bluuebunny/crossref_metadata_2025 huggingface dataset:
Irving Fisher and the Quantity Theory of Money: The Last Phase
Authors: Dimand Robert W.
Published: July 2002

Frank Steindl poses a surprising question in the title of his 1997 article, “Was Fisher a Practicing Quantity Theorist?” and reaches the conclusion that, “Clearly, with the decade of the Great Depression, Fisher was no longer a practicing quantity theorist” (Steindl 1997, p. 259). Such a change in Fisher's monetary economics would sharply revise the view of Irving Fisher generally prevailing in the history of monetary economics, which is based primarily onThe Purchasing Power of Money(Fisher with Brown 1911). Fisher's photograph (along with photographs of Marshall and Wicksell) appears on the cover ofThe Golden Age of the Quantity Theory(Laidler 1991). As Mark Blaug (1995, p. 3) put it, “isn't Irving Fisher the quintessential quantity theorist if there ever was one [?]” Perhaps the most striking tribute to Fisher in the quantity theory tradition is from Milton Friedman, who, addressing the American Economic Association on the question “Have Monetary Policies Failed?” and having quoted from Fisher's 1910 exchange with J. L. Laughlin, remarked “And now I must cease quoting from Fisher, with whom I am in full agreement, and proceed instead to plagiarize him—albeit with modifications to bring him down to date” (Friedman 1972, p. 12).
Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1
Authors: Hagting Anja , den Elzen Nicole , Vodermaier Hartmut C. , Waizenegger Irene C. , Peters Jan-Michael , Pines Jonathon
Published: July 2002

Progress through mitosis is controlled by the sequential destruction of key regulators including the mitotic cyclins and securin, an inhibitor of anaphase whose destruction is required for sister chromatid separation. Here we have used live cell imaging to determine the exact time when human securin is degraded in mitosis. We show that the timing of securin destruction is set by the spindle checkpoint; securin destruction begins at metaphase once the checkpoint is satisfied. Furthermore, reimposing the checkpoint rapidly inactivates securin destruction. Thus, securin and cyclin B1 destruction have very similar properties. Moreover, we find that both cyclin B1 and securin have to be degraded before sister chromatids can separate. A mutant form of securin that lacks its destruction box (D-box) is still degraded in mitosis, but now this is in anaphase. This destruction requires a KEN box in the NH2 terminus of securin and may indicate the time in mitosis when ubiquitination switches from APCCdc20 to APCCdh1. Lastly, a D-box mutant of securin that cannot be degraded in metaphase inhibits sister chromatid separation, generating a cut phenotype where one cell can inherit both copies of the genome. Thus, defects in securin destruction alter chromosome segregation and may be relevant to the development of aneuploidy in cancer.
Integrin (α6β4) regulation of eIF-4E activity and VEGF translation
Authors: Chung Jun , Bachelder Robin E. , Lipscomb Elizabeth A. , Shaw Leslie M. , Mercurio Arthur M.
Published: July 2002

We define a novel mechanism by which integrins regulate growth factor expression and the survival of carcinoma cells. Specifically, we demonstrate that the α6β4 integrin enhances vascular endothelial growth factor (VEGF) translation in breast carcinoma cells. The mechanism involves the ability of this integrin to stimulate the phosphorylation and inactivation of 4E-binding protein (4E-BP1), a translational repressor that inhibits the function of eukaryotic translation initiation factor 4E (eIF-4E). The regulation of 4E-BP1 phosphorylation by α6β4 derives from the ability of this integrin to activate the PI-3K–Akt pathway and, consequently, the rapamycin-sensitive kinase mTOR that can phosphorylate 4E-BP1. Importantly, we show that this α6β4-dependent regulation of VEGF translation plays an important role in the survival of metastatic breast carcinoma cells by sustaining a VEGF autocrine signaling pathway that involves activation of PI-3K and Akt. These findings reveal that integrin-mediated activation of PI-3K–Akt is amplified by integrin-stimulated VEGF expression and they provide a mechanism that substantiates the reported role of α6β4 in carcinoma progression.
MAP2 and tau bind longitudinally along the outer ridges of microtubule protofilaments
Authors: Al-Bassam Jawdat , Ozer Rachel S. , Safer Daniel , Halpain Shelley , Milligan Ronald A.
Published: July 2002

MAP2 and tau exhibit microtubule-stabilizing activities that are implicated in the development and maintenance of neuronal axons and dendrites. The proteins share a homologous COOH-terminal domain, composed of three or four microtubule binding repeats separated by inter-repeats (IRs). To investigate how MAP2 and tau stabilize microtubules, we calculated 3D maps of microtubules fully decorated with MAP2c or tau using cryo-EM and helical image analysis. Comparing these maps with an undecorated microtubule map revealed additional densities along protofilament ridges on the microtubule exterior, indicating that MAP2c and tau form an ordered structure when they bind microtubules. Localization of undecagold attached to the second IR of MAP2c showed that IRs also lie along the ridges, not between protofilaments. The densities attributable to the microtubule-associated proteins lie in close proximity to helices 11 and 12 and the COOH terminus of tubulin. Our data further suggest that the evolutionarily maintained differences observed in the repeat domain may be important for the specific targeting of different repeats to either α or β tubulin. These results provide strong evidence suggesting that MAP2c and tau stabilize microtubules by binding along individual protofilaments, possibly by bridging the tubulin interfaces.
Tiny dancers
Authors: Smyth Susan S. , Patterson Cam
Published: July 2002

