text:
Summary: Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase
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GHKL domain Edit Wikipedia article
|Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase
Structure of the N-terminal domain of the yeast Hsp90 chaperone.[1]
The GHKL domain (Gyrase, Hsp90, Histidine Kinase, MutL) is an evolutionary conserved protein domain.[2]
This family represents the structurally related ATPase domains of histidine kinase, DNA gyrase B and HSP90. This domain is found in several ATP-binding proteins for example: histidine kinase, DNA gyrase B, topoisomerases,[3] heat shock protein HSP90,[4][5][6] phytochrome-like ATPases and DNA mismatch repair proteins. More information about this protein can be found at Protein of the Month: DNA Topoisomerase.[7]
- ^ Prodromou C, Roe SM, Piper PW, Pearl LH (June 1997). "A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone". Nat. Struct. Biol. 4 (6): 477–82. doi:10.1038/nsb0697-477. PMID 9187656.
- ^ Dutta R, Inouye M (January 2000). "GHKL, an emergent ATPase/kinase superfamily". Trends Biochem. Sci. 25 (1): 24–8. doi:10.1016/S0968-0004(99)01503-0. PMID 10637609.
- ^ Bellon S, Parsons JD, Wei Y, Hayakawa K, Swenson LL, Charifson PS, Lippke JA, Aldape R, Gross CH (May 2004). "Crystal Structures of Escherichia coli Topoisomerase IV ParE Subunit (24 and 43 Kilodaltons): a Single Residue Dictates Differences in Novobiocin Potency against Topoisomerase IV and DNA Gyrase". Antimicrob. Agents Chemother. 48 (5): 1856–64. doi:10.1128/AAC.48.5.1856-1864.2004. PMC 400558. PMID 15105144.
- ^ Immormino RM, Dollins DE, Shaffer PL, Soldano KL, Walker MA, Gewirth DT (October 2004). "Ligand-induced conformational shift in the N-terminal domain of GRP94, an Hsp90 chaperone". J. Biol. Chem. 279 (44): 46162–71. doi:10.1074/jbc.M405253200. PMID 15292259.
- ^ Roe SM, Ali MM, Meyer P, Vaughan CK, Panaretou B, Piper PW, Prodromou C, Pearl LH (January 2004). "The Mechanism of Hsp90 regulation by the protein kinase-specific cochaperone p50(cdc37)". Cell. 116 (1): 87–98. doi:10.1016/S0092-8674(03)01027-4. PMID 14718169.
- ^ Wright L, Barril X, Dymock B, Sheridan L, Surgenor A, Beswick M, Drysdale M, Collier A, Massey A, Davies N, Fink A, Fromont C, Aherne W, Boxall K, Sharp S, Workman P, Hubbard RE (June 2004). "Structure-activity relationships in purine-based inhibitor binding to HSP90 isoforms". Chem. Biol. 11 (6): 775–85. doi:10.1016/j.chembiol.2004.03.033. PMID 15217611.
- ^ McDowall J (2006). "DNA Topoisomerase". Protein of the month. InterPro.
This article incorporates text from the public domain Pfam and InterPro IPR003594
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Hsp90 Edit Wikipedia article
|Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase
|Pfam clan
|1ei1 / SUPFAM
|Hsp90 protein
Structure of the N-terminal domain of the yeast Hsp90 chaperone.[2]
|1ah6 / SUPFAM
Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, which is why Hsp90 inhibitors are investigated as anti-cancer drugs.
Heat shock proteins, as a class, are among the most highly expressed cellular proteins across all species.[3] As their name implies, heat shock proteins protect cells when stressed by elevated temperatures. They account for 1–2% of total protein in unstressed cells. However, when cells are heated, the fraction of heat shock proteins increases to 4–6% of cellular proteins.[4]
Heat shock protein 90 (Hsp90) is one of the most common of the heat-related proteins. The "90" comes from the fact that it weighs roughly 90 kiloDaltons. A 90 kDa protein is considered fairly large for a non-fibrous protein. Hsp90 is found in bacteria and all branches of eukarya, but it is apparently absent in archaea.[5] Whereas cytoplasmic Hsp90 is essential for viability under all conditions in eukaryotes, the bacterial homologue HtpG is dispensable under non-heat stress conditions.[6]
This protein was first isolated by extracting proteins from cells stressed by heating, dehydrating or by other means, all of which caused the cell's proteins to begin to denature.[7] However it was later discovered that Hsp90 also has essential functions in unstressed cells.
- 1 Isoforms
- 2 Structure
- 3 Mechanism
- 4 Function
- 5 Clinical significance
- 6 Evolution
- 7 See also
- 8 References
- 9 External links
Hsp90 is highly conserved and expressed in a variety of different organisms from bacteria to mammals – including the prokaryotic analogue HtpG (high-temperature protein G) with 40% sequence identity and 55% similarity to the human protein.[5] Yeast Hsp90 is 60% identical to human Hsp90α.
In mammalian cells, there are two or more genes encoding cytosolic Hsp90 homologues,[5] with the human Hsp90α showing 85% sequence identity to Hsp90β.[8] The α- and the β-forms are thought to be the result of a gene duplication event that occurred millions of years ago.[5]
The five functional human genes encoding Hsp90 protein isoforms are listed below:[8]
(constitutively expressed)
|TNF Receptor-
Associated Protein 1
There are 12 human pseudogenes (non-functional genes) that encode additional Hsp90 isoforms that are not expressed as proteins.
A membrane-associated variant of cytosolic Hsp90, lacking an ATP-binding site, has recently been identified and was named Hsp90N.[9] This HSP90α-Δ-N transcript is a chimera, with the first 105 bp of the coding sequence derived from the CD47 gene on chromosome 3q13.2, and the remaining coding sequence derived from HSP90AA1.[8] However, gene-encoding Hsp90N was later proven to be non-existent in human genome. It is possibly a cloning artifact or a product of chromosomal rearrangement occurring in a single cell line.[10]
Common features
The overall structure of Hsp90 is similar to that of other proteins in that it contains all of the common secondary structural elements (i.e., alpha helixes, beta pleated sheets, and random coils). Being a cytoplasmic protein requires that the protein be globular in structure, that is largely non-polar on the inside and polar on the outside, so as to be dissolved by water. Hsp90 contains nine helices and eight anti-parallel beta pleated sheets, which combine to form several alpha/beta sandwiches. The 310 helices make up approximately 11% of the protein's amino acid residues, which is much higher than the average 4% in other proteins.[11]
Domain structure
Hsp90 consists of four structural domains:[12][13][14]
- a highly conserved N-terminal domain (NTD) of ~25 kDa
- a "charged linker" region, that connects the N-terminus with the middle domain
- a middle domain (MD) of ~40 kDa
- a C-terminal domain (CTD) of ~12 kDa.
Crystal structures are available for the N-terminal domain of yeast and human Hsp90,[15][16][17] for complexes of the N-terminus with inhibitors and nucleotides,[15][16] and for the middle domain of yeast Hsp90.[18] Recently structures for full length Hsp90 from E. coli (2IOP, 2IOQ),[19] yeast (2CG9, 2CGE),[20] and the dog endoplasmic reticulum (2O1U, 2O1V)[21] were elucidated.[22]
Hsp90 forms homodimers where the contact sites are localized within the C-terminus in the open conformation of the dimer. The N-termini also come in contact in the closed conformation of the dimer.[18]
N-terminal domain
The N-terminal domain shows homology not only among members of the Hsp90 chaperone family but also to members of the ATPase/kinase GHKL (Gyrase, Hsp90, Histidine Kinase, MutL) superfamily.[13]
A common binding pocket for ATP and the inhibitor geldanamycin is situated in the N-terminal domain.[15][16] Amino acids that are directly involved in the interaction with ATP are Leu34, Asn37, Asp79, Asn92, Lys98, Gly121, and Phe124. In addition, Mg2+ and several water molecules form bridging electrostatic and hydrogen bonding interactions, respectively, between Hsp90 and ATP. In addition, Glu33 is required for ATP hydrolysis.
Middle domain
The middle domain is divided into three regions:
- a 3-layer α-β-α sandwich
- a 3-turn α-helix and irregular loops
- a 6-turn α-helix.[13]
The MD is also involved in client protein binding. For example, proteins known to interact this the Hsp90 MD include PKB/Akt1, eNOS,[23][24] Aha1, Hch1. Furthermore, substrate binding (e.g., by Aha1 and Hch1) to the MD is also known to increase the ATPase activity of Hsp90.[18][25]
C-terminal domain
The C-terminal domain possesses an alternative ATP-binding site, which becomes accessible when the N-terminal Bergerat pocket is occupied.[26][27]
At the very C-terminal end of the protein is the tetratricopeptide repeat (TPR) motif recognition site, the conserved MEEVD pentapeptide, that is responsible for the interaction with co-factors such as the immunophilins FKBP51 and FKBP52, the stress induced phosphoprotein 1 (Sti1/Hop), cyclophilin-40, PP5, Tom70, and many more.[28]
The Hsp90 protein contains three functional domains, the ATP-binding, protein-binding, and dimerizing domain, each of which playing a crucial role in the function of the protein.
ATP binding
The region of the protein near the N-terminus has a high-affinity ATP-binding site. The ATP binds to a sizable cleft in the side of protein, which is 15 Å (1.5 nanometres) deep. This cleft has a high affinity for ATP, and when given a suitable protein substrate, Hsp90 cleaves the ATP into ADP and Pi. Direct inhibitors of ATP binding or allosteric inhibitors of either ATP binding or ATPase activity can block Hsp90 function.[11] Another interesting feature of the ATP-binding region of Hsp90 is that it has a "lid†that is open during the ADP-bound state and closed in the ATP-bound state.[29] In the open conformation, the lid has no intraprotein interaction, and when closed comes into contact with several residues.[30] The contribution of this lid to the activity of Hsp90 has been probed with site-directed mutagenesis. The Ala107Asp mutant stabilizing the closed conformation of the protein through the formation of additional hydrogen bonds substantially increases ATPase activity while leaving the AMP+PnP conformation unchanged.[30]
The ATPase-binding region of Hsp90 is currently under intense study, because it is the principal binding site of drugs targeting this protein.[31] Antitumor drugs targeting this section of Hsp90 include the antibiotics geldanamycin,[11][32] herbimycin, radicicol, deguelin,[33] derrubone,[34] macbecin,[35] and beta-lactams.[36]
Protein binding
The protein-binding region of Hsp90 is located toward the C-terminus of the amino sequence. The Hsp90 protein can adopt two major conformational states. The first is an open ATP-bound state and the second is a closed ADP-bound state. Thus, ATP hydrolysis drives what is commonly referred to as a "pincer-type†conformational change in the protein binding site.[37]
Hsp90, while in the open conformation, leaves some hydrophobic residues exposed, to which unfolded and misfolded proteins that have unusual hydrophobic regions exposed are recruited with high affinity.[38] When a bound substrate is in place, the energy-releasing ATP hydrolysis by the ATPase function near the N-terminal domain forces conformational changes that clamp the Hsp90 down onto the substrate.[30] In a reaction similar to that of other molecular clamp proteins like GyrB and MutL, this site drives virtually all of the protein folding functions that Hsp90 plays a role in. In contrast, MutL and GyrB function as topoisomerases and use a charge clamp with a high amount of positively charged sidechains that is electrostatically attracted to the negative backbone of DNA.[39]
The ability of Hsp90 to clamp onto proteins allows it to perform several functions including assisting folding, preventing aggregation, and facilitating transport.
Normal cells
In unstressed cells, Hsp90 plays a number of important roles, which include assisting folding, intracellular transport, maintenance, and degradation of proteins as well as facilitating cell signaling.
Protein folding and role as chaperone
Hsp90 is known to associate with the non-native structures of many proteins, which has led to the proposal that Hsp90 is involved in protein folding in general.[40] Furthermore, Hsp90 has been shown to suppress the aggregation of a wide range of "client" or "substrate" proteins and hence acts as a general protective chaperone.[41][42][43] However Hsp90 is somewhat more selective than other chaperones.[44]
Protein degradation
Eukaryotic proteins that are no longer needed or are misfolded or otherwise damaged are usually marked for destruction by the polyubiquitation pathway. These ubiquitinated proteins are recognized and degraded by the 26S proteasome.[45][46] Hence the 26S proteasome is an integral part of the cell's mechanism to degrade proteins. Furthermore, a constant supply of functional Hsp90 is needed to maintain the tertiary structure of the proteasome.[47] Finally experiments done with heat sensitive Hsp90 mutants and the 26S proteasome suggest that Hsp90 is responsible for most, if not all, of the ATPase activity of the proteasome.[45]
Interaction with steroid receptors
The glucocorticoid receptor (GR) is the most thoroughly studied example of a steroid receptor whose function is crucially dependent on interactions with Hsp90.[50][51] In the absence of the steroid hormone cortisol, GR resides in the cytosol complexed with several chaperone proteins including Hsp90 (see figure to the right). These chaperones maintain the GR in a state capable of binding hormone. A second role of Hsp90 is to bind immunophilins (e.g., FKBP52) that attach the GR complex to the dynein protein trafficking pathway, which translocates the activated receptor from the cytoplasm into the nucleus.[52] Once in the nucleus, the GR dimerizes and binds to specific sequences of DNA and thereby upregulates the expression of GR responsive genes. Hsp90 is also required for the proper functioning of several other steroid receptors, including those responsible for the binding of aldosterone,[53] androgen,[54] estrogen,[55] and progesterone.[56]
Cancerous cells
Cancerous cells overexpress a number of proteins, including growth factor receptors, such as EGFR,[57] or signal transduction proteins such as PI3K and AKT (Inhibition of these proteins may trigger apoptosis). Hsp90 stabilizes various growth factor receptors[58] and some signaling molecules including PI3K and AKT proteins. Hence inhibition of Hsp90 may induce apoptosis through inhibition of the PI3K/AKT signaling pathway and growth factor signaling generally.[15][59]
Another important role of Hsp90 in cancer is the stabilization of mutant proteins such as v-Src, the fusion oncogene Bcr/Abl, and mutant forms of p53 that appear during cell transformation. It appears that Hsp90 can act as a "protector" of less stable proteins produced by DNA mutations.[60]
Hsp90 is also required for induction of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS).[24] Both are important for de novo angiogenesis that is required for tumour growth beyond the limit of diffusion distance of oxygen in tissues.[60] It also promotes the invasion step of metastasis by assisting the matrix metalloproteinase MMP2.[61] Together with its co-chaperones, Hsp90 modulates tumour cell apoptosis "mediated through effects on AKT,[23] tumor necrosis factor receptors (TNFR) and nuclear factor-κB (NF-κB) function."[62] Also, Hsp90 participates in many key processes in oncogenesis such as self-sufficiency in growth signals, stabilization of mutant proteins, angiogenesis, and metastasis.
Clinical significance
Hsp90 plays apparently conflicting roles in the cell, as it is essential for both the creation and the maintenance as well as the destruction of proteins. Its normal function is critical to maintaining the health of cells, whereas its dysregulation may contribute to carcinogenesis. The ability of this chaperone to both stabilize the 26S proteasome (which enables the cell to degrade unwanted and/or harmful proteins) and to stabilize kinases against the same proteasome demonstrates its functional diversity. The uses of Hsp90 inhibitors in cancer treatment highlight Hsp90's importance as a therapeutic target.[63]
Targeting Hsp90 with drugs has shown promising effects in clinical trials. For example, the Hsp90 inhibitor geldanamycin has been used as an anti-tumor agent.[11] The drug was originally thought to function as a kinase inhibitor but was subsequently shown to be an Hsp90 inhibitor where it uses a compact conformation to insert itself into the ATP binding site.[11]
HSP90 beta has been identified as one of the autoantigenic biomarkers and targets involved in human ovarian autoimmune disease leading to ovarian failure and thereby infertility.[64]
Prediction and validation of the immunodominant epitope/s of HSP90 beta protein has been demonstrated using sera from infertile women having anti-HSP90 autoantibodies. The decapeptide EP6 (380-389)is a major immunogenic epitope of HSP90 followed by EP1 (1-12) and EP8 (488-498). Knowledge of binding epitopes on the autoantigen is necessary to understand the subsequent pathologic events. Predicted 3D structures of these peptides demonstrated that they exist in the loop conformation, which is the most mobile part of the protein. Also, analysis of the sequences of HSP90 beta across several species reveals that EP6 peptide forms a part of a well-conserved motif. A polyclonal antibody generated to the immunodominant epitope- EP6 confirms similar biochemical and cellular immunoreactivity as seen with the patients' sera with anti-HSP90 autoantibodies. The study might generate new tools for the detection of disease-inducing epitopes and a possible therapeutic intervention.[65]
