years of fiction and documentary production, we realised that documentary was really what made us tick! We focus mainly on creative documentaries, with a recurring leitmotiv: offering authors the time and expertise they deserve to develop their ideas.
We are particularly drawn to society, art and history topics, and tend to keep a very strong humanistic focus throughout the films we produce.
Our productions have travelled on TV screens and festivals around the world, and we were nominated for the Procirep French Producer Award 2010.
We are very happy to have joined forces with the Point du Jour team since 2013."
The company has been awarded "French Producer of the Year 2019" in the documentary category.


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Q&A with NCAA National Champion Dan Perdew
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UC San Diego sophomore Dan Perdew was named Male Swimmer of the Meet at last week's NCAA Division II Swimming & Diving Championships in Columbia, MO after winning both the 50 (20.07) and 100 (44.23) freestyle events in school record time. He was also part of three top five relay teams, including the 200 freestyle quartet that set another UCSD record with a time of 1:21.54. "Winning the two freestyle sprints is extremely difficult," said UCSD Head Coach Scott McGihon. "On paper it looks easy but they're two completely different events. Dan's performance at the NCAA Championships was one of the best I've seen in my time at UCSD." The 6-2 graduate of
Q�What was the best part of the NCAA Championships?
PERDEW�The best part was how successful we were as a team. Every person who went got a best time in at least one event. Personal success is one thing, but being able to share that enjoyment with your teammates is what sports is about.
Q�Which of your two individual wins was more gratifying? Why?
PERDEW�I would have to say the 50 freestyle. If you make one mistake you lose. In the hundred I felt there could have been some improvements. In the 50, if I had made even a little mistake I would have lost, especially since the margin of victory was so small.
Q�When you and Coach Scott McGihon talked before the season and plotted your training, was winning two NCAA titles part of the conversation?
PERDEW�Yes it was. We talked last spring and set goals for the upcoming season. Winning the 50 and 100 free were a part of those goals, along with other team-oriented goals.
Q�Now that you've won two NCAA titles, how do you stay motivated?
PERDEW�It's easy actually. A team national title. That motivates me every day. If it were just about me, I probably wouldn't have won any events. Winning a team national title would be the greatest accomplishment we could achieve�until that happens motivation really isn't a problem.
Q�Have you given any thought to your individual swimming goals going forward?
PERDEW�Over spring quarter I hope to get my Olympic Trials cuts in the 50 and 100 free, which will be held over the summer. As for next season, I'll see if I can add another event at NCAAs to hopefully score more points for the team.
Q�What is the single most important aspect in terms of success in the 50 freestyle? The 100 freestyle?
PERDEW�In the 50 it's really the ability to just let go physically and keep an intense mental focus. In the 100 it's taking that pure speed and adapting it to a race strategy that will last over the course of 100 yards.
Q�Is it beneficial having another fast sprinter like Todd Langland on the team? Why?
PERDEW�It is extremely beneficial. I can't imagine what my season would have been like if Todd wasn't there. I owe a large part of my success to him. Having him there pushing me every day in practice is amazing. We're both competitors and racing each other every day has been a huge benefit to both of us.
Q�Outside of yourself, what did you think was UCSD's best performance at the NCAA meet? The most surprising?
PERDEW�I can't say there was one best performance, even including myself. There were so many great swims, it is hard to choose one. It was really a once in a lifetime thing. There were some surprising swims, especially in the women's 200 free. Aubrey (Panis) breaking the school record by a second and two other girls within tenths is truly amazing.
Q�What was your favorite non-competitive moment/activity in
PERDEW�I would have to say the senior tribute on the last night. It really makes you appreciate the time you have left and the people you get to spend it with.
Q�Is it difficult re-adjusting to the "real world" and finals after a trip like this?
PERDEW�It definitely is, especially after such a great meet. It felt like we were on a constant high all week long. It's hard returning to school after being a part of something that special.
Q�What event would you never want to have to swim competitively? Why?