A vital step in growth factor–driven angiogenesis is the coordinated engagement of endothelial integrins with the extracellular matrix. The molecular mechanisms that partner growth factors and integrins are being elucidated, revealing an intricate interaction of surface receptors and their signaling pathways.
The roles of Fzy/Cdc20 and Fzr/Cdh1 in regulating the destruction of cyclin B in space and time
Authors: Raff Jordan W. , Jeffers Kim , Huang Jun-yong
Published: July 2002

In Drosophila cells cyclin B is normally degraded in two phases: (a) destruction of the spindle-associated cyclin B initiates at centrosomes and spreads to the spindle equator; and (b) any remaining cytoplasmic cyclin B is degraded slightly later in mitosis. We show that the APC/C regulators Fizzy (Fzy)/Cdc20 and Fzy-related (Fzr)/Cdh1 bind to microtubules in vitro and associate with spindles in vivo. Fzy/Cdc20 is concentrated at kinetochores and centrosomes early in mitosis, whereas Fzr/Cdh1 is concentrated at centrosomes throughout the cell cycle. In syncytial embryos, only Fzy/Cdc20 is present, and only the spindle-associated cyclin B is degraded at the end of mitosis. A destruction box–mutated form of cyclin B (cyclin B triple-point mutant [CBTPM]–GFP) that cannot be targeted for destruction by Fzy/Cdc20, is no longer degraded on spindles in syncytial embryos. However, CBTPM–GFP can be targeted for destruction by Fzr/Cdh1. In cellularized embryos, which normally express Fzr/Cdh1, CBTPM–GFP is degraded throughout the cell but with slowed kinetics. These findings suggest that Fzy/Cdc20 is responsible for catalyzing the first phase of cyclin B destruction that occurs on the mitotic spindle, whereas Fzr/Cdh1 is responsible for catalyzing the second phase of cyclin B destruction that occurs throughout the cell. These observations have important implications for the mechanisms of the spindle checkpoint.
A phosphatidylinositol (4,5)-bisphosphate binding site within μ2-adaptin regulates clathrin-mediated endocytosis
Authors: Rohde Gundula , Wenzel Dirk , Haucke Volker
Published: July 2002

The clathrin adaptor complex AP-2 serves to coordinate clathrin-coated pit assembly with the sorting of transmembrane cargo proteins at the plasmalemma. How precisely AP-2 assembly and cargo protein recognition at sites of endocytosis are regulated has remained unclear, but recent evidence implicates phosphoinositides, in particular phosphatidylinositol (4,5)-bisphosphate (PI[4,5]P2), in these processes. Here we have identified and functionally characterized a conserved binding site for PI(4,5)P2 within μ2-adaptin, the medium chain of the clathrin adaptor complex AP-2. Mutant μ2 lacking a cluster of conserved lysine residues fails to bind PI(4,5)P2 and to compete the recruitment of native clathrin/AP-2 to PI(4,5)P2-containing liposomes or to presynaptic membranes. Moreover, we show that expression of mutant μ2 inhibits receptor-mediated endocytosis in living cells. We suggest that PI(4,5)P2 binding to μ2-adaptin regulates clathrin-mediated endocytosis and thereby may contribute to structurally linking cargo recognition to coat formation.
The Developmentally Regulated Expression of Twisted Gastrulation Reveals a Role for Bone Morphogenetic Proteins in the Control of T Cell Development
Authors: Graf Daniel , Nethisinghe Suran , Palmer Donald B. , Fisher Amanda G. , Merkenschlager Matthias
Published: July 2002

The evolutionarily conserved, secreted protein Twisted gastrulation (Tsg) modulates morphogenetic effects of decapentaplegic (dpp) and its orthologs, the bone morphogenetic proteins 2 and 4 (BMP2/4), in early Drosophila and vertebrate embryos. We have uncovered a role for Tsg at a much later stage of mammalian development, during T cell differentiation in the thymus. BMP4 is expressed by thymic stroma and inhibits the proliferation of CD4−CD8− double-negative (DN) thymocytes and their differentiation to the CD4+CD8+ double-positive (DP) stage in vitro. Tsg is expressed by thymocytes and up-regulated after T cell receptor signaling at two developmental checkpoints, the transition from the DN to the DP and from the DP to the CD4+ or CD8+ single-positive stage. Tsg can synergize with the BMP inhibitor chordin to block the BMP4-mediated inhibition of thymocyte proliferation and differentiation. These data suggest that the developmentally regulated expression of Tsg may allow thymocytes to temporarily withdraw from inhibitory BMP signals.
Protein Kinase C β Controls Nuclear Factor κB Activation in B Cells Through Selective Regulation of the IκB Kinase α
Authors: Saijo Kaoru , Mecklenbräuker Ingrid , Santana Angela , Leitger Michael , Schmedt Christian , Tarakhovsky Alexander
Published: July 2002

