bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive stochastic-deterministic chemical kinetic simulations
Authors: Vasudeva Karan , Bhalla Upinder S.
Published: December 2003

Motivation: Biochemical signaling pathways and genetic circuits often involve very small numbers of key signaling molecules. Computationally expensive stochastic methods are necessary to simulate such chemical situations. Single-molecule chemical events often co-exist with much larger numbers of signaling molecules where mass-action kinetics is a reasonable approximation. Here, we describe an adaptive stochastic method that dynamically chooses between deterministic and stochastic calculations depending on molecular count and propensity of forward reactions. The method is fixed timestep and has first order accuracy. We compare the efficiency of this method with exact stochastic methods.

Results: We have implemented an adaptive stochastic-deterministic approximate simulation method for chemical kinetics. With an error margin of 5%, the method solves typical biologically constrained reaction schemes more rapidly than exact stochastic methods for reaction volumes >1–10 µm3. We have developed a test suite of reaction cases to test the accuracy of mixed simulation methods.

Availability: Simulation software used in the paper is freely available from http://www.ncbs.res.in/kinetikit/download.html

Supplementary information: A GENESIS/Kinetikit implementation of models and the test suite used in this paper are available from http://www.ncbs.res.in/kinetikit/download.html and also from the DOQCS database, http://doqcs.ncbs.res.in
HomGL—comparing genelists across species and with different accession numbers
Authors: Blüthgen Nils , Kiełbasa Szymon M. , Čajavec Branka , Herzel Hanspeter
Published: December 2003

Summary:Homology Gene List (HomGL) is a web-based tool for comparing gene lists with different accession numbers and identifiers and between different organisms. UniGene, LocusLink, HomoloGene and Ensembl databases are utilized to map between these lists and to retrieve upstream or transcribed sequences for genes in these lists. We illustrate the use of HomGL with respect to microarray studies and promoter analysis.

Availability:  http://homgl.biologie.hu-berlin.de/
A generalized likelihood ratio test to identify differentially expressed genes from microarray data
Authors: Wang Song , Ethier Stewart
Published: December 2003

Motivation: Microarray technology emerges as a powerful tool in life science. One major application of microarray technology is to identify differentially expressed genes under various conditions. Currently, the statistical methods to analyze microarray data are generally unsatisfactory, mainly due to the lack of understanding of the distribution and error structure of microarray data.

Results: We develop a generalized likelihood ratio (GLR) test based on the two-component model proposed by Rocke and Durbin to identify differentially expressed genes from microarray data. Simulation studies show that the GLR test is more powerful than commonly used methods, like the fold-change method and the two-sample t-test. When applied to microarray data, the GLR test identifies more differentially expressed genes than the t-test, has a lower false discovery rate and shows more consistency over independently repeated experiments.

Availability: The approach is implemented in software called GLR, which is freely available for downloading at http://www.cc.utah.edu/~jw27c60
Essentiality and damage in metabolic networks
Authors: Lemke Ney , Herédia Fabiana , Barcellos Cláudia K. , dos Reis Adriana N. , Mombach José C. M.
Published: December 2003

Understanding the architecture of physiological functions from annotated genome sequences is a major task for postgenomic biology. From the annotated genome sequence of the microbe Escherichia coli, we propose a general quantitative definition of enzyme importance in a metabolic network. Using a graph analysis of its metabolism, we relate the extent of the topological damage generated in the metabolic network by the deletion of an enzyme to the experimentally determined viability of the organism in the absence of that enzyme. We show that the network is robust and that the extent of the damage relates to enzyme importance. We predict that a large fraction (91%) of enzymes causes little damage when removed, while a small group (9%) can cause serious damage. Experimental results confirm that this group contains the majority of essential enzymes. The results may reveal a universal property of metabolic networks.
PARIS: a proteomic analysis and resources indexation system
Authors: Wang Juhui , Caron Christophe , Mistou Michel-Yves , Gitton Christophe , Trubuil Alain
Published: December 2003

Summary: We developed a system for managing data from two-dimensional electrophoresis-based proteomic experiments. Named PARIS, the system stores gel image and information about experiments and analysis procedures, allows the user to search and navigate in genomic and proteomic data, supports visual verification and validation of the analysis results, and provides tools for cross multi-experiment and multi-experimenter data validation and exploration.