PERDEW�400 IM. By far the most grueling race there is. I've done it once long course and let's just say it wasn't pretty. Training for that event wouldn't be much fun either.
Q�What's the one thing that you'll be able to do now that the season's over that you couldn't do leading up to the NCAA Championships?
PERDEW�Sleep. I think I'm going to sleep straight through spring break.
Previous Q&A Articles
Evan Hsiao (Swimming) March 9, 2008Eric Rubens (Men's Tennis) February 27, 2008
Melissa Ward (Softball) February 20, 2008
Cameron Sprowles (Fencing) February 13, 2008
Kim Hockett (Women's Water Polo) February 6, 2008
Trevor Decker (Baseball) January 31, 2008
Jordan Lawley (Men's Basketball) January 23, 2008
Jason Spangler (Men's Volleyball) January 5, 2008
Andrew Skewes (Men's Diving) December 26, 2007
Alexis Gaskin (Women's Basketball) December 17, 2007
Aubrey Panis (Women's Swimming) December 2, 2007
Andrew Hatch (Men's Basketball) November 26, 2007
Kevin Klein (Men's Cross Country) November 12, 2007
Kim Adams (Women's Volleyball) November 7, 2007
Ben Miller (Men's Water Polo) October 31, 2007
Alie Avina (Women's Soccer) October 19, 2007
Charity Elliott (Women's Basketball Head Coach) October 15, 2007
Jason Le (Men's Soccer ) October 3, 2007
Rebecca Bailey (Women's Volleyball) September 18, 2007
Amanda Burkhardt (Women's Cross Country) September 10, 2007
Curtis Williamson (Men's Water Polo) September 4, 2007
Ali Lai (Women's Soccer) August 25, 2007
Nate Garcia (Head Coach of Cross Country) August 13, 2007
Tony Choi (Men's Soccer) July 25, 2007
Natalie Facchini (Women's Volleyball) July 9, 2007
Chris Carlson (Head Coach of Men's Basketball) June 22, 2007


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Art Anthology has announced that they have purchased Basically Bare from founders Angela Pruitt and Carol Jackson.
Basically Bare, known for their chipboard and cardboard albums and die cuts, was founded in 2010 and was based in Georgia. Operations are being moved to Huntington Beach, CA as part of the sale. Pruitt will remain with the company as Basically Bare's design specialist after the move.


text:
Grapes have been taken off the menu at Pizza Hut restaurants nationwide following the tragic death of Hartlepool toddler Jacob Jenkins.
The two-year-old died on Wednesday, five days after choking on a grape at the town's branch of the pizza chain.
A Pizza Hut spokesperson said: "As a mark of respect, and in light of the tragic death of Jacob Jenkins, we have removed grapes from our menu with immediate effect.
"The well-being of our guests is always our number one priority, and our hearts go out to his family."
What to do if the child is unconscious
If the child is unconscious put them on a firm, flat surface and shout for help.
Call 999 and put the phone on loudspeaker so your hands are free.
Again don't leave the child at any stage.
Start cardiopulmonary resuscitation (CPR).
The 999 operator will give you details of how to give CPR to a child.
Our hearts go out to his familyPizza Hut spokesman
More official information on how to resucitate a child at nhs.co.uk.
See British Red Cross first aid training courses in your area.


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This 7'4' troll is looking for a new roommate in the D.C. area and he's hoping that it will be you. Like all trolls, this fiscally responsible guy really cares about making sure rent is covered and other bills are paid (he especially cares about tolls). But don't let this payment punctuality overshadow his wild side. This kickball-loving, happy hour hopping wild wonder likes to have a good time.
About Me
I am 328 lbs, 7 feet tall (7' 4" if you count horn height), yellow/greenish eyes and a heart-warming smile. Happy hour? Free networking event? Kickball?... I'm there. I love being fiscally responsible and making sure all debts are paid, tolls collected, and budgets balanced.