Sequence alignments of Hsp90 have shown the protein to have about 40% sequence identity across all homologs, indicating that it is a highly conserved protein. There are two homologs, found in the cytosol and endoplasmic reticulum respectively. The presence of these two homologs was likely caused by a gene duplication event very early in the evolution of eukaryotes that may have accompanied the evolution of the endoplasmic reticulum or the nucleus. This inference is supported by the fact that the duplication is found in Giardia lamblia, one of the earliest branching eukaryotic species. At least 2 other subsequent gene duplications occurred, which explains the different forms of Hsp90 found in fungi and vertebrates. One divergence produced cognate and heat-induced forms of Hsp90 in Saccharomyces cerevisiae, while the second gene duplication event in the cytosolic branch produced the alpha and beta subfamilies of sequences that are found in all vertebrates. In a phylogenetic tree based on Hsp90 sequences, it was found that plants and animals are more closely related to each other than to fungi.[66] Similar to the Hsp90 protein, the gene for Hsp70 protein also underwent duplication at a very early stage in the formation of eukaryotic cells and the homologs in the cytosol and endoplasmic reticulum resulted from this gene duplication event.[67] These gene duplication events are important in terms of the origin of the eukaryotic cell and of the endoplasmic reticulum.[68][69]
See also
- ^ a b c PDB: 2CG9; Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH (April 2006). "Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex". Nature. 440 (7087): 1013–7. doi:10.1038/nature04716. PMC 5703407. PMID 16625188.
- ^ Prodromou C, Roe SM, Piper PW, Pearl LH (June 1997). "A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone". Nat. Struct. Biol. 4 (6): 477–82. doi:10.1038/nsb0697-477. PMID 9187656.
- ^ Csermely P, Schnaider T, Soti C, Prohászka Z, Nardai G (August 1998). "The 90-kDa molecular chaperone family: structure, function, and clinical applications. A comprehensive review". Pharmacol. Ther. 79 (2): 129–68. doi:10.1016/S0163-7258(98)00013-8. PMID 9749880.
- ^ Crevel G, Bates H, Huikeshoven H, Cotterill S (1 June 2001). "The Drosophila Dpit47 protein is a nuclear Hsp90 co-chaperone that interacts with DNA polymerase alpha". J. Cell Sci. 114 (Pt 11): 2015–25. PMID 11493638.
- ^ a b c d Chen B, Zhong D, Monteiro A (2006). "Comparative genomics and evolution of the HSP90 family of genes across all kingdoms of organisms". BMC Genomics. 7: 156. doi:10.1186/1471-2164-7-156. PMC 1525184. PMID 16780600.
- ^ Thomas JG, Baneyx F (October 1998). "Roles of the Escherichia coli Small Heat Shock Proteins IbpA and IbpB in Thermal Stress Management: Comparison with ClpA, ClpB, and HtpG In Vivo". J. Bacteriol. 180 (19): 5165–72. PMC 107554. PMID 9748451.
- ^ Prodromou C, Panaretou B, Chohan S, Siligardi G, O'Brien R, Ladbury JE, Roe SM, Piper PW, Pearl LH (August 2000). "The ATPase cycle of Hsp90 drives a molecular 'clamp' via transient dimerization of the N-terminal domains". EMBO J. 19 (16): 4383–92. doi:10.1093/emboj/19.16.4383. PMC 302038. PMID 10944121.
- ^ a b c Chen B, Piel WH, Gui L, Bruford E, Monteiro A (December 2005). "The HSP90 family of genes in the human genome: insights into their divergence and evolution". Genomics. 86 (6): 627–37. doi:10.1016/j.ygeno.2005.08.012. PMID 16269234.
- ^ Grammatikakis N, Vultur A, Ramana CV, Siganou A, Schweinfest CW, Watson DK, Raptis L (March 2002). "The role of Hsp90N, a new member of the Hsp90 family, in signal transduction and neoplastic transformation". J. Biol. Chem. 277 (10): 8312–20. doi:10.1074/jbc.M109200200. PMID 11751906.
- ^ Zurawska A, Urbanski J, Bieganowski P (November 2008). "Hsp90n - An accidental product of a fortuitous chromosomal translocation rather than a regular Hsp90 family member of human proteome". Biochimica et Biophysica Acta. 1784 (11): 1844–6. doi:10.1016/j.bbapap.2008.06.013. PMID 18638579.
- ^ a b c d e Goetz MP, Toft DO, Ames MM, Erlichman C (August 2003). "The Hsp90 chaperone complex as a novel target for cancer therapy". Ann. Oncol. 14 (8): 1169–76. doi:10.1093/annonc/mdg316. PMID 12881371.
- ^ Pearl LH, Prodromou C (February 2000). "Structure and in vivo function of Hsp90". Curr. Opin. Struct. Biol. 10 (1): 46–51. doi:10.1016/S0959-440X(99)00047-0. PMID 10679459.
- ^ a b c Prodromou C, Pearl LH (October 2003). "Structure and functional relationships of Hsp90". Curr Cancer Drug Targets. 3 (5): 301–23. doi:10.2174/1568009033481877. PMID 14529383.
- ^ Pearl LH, Prodromou C (2001). Structure, function, and mechanism of the Hsp90 molecular chaperone. Adv. Protein Chem. Advances in Protein Chemistry. 59. pp. 157–86. doi:10.1016/S0065-3233(01)59005-1. ISBN 978-0-12-034259-4. PMID 11868271.
- ^ a b c d Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP (April 1997). "Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent". Cell. 89 (2): 239–50. doi:10.1016/S0092-8674(00)80203-2. PMID 9108479.
- ^ a b c Prodromou C, Roe SM, O'Brien R, Ladbury JE, Piper PW, Pearl LH (July 1997). "Identification and structural characterization of the ATP/ADP-binding site in the Hsp90 molecular chaperone". Cell. 90 (1): 65–75. doi:10.1016/S0092-8674(00)80314-1. PMID 9230303.
- ^ Prodromou C, Roe SM, Piper PW, Pearl LH (June 1997). "A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone". Nat. Struct. Biol. 4 (6): 477–82. doi:10.1038/nsb0697-477. PMID 9187656.
- ^ a b c Meyer P, Prodromou C, Hu B, Vaughan C, Roe SM, Panaretou B, Piper PW, Pearl LH (March 2003). "Structural and functional analysis of the middle segment of hsp90: implications for ATP hydrolysis and client protein and cochaperone interactions". Mol. Cell. 11 (3): 647–58. doi:10.1016/S1097-2765(03)00065-0. PMID 12667448.
- ^ Shiau AK, Harris SF, Southworth DR, Agard DA (October 2006). "Structural Analysis of E. coli hsp90 reveals dramatic nucleotide-dependent conformational rearrangements". Cell. 127 (2): 329–40. doi:10.1016/j.cell.2006.09.027. PMID 17055434.
- ^ Ali MM, Roe SM, Vaughan CK, Meyer P, Panaretou B, Piper PW, Prodromou C, Pearl LH (April 2006). "Crystal structure of an Hsp90-nucleotide-p23/Sba1 closed chaperone complex". Nature. 440 (7087): 1013–7. doi:10.1038/nature04716. PMC 5703407. PMID 16625188.
- ^ Dollins DE, Warren JJ, Immormino RM, Gewirth DT (October 2007). "Structures of GRP94-nucleotide complexes reveal mechanistic differences between the hsp90 chaperones". Mol. Cell. 28 (1): 41–56. doi:10.1016/j.molcel.2007.08.024. PMC 2094010. PMID 17936703.
- ^ Wandinger SK, Richter K, Buchner J (July 2008). "The hsp90 chaperone machinery". J. Biol. Chem. 283 (27): 18473–7. doi:10.1074/jbc.R800007200. PMID 18442971.
- ^ a b Sato S, Fujita N, Tsuruo T (September 2000). "Modulation of Akt kinase activity by binding to Hsp90". Proc. Natl. Acad. Sci. U.S.A. 97 (20): 10832–7. doi:10.1073/pnas.170276797. PMC 27109. PMID 10995457.
- ^ a b Fontana J, Fulton D, Chen Y, Fairchild TA, McCabe TJ, Fujita N, Tsuruo T, Sessa WC (May 2002). "Domain mapping studies reveal that the M domain of hsp90 serves as a molecular scaffold to regulate Akt-dependent phosphorylation of endothelial nitric oxide synthase and NO release". Circ. Res. 90 (8): 866–73. doi:10.1161/01.RES.0000016837.26733.BE. PMID 11988487.
- ^ Panaretou B, Siligardi G, Meyer P, Maloney A, Sullivan JK, Singh S, Millson SH, Clarke PA, Naaby-Hansen S, Stein R, Cramer R, Mollapour M, Workman P, Piper PW, Pearl LH, Prodromou C (December 2002). "Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1". Mol. Cell. 10 (6): 1307–18. doi:10.1016/S1097-2765(02)00785-2. PMID 12504007.
- ^ Marcu MG, Chadli A, Bouhouche I, Catelli M, Neckers LM (November 2000). "The heat shock protein 90 antagonist novobiocin interacts with a previously unrecognized ATP-binding domain in the carboxyl terminus of the chaperone". J. Biol. Chem. 275 (47): 37181–6. doi:10.1074/jbc.M003701200. PMID 10945979.
- ^ Söti C, Rácz A, Csermely P (March 2002). "A Nucleotide-dependent molecular switch controls ATP binding at the C-terminal domain of Hsp90. N-terminal nucleotide binding unmasks a C-terminal binding pocket". J. Biol. Chem. 277 (9): 7066–75. doi:10.1074/jbc.M105568200. PMID 11751878.
- ^ Young JC, Obermann WM, Hartl FU (July 1998). "Specific binding of tetratricopeptide repeat proteins to the C-terminal 12-kDa domain of hsp90". J. Biol. Chem. 273 (29): 18007–10. doi:10.1074/jbc.273.29.18007. PMID 9660753.
- ^ Didenko T, Duarte AM, Karagöz GE, Rüdiger SG (March 2012). "Hsp90 structure and function studied by NMR spectroscopy". Biochim. Biophys. Acta. 1823 (3): 636–47. doi:10.1016/j.bbamcr.2011.11.009. PMID 22155720.
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- ^ Chiosis G, Caldas Lopes E, Solit D (June 2006). "Heat shock protein-90 inhibitors: a chronicle from geldanamycin to today's agents". Curr Opin Investig Drugs. 7 (6): 534–41. PMID 16784024.
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- ^ Oh SH, Woo JK, Yazici YD, Myers JN, Kim WY, Jin Q, Hong SS, Park HJ, Suh YG, Kim KW, Hong WK, Lee HY (June 2007). "Structural basis for depletion of heat shock protein 90 client proteins by deguelin". J. Natl. Cancer Inst. 99 (12): 949–61. doi:10.1093/jnci/djm007. PMID 17565155.
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- ^ O'Boyle NM, Knox AJ, Price TT, Williams DC, Zisterer DM, Lloyd DG, Meegan MJ (October 2011). "Lead identification of β-lactam and related imine inhibitors of the molecular chaperone heat shock protein 90". Bioorg. Med. Chem. 19 (20): 6055–68. doi:10.1016/j.bmc.2011.08.048. PMID 21920765.
- ^ Grenert JP, Sullivan WP, Fadden P, Haystead TA, Clark J, Mimnaugh E, Krutzsch H, Ochel HJ, Schulte TW, Sausville E, Neckers LM, Toft DO (September 1997). "The amino-terminal domain of heat shock protein 90 (hsp90) that binds geldanamycin is an ATP/ADP switch domain that regulates hsp90 conformation". J. Biol. Chem. 272 (38): 23843–50. doi:10.1074/jbc.272.38.23843. PMID 9295332.
- ^ Xu Z, Horwich AL, Sigler PB (August 1997). "The crystal structure of the asymmetric GroEL-GroES-(ADP)7 chaperonin complex". Nature. 388 (6644): 741–50. doi:10.1038/41944. PMID 9285585.
- ^ Kampranis SC, Bates AD, Maxwell A (July 1999). "A model for the mechanism of strand passage by DNA gyrase". Proc. Natl. Acad. Sci. U.S.A. 96 (15): 8414–9. doi:10.1073/pnas.96.15.8414. PMC 17530. PMID 10411889.
- ^ Buchner J (April 1999). "Hsp90 & Co. - a holding for folding". Trends Biochem. Sci. 24 (4): 136–41. doi:10.1016/S0968-0004(99)01373-0. PMID 10322418.
- ^ Miyata Y, Yahara I (April 1992). "The 90-kDa heat shock protein, Hsp90, binds and protects casein kinase II from self-aggregation and enhances its kinase activity". J. Biol. Chem. 267 (10): 7042–7. PMID 1551911.
- ^ Wiech H, Buchner J, Zimmermann R, Jakob U (July 1992). "Hsp90 chaperones protein folding in vitro". Nature. 358 (6382): 169–70. doi:10.1038/358169a0. PMID 1614549.
- ^ Jakob U, Lilie H, Meyer I, Buchner J (March 1995). "Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase. Implications for heat shock in vivo". J. Biol. Chem. 270 (13): 7288–94. doi:10.1074/jbc.270.13.7288. PMID 7706269.
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- ^ a b Imai J, Maruya M, Yashiroda H, Yahara I, Tanaka K (July 2003). "The molecular chaperone Hsp90 plays a role in the assembly and maintenance of the 26S proteasome". EMBO J. 22 (14): 3557–67. doi:10.1093/emboj/cdg349. PMC 165619. PMID 12853471.
- ^ Correia MA, Sadeghi S, Mundo-Paredes E (2005). "Cytochrome P450 ubiquitination: branding for the proteolytic slaughter?". Annu. Rev. Pharmacol. Toxicol. 45: 439–64. doi:10.1146/annurev.pharmtox.45.120403.100127. PMID 15822184.
- ^ Kimura Y, Matsumoto S, Yahara I (March 1994). "Temperature-sensitive mutants of hsp82 of the budding yeast Saccharomyces cerevisiae". Mol. Gen. Genet. 242 (5): 517–27. doi:10.1007/BF00285275. PMID 8121410.
- ^ Davies TH, Ning YM, Sánchez ER (February 2002). "A new first step in activation of steroid receptors: hormone-induced switching of FKBP51 and FKBP52 immunophilins". J. Biol. Chem. 277 (7): 4597–600. doi:10.1074/jbc.C100531200. PMID 11751894.
- ^ Pałyga J, Kozłowski Š(2007). "Structure and function of molecular chaperone HSP90". Sowriemiennyj Naucznyj Wiestnik Ser. Biologija Chimija. 15 (23): 46–65.
- ^ Pratt WB, Morishima Y, Murphy M, Harrell M (2006). Chaperoning of glucocorticoid receptors. Handb Exp Pharmacol. Handbook of Experimental Pharmacology. 172. pp. 111–38. doi:10.1007/3-540-29717-0_5. ISBN 978-3-540-25875-9. PMID 16610357.
- ^ Grad I, Picard D (September 2007). "The glucocorticoid responses are shaped by molecular chaperones". Mol. Cell. Endocrinol. 275 (1–2): 2–12. doi:10.1016/j.mce.2007.05.018. PMID 17628337.
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- ^ Catelli MG, Binart N, Jung-Testas I, Renoir JM, Baulieu EE, Feramisco JR, Welch WJ (December 1985). "The common 90-kd protein component of non-transformed '8S' steroid receptors is a heat-shock protein". EMBO J. 4 (12): 3131–5. doi:10.1002/j.1460-2075.1985.tb04055.x. PMC 554632. PMID 2419124.
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- ^ Sawai A, Chandarlapaty S, Greulich H, Gonen M, Ye Q, Arteaga CL, Sellers W, Rosen N, Solit DB (January 2008). "Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel". Cancer Res. 68 (2): 589–96. doi:10.1158/0008-5472.CAN-07-1570. PMC 4011195. PMID 18199556.
- ^ Mohsin SK, Weiss HL, Gutierrez MC, Chamness GC, Schiff R, Digiovanna MP, Wang CX, Hilsenbeck SG, Osborne CK, Allred DC, Elledge R, Chang JC (April 2005). "Neoadjuvant trastuzumab induces apoptosis in primary breast cancers". J. Clin. Oncol. 23 (11): 2460–8. doi:10.1200/JCO.2005.00.661. PMID 15710948.
- ^ a b Calderwood SK, Khaleque MA, Sawyer DB, Ciocca DR (March 2006). "Heat shock proteins in cancer: chaperones of tumorigenesis". Trends Biochem. Sci. 31 (3): 164–72. doi:10.1016/j.tibs.2006.01.006. PMID 16483782.
- ^ Eustace BK, Sakurai T, Stewart JK, Yimlamai D, Unger C, Zehetmeier C, Lain B, Torella C, Henning SW, Beste G, Scroggins BT, Neckers L, Ilag LL, Jay DG (June 2004). "Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness". Nat. Cell Biol. 6 (6): 507–14. doi:10.1038/ncb1131. PMID 15146192.
- ^ Whitesell L, Lindquist SL (October 2005). "Hsp90 and the chaperoning of cancer". Nat. Rev. Cancer. 5 (10): 761–72. doi:10.1038/nrc1716. PMID 16175177.
- ^ Kim YS, Alarcon SV, Lee S, Lee MJ, Giaccone G, Neckers L, Trepel JB (2009). "Update on Hsp90 inhibitors in clinical trial". Curr Top Med Chem. 9 (15): 1479–92. doi:10.2174/156802609789895728. PMID 19860730.
- ^ Pires ES, Khole VV (2009). "A block in the road to fertility: autoantibodies to heat-shock protein 90-beta in human ovarian autoimmunity". Fertil Steril. 92 (4): 1395–1409. doi:10.1016/j.fertnstert.2008.08.068. PMID 19022436.
- ^ Pires ES, Choudhury AK, Idicula-Thomas S, Khole VV (2011). "Anti-HSP90 autoantibodies in sera of infertile women identify a dominant, conserved epitope EP6 (380-389) of HSP90 beta protein". Reprod Biol Endocrinol. 9 (16): 13. doi:10.1186/1477-7827-9-16. PMC 3039567. PMID 21272367.
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- ^ Gupta RS, Aitken K, Falah M, Singh B (April 1994). "Cloning of Giardia lamblia heat shock protein HSP70 homologs: implications regarding origin of eukaryotic cells and of endoplasmic reticulum". Proc. Natl. Acad. Sci. U.S.A. 91 (8): 2895–9. doi:10.1073/pnas.91.8.2895. PMC 43480. PMID 8159675.
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External links
|Wikimedia Commons has media related to HSP90 heat-shock proteins.
- Hsp90+Heat-Shock+Proteins at the US National Library of Medicine Medical Subject Headings (MeSH)
- Didier Picard. "Hsp90 web site". VisibilityWeb. Archived from the original on 2004-11-23. Retrieved 2008-07-07.
A web site for the community of scientists interested in the Hsp90 molecular chaperone machine.
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.
Histidine kinase-, DNA gyrase B-, and HSP90-like ATPase Provide feedback
This family represents the structurally related ATPase domains of histidine kinase, DNA gyrase B and HSP90.
Literature references
Li Y, Bahti P, Shaw N, Song G, Chen S, Zhang X, Zhang M, Cheng C, Yin J, Zhu JY, Zhang H, Che D, Xu H, Abbas A, Wang BC, Liu ZJ;, Proteins 2008;71:2109-13.: Crystal structure of a novel non-Pfam protein AF1514 from Archeoglobus fulgidus DSM 4304 solved by S-SAD using a Cr X-ray source. PUBMED:18361456 EPMC:18361456
Internal database links
|HATPase_c_2 HATPase_c_3 HATPase_c_5 HPTransfase
|Similarity to PfamA using HHSearch:
|HATPase_c_2 HATPase_c_3 HATPase_c_5
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR003594
This domain is found in several ATP-binding proteins, including: histidine kinase [PUBMED:15157101], DNA gyrase B, topoisomerases [PUBMED:15105144], heat shock protein HSP90 [PUBMED:15292259, PUBMED:14718169, PUBMED:15217611], phytochrome-like ATPases and DNA mismatch repair proteins. The fold of this domain consists of two layers, alpha/beta, which contains an 8-stranded mixed beta-sheet.
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.
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Pfam Clan
This family is a member of clan His_Kinase_A (CL0025), which has the following description:
This is the dimerisation and phospho-acceptor domain of a sub-family of histidine kinases. It shares sequence similarity with Pfam:PF00512 and Pfam:PF07536. It is usually found adjacent to a C-terminal ATPase domain (Pfam:PF02518). This domain is found in a wide range of Bacteria and also several Archaea. It comprises one of the fundamental units of the two-component signal transduction system [2-7].
The clan contains the following 10 members:H-kinase_dim HATPase_c HATPase_c_2 HATPase_c_3 HATPase_c_5 HisKA HisKA_2 HisKA_3 HPTransfase HWE_HK
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:
|SMART, Griffiths-Jones SR
|Number in seed:
|Number in full:
|Average length of the domain:
|116.50 aa
|Average identity of full alignment:
|25 %
|Average coverage of the sequence by the domain:
|18.01 %
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
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Selected sequences
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- 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 25 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 HATPase_c domain has been found. There are 875 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.
Loading structure mapping...