Availability: The software is freely available from http://www.inra.fr/bia/J/imaste/Projets/PARIS/index.html
Meningioma of the Jugular Foramen: Glomus Jugulare Mimic and Surgical Challenge
Authors: Gilbert M. Erik , Shelton Clough , McDonald Andre , Salzman Karen L. , Harnsberger H. Ric , Sharma Pramod K. , Jensen Randy L.
Published: December 2003

Objectives Meningiomas involving the jugular foramen are rare lesions, with approximately 34 cases reported in the English literature. Clinically, these tumors mimic the more common glomus jugulare tumor. After surgical resection, meningiomas have worse cranial nerve outcomes and higher recurrence rates than glomus tumors. There is controversy regarding the selection of surgical approach, particularly with regard to management of the facial nerve. A reliable means of accurate preoperative diagnosis would help surgical planning and patient counseling.

Study Design We present a series of six consecutive large jugular foramen meningiomas resected by a single surgeon from 1996 to 2002.

Methods Retrospective case series (chart review).

Results The preoperative diagnosis was correct in nearly all (6/7) cases on the basis of the characteristic imaging findings seen with a combination of temporal bone dedicated computed tomography and high‐resolution enhanced magnetic resonance imaging. Five of six patients had lateral facial nerve rerouting (infratemporal fossa Fisch type A), and three patients also had posterior rerouting (transcochlear approach with division of greater superficial petrosal nerve). Total tumor removal was accomplished in 83%. One patient suffered recurrence over a mean follow‐up period of 2.5 years. New postoperative vocal cord palsies occurred in 50% of patients, and all required vocal cord medialization. At 1 year, 50% of patients had normal or near normal (House‐Brackmann I or II) facial function. Postoperative cerebrospinal fluid leaks occurred in two patients, and both eventually required ventriculoperitoneal shunts.

Conclusions Meningiomas involving the jugular foramen are surgically challenging tumors that pose unique diagnostic issues. The majority of these lesions can be completely resected. A relatively high postoperative complication rate, which can be controlled with appropriate intervention, is seen with these surgeries.
Results With Titanium Ossicular Reconstruction Prostheses
Authors: Gardner Edward K. , Jackson C. Gary , Kaylie David M.
Published: December 2003

Objectives/Hypothesis Despite the enthusiasm of recent short‐term reviews, no center in the United States has published results meeting American Academy of Otolaryngology—Head and Neck Surgery guidelines with titanium‐based prostheses. The purpose of the study was threefold. The first purpose was to review results with a titanium prosthesis system in cases meeting American Academy of Otolaryngology—Head and Neck Surgery reporting guidelines. The second was to compare these results with previously published results using non–titanium‐based prostheses. The third was to examine the authors' results for any evidence of a “learning curve.”

Study Design Retrospective chart review was performed for the period from February 2000 to August 2001 and for the period from July 2002 to February 2003.

Methods Of 313 cases, 130 consecutive cases were identified in the first period and 65 in the second time period. One hundred two patients had adequate follow‐up for published guidelines. All cases were performed by the senior author (c.g.j.). Comparison data were obtained from a previous publication involving the senior author.

Results Successful rehabilitation (≤20 dB pure‐tone average air–bone gap) of conductive hearing loss was obtained in 70% of partial ossicular chain reconstructions and 44% of total ossicular chain reconstructions when titanium prostheses were used. Comparison data revealed successful rehabilitation in 48% and 21% of non–titanium‐based partial and total reconstructions, respectively. Postoperative pure‐tone average air–bone gaps were not significantly different when compared with results in the period from July 2002 to February 2003.

Conclusion Newer titanium‐based ossicular reconstruction devices represent an improvement over previously used non–titanium‐based prostheses. The authors think that this improvement is realized rapidly because no learning curve existed in their data.
Granular Cell Tumor of the Trachea in Pregnancy: A Case Report and Review of Literature
Authors: Ipakchi Ramin , Zager Warren H. , de Baca Monica E. , Bloedon Esa , McCue Peter A. , Zwillenberg David
Published: December 2003

Objectives/Hypothesis The objectives were to present a case report of a woman with recurrent disease during consecutive pregnancies and to discuss the diagnosis and management of granular cell tracheal tumors, with particular attention to pregnancy and hyperestrogenic states.

Study Design Case report and literature review.

Methods A Medline search and comprehensive review of literature to assess all cases of granular cell tumors of the trachea were compared and collected, with particular attention to individual cases of pregnancy or cases related to the hyperestrogenic state.

Results Thirty‐two cases of granular cell tumors of the trachea were found. Only a few cases related to the hyperestrogenic state were obtained. The case report describes a woman with recurrent disease in subsequent pregnancies during the later stages of pregnancy.

Conclusion Few cases of granular cell tumors of the trachea have been reported, with even fewer being pregnancy related. The diagnosis and management of these tumors include careful attention to patient symptoms and airway management.
Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma
Authors: Aguirre Andrew J. , Bardeesy Nabeel , Sinha Manisha , Lopez Lyle , Tuveson David A. , Horner James , Redston Mark S. , DePinho Ronald A.
Published: December 2003

Pancreatic ductal adenocarcinoma ranks among the most lethal of human malignancies. Here, we assess the cooperative interactions of two signature mutations in mice engineered to sustain pancreas-specific Cre-mediated activation of a mutant Kras allele (KrasG12D) and deletion of a conditional Ink4a/Arf tumor suppressor allele. The phenotypic impact of KrasG12D alone was limited primarily to the development of focal premalignant ductal lesions, termed pancreatic intraepithelial neoplasias (PanINs), whereas the sole inactivation of Ink4a/Arf failed to produce any neoplastic lesions in the pancreas. In combination, KrasG12D expression and Ink4a/Arf deficiency resulted in an earlier appearance of PanIN lesions and these neoplasms progressed rapidly to highly invasive and metastatic cancers, resulting in death in all cases by 11 weeks. The evolution of these tumors bears striking resemblance to the human disease, possessing a proliferative stromal component and ductal lesions with a propensity to advance to a poorly differentiated state. These findings in the mouse provide experimental support for the widely accepted model of human pancreatic adenocarcinoma in which activated KRAS serves to initiate PanIN lesions, and the INK4A/ARF tumor suppressors function to constrain the malignant conversion of these PanIN lesions into lethal ductal adenocarcinoma. This faithful mouse model may permit the systematic analysis of genetic lesions implicated in the human disease and serve as a platform for the identification of early disease markers and for the efficient testing of novel therapies.
Nurr1-RXR heterodimers mediate RXR ligand-induced signaling in neuronal cells
Authors: Wallén-Mackenzie Åsa , Mata de Urquiza Alexander , Petersson Susanna , Rodriguez Francisco J. , Friling Stina , Wagner Joseph , Ordentlich Peter , Lengqvist Johan , Heyman Richard A. , Arenas Ernest , Perlmann Thomas
Published: December 2003

The retinoid X receptor (RXR) is essential as a common heterodimerization partner of several nuclear receptors (NRs). However, its function as a bona fide receptor for endogenous ligands has remained poorly understood. Such a role would depend on the existence of RXR activating ligands in vivo and on the ability of such ligands to influence relevant biological functions. Here we demonstrate the presence of endogenous RXR ligands in the embryonic central nervous system (CNS) and show that they can activate heterodimers formed between RXR and the orphan NR Nurr1 in vivo. Moreover, RXR ligands increase the number of surviving dopaminergic cells and other neurons in a process mediated by Nurr1-RXR heterodimers. These results provide evidence for a role of Nurr1 as a ligand-independent partner of RXR in its function as a bona fide ligand-activated NR. Finally, our findings identify RXR-Nurr1 heterodimers as a potential target in the treatment of neurodegenerative disease.
Thermodynamics and stability of a β‐sheet complex: Molecular dynamics simulations on simplified off‐lattice protein models
Authors: Jang Hyunbum , Hall Carol K. , Zhou Yaoqi
Published: December 2003

We have performed discontinuous molecular dynamics simulations of the thermodynamics and stability of a tetrameric β‐sheet complex that contains four identical four‐stranded antiparallel β‐sheet peptides. The potential used in the simulation is a hybrid Go‐type potential characterized by the bias gap parameter g, an artificial measure of the preference of a model protein for its native state, and the intermolecular contact parameter η, which measures the ratio of intermolecular to intramolecular native attractions. Despite the simplicity of the model, a complex set of thermodynamic transitions for the β‐sheet complex is revealed that shows there are three distinct oligomer (partially ordered, ordered, and highly ordered β‐sheet complex) states and four noninteracting monomers phases. The thermodynamic properties of the three oligomer states strongly depend on both the size of the intermolecular contact parameter η and the temperature. The partially ordered β‐sheet complex is made up of four ordered globules and is observed at intermediate to large η at high temperatures. The ordered β‐sheet complex contains four native β‐sheets and is located at small to intermediate η at low temperatures in the phase diagram. The highly ordered β‐sheet complex has fully‐stiff β‐sheet strands, the same as the global energy minimum structure, and is observed for all η at low temperatures.
Understanding the determinants of stability and folding of small globular proteins from their energetics
Authors: Tiana Guido , Simona Fabio , De Mori Giacomo M.S. , Broglia Ricardo A. , Colombo Giorgio
Published: December 2003

The results of minimal model calculations indicate that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few “hot” sites. By means of molecular dynamics simulations around the native conformation, which describe the protein and the surrounding solvent at the all‐atom level, an accurate and compact energetic map of the native state of the protein is generated. This map is further simplified by means of an eigenvalue decomposition. The components of the eigenvector associated with the lowest eigenvalue indicate which hot sites are likely to be responsible for the stability and for the rapid folding of the protein. The comparison of the results of the model with the findings of mutagenesis experiments performed for four small proteins show that the eigenvalue decomposition method is able to identify between 60% and 80% of these (hot) sites.
Differences in aggregation properties of three site‐specific mutants of recombinant human stefin B
Authors: Kenig Manca , Berbić Selma , Krijes̆torac Aida , Kroon‐Z̆itko Louise , Tus̆ek Magda , Pompe‐Novak Marus̆a , Z̆erovnik Eva
Published: December 2003

We describe expression, purification, and characterization of three site‐specific mutants of recombinant human stefin B: H75W, P36G, and P79S. The far‐ and near‐UV CD spectra have shown that they have similar secondary and tertiary structures to the parent protein. The elution on gel‐filtration suggests that recombinant human stefin B and the P36G variant are predominantly monomers, whereas the P79S variant is a dimer. ANS dye binding, reflecting exposed hydrophobic patches, is highest for the P36G variant, both at pH 5 and 3. ANS dye binding also is increased for stefin B and the other two variants at pH 3. Under the chosen conditions the highest tendency to form amyloid fibrils has been shown for the recombinant human stefin B. The P79S variant demonstrates a longer lag phase and a lower rate of fibril formation, while the P36G variant is most prone to amorphous aggregation. This was demonstrated by ThT fluorescence as a function of time and by transmission electron microscopy.
Thermostability of multidomain proteins: Elongation factors EF‐Tu from Escherichia coli and Bacillus stearothermophilus and their chimeric forms
Authors: Šanderová Hana , Hůlková Marta , Maloň Petr , Kepková Markéta , Jonák Jiří
Published: December 2003

Recombinant mesophilic Escherichia coli (Ec) and thermophilic Bacillus stearothermophilus (Bst) elongation factors EF‐Tus, their isolated G‐domains, and six chimeric EF‐Tus composed of domains of either EF‐Tu were prepared, and their GDP/GTP binding activities and thermostability were characterized. BstEF‐Tu and BstG‐domain bound GDP and GTP with affinities in nanomolar and submicromolar ranges, respectively, fully comparable with those of EcEF‐Tu. In contrast, the EcG‐domain bound the nucleotides with much lower, micromolar affinities. The exchange of domains 2 and 3 had essentially no effect on the GDP‐binding activity; all complexes of chimeric EF‐Tus with GDP retained Kd values in the nanomolar range. The final thermostability level of either EF‐Tu was the result of a cooperative interaction between the G‐domains and domains 2 + 3. The G‐domains set up a “basic” level of the thermostability, which was ∼20°C higher with the BstG‐domain than with the EcG‐domain. This correlated with the growth temperature optimum difference of both bacteria and two distinct thermostabilization features of the BstG‐domain: an increase of charged residues at the expense of polar uncharged residues (CvP bias), and a decrease in the nonpolar solvent‐accessible surface area. Domains 2 + 3 contributed by further stabilization of α‐helical regions and, in turn, the functions of the G‐domains to the level of the respective growth temperature optima. Their contributions were similar irrespective of their origin but, with Ecdomains 2 + 3, dependent on the guanine nucleotide binding state. It was lower in the GTP conformation, and the mechanism involved the destabilization of the α‐helical regions of the G‐domain by Ecdomain 2.
PFIT and PFRIT: Bioinformatic algorithms for detecting glycosidase function from structure and sequence
Authors: Kleiger Gary , Panina Ekaterina M. , Mallick Parag , Eisenberg David
Published: December 2003

The identification of the enzymes involved in the metabolism of simple and complex carbohydrates presents one bioinformatic challenge in the post‐genomic era. Here, we present the PFIT and PFRIT algorithms for identifying those proteins adopting the α/β barrel fold that function as glycosidases. These algorithms are based on the observation that proteins adopting the α/β barrel fold share positions in their tertiary structures having equivalent sets of atomic interactions. These are conserved tertiary interaction positions, which have been implicated in both structure and function. Glycosidases adopting the α/β barrel fold share more conserved tertiary interactions than α/β barrel proteins having other functions. The enrichment pattern of conserved tertiary interactions in the glycosidases is the information that PFIT and PFRIT use to predict whether any given α/β barrel will function as a glycosidase or not. Using as a test set a database of 19 glycosidase and 