Apartment Requirements
Space is no issue! I am great in tight spaces so am happy to claim an unused den or living room corner. I am also quite prepared to sleep under your bed or chill out in the closet. NOTE: I suffer from frequent, violent night terrors brought on by fiscal stress. So let's keep our budget in check when we're bunking up, OK? We will need to convene weekly budget meetings to discuss utility bills -- keeping costs down keeps spirits up!
Outstanding Questions
What is our toll rate for pedestrians walking by outside? Is it strictly enforced or a catch-and-release program? Do you have a dedicated sheep/goat herder, or do you just hire freelancers?
Interested in learning more about this guy? Check him out on Tumblr or follow him on Twitter. Maybe you'll be the next one to have him make your house a...bridge overpass.


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Miller Electric team members live in the communities we service and our company enjoys supporting many of the community based organizations in Muskego, WI. All of us at Miller Electric Thank You for letting us service your electrical and equipment needs.


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Latest News
Some in Congress see just one option for NSA spying: Scrap it
Democrats and Republicans on the House Judiciary Committee blasted the government's bulk collection of Americans' telephone records on Tuesday and said it's a misuse of authority granted by Congress under the Patriot Act.
"Congress never intended to allow bulk collections," said Rep. Jim Sensenbrenner, R-Wis., author of the 2001 Patriot Act.
Debate is intensifying in Congress over whether to scrap the massive data collection effort or to modify it. There's widespread skepticism among both parties over President Barack Obama's plans for the program's future and a desire for Congress to curb the National Security Agency.
"In my district, and many others, NSA has become not a three-letter word but a four-letter word," Rep. Doug Collins, R-Ga., said at a Tuesday hearing on the surveillance effort.
Rep. John Conyers, D-Mich., said Congress needs to end the bulk collection.
"Consensus is growing that it is largely ineffective, inconsistent with our national values, and inconsistent with the statute as this committee wrote it," said Conyers, the top Democrat on the Judiciary Committee.
An independent federal privacy board reviewed the spy program and said there was no evidence it had made a real difference in thwarting any terrorist operations.
David Medine, who chairs the Privacy and Civil Liberties Oversight Board, told the Judiciary Committee on Tuesday that the program should come to an end.
"We conclude the benefits of the program are modest at best and they are outweighed by the privacy and civil liberties consequences," Medine said.
A senior Justice Department official defended the surveillance program, saying it's needed for security, and said the Obama administration is seeking to alter how the program works.
"These are things that if you don't collect them and something blows up, people are going to be very angry," Deputy Attorney General James Cole told the lawmakers.
Cole said the bulk collection of phone records is a useful tool that helps connect dots between suspected terrorists and people who may be assisting their operations.
Obama wants to keep the spy program, although he's proposed several changes in the wake of the public furor that followed news of its existence. Leaks from former defense contractor Edward Snowden revealed the previously undisclosed scope of the surveillance effort, in which the National Security Agency collects millions of Americans' phone records.
House Judiciary Committee Chairman Bob Goodlatte said the program needs to be changed. But the Virginia Republican said he's skeptical of Obama's approach.
Obama wants someone other than the federal government to store the massive database of phone records, which includes numbers dialed and the duration of calls but not the content of the calls. The president didn't say who should keep the data and the Justice Department is weighing options, including the telephone companies themselves.
Goodlatte said that could raise its own privacy problems.
"We need look no further than last month's Target breach or last week's Yahoo breach to know that private information held by private companies is susceptible to cyberattacks," he said.
A presidentially appointed review panel has urged the database be removed from the government's hands, suggesting that could ease public concerns about abuse.
Cole said the Justice Department is working hard to figure out exactly who should store the phone records, whether it should be the telephone companies or some other third party.
"We're also trying to think outside the box and see if there are other options that we can come up with," he said.