text:
Potato Nests
Wash, pare and cut potatoes in thin strips, using same slicer as for Lattice Potatoes. Soak in cold water fifteen minutes, drain, and dry between towels. Line a fine wire strainer of four-inch diameter, and having a wire handle, with potatoes, place a similar strainer, having a two and one-half inch diameter, in larger strainer, thus holding potatoes in nest shapes. Fry in deep fat, taking care that the fat does not reach too high a temperature at first. Keep the small strainer in place during frying with a long handled spoon. Carefully remove nests from strainers. Drain on brown paper, and sprinkle with salt. Fill with small fillets of fried fish or fried smelts.
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BY Ysabell On Jun 13, 2018 Template
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ORANGE, Calif. – The Chapman University football team has become accustomed to opening the season with a win. Rarely have those wins come with such firepower as Saturday night's 55-35 defeat of visiting University of Puget Sound. The Panthers and Loggers combined for 1,141 yards of total offense and 90 points in a slugfest that lasted over three hours at Ernie Chapman Stadium in Saturday night.
Chapman (1-0), making its 2012 debut, scored on its first four possessions of the game to build a 28-0 lead after one quarter. That included a 100-yard touchdown return by junior RB Austin Maranville on the game's opening kickoff – a school record. It was just the sixth kick return for a touchdown in Chapman history, the last by Kevin Krail in 2009.
On their second possession, sophomore QB Kean Stancil led the Panthers 86 yards on 10 plays and scored his first of four touchdowns in the game, scampering 7 yards for the score. Stancil would run for two touchdowns and pass for two more before his night was done.
Once again, Chapman began its third drive on the 14 yard line and went another 86 yards for the score. Stancil and senior WR Kali'i Kunitomo connected on a 60-yard pass play for a touchdown with 6:38 left in the first quarter.
For good measure, the Panthers finished the first quarter flurry with a 51-yard drive that ended on a 13-yard touchdown pass from Stancil to junior WR Robin Harris with 2:08 left, giving Chapman a 28-0 lead. The Panthers had 223 yards of total offense in the first 12:52 of the game.
In the second quarter it was sophomore RB Jeremiah McKibbins' turn. Making his first career start at tailback, McKibbins rushed 10 times in the second quarter for 86 of his career-high 154 yards and scored a pair of touchdowns from 10 and 4 yards out. That gave Chapman a 42-14 lead at halftime.
In the half, Stancil was 19 of 20 passing for 267 yards, 138 of which went to Kunitomo on seven receptions. Kunitomo finished the game with eight catches for 152 yards, just 1 yard shy of his career-high set against Redlands last season.
Meanwhile, Stancil's debut may have been the best for a quarterback in school history. The sophomore completed 26 of 32 passes for 339 yards – the most for a Chapman playcaller in his first game. He also ran for 33 yards and two scores.
Puget Sound (0-2) never did recover from the early deficit but racked up some offense, particularly in the second half where the Loggers scored three times. Sophomore QB Braden Foley and senior All-America WR Adam Kniffin torched the Chapman secondary, connecting for a school-record 267 yards and four touchdowns for Kniffin. Foley finished 31 of 55 for a career-high 470 yards passing and five TDs.
The Loggers finished with 526 yards of total offense in the game.
Chapman's senior K Mauricio Alfonso tied a school record with his 17th and 18th career field goals from 40 and 35 yards in the second half. He was also a perfect 7-for-7 in PAT attempts, running his career streak to 54 in a row.
The Panthers' 615 yards of total offense is the most they've produced since setting a school record with 644 yards in a game against Redlands in 1996. Chapman improved to 6-1 in season openers over the past seven seasons.