Activation of the nuclear factor (NF)-κB transcription complex by signals derived from the surface expressed B cell antigen receptor controls B cell development, survival, and antigenic responses. Activation of NF-κB is critically dependent on serine phosphorylation of the IκB protein by the multi-component IκB kinase (IKK) containing two catalytic subunits (IKKα and IKKβ) and one regulatory subunit (IKKγ). Using mice deficient for protein kinase C β (PKCβ) we show an essential role of PKCβ in the phosphorylation of IKKα and the subsequent activation of NF-κB in B cells. Defective IKKα phosphorylation correlates with impaired B cell antigen receptor–mediated induction of the pro-survival protein Bcl-xL. Lack of IKKα phosphorylation and defective NF-κB induction in the absence of PKCβ explains the similarity in immunodeficiencies caused by PKCβ or IKKα ablation in B cells. Furthermore, the well established functional cooperation between the protein tyrosine kinase Bruton's tyrosine kinase (Btk), which regulates the activity of NF-κB and PKCβ, suggests PKCβ as a likely serine/threonine kinase component of the Btk-dependent NF-κB activating signal transduction chain downstream of the BCR.
Channel Openings Are Necessary but not Sufficient for Use-dependent Block of Cardiac Na+ Channels by Flecainide
Authors: Liu Huajun , Tateyama Michihiro , Clancy Colleen E. , Abriel Hugues , Kass Robert S.
Published: July 2002

Na+ channel blockers such as flecainide have found renewed usefulness in the diagnosis and treatment of two clinical syndromes arising from inherited mutations in SCN5A, the gene encoding the α subunit of the cardiac voltage–gated Na+ channel. The Brugada syndrome (BrS) and the LQT-3 variant of the Long QT syndrome are caused by disease-linked SCN5A mutations that act to change functional and pharmacological properties of the channel. Here we have explored a set of SCN5A mutations linked both to BrS and LQT-3 to determine what disease-modified channel properties underlie distinct responses to the Na+ channel blocker flecainide. We focused on flecainide block that develops with repetitive channel activity, so-called use-dependent block (UDB). Our results indicate that mutation-induced changes in the voltage-dependence of channel availability (inactivation) may act as determinants of flecainide block. The data further indicate that UDB by flecainide requires channel opening, but is not likely due to open channel block. Rather, flecainide appears to interact with inactivation states that follow depolarization-induced channel opening, and mutation-induced changes in channel inactivation will alter flecainide block independent of the disease to which the mutation is linked. Analysis of flecainide block of mutant channels linked to these rare disorders has provided novel insight into the molecular determinants of drug action.
Cysteine Mutagenesis and Computer Modeling of the S6 Region of an Intermediate Conductance IKCa Channel
Authors: Simoes Manuel , Garneau Line , Klein Hélène , Banderali Umberto , Hobeila Fadi , Roux Benoit , Parent Lucie , Sauvé Rémy
Published: July 2002

Cysteine-scanning mutagenesis (SCAM) and computer-based modeling were used to investigate key structural features of the S6 transmembrane segment of the calcium-activated K+ channel of intermediate conductance IKCa. Our SCAM results show that the interaction of [2-(trimethylammonium)ethyl] methanethiosulfonate bromide (MTSET) with cysteines engineered at positions 275, 278, and 282 leads to current inhibition. This effect was state dependent as MTSET appeared less effective at inhibiting IKCa in the closed (zero Ca2+ conditions) than open state configuration. Our results also indicate that the last four residues in S6, from A283 to A286, are entirely exposed to water in open IKCa channels, whereas MTSET can still reach the 283C and 286C residues with IKCa maintained in a closed state configuration. Notably, the internal application of MTSET or sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) caused a strong Ca2+-dependent stimulation of the A283C, V285C, and A286C currents. However, in contrast to the wild-type IKCa, the MTSET-stimulated A283C and A286C currents appeared to be TEA insensitive, indicating that the MTSET binding at positions 283 and 286 impaired the access of TEA to the channel pore. Three-dimensional structural data were next generated through homology modeling using the KcsA structure as template. In accordance with the SCAM results, the three-dimensional models predict that the V275, T278, and V282 residues should be lining the channel pore. However, the pore dimensions derived for the A283–A286 region cannot account for the MTSET effect on the closed A283C and A286 mutants. Our results suggest that the S6 domain extending from V275 to V282 possesses features corresponding to the inner cavity region of KcsA, and that the COOH terminus end of S6, from A283 to A286, is more flexible than predicted on the basis of the closed KcsA crystallographic structure alone. According to this model, closure by the gate should occur at a point located between the T278 and V282 residues.
Na Self Inhibition of Human Epithelial Na Channel
Authors: Chraïbi Ahmed , Horisberger Jean-Daniel
Published: July 2002