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Game #146: Yanks at Jays pregame
New York (83-62) at Toronto (72-73)
at 7:07 p.m. ET at the Rogers Centre
Today's lineups:
Johnny Damon, LF
Derek Jeter, SS
Bobby Abreu, RF
Alex Rodriguez, 3B
Hideki Matsui, DH
Robinson Cano, 2B
Melky Cabrera, CF
Wilson Betemit, 1B
Jose Molina, C
PITCHING: RHP Ian Kennedy (1-0, 2.25 ERA)
Reed Johnson, LF
Russ Adams, 3B
Alex Rios, CF
Frank Thomas, DH
Matt Stairs, RF
Aaron Hill, 2B
Lyle Overbay, 1B
Gregg Zaun, C
John McDonald, SS
PITCHING: RHP A.J. Burnett (8-7, 3.56 ERA)
NOTES: Blue Jays manager John Gibbons said CF Vernon Wells was simply given the day off — that his absence from the lineup was not related to his injured left shoulder. … CL B.J. Ryan is expected to be in Toronto on Monday. … 3B Troy Glaus has left the club and headed to L.A., where he will undergo surgery on his left foot as early as Monday.
entering Thursday
1. New York 83-62 (–)
2. Detroit 80-67 (4)
3. Seattle 76-68 (6.5)
4. Toronto 72-73 (11)
OVER AND OUT…Since 1995, the runner-up in the AL Wild Card race has finished with an average of 89 victories. With 17 games left, it is now impossible for the Blue Jays to reach 90 wins.
So, let's go with this one instead:
BREAKING EVEN…Toronto needs to post a 10-7 record over its final 17 games to finish the season above .500.
93 Comments
I hope we get Ace some rn support-his stuff is nasty again tonight.
can you say Burnett is the best…CY next year you heard it from me 2nd.
Yeah, with JP's luck AJ wins the CY and opt's out in search of a bigger pay day.
Instead of looking dumb for giving an injury prone SP a 5 year deal JP'll look bad for giving him and opt out clause.
I can't believe we're not hitting Kennedy. He throws consistent speed, little break and we're making him look like Cy Young
He wont opt out he likes it here
hey Robert-have you noticed Ace is turnng into a pitcher instead of a thrower
I doubt AJ can stay healthy for an entire season.
I dont know, but the way he's starting to pitch is a good start to being healthy all season. Now as long as Abner doesnt leave him out there for 130 pitches a game he'll be fine
Why damon I can't stand the ego tripper.
Zaun you bonehead go talk to AJ.
Beckett won't win the CY Young it will probably go to Santana or Escobar or a pitcher who has better stats. Total wins alone aren't going to do it. beckett is a s r e t a r d e d as bosox.
Burnett throwing very well tonight. A jam here in the 6th.
Jays bats are doing nothing against Kennedy. Thomas has had some nice swings against the kid. Kennedy has a great delivery and definetly knows how to spot his fastball, location and command. He doesn't have overpowering stuff but the kid looks like he has been in the big leagues for about 5 years.
amire-so why dont you go post that on the red sox site
Santana has hurt himself by losing to the Indians 5 times but he is definately a pitcher I wouldn't want to face in a game 7.
amire is sentinel…I am sure you have already figured that out….
yes, I like Santana-wish we had him
bosox-yes from his very first post. He seems to follow you around-any particular reason?
Santana is the best pitcher in baseball. The guy has a great fastball at 95 m.p.h. and the best changeup in the game. If Zito is worth 120 million, what is Santana worth?
Imagine if Santana was on a team like Boston or N.Y. The guy could win 23 games. I think his frustration with the front office/ownership has shown in his pitching. He has been vocal about his thoughts regarding the Twins. He believes they should sign Hunter and don't let him go. Santana knows how valuable a c.f. is, he has seen so many great catches by Hunter over the years.
Great job by Burnett to get out of the jam. If you have A-Rod up with 2 on and 1 out, that is usually a run for sure.
Kennedy does have poise. But no change of speed on the fastball and very little movement on it; although he is throwing to both sides of the plate.
Now I am not *** but I would rather be than be you.