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Unable to find a home here in the good ol' U.S. of A., Will Arnett, David Cross and Spike Jonze took their talents across the pond to create "The Increasingly Poor Decisions of Todd Margaret," an office sitcom that apparently nobody stateside would finance.
The British Comedy Guide's synopsis of the show reads:
American Todd Margaret bluffs his way into an apparently great job opportunity, heading up the sales team in his employer's London office. All he has to do is sell a dozen container loads of dodgy Korean energy drink before his psychotic boss visits him in a week. Simple. Apart from the fact that he knows nothing about British culture and nothing about sales. He also only has one employee to assist him, Dave, who is perhaps the most wilfully unhelpful employee ever.
Todd's life is further complicated when he lies continuously to cover his ignorance and spectacularly fails to impress beautiful cafe owner Alice. Dave soon takes full advantage of Todd's situation and chaos ensues.
But so you really need to know the concept? Weren't you sold by the names Arnett, Cross and Jonze? If you just can't stand the idea of waiting until it's available on DVD, the folks at Vulture discovered the entire first episode is online, broken into three segments. And take heart, there will be more episodes forthcoming as the show got picked up for a full season.
So now all you have to ask yourself is, do you watch it in sections throughout the workday or blow through the whole thing at lunch?
Here it is -- but be warned, it was made for British TV, where they acknowledge that grownups do in fact use dirty words:


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Storm Chaser Reed Timmer's Tips to Minimize Storm Damage at Home
Storms happen. It's a fact of life we've all come to understand, and most of the time the raucous weather runs its course and moves on. But some storms leave their mark, both on the countryside and, unfortunately, on people's homes and lives.
Luckily, there are ways to limit the damage these storms can cause.
While I'm not an arborist, I am a professional storm chaser, and I've seen countless trees taken down by high winds, heavy snowfall, and even hail. I can offer some helpful tips I've picked up along the way that may be able to save you from unnecessary damage to your home.
Strong Wind + Trees = Potential Damage
First, let me address trees and the potential for destruction. Having a tree in your yard may be aesthetically pleasing, but in the right (or wrong) circumstances, it has the potential to damage your home. Strong wind is the primary catalyst for turning beautiful trees into house-harming annoyances. Consider these factors when evaluating the pros and cons of the trees in your own yard:
What Trees Do You Have?
The best advice is to get to know the trees in your yard. If you're confident in your ability to identify different types of trees, diagram your yard and identify each tree and its location along with its species. If you're not sure, it's best to find a local arborist.
Depending on what kinds of trees you have, proactive steps might be needed to help prevent an incident. Younger trees are more flexible and are less likely to snap or fall. Over time, bigger and older trees can become brittle due to harmful insects and disease and have a higher potential to fall. If you have older trees, performing regular maintenance on them can help avoid an incident during a storm. Keep in mind the trees on the west side of your house are more prone to fall, as strong straight-line winds usually move west to east — obviously, winds associated with tornadoes, hurricanes and nor'easters can come from opposite directions.
Different Season, Different Maintenance.
Trees that provide large canopies of shade, such as a willow tree, are awesome in the summer, but keep in mind the same parts of the tree that provide the shade can also form the equivalent of a wind sail in a large storm and easily pull the tree out of the ground, especially if it's an older tree. Some common minimum tree maintenance should include regular trimming and pruning.
Beware of Branches.
Make sure you're aware if your trees have large, horizontal branches coming out from the trunk. This changes the center of gravity, making the tree more top-heavy and potentially more susceptible to falling over in a storm. Also, try to eliminate branches hanging over your roof or driveway by cutting these down early. It can save you from a big headache if they grow too big or if they break off in severe weather.
Safer Trees to Plant.
If you're considering planting new trees, birch or quaking aspens are safe options, according to the National Park Service. These trees have roots that are interconnected, so they're incredibly strong. These trees have been known to stay standing even after the harshest storms.
Author Reed Timmer is a meteorologist and storm chaser who starred on the reality show 'Storm Chasers' on the Discovery Channel from 2007-2012. He has up-close and personal experience with a number of different types of extreme weather, and here he provides his opinions on how to handle certain situations in an effort to help you limit the potential damage you may incur in a storm. His advice is not meant as the definitive word in safety, but rather, a logical springboard for people to make their own decisions with regard to their particular situation.