The regulation of the open probability of the epithelial Na+ channel (ENaC) by the extracellular concentration of Na+, a phenomenon called “Na+ self inhibition,” has been well described in several natural tight epithelia, but its molecular mechanism is not known. We have studied the kinetics of Na+ self inhibition on human ENaC expressed in Xenopus oocytes. Rapid removal of amiloride or rapid increase in the extracellular Na+ concentration from 1 to 100 mM resulted in a peak inward current followed by a decline to a lower quasi-steady-state current. The rate of current decline and the steady-state level were temperature dependent and the current transient could be well explained by a two-state (active-inactive) model with a weakly temperature-dependent (Q10act = 1.5) activation rate and a strongly temperature-dependant (Q10inact = 8.0) inactivation rate. The steep temperature dependence of the inactivation rate resulted in the paradoxical decrease in the steady-state amiloride-sensitive current at high temperature. Na+ self inhibition depended only on the extracellular Na+ concentration but not on the amplitude of the inward current, and it was observed as a decrease of the conductance at the reversal potential for Na+ as well as a reduction of Na+ outward current. Self inhibition could be prevented by exposure to extracellular protease, a treatment known to activate ENaC or by treatment with p-CMB. After protease treatment, the amiloride-sensitive current displayed the expected increase with rising temperature. These results indicate that Na+ self inhibition is an intrinsic property of sodium channels resulting from the expression of the α, β, and γ subunits of human ENaC in Xenopus oocyte. The extracellular Na+-dependent inactivation has a large energy of activation and can be abolished by treatment with extracellular proteases.
Lateral hopping conductivity and large negative
magnetoresistance in InAs/AlGaAs self-organized quantum dots
Authors: B Kochman  , S Ghosh  , J Singh  , P Bhattacharya
Published: July 2002

We report experimental studies on lateral transport in
self-organized quantum dots. We find that below 100 K, conduction occurs
through interdot hopping and that experimental results are described
quite well by a variable-range hopping model. In the hopping regime, the
in-plane conductance varies as G = G
0exp [(-T
0/T)1/3], and
T
0 is found to be 7100-9400 K. We have also observed a large
negative magnetoresistance in this structure.
Suppression of Integrin Activation by Activated Ras or Raf Does Not Correlate with Bulk Activation of ERK MAP Kinase
Authors: Hughes Paul E. , Oertli Beat , Hansen Malene , Chou Fan-Li , Willumsen Berthe M. , Ginsberg Mark H.
Published: July 2002

The rapid modulation of ligand-binding affinity (“activation”) is a central property of the integrin family of cell adhesion receptors. The Ras family of small GTP-binding proteins and their downstream effectors are key players in regulating integrin activation. H-Ras can suppress integrin activation in fibroblasts via its downstream effector kinase, Raf-1. In contrast, to H-Ras, a closely related small GTP-binding protein R-Ras has the opposite activity, and promotes integrin activation. To gain insight into the regulation of integrin activation by Ras GTPases, we created a series of H-Ras/R-Ras chimeras. We found that a 35-amino acid stretch of H-Ras was required for full suppressive activity. Furthermore, the suppressive chimeras were weak activators of the ERK1/2 MAP kinase pathway, suggesting that the suppression of integrin activation may be independent of the activation of the bulk of ERK MAP kinase. Additional data demonstrating that the ability of H-Ras or Raf-1 to suppress integrin activation was unaffected by inhibition of bulk ERK1/2 MAP kinase activation supported this hypothesis. Thus, the suppression of integrin activation is a Raf kinase induced regulatory event that can be mediated independently of bulk activation of the ERK MAP-kinase pathway.
Sarcolemmal Organization in Skeletal Muscle Lacking Desmin: Evidence for Cytokeratins Associated with the Membrane Skeleton at Costameres
Authors: O'Neill Andrea , Williams McRae W. , Resneck Wendy G. , Milner Derek J. , Capetanaki Yassemi , Bloch Robert J.
Published: July 2002

The sarcolemma of fast-twitch muscle is organized into “costameres,” structures that are oriented transversely, over the Z and M lines of nearby myofibrils, and longitudinally, to form a rectilinear lattice. Here we examine the role of desmin, the major intermediate filament protein of muscle in organizing costameres. In control mouse muscle, desmin is enriched at the sarcolemmal domains that lie over nearby Z lines and that also contain β-spectrin. In tibialis anterior muscle from mice lacking desmin due to homologous recombination, most costameres are lost. In myofibers from desmin −/− quadriceps, by contrast, most costameric structures are stable. Alternatively, Z line domains may be lost, whereas domains oriented longitudinally or lying over M lines are retained. Experiments with pan-specific antibodies to intermediate filament proteins and to cytokeratins suggest that control and desmin −/− muscles express similar levels of cytokeratins. Cytokeratins concentrate at the sarcolemma at all three domains of costameres when the latter are retained in desmin −/− muscle and redistribute with β-spectrin at the sarcolemma when costameres are lost. Our results suggest that desmin associates with and selectively stabilizes the Z line domains of costameres, but that cytokeratins associate with all three domains of costameres, even in the absence of desmin.
Biogenesis of Nanotubular Network inToxoplasmaParasitophorous Vacuole Induced by Parasite Proteins
Authors: Mercier Corinne , Dubremetz Jean-François , Rauscher Béatrice , Lecordier Laurence , Sibley L. David , Cesbron-Delauw Marie-France
Published: July 2002