Well Terry Ryan quit today, so maybe he thinks Santans is going to leave along with Hunter.
Yes, Burnett's making making a habit out of that since he came back-just lights out each and every start.
I guess he doesn't like me…
I guess I have a stalker here….
Why couldn't that stalker be Halle Berry…..LOL….
Kennedy is going to be around for a long time….
He has a very sound delivery…If I am a Yankee fan, I am very happy from what I see from him and some of the other young arms…
Scary on what could happen down the road with the young pitching and the $$$$$ they can spend….
woops sorry for the spelling mistakes and double words
Terry Ryan quit and he doesn't look so bad when Hunter goes.
The next g.m. ( they're going to promote from within ) has to make the descion on Santana. He's thrown right into the fire on that one.
Ryan has his hands clean on that situation in Minnesota.
ya, I'd go for Hale Berry as well.
It looks like Cashman's plan is working doesn't it? But, from what I've seen this series, their young arms are solid but no star material.
But, I like our young arms too, even better than theirs. I just don't see that much on your team.
That was great what Damon did. That is just AWESOME!!!! Damon always has alot of fun when he plays. I have never seen that one before!!!
"Ace" Roy Halladay (I'm sorry but he's the only one on the team) IS a pitcher and not just a thrower.
But you are correct AJ is maturing into a pitcher. The change-up is the key. There's a term for a 2 pitch pitchers – relievers. How it is that AJ was never forced to learn (and actually use) a 3rd pitch before this year is a mystery to me.
As far as liking it here, they all say that.
As far as his health: he's thown 32 games in a season one time, 31 games also just one time, and 27 one time. Those are his 3 longest seasons. I'll believe he's capible of a full season (34 starts for a #2 guy) when I see it.
The good news is that 31 came in 2002, 32 came in 2005, *hopefully* the trend continues and he takes the mound 33 times next year.
Apparently his assistant Bill Smith will replace him. Not a pretty picture to step into-they won't be anywhere near the team without Hunter and Santana.
gsumner Abner is going to have a hard time taking AJ out after what happend last time.
Kennedy is a kid that was drafted a year ago. He has composure of a veteran out there. Chamberlain throws gas and he has changed the look of the Yankee pen for the rest of the year.
Ramirez in the Yankee pen is nothing in my opinion. Yankees and Sox have done a good job with devolping some good young arms and winning at the same time. Not an easy thing to do but they're both doing it. Credit the front office's there.
Way to go AJ-7 innings, 8 k's, 4 hits, 1 run, 100 pitchers and he's still throwing at 99 mph.
Now we need to get him a few runs and bring the pen in.
If Burnett could stay healthy ( chances are slim ) He would rack up 225 innings and probably win close to 20 games. He has dominating stuff but he just can't stay healthy. That is what makes the Jays frustrated with Burnett, he has so much talent.
Of the 3, I think I like Kennedy the best. Chamberlain didnt impress me all that much-he throws gas,but no movement. I agree on Ramirez.
Kennedy is set to get married in early October. Yankees will be in the playoffs and playing in the 1st rd.
Safe to say the marriage is on hold. I hope his fiance' understands. I assume she does, she knows where the bread is buttered.
He'll stay healthy as long as our dumb *** manager doesn't have him throw 475 pitches in 3 games back to back-that's what caused the DL visit this time.
No worry A-Rod will take good care of her-providng she's a blond
Kennedy and Chamberlain are 2 totally opposite pitchers. Chamberlain throws gas and can get away with mistakes. Kennedy relies on the command of his fastball.
Hughes to me is the one that has the most potential but also the most pressure.
A-Rod scores on and off the field.
His last trip to Toronto, what will all the gals up there do?
His last trip to Boston, a bunch of fans wore blonde wigs.
I don't agree about Chamberlain. It doesn't seem to matter how fast they throw if it straight lines in like he does. Give him a couple of times through the league and he'll get hammered.
A very rare Yankee game that could go under 3 hours.