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Showing: 1 to 20 of 20
In this section are the crème de la crème of our Cognacs – rare discontinued bottlings, ancient vintages from long-forgotten producers and priceless special blends from the world's most famous houses: in other words, some of the finest spirits ever made.
Enjoy responsibly
Copyright © The Whisky Exchange 1999-2019. All Rights Reserved.
The Whisky Exchange is the registered trademark of Speciality Drinks Limited.
Registered in England and Wales (Company No. 4449145). Registered Office: Elixir House, Whitby Avenue, Park Royal, London NW10 7SF, UK.


text: Monday, December 12, 2011 APTA Launches Holiday-Themed Contest for Consumers Today, APTA launched its "12 days of Fitness" scavenger hunt contest. The goal of the holiday-themed contest is to expand Move Forward's presence on Twitter and Facebook and drive traffic to MoveForwardPT.com to learn who and what physical therapists treat and where patients can find one. At 10 am ET from December 12-23, APTA will post a clue to its consumer Twitter and Facebook pages linking new and current followers back MoveForwardPT.com to find the clue's answer. Participants will have to watch a video or read content to find the correct answer and submit it by midnight ET. Three winners will be selected at random to receive a prize. Encourage your patients, colleagues, friends, and families to participate in the contest.


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via press release:
Aerial Tour of the 50 States Continues With Louisiana, New Mexico, Michigan, Nevada, Colorado, Pennsylvania, Mississippi and More
New Year's Day 24-Hour Marathon Features Encore Presentations of
All Previously Aired Episodes
New York, NY – December 22, 2011 – Smithsonian Channel's overhead tour of the 50 states continues as it rolls out nine new episodes of AERIAL AMERICA beginning Sunday, January 8 at 8 p.m. ET/PT. The most expansive aerial television project ever produced, AERIAL AMERICA provides rare glimpses of some of our nation's most treasured and unusual landmarks, telling stories that can only be revealed from the air.
For those looking to get caught up on the series, Smithsonian Channel is presenting a 24-hour AERIAL AMERICA marathon starting at 6 a.m. on New Year's Day, January 1. Some of the states featured during the marathon include New York, California, Rhode Island, Connecticut, Hawaii, New Hampshire, North Carolina, Tennessee and others.
Upcoming AERIAL AMERICA premiere episodes:
AERIAL AMERICA: LOUISIANA – Premieres Sunday, January 8 at 8 p.m. ET/PT
Visit the state where the Big Muddy comes to an end and the Big Easy comes to life. Louisiana is home to both great celebrations and great devastation. From cool jazz to hot cooking, from a vast paradise of wetlands to the giant industries endangering its fragile ecosystems, explore the stark contradictions of the Sugar State from soaring heights. Having survived natural and manmade disasters, Louisiana proves it has never lost its festive, fighting spirit.
AERIAL AMERICA: NEW MEXICO – Premieres Sunday, January 15 at 8 p.m. ET/PT
With 121,000 square miles and a population of just two million, New Mexico may appear to be a lonely state, but its natural wonders and rich diversity help make it an extremely popular tourist destination. Here, past, present, and future rub shoulders every day. Mexican-American culture thrives in a land settled by missionaries and conquistadors. Filmmakers keep the state's Wild West history alive. Traditional Native-American dwellings inspire modern architects. And rumors of a spaceship cover-up in Roswell have curiosity-seekers scanning the skies.
AERIAL AMERICA: NEVADA – Premieres Sunday, January 22 at 8 p.m. ET/PT
It is the nation's driest state and home to the brightest city in the world. Nevada is a state of extremes, of enormous booms and busts. Since 1852, dreamers have flocked to the Silver State in search of great riches, and their stories of success and failure define the state's high-stakes ethos. Join us on an aerial tour of Nevada's vast landscape, offering breathtaking views of neon-lit streets, sun-baked deserts and dazzling lakes as we expose the unique mix of glitz and grit, fantasy and reality, which make Nevada one of a kind.


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These are all the News & Announcements posted in December, 2011.
Monday, 19
Holiday Hours
The Logan Library will be closed the following days for the Christmas and New Year's holidays:
Happy Holidays!
Posted By Logan Library at 9:36 AM / Category:Library Closed
Thursday, 15
Staff Reading Pick
Here is another reading pick from the Logan Library Staff.
Book: My Cat, the Silliest Cat in the World
by Gilles Bachelet
Recommended by: Debbie, Associate Librarian
If you like cats, or elephants, or both, you'll love this picture book. The author is describing his pet, comparing his "cat" to what other people say cats are like. Just reading the words, you'd never know his pet was anything other than an ordinary house cat. However, in the illustrations, his "cat" is actually an elephant. It's really quite funny.
Want more reading suggestions? View previous staff picks.
Posted By Logan Library at 12:02 PM / Category:Staff Picks
Monday, 12
Library Board Meeting
The Logan Library would like to invite the public to join library staff and board members in discussing the library's future. Logan Library Board meeting will be held on the 2nd Tuesday of the month at 5:30 p.m. in the Logan Library Archives Room. The next meeting will be on December 13th - here is the agenda.
Please feel welcome in attending and having an active role in the library!
Posted By Logan Library at 10:24 AM / Category:Community
The Latest News!
Oct 16, 2018
» Community Book Discussion Oct 10, 2018
» The Dead Awaken Oct 5, 2018
» Library Closed Columbus Day


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These seeds are ready for the press. The fruit itself is turned into "Palm oil", while the nut is used for "Palmiste oil". This is the local variety grown by smallholders. Herakles Farms plan to grow improved varieties that are sold to them by IRAD, a Cameroon institute who also issued the controversial ecological assessment stating that plantations are only secondary degraded forest.02/19/2012degradated forest.02/19/2012
© Jan-Joseph Stok / Greenpeace
1 - 12 of 5650 results.


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"Bella's Lullaby" was a song composed by Edward in Twilight on the piano. He first plays it when Bella first comes to his house in this story. Edward frequently hums the song to Bella when she is falling asleep or when she has a bad dream. In New Moon, Edward makes a CD for Bella which has all the songs he composed, and the first one is the lullaby. This was given to Bella on her birthday. When Edward and his family leave Forks, she finds that all the gifts they gave her, including the CD, are gone. Later on in the book, Edward reveals that he hid all the gifts under the floorboards. For the movie, the song was composed by Carter Burwell. The song appears on the film's soundtrack and score.
"Bella's Lullaby" is featured once again in Breaking Dawn - Part 1 and Part 2.
Carter Burwell's "Bella's Lullaby" is in the key of E minor, and in the time signature of 4/4. Edward's key signature and time signature are unspecified in the novels and films.