The intracellular parasite Toxoplasma gondiidevelops within a nonfusogenic vacuole containing a network of elongated nanotubules that form connections with the vacuolar membrane. Parasite secretory proteins discharged from dense granules (known as GRA proteins) decorate this intravacuolar network after invasion. Herein, we show using specific gene knockout mutants, that the unique nanotubule conformation of the network is induced by the parasite secretory protein GRA2 and further stabilized by GRA6. The vacuolar compartment generated by GRA2 knockout parasites was dramatically disorganized, and the normally tubular network was replaced by small aggregated material. The defect observed inΔgra2 parasites was evident from the initial stages of network formation when a prominent cluster of multilamellar vesicles forms at a posterior invagination of the parasite. The secretory protein GRA6 failed to localize properly to this posterior organizing center in Δgra2 cells, indicating that this early conformation is essential to proper assembly of the network. Construction of a Δgra6 mutant also led to an altered mature network characterized by small vesicles instead of elongated nanotubules; however, the initial formation of the posterior organizing center was normal. Complementation of the Δgra2knockout with mutated forms of GRA2 showed that the integrity of both amphipathic alpha-helices of the protein is required for correct formation of the network. The induction of nanotubues by the parasite protein GRA2 may be a conserved feature of amphipathic alpha-helical regions, which have also been implicated in the organization of Golgi nanotubules and endocytic vesicles in mammalian cells.
Visualizing metabolic activity on a genome-wide scale
Authors: Luyf A. C. M. , de Gast J. , van Kampen A. H. C.
Published: July 2002

Motivation: To enhance the exploration of gene expression data in a metabolic context, one requires an application that allows the integration of this data and which represents this data in a (genome-wide) metabolic map. The layout of this metabolic map must be highly flexible to enable discoveries of biological phenomena. Moreover, it must allow the simultaneous representation of additional information about genes and enzymes. Since the layout and properties of existing maps did not fulfill our requirements, we developed a new way of representing gene expression data in metabolic charts.

Results: ViMAc generates user-specified (genome-wide) metabolic maps to explore gene expression data. To enhance the interpretation of these maps information such as sub-cellular localization is included. ViMAc can be used to analyse human or yeast expression data obtained with DNA microarrays or SAGE. We introduce our metabolic map method and demonstrate how it can be applied to explore DNA microarray data for yeast.

Availability: ViMAc is freely available for academic institutions on request from the authors.

Contact: a.h.vankampen@amc.uva.nl

* To whom correspondence should be addressed.
Adaptive algorithm of automated annotation
Authors: Leontovich A. M. , Brodsky L. I. , Drachev V. A. , Nikolaev V. K.
Published: July 2002

Motivation: It is common knowledge that the avalanche of data arriving from the sequencing projects cannot be annotated either experimentally or manually by experts. The need for a reliable and convenient tool for automated sequence annotation is broadly recognized.

Results: Here, we describe the Adaptive Algorithm of Automated Annotation (A4) based on a statistical approach to this problem. The mathematical model relates a set of homologous sequences and descriptions of their functional properties, and calculates the probabilities of transferring a sequence description onto its homologue.

The proposed model is adaptive, its parameters (distribution characteristics, transference probabilities, thresholds, etc.) are dynamic, i.e. are generated individually for the sequences and various functional properties (words of the description).

The proposed technique significantly outperforms the widely used test for frequency threshold, which is a special case of our model realized for the simplest set of parameters.

The prediction technique has been realized as a computer program and tested on a random sequence sampling from SWISS-PROT.

Availability: The automated annotation program based on the proposed algorithm is available through the Web browser at http://www.genebee.msu.su/services/annot/basic.html

Contact: nik@genebee.msu.su

* To whom correspondence should be addressed.
SST: an algorithm for finding near-exact sequence matches in
time proportional to the logarithm of the database size
Authors: Giladi Eldar , Walker Michael G. , Wang James Z. , Volkmuth Wayne
Published: July 2002

Motivation: Searches for near exact sequence matches are performed frequently in large-scale sequencing projects and in comparative genomics. The time and cost of performing these large-scale sequence-similarity searches is prohibitive using even the fastest of the extant algorithms. Faster algorithms are desired.

Results: We have developed an algorithm, called SST (Sequence Search Tree), that searches a database of DNA sequences for near-exact matches, in time proportional to the logarithm of the database size n. In SST, we partition each sequence into fragments of fixed length called ‘windows’ using multiple offsets. Each window is mapped into a vector of dimension 4k which contains the frequency of occurrence of its component k-tuples, with k a parameter typically in the range 4–6. Then we create a tree-structured index of the windows in vector space, with tree-structured vector quantization (TSVQ). We identify the nearest neighbors of a query sequence by partitioning the query into windows and searching the tree-structured index for nearest-neighbor windows in the database. When the tree is balanced this yields an O(logn) complexity for the search. This complexity was observed in our computations. SST is most effective for applications in which the target sequences show a high degree of similarity to the query sequence, such as assembling shotgun sequences or matching ESTs to genomic sequence. The algorithm is also an effective filtration method. Specifically, it can be used as a preprocessing step for other search methods to reduce the complexity of searching one large database against another. For the problem of identifying overlapping fragments in the assembly of 120 000 fragments from a 1.5 megabase genomic sequence, SST is 15 times faster than BLAST when we consider both building and searching the tree. For searching alone (i.e. after building the tree index), SST 27 times faster than BLAST.

Availability: Request from the authors.

Contact: egiladi@incyte.commwalker@incyte.com

* To whom correspondence should be addressed.
AiO, combining DNA/protein programs and oligo-management
Authors: Karreman Christiaan
Published: July 2002

Summary: AiO (All in One) is a program for Windows, that combines typical DNA/protein features such as plasmid map drawing, finding of ORFs, translate, backtranslate and high quality printing with a number of databases. These databases allow the management of oligonucleotides, oligonucleotide-manufacturers, restriction enzymes, structural DNA and program users in a multi-user/multi-group environment.