When the Yankees and Sox go at it. The games last 3 hours and 30 minutes on the average. Long games…..
Well actually I'm not sure I'd call her a gal-she was a dancer of ill repute at the club they went to
I don't know if Chamberlain will get hammered.
His breaking ball is a knee buckler. I wish he was with the Red Sox as opposed to the Yankees. He comes right at you and he usually blows it right by people.
I like the fast ones, like Halliday and Bruehle-2 hoursand a bit-may another 30 minutes. 3 1/2 is too long.
You guys are going to have your hands full with the Yanks. Man they are playing well
Ok, I get your point (and I haven't looked it up) but there's no way he was throwing 158 pitches a game (475/3).
He was spotted with a blonde down here in the Tampa area.
When you have all that fame and fortune, they'll be climbing all over you.
He is married and has a kid. He has a children's book out and then he is out in Toronto with some HO. Great player but as a human beign CLASSLESS!!!!
I still think to be successfull long term ne needs movement on his fastball or guys will just start sitting on it and let the breaking ball go by.
Classless-agreed. He doesn't deserve the talent he's got.
Over 100 pitches and he throws 96-97-98-97 my god.
Yankees are playing great in the last 3 months.
Sox are a better team at home of course.
Ramirez might return to the Boston lineup tomm night. I think the Sox should take 2 of 3 but then again I didn't think they would have gotten swept in late August. Sox take 2 this weekend and the division is over.
One thing for sure the Sox go to Toronto and the next game those 2 teams always lose.
This ball and strike in the corner on Rogers t.v. is always off.
Someone is sleeping in that t.v. truck.
we had better have someone ready if he losses Dieter hes now up to 118
Now that was a great outing by Burnett. 1 run in 8 innings. Very impressed. His next start is vs Boston!!!
It's going to depend on dicek and how well he does no friday. YOur starters are showing serious signs of fatigue
I'm not worried about the pitching. It's the Sox bats and especially when guys are on base.
Sox bullpen is the best in the bigs. The starters had a couple of rough starts this past week. That to me is baseball, a long season and that is how it goes sometimes. Dice-K. is pitching on 5 days rest. I wonder if he is out of gas. He hit the wall in the 6th inning vs Toronto.
Kennedy pitched great.
The kid looks like a veteran out there. He pitches as if he belongs and he'll be around for a long time.
With a name like Kennedy, he should be pitching in Boston.
hey guess what Abner found this new guy on the bench called Thigpen-how about that
Problem is in Japan pitchers only take the mound every 7 days.
The US style of every 5 days has got to be tough.
Jays actually bunted…..
Perhaps the Sox might bunt this weekend!!!!!
Dice-k's hit the wall in his last 3 starts.
Multiple reasons with Dice-K struggling. Longer season, shorter rest between starts, better hitters.
Different culture as well.
Okajima went thru a rough time recently. He looks like that is past him.
hey Abner woke up and called a bunt-Nahhhh. Johnny Mac probably did it on his own
I want this game to about 20 innings. That would be great….
Wear out that Yankee pen….
The young arms for the Yanks are nice to see for a change. You dont need star pitchers, just steady ones. As far as flamethrowers-Greg Maddux made a living hitting the corners with an average fastball. Granted he got all the close calls on the corner.
Maddox always had good movement on his fastball-that and living on the edge served him well.
maybe stray rod was out last night-we've got him 3 of 4 times tonight with 2 k's. I like that
well Abner you'd better hope we win in the bottom of the 9th-pulling Janssen all that quickly. Matsui hits about the same against lefties or righties and Cano is stonger against lefties.
If we win in the bottom of the 9th no problem, but if it goes tied into the 10th, it would have been **** nice to have Downs available then
holy **** a SB!!!!!!!!!!!!!!
What a stolen base-call the cops we don't do that sort of thing around here.
look what happens when you play baseball not powerball.