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February 1996, four years after being given my HIV diagnosis, I found myself lying in a hospital bed and hearing that I now had AIDS. My CD4 count was 131. I needed to add more medication. When I was initially diagnosed in 1992, I had a CD4 count of 896 and my first doctor put me on AZT (Retrovir, zidovudine) monotherapy. After a friend found an infectious disease specialist, I was switched to Zerit (stavudine, d4T) and Epivir (3TC, lamivudine).
Now lying in the hospital, my doctor came in and said there was this new drug available called Crixivan (indinavir) and he strongly recommended that I add this to my current regime. My viral load was 159,000 and these new meds had shown that they could reduce the virus in my system, therefore prolonging my life. So of course I said yes. By August, my viral load was undetectable, less than 200, and my CD4 count was finally up over 200.
My medication journey since the beginning has been varied and tough and full of side effects, but I held the attitude that without them I would not be here. I have been determined to fight this since the beginning.
After years of Crixivan and drinking lots of water and it interfering with my quality of life, I asked my doctor if we could switch to a twice-a-day regimen. I tried several regimens that were all successful in keeping my HIV in check; I just couldn't handle the side effects. Finally, six years ago, I found the regimen that works. My HIV is undetectable, less than 20, and my CD4 count is over 1,000.
A few years ago I started to wonder about switching or stopping meds for a while. Then I met the man who would become my husband. He is HIV negative and I know that keeping my viral load down is crucial to maintaining a healthy sex life and reducing the risk of transmission to him. The side effects are manageable and I am here, 21 years later, because of these medications. It was the smartest decision I've made.
Shannon Southall is the executive director and medical care manager at Rocky Mountain CARES, an HIV/AIDS service organization in Denver, Colo. She's also an expert in TheBody.com's "Ask the Experts" Forum on Safe Sex and HIV Prevention.


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KVISTGAARD, Denmark, January 21, 2013 - Bavarian Nordic A/S (OMX: BAVA) today announced that Reiner Laus, Executive Vice President and Division President Cancer Vaccines will leave his position effective as of today.
Reiner Laus has headed Bavarian Nordic's California-based cancer vaccine division, BN ImmunoTherapeutics since 2005, where it was founded to develop active immunotherapies within the cancer field based on the company's MVA-BN® technology. During his tenure, Dr. Laus has been instrumental in the development of the company's clinical pipeline, including the preparations for the current late-stage clinical development of PROSTVAC®. The company has initiated a search for a replacement to fill his position which is expected to be concluded soon.
Asger Aamund
Chairman of the Board
Anders Hedegaard, President & CEO. Phone +45 23 20 30 64
About Bavarian Nordic
Bavarian Nordic is a vaccine-focused biotechnology company developing and producing novel vaccines for the treatment and prevention of life-threatening diseases with a large unmet medical need. The company's pipeline targets cancer and infectious diseases, and includes ten development programs. In oncology, the company's lead program is PROSTVAC®, a therapeutic vaccine candidate for advanced prostate cancer that is the subject of an ongoing pivotal Phase 3 trial and is being developed under a collaboration agreement with the National Cancer Institute. In clinical Phase 1 and Phase 2 trials, PROSTVAC® has been tested in nearly 600 patients. In infectious diseases, the company's lead program is IMVAMUNE®, a non-replicating smallpox vaccine candidate that is being developed and supplied for emergency use to the U.S. Strategic National Stockpile under a contract with the U.S. Government. For more information, visit www.bavarian-nordic.com
Forward-looking statements
This announcement includes "forward-looking statements" that involve risks, uncertainties and other factors, many of which are outside of our control that could cause actual results to differ materially from the results discussed in the forward-looking statements. Forward-looking statements include statements concerning our plans, objectives, goals, future events, performance and/or other information that is not historical information. We undertake no obligation to publicly update or revise forward-looking statements to reflect subsequent events or circumstances after the date made, except as required by law.


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Dr. Will Kirby (aka "the evil doctor" who won Big Brother 2) visited The Doctors today to talk about — and extract — open comedos... otherwise known as blackheads.
According to Dr. Will, blackheads are clogged hair follicles, while pimples are infected hair follicles, and neither should be extracted or popped using fingers (which all the experts say, but how can you resist?). Dr. Will used a little metal tool on one audience member to extract a blackhead from her back. After seeing that, I ordered one online. It comes with a lance!
Earlier: Gross YouTube Genre Is Populated By Pimple-Loving Girls


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Exploring the other side of a global golf mecca. While wearing a kilt. And riding a Segway.
Author Jeff Wallach
THE MERE FACT THAT I'm wearing a kilt and white kneesocks isn't what's making today's round at The Westin Kierland Resort feel a bit unusual. It's that I'm dressed in a kilt and I'm about to ride out to my first tee shot on a Segway like some kind of Scottish charioteer.
Having hit my opening drive, I mount the scooter and lean forward. The manicured grass beneath me flies past in a green blur as I teeter, trying to maintain both balance and dignity. Following a successful (if inelegant) dismount, I grab a 5-wood and hit just short of the first putting surface into a sloping, tightly mown collection area. From here I get up and down, thanks to a beautiful rolling pitch shot.
I'd bow, but given my outfit, it might be safer if I curtsied.
Golfers who've been to Scotland more than once know that the most satisfying golf experiences are often found away from the trophy courses. So it is here in Scottsdale, Ariz., where—beyond bucket-list venues like Champions and Stadium at TPC, We-Ko-Pa and Grayhawk—you'll discover a wealth of lesser-known spots offering unusual new programs, unexpected quality, smaller crowds and lower green fees. Kierland's Scottish-themed package, for instance, includes a loan of formal Scottish attire and a bagpiper calling you in at the 18th green to sip Johnnie Walker at the Caledonian-influenced gastropub Brittlebush.
Kierland's three nine-hole golf loops, designed by Scott Miller, feature golden desert grasses, elevation changes, dry washes and more than 300 bunkers of every shape and size filled with gleaming white sand. Ribbons of sandy waste areas and dun-colored dormant grasses frame many holes and accentuate the targets. Gently rolling mounds may reward slightly errant shots or create sidehill lies that will challenge your iron game. They will also challenge your Segway skills (though you can opt for a cart with an air-cooled mister, which comes in handy when the mercury soars into triple digits).
While the name of five-diamond resort The Phoenician suggests a leap back in history, the property is in fact a paean to modern luxury. One morning I roamed the cactus garden across from the lobby, admiring barrel cacti, smooth-barked palo verde trees and other local flora while sipping my coffee. In the evening, we sat by a fire pit and watched the sky turn purple and the stars pop out above Camelback Mountain, just behind the sprawling wings of the hotel.
The Phoenician proves that a course doesn't have to be long and difficult to be, well, difficult. These 27 holes are all about subtlety—and they're also about Camelback Mountain, which the golf course meanders around and sometimes nearly over and back down. Camelback quietly influences not just putts, but also club selection, stance and maybe even your mood. At times during my round, I lost track of the mountain, focusing instead on the task at hand (i.e., getting the golf ball to land somewhere near the pin). But then I'd leave a 3-foot putt a foot short on a seemingly flat green, look up to see the mountain lurking and realize that the green was practically straight uphill.
The Desert/Canyon routing commences amid a tranquil setting of flower beds, palms and mesquite, winds past resort facilities and stately Spanish-style houses, then transitions into a wilder terrain of rock and brush. As we were deciding what club to hit for our tee shots on the Desert's par-3 sixth, which drops 100 feet to a glimmering island of green, some hikers stopped to watch—and we suddenly realized that laughter, particularly the derisive kind, echoes here (in other words: choose carefully). The Canyon has even more elevation changes and, at the seventh and eighth holes, back-to-back par-3s decorated with streams, gardens and waterfalls.
Fountain Hills' SunRidge Canyon Golf Club is home to the Jim McLean Golf School, which is convenient, as you'll need an improved short game to master 18 holes that blend into the land as if they were carved by the movement of water and wind over millennia. Architect Keith Foster sited the holes in red rock canyons and atop boulder-strewn ridges—creating distinctly different canvases of gorgeously rendered golf features.
The opening salvo descends gradually before doubling back to climb on the way in. Don't forget this, as you'll want to make your pars and birdies early. Ravine crossings are often required, but always present themselves clearly (so you'll have only yourself to blame if you duff it, as when I landed in a dry arroyo after stubbing a 3-wood on the 12th). No. 13 kicks off the so-called Wicked Six, which plays mostly uphill into the wind, and encompasses water, steep drops around elevated greens, and other features that are maddening and entertaining by turns.
The Native American-owned Talking Stick Resort boasts two golf layouts designed by Coore & Crenshaw. I ventured out on the North Course, which opens with a couple of wide, welcoming fairways that seem impossible to miss off the tee (note: seem) before narrowing toward the first few greens. The latter reside awfully close to rough desert scrub, where we actually saw a herd of wild horses grazing. By the third hole, bunker pods and waste areas grow increasingly prevalent and closer to the fields of play.
No. 12 proved to be one of my favorites: a 392-yard dogleg called Red Mountain Gambler. Golfers choosing to take a chance must carry 204 yards of sandy waste area with their drives. Less adventuresome players can bail out to the right—or, like me, opt to carry the sand but hit it to the right anyway, by accident, leaving a long approach that must carry an arroyo in front of the green. And the greens themselves (newly rebuilt, lovely to look at, completely unforgiving) have a way of trampolining good shots to the back of, or clean over, the putting surfaces.
Six thousand Georgia pines distinguish Raven Golf Club—formerly known as The Raven at South Mountain—from the area golf courses that accentuate their Sonoran cred. In addition to the new name, the Phoenix facility spotlights a new trend in golf: a set of family tees shrunk down to 4,100 yards.
Gary Panks and David Graham, designers known for their desert golf architecture, let the cacti and rattlesnakes remain in the background on a lush, expansive layout. Subtleties abound, such as the sloped embankments lining the first hole that work to guide slightly mis-hit shots back to the fairway. Also at work is a design that requires strategy to ensure the best "leaves," as in billiards. Angles of attack matter here, so proficient players will want to think a shot or two ahead. No. 5 is the signature hole—a super-short par-4 where wise golfers will hit an iron to the left off the tee and then avoid both the false front before the green and the deep retention area behind it (wiser golfers than I, who experienced both). The back nine plays a few shots easier than the front. Stadium-size putting surfaces may affect the yardages on many holes, so check pin positions before firing.
When you've finished with golf, refuel at any number of great clubhouse and resort restaurants close by the courses, such as Relish Burger Bistro at The Phoenician (I recommend the Kobe beef burger in particular) and Deseo at The Westin Kierland, whose spicy Nuevo Latino cuisine is the perfect counterpoint to a breeze blowing up your kilt.
JEFF WALLACH is executive editor of the websites The A Position and Golf Road Warriors.