Availability: An AiO specific website, with the possibility to download is at: http://134.99.88.55/aio/

Contact: karreman@onkochemie.uni-duesseldorf.de

Supplementary Information: Examples with screen shots— http://134.99.88.55/aio/ : Manual (in PDF format)—http://134.99.88.55/aio/manual.pdf
CS-PSeq-Gen: Simulating the evolution of protein sequence under constraints
Authors: Tufféry P.
Published: July 2002

Summary: CS-PSeq-Gen is a program derived from PSeq-Gen, designed to perform simulations of the evolution of protein sequences under the constraints of a reconstructed phylogeny. It also provides a basis for the investigation of the correlated evolution of sites.

Availability: http://condor.urbb.jussieu.fr/CS-PSeq-Gen.html

Contact: tuffery@urbb.jussieu.fr
Patika: an integrated visual environment
for collaborative construction and analysis of cellular
pathways
Authors: Demir E. , Babur O. , Dogrusoz U. , Gursoy A. , Nisanci G. , Cetin-Atalay R. , Ozturk M.
Published: July 2002

Motivation: Availability of the sequences of entire genomes shifts the scientific curiosity towards the identification of function of the genomes in large scale as in genome studies. In the near future, data produced about cellular processes at molecular level will accumulate with an accelerating rate as a result of proteomics studies. In this regard, it is essential to develop tools for storing, integrating, accessing, and analyzing this data effectively.

Results: We define an ontology for a comprehensive representation of cellular events. The ontology presented here enables integration of fragmented or incomplete pathway information and supports manipulation and incorporation of the stored data, as well as multiple levels of abstraction. Based on this ontology, we present the architecture of an integrated environment named Patika (Pathway Analysis Tool for Integration and Knowledge Acquisition). Patika is composed of a server-side, scalable, object-oriented database and client-side editors to provide an integrated, multi-user environment for visualizing and manipulating network of cellular events. This tool features automated pathway layout, functional computation support, advanced querying and a user-friendly graphical interface.

We expect that Patika will be a valuable tool for rapid knowledge acquisition, microarray generated large-scale data interpretation, disease gene identification, and drug development.

Availability: A prototype of Patika is available upon request from the authors.

Contact: patika@cs.bilkent.edu.tr

* To whom correspondence should be addressed.
POLITICAL AND ECONOMIC FREEDOM, FISCAL POLICY, AND GROWTH NEXUS: SOME EMPIRICAL RESULTS FOR FIJI
Authors: Gounder Rukmani
Published: July 2002

This article presents an empirical analysis of the relationship between political and civil liberty, economic freedom, and growth for Fiji. Fiji's experience of two military coups in 1987, the delay to resolve the agricultural land lease issues, and the implementation of the 1990 Constitution have been major setbacks in terms of Fiji's nondemocratic political environment and uncertain economic policies, a decline in the private investment and exports, and an exodus of skilled labor. This experience severely damaged the growth prospects whereby unstable sociopolitical institutions undermined the importance of economic freedom and civil liberties of its citizens and foreign investors. Empirical results presented here support the view that democratic values and economic freedom are significant for growth. A statistical test for the endogeneity of democracy variable rejects the null, thus the reverse causality, so democratic environment and economic freedom lead to higher economic growth.
A COLLABORATIVE LEARNING LAB: DOES THE FORM MATTER?
Authors: Brooks Taggert J. , Khandker A. Wahhab
Published: July 2002

A recent paper found that adding a collaborative learning lab (CLL) component to a traditional introductory microeconomics class significantly improved students' scores on a standardized final exam. Here, the authors reconsider these results in two fundamental ways. First, this article is able to include student‐specific factors, such as standardized test scores and age, to control for a student's desire and ability to perform. These results suggest that they slightly underestimate the gains from CLL classes. The second question addressed concerns the implementation of the CLL component. In the original work, the CLL class contained only 24 students in class (small‐CLL). This paper introduces the CLL component into a class with 48 students (largE‐CLL). The authors found students attending a large in‐class CLL failed to perform significantly better on a standardized test than students attending classes without an in‐class CLL. They also performed significantly worse than students in a small‐CLL environment. This article suggests that a CLL can improve scores if care is taken to both maintain an environment that maximizes student–instructor interaction and monitors student collaboration.
Provider Selection, Bargaining, and Utilization Management in Managed Care
Authors: Lindrooth Richard C. , Norton Edward C. , Dickey Barbara
Published: July 2002

Managed care controls cost through a combination of provider selection, bargaining, and utilization management. Provider selection will reduce expenditures if patients are funneled to efficient providers. Bargaining will reduce expenditures through lower rates. Utilization management will reduce expenditures if providers reduce treatment intensity due to monitoring. We estimate that about 30% of the reduction in inpatient expenditures in a mental health carve‐out was due to provider selection, 5% was due to bargaining, and the remaining 65% was due to utilization management. We find that both the provider selection and utilization management effects were likely to be welfare improving.
Government Organization and Power
Authors: Brown Stephen P. A. , Saving Jason L.
Published: July 2002

We develop a theoretical framework to examine how government organization affects its power and size. The framework abstracts from distortions that arise from the means of government finance and separates government power into two dimensions—pure coercive power and pure pricing power. A government can exert its coercive power to shift the demand for its services outward and grow too large. It can simultaneously exert its pricing power to restrict output along a given demand curve to earn rents. Consequently, neither size nor rents alone are reliable indicators of the extent to which government provision of services is nonoptimal.
Buying a Dream: Alternative Models of Demand for Lotto
Authors: Forrest David , Simmons Robert , Chesters Neil
Published: July 2002

Existing lotto demand models utilize effective price, computed as the face value of a ticket minus the expected value of prize money per ticket, as their primary explanatory variable. By contrast, this article proposes a key role for consumption benefit or “fun” in the demand for gambling in general and lotto demand in particular. It develops an alternative model of lotto demand that focuses on the maximum possible prize. When this is tested against the traditional model using data from the U.K. National Lottery, we find that jackpot considerations exert an influence over and above that of variations in effective price.
Institutional Constraints and Deforestation: An Application to Mexico
Authors: Barbier Edward B.
Published: July 2002

Following North (1990), this article hypothesizes that effective rural institutions may impose additional costs on tropical deforestation through agricultural conversion. This allows a formal agricultural household analysis of institutional constraints on deforestation and therefore a method of empirically testing whether there is any significant difference in the actual level of forest land conversion under institutional constraints compared to the level of conversion under pure open access. A dynamic panel analysis for agricultural planted area in Mexico at state level and over the 1960–85 period confirms that institutional constraints on land clearing affected deforestation during the pre‐NAFTA era.
Inscuteable‐independent apicobasally oriented asymmetric divisions in the Drosophila embryonic CNS
Authors: Rath Priyadarshini , Lin Shuping , Udolph Gerald , Cai Yu , Yang Xiaohang , Chia William
Published: July 2002

Inscuteable is the founding member of a protein complex localised to the apical cortex of Drosophila neural progenitors that controls their asymmetric division. Aspects of asymmetric divisions of all identified apicobasally oriented neural progenitors characterised to date, in both the central and peripheral nervous systems, require inscuteable. Here we examine the generality of this requirement. We show that many identified neuroblast lineages, in fact, do not require inscuteable for normal morphological development. To elucidate the requirements for apicobasal asymmetric divisions in a context where inscuteable is not essential, we focused on the MP2 > dMP2 + vMP2 division. We show that for MP2 divisions, asymmetric localisation and segregation of Numb and the specification of distinct dMP2 and vMP2 identities require bazooka but not inscuteable. We conclude that inscuteable is not required for all apicobasally oriented asymmetric divisions and that, in some cellular contexts, bazooka can mediate apicobasal asymmetric divisions without inscuteable.
A complex prediction: three‐dimensional model of the yeast exosome
Authors: Aloy Patrick , Ciccarelli Francesca D , Leutwein Christina , Gavin Anne‐Claude , Superti‐Furga Giulio , Bork Peer , Böttcher Bettina , Russell Robert B
Published: July 2002

We present a model of the yeast exosome based on the bacterial degradosome component polynucleotide phosphorylase (PNPase). Electron microscopy shows the exosome to resemble PNPase but with key differences likely related to the position of RNA binding domains, and to the location of domains unique to the exosome. We use various techniques to reduce the many possible models of exosome subunits based on PNPase to just one. The model suggests numerous experiments to probe exosome function, particularly with respect to subunits making direct atomic contacts and conserved, possibly functional residues within the predicted central pore of the complex.
The Arabidopsis BODENLOS gene encodes an auxin response protein inhibiting MONOPTEROS-mediated embryo patterning
Authors: Hamann Thorsten , Benkova Eva , Bäurle Isabel , Kientz Marika , Jürgens Gerd
Published: July 2002

Developmental responses to the plant hormone auxin are thought to be mediated by interacting pairs from two protein families: short-lived inhibitory IAA proteins and ARF transcription factors binding to auxin-response elements. monopteros mutants lacking activating ARF5 and the auxin-insensitive mutant bodenlos fail to initiate the root meristem during early embryogenesis. Here we show that thebodenlos phenotype results from an amino-acid exchange in the conserved degradation domain of IAA12. BODENLOS and MONOPTEROS interact in the yeast two-hybrid assay and the two genes are coexpressed in early embryogenesis, suggesting that BODENLOS inhibits MONOPTEROS action in root meristem initiation.
Characterization of HCP-6, a C. elegans protein required to prevent chromosome twisting and merotelic attachment
Authors: Stear Jeffrey H. , Roth Mark B.
Published: July 2002

Previous studies of mitosis show that capture of single kinetochores by microtubules from both centrosomes (merotelic orientation) is a major cause of aneuploidy. We have characterized hcp-6, a temperature-sensitive chromosome segregation mutant in C. elegans that exhibits chromosomes attached to both poles via a single sister kinetochore. We demonstrate that the primary defect in this mutant is a failure to fully condense chromosomes during prophase. Although centromere formation and sister centromere resolution remain unaffected in hcp-6, the chromosomes lack the rigidity of wild-type chromosomes and twist around the long axis of the chromosome. As such, they are unable to establish a proper orientation at prometaphase, allowing individual kinetochores to be captured by microtubules from both poles. We therefore propose that chromosome rigidity plays an essential role in maintaining chromosome orientation to prevent merotelic capture.
JunB potentiates function of BRCA1 activation domain 1 (AD1) through a coiled-coil-mediated interaction
Authors: Hu Yan-Fen , Li Rong
Published: July 2002

BRCA1 is involved in the regulation of multiple nuclear events including transcription. AD1, one of the two trans-activation domains in BRCA1, stimulates transcription in a cell context-dependent manner. Here, it is shown that BRCA1 interacts with Jun proteins via a coiled-coil motif in AD1 and the basic leucine zipper (bZIP) region of the Jun proteins. The Jun-interacting domain in BRCA1 is critical for AD1-mediated transcriptional activation. In particular, the strength of AD1 in transcriptional activation is limited by the JunB level and ectopic expression of JunB potentiates the transcriptional activity of AD1. Furthermore, JunB mRNA expression is down-regulated in many ovarian tumor tissues examined. Thus, the coiled-coil-mediated cooperation between BRCA1 and JunB may facilitate the function of these proteins in tissue-specific transcriptional regulation and tumor suppression.
Validation of DNA Sequences Using Mass Spectrometry Coupled with Nucleoside Mass Tagging
Authors: Abdi Fadi A. , Mundt Mark , Doggett Norman , Bradbury E. Morton , Chen Xian
Published: July 2002

We present a mass spectrometry (MS)-based nucleoside-specific mass-tagging method to validate genomic DNA sequences containing ambiguities not resolved by gel electrophoresis. Selected types of13C/15N-labeled dNTPs are used in PCR amplification of target regions followed by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF)-MS analysis. From the mass difference between the PCR products generated with unlabeled nucleosides and products containing 13C/15N-labeled nucleosides, we determined the base composition of the genomic regions of interest. Two approaches were used to verify the target regions: The first approach used nucleosides partially enriched with stable isotopes to identify a single uncalled base in a gel electrophoresis-sequenced region. The second approach used mass tags with 100% heavy nucleosides to examine a GC-rich region of a polycytidine string with an unknown number of cytidines. By use of selected13C/15N-labeled dNTPs (dCTPs) in PCR amplification of the target region in tandem with MALDI-TOF-MS, we determined precisely that this string contains 11 cytidines. Both approaches show the ability of our MS-based mass-tagging strategy to solve critical questions of sequence identities that might be essential in determining the proper reading frames of the targeted regions.
Interactive Exploration of Microarray Gene Expression Patterns in a Reduced Dimensional Space
Authors: Misra Jatin , Schmitt William , Hwang Daehee , Hsiao Li-Li , Gullans Steve , Stephanopoulos George , Stephanopoulos Gregory
Published: July 2002

The very high dimensional space of gene expression measurements obtained by DNA microarrays impedes the detection of underlying patterns in gene expression data and the identification of discriminatory genes. In this paper we show the use of projection methods such as principal components analysis (PCA) to obtain a direct link between patterns in the genes and patterns in samples. This feature is useful in the initial interactive pattern exploration of gene expression data and data-driven learning of the nature and types of samples. Using oligonucleotide microarray measurements of 40 samples from different normal human tissues, we show that distinct patterns are obtained when the genes are projected on a two-dimensional plane spanned by the loadings of the two major principal components. These patterns define the particular genes associated with a sample class (i.e., tissue). When used separately from the other genes, these class-specific (i.e., tissue-specific) genes in turn define distinct tissue patterns in the projection space spanned by the scores of the two major principal components. In this study, PCA projection facilitated discriminatory gene selection for different tissues and identified tissue-specific gene expression signatures for liver, skeletal muscle, and brain samples. Furthermore, it allowed the classification of nine new samples belonging to these three types using the linear combination of the expression levels of the tissue-specific genes determined from the first set of samples. The application of the technique to other published data sets is also discussed.

[Online supplementary material available atwww.genome.org.]
Transcript Profiling of Functionally Related Groups of Genes During Conditional Differentiation of a Mammalian Cochlear Hair Cell Line
Authors: Rivolta Marcelo N. , Halsall Antony , Johnson Claire M. , Tones Michael A. , Holley Matthew C.
Published: July 2002

We have used Affymetrix high-density gene arrays to generate a temporal profile of gene expression during differentiation of UB/OC-1, a conditionally immortal cell line derived from the mouse cochlea. Gene expression was assessed daily for 14 days under differentiating conditions. The experiment was replicated in two separate populations of cells. Profiles for selected genes were correlated with those obtained by RT-PCR, TaqMan analysis, immunoblotting, and immunofluorescence. The results suggest that UB/OC-1 is derived from a population of nonsensory epithelial cells in the greater epithelial ridge that have the potential to differentiate into a hair-cell-like phenotype, without the intervention of Math1. Elements of the Notch signaling cascade were identified, including the receptorNotch3, with a transient up-regulation that suggests a role in hair cell differentiation. Several genes showed a profile similar toNotch3, including the transcriptional co-repressorGroucho1. UB/OC-1 also expressed Me1, a putative partner of Math1 that may confer competence to differentiate into hair cells. Cluster analysis revealed expression profiles for neural guidance genes associated with Gata3. The temporal dimension of this analysis provides a powerful tool to study genetic mechanisms that underlie the conversion of nonsensory epithelial cells into hair cells.

[The entire data set published in this paper has been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus Database (http://www.ncbi.nlm.nih.gov/geo/) under the series accession no. GSE36 and sample numbers contained therein. Supplementary material is available online at http://www.genome.org. The following individuals kindly provided reagents, samples or unpublished information as indicated in the paper: T. Hasson, C. Petit, and P. Matsudaira]