Garry-do you like the big hurt now?
can you say thanks.
ya Bosox, give Garry a hug-hes into that sort of thing at the moment. lol
well since Ace has been back he's had 7 starts. In those starts he's went 50.2 innings and has an era of 1.79.
His record in those 7 games is 3-1 and 3 no decisions. If he'd got any run support at all-it'd been 7-0.
You cannot blame a pitcher sometimes for his record. This is a perfect case in point.
Chris Britton is a slob!! They didn't want to burn the pen tonight and it was obvious. The win streak had to end sometime.
No more hugs.
I don't hurt anymore lol.
Where did that base go Rios took it home lol.
so Garry tell me what you think of Frank Thomas tonight. lol
gsumner I said I don't hurt anymore.
The Blue Jays brass[***] is going to keep Abner[gibbins]for another season puke.
I'm finding it hard to watch this team under his guidance now all I have to look forward to next year is the same garbage,It's going to be a very bleak winter to say the least.
The word was brass[****]
If Thomas had found his bat at the start of the season maybe just maybe =35-HR–125-RBI and if Glaus had the operation last winter maybe =35-HR–125-RBI And Wells claims his shoulder botherd him last winter why hide it,Reason big contract in the stars,I don't care who you are money talks,That hurt this team but now that he has his contract gets the shoulder fixed he will come back next year.Also I belive Glaus will and now that Thomas is settled in he will be good next year.
I wonder why they are keping Wells with the team when he should be getting his shoulder operated on so he has lots of time to heal.
It looks like Janssen may have a shot at a starters role next year sounds good to me.
After watching Burnett last night you can see that he has finaly started to keep his kool when he is in trouble and pitch his way out of it,Now he is the # 2 starter we paid for.
Well, there's Janssen, Chacin and Litsch so we should be in good shape.
Next year-I'd bet Burnett has the best record of any of our pitchers-assuming he gets equal run support. He's coming into his own.
As I said Cy Young
To bad about Abner.
I hope our big bats come out of the repair shop and do their job all of our pitchers will benefit from it.
I'm watching Stieb throw his no hitter on ESPNC great game
garry-where did you hear Abner is coming back next year?
Pathetic decision
Si reported today that Tony LaCava, Jays Director of Player Personal was interviewed for the BucsGM job by Frank Coonelly, New Pirates CEO.
I decided to send Frank an email and suggest he talk to Abner instead. I reiterated that Abner is truly the genious behind the Jays.
I'm not sure he bought it. lol
Thigpen should shove that gum up his a-ss and pay attention to what he is doing.
Wanted pitchers looking for a good record come pitch against Toronto you can't fail.
Garry the next game has been posted come there


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October 20, 2011
USDA researcher, former Cargill exec receiving alumni awards from College of Arts and Sciences
Submitted by Communications and Marketing
Two distinguished alumni of Kansas State University's College of Arts and Sciences will receive alumni awards from the college at a ceremony Thursday, Oct. 27.
Recipients are Jim Haymaker, a 1969 bachelor's graduate in economics, French and Spanish, who will receive the Alumni Merit Award, and Jeff Fabrick, a 1995 bachelor's graduate in biochemistry and a 2003 doctoral graduate in biochemistry, who will receive the Young Alumni Award. Joe Aistrup, interim dean of the College of Arts and Sciences, will make the presentations.
Bill Blankenau, head of the university's department of economics, nominated Haymaker for the College of Arts and Sciences Alumni Merit Award. Blankenau recognized Haymaker's entrepreneurial role in developing and implementing a paradigm shift at Cargill Inc. known as Strategic Intent.
"Strategic Intent was a huge success," Blankenau said. "Jim demonstrated that the principles of entrepreneurship could thrive in a corporate environment and that a large company could be nimble in a changing environment. His contributions sharply increased Cargill's earnings and the company was also able to implement a variety of new services and innovations to benefit customers."
Haymaker, who also earned a master of business administration in finance/international business from the University of Chicago in 1971, held a number of leadership positions in his successful career with Cargill. He recently retired and lives in Edina, Minn., with his wife, Kathy.
Fabrick is a research entomologist at the Pest Management and Biological Control Research Unit in the U.S. Department of Agriculture-Agricultural Research Service's U.S. Arid-Land Agricultural Research Center in Maricopa, Ariz. He was nominated for the Young Alumni Award by Mike Kanost, university distinguished professor and head of the department of biochemistry.
"Jeff has made significant contributions to the area of insect immunity. His published journal articles are among the very few biochemical papers in that field that deal with a significant pest species," Kanost said. "Jeff has excelled as an independent scientist, continuing to work on basic studies of insect biochemistry with important implications for agriculture, particularly in insect pests of cotton."
In 2010, Fabrick was named the Agricultural Research Service's Pacific West Area Early Career Research Scientist of the Year.
Both of the College of Arts and Sciences' awards are being presented at the second annual Eisenhower Circle Celebration, a special event recognizing loyal alumni and friends who give $250 or more to the college annually. The Eisenhower Circle recognition society is named for Milton S. Eisenhower, the ninth president of the university and for whom Eisenhower Hall is named for. The hall is home to the dean's offices of the College of Arts and Sciences.


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A modern retelling of "The Beauty and The Beast" starring Vanesa Hudgens, Alex Pettyfer, Neil Patrick Harris and Mary-Kate Olsen
We don't waste our time on anything not worth your time. We celebrate the best of what's coming on film and TV. We cheer when our expectations are met and criticize when we're let down.


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Join CrossFit 212, in New York's TriBeCa neighborhood
Drop-ins from out of town are welcome. Contact us to let us know you're coming.
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Interested in joining but want to understand the class experience before committing? Try our Saturday 11:30am class at CrossFit TriBeCa on 281 Broadway where we'll lead you through a classic CrossFit benchmark WOD, scaled appropriately to your current level of fitness. This class is for newbies only, no out of town drop-ins. If you're ready to get started, sign up for our next Foundations course.
Laura Skoda
Amazing coaches, facilities and programming. The sense of community & support at CrossFit 212 and their sister Box CrossFit TriBeca cannot be beat!!
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This isn't just another CrossFit affiliate but rather a dedicated family that will work with you to make you feel at home and comfortable with all aspects of the programming. Jim and his coaches go above and beyond.
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Simply #TheBest. Great facility and fantastic coaching staff. Best box in NYC.


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Fun, friendship and laughter in bucket loads. Come and enjoy the pleasure of familiar books and poetry. The group meets every Thursday morning from 10.30 to 12 noon in the Parish Room, Bakery Square in Yealmpton.
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Shared Reading Group
February 7 @ 10:30 am - 12:00 pm
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An event every week that begins at 10:30 am on Thursday, repeating indefinitely


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Workshop Description
Methods of automated reasoning have solved a large number of problems in Computer Science by using formal ontologies expressed in logic. Over the years, though, each problem or class of problems has required a different ontology, and sometimes a different version of logic. Moreover, the processes of conceiving, controlling and maintaining an ontology and its versions have turned out to be inherently complex. All this has motivated much investigation in a wide range of disparate disciplines - from logic-based Knowledge Representation and Reasoning to Software Engineering, from Databases to Multimedia - about how ontologies relate to one another and evolve.
ARCOE aims at bringing together researchers and practitioners from core areas of Artificial Intelligence (Knowledge Representation and Reasoning, Contexts, and Ontologies) to discuss these kinds of problems and relevant results.
Next EditionARCOE-Logic 2014 will be held on November 24-25, 2014 at EKAW 2014, Linköping, Sweden
Special Issue of the Journal of Web SemanticsThe Special Issue of the Journal of Web Semantics on Reasoning with context in the Semantic Web is now available online.
Past Editions
For past editions see the workshops section. Proceedings and presentations can be found in the download section.
Please send all enquiries and communications to: organization [at] arcoe [dot] org
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