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Accounting Research BULLETINS • Issued by the Committee on Accounting Procedure, American Institute of Accountants, 270 Madison Avenue. New York 16, N. Y. Copyright 1950 by American institute of Accountants 1. Whenever two or more corporations are brought together, or combined, for the purpose of carrying on in a single corporation the previously conducted businesses, the accounting to give effect to the combination will vary depending upon whether there is a continuance of the former ownership or a new ownership.1 This statement has been prepared (a) for the purpose of differentiating between these two types of corporate combinations, the first of which is designated herein as a pooling of interests and the second as a purchase, and (b) to indi-cate the nature of the accounting treatment appropriate to each type. 2. For accounting purposes, the distinction between a pooling of interests and a purchase is to be found in the attendant circumstances rather than in the legal designation as a merger or a consolidation, or legal considerations with respect to availability of net assets for divi-dends, or provisions of the Internal Revenue Code with respect to in-come taxes. In a pooling of interests, all or substantially all of the equity interests in predecessor corporations continue, as such, in a surviving corporation1 which may be one of the predecessor corpora-tions, or in a new one created for the purpose. In a purchase, on the other hand, part or all of the ownership of the acquired corporation is eliminated. A plan or firm intention and understanding to retire capi-tal stock issued to the owners of one or more of the corporate parties, or substantial changes in ownership occurring immediately before or after the combination, would also tend to indicate that the combina-tion is a purchase. 3. Other factors to be taken into consideration in determining whether a purchase or a pooling of interests is involved are the rela-tive size of the constituent companies and the continuity of manage-ment or power to control the management. Thus, a purchase may be indicated when one corporate party to a combination is quite minor 1 several owners of one of the predecessor companies are not substantially in proportion to their respective interests in the predecessor company, a new ownership or purchase of such company is presumed to result. 299 September, 1950 No. 40 Business Combinations


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Behind the Scenes: Making Lockwood's Baconfest-Winning Slow-Poached Egg with Bacon Hash
At this year's Baconfest Chicago, held on April 20, chef Joseph Rose of Lockwood took home one of the coveted Golden Rasher awards for most creative use of bacon at the event's lunch session. Beating out a tough field that included chefs from Browntrout, Untitled, and Barn & Company, Rose won with an Asian-flavored take on the classic combination of bacon and eggs: a slow-poached egg with bacon-and-onion hash, bacon dashi, and nori flakes.
At Baconfest, Rose presented his creation in cups (shown above), so that attendees could down all the ingredients at once, in one shot. "The whole point was to beat [the egg] up and slurp it down," Rose told me when I recently met up with him in the sprawling kitchen at the Palmer House HIlton, where Lockwood is the principal restaurant. Rose, who came to Lockwood following stints at Sixteen and the Pump Room, graciously walked me through how he prepares this crowd-pleasing dish, which he conceived especially for Baconfest. "We ended up doing about 530 portions with the egg," he added. Once the team's supply of eggs ran out, Rose said, they carried on with the remaining ingredients and served 150 more servings.
Rose is a big fan of Asian ingredients, Japanese and Thai in particular, and this dish is a strong reflection of his tastes, as an eater and chef alike. "I used the flavors that I like and the flavors I like to cook with," Rose said. Even though his dish thrilled the Baconfest crowd, he has no immediate plans to add the egg, hash, and dashi combination to the menu at Lockwood. That said, Rose did permit that it just might turn up again come fall. In the meantime, check out the slideshow to see how chef Rose creates this Golden Rasher-worthy play on gold old bacon and eggs.
17 East Monroe Street, Chicago, IL 60603 (map)
All products linked here have been independently selected by our editors. We may earn a commission on purchases, as described in our affiliate policy.


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- Cross-Body Hipsters
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- Leather Cowboy Boot Cross-Body Hipster
Leather Cowboy Boot Cross-Body Hipster
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Cowboy Boot Messenger/Cross Body bags are hand-crafted one-of-a-kind small Hipster bags created from a cowboy boot and a half. Each heirloom bag is adorned with genuine western conchos and feature magnetic closures and removable strap so you can attach them directly to your belt loops, waistband or larger travel bag.
Measurements are approximately 9.5" x 6" or 6.5" with a removable 1/2" leather strap approx. 40" long. If you need an exact strap measurement please contact me with your requirements.
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HIV/AIDS News
Dr. Carole Heilman Named Director of NIAID's Division of Microbiology and Infectious Diseases
Carole A. Heilman, Ph.D., was recently named director of the Division of Microbiology and Infectious Diseases (DMID) of the National Institute of Allergy and Infectious Diseases (NIAID). She comes to this position from NIAID's Division of AIDS, where she served as deputy director for the past three years.
"Dr. Heilman brings considerable experience and expertise to her new position," says Anthony S. Fauci, M.D., director of NIAID. "I am confident that she will bring her imaginative and creative leadership to address the future challenges in infectious disease research."
Dr. Heilman began her career at NIH in 1978 as a postdoctoral research associate with the National Cancer Institute where she carried out research on the regulation of gene expression during cancer development. In 1986, she came to NIAID as the influenza and viral respiratory diseases program officer in DMID and, in 1988, she was appointed chief of the respiratory diseases branch where she coordinated the development of acellular pertussis vaccines.
She joined the Division of AIDS as deputy director in 1997 and was responsible for developing the Innovation Grant Program for Approaches in HIV Vaccine Research. This program was created to encourage novel ideas and approaches in HIV vaccine research while stimulating interest from a new group of scientists, including those who had not been involved in HIV research. The program was designed to speed the pace of discovery and development of vaccines to prevent HIV infection.
As a member of the HIV Vaccine Innovation Grants Team, Dr. Heilman received the 1998 NIH Director's Award "for exceptional initiative, creativity and sustained productivity required for creation and implementation of the HIV Vaccine Innovation Grants Program." Most recently, she received the Secretary's Award for Distinguished Service for "exceptional leadership of the global efforts to identify a safe and effective vaccine to prevent AIDS." She also received the 1992 NIH Director's Award and the 1990 NIH Merit Award for her efforts in developing and implementing Cooperative Research and Development Agreements (CRADAs), collaborations between NIAID scientists and industry to enhance product development for improving public health.
Dr. Heilman received her bachelor's degree in biology from Boston University in 1972, and earned her master's degree and doctorate in microbiology from Rutgers University in 1976 and 1979, respectively.
Throughout her extramural career, Dr. Heilman has contributed articles on vaccine design and development to many scientific journals and has served as consultant to the World Bank and the World Health Organization in this area.
She is also a member of several professional societies, including the Infectious Diseases Society of America; the American Society for Microbiology; and the American Society for Virology.
NIAID is a component of the National Institutes of Health (NIH). NIAID conducts and supports research to prevent, diagnose and treat illnesses such as HIV disease and other sexually transmitted diseases, tuberculosis, malaria, asthma and allergies. NIH is an agency of the U.S. Department of Health and Human Services.
Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.


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According to AT&T exec John Stankey, the long-suffering cities of San Francisco, New York, and Chicago will see the number of available cell sites increase up to 45% when AT&T and T-Mobile get together. Sure, the companies will be cutting some "redundant" cell sites, but one of the first steps in the proposed merger would be to dual-band sites in major urban areas so that customers from both carriers can benefit. Sweet relief! But how long will it take?
Stankey said that in certain markets you'll see the improvements within a year of the deal closing, and that everyone will see the benefits within two years of close. Any corporate combination of this magnitude is bound to hit some regulatory roadblocks, so don't hold your breath—even the incredibly optimistic AT&T estimates that FCC approval will take at least year. And honestly, by the time all of these gears are finally in motion, it's not like Verizon and Sprint are going to let their 4G advantage go to waste. [AT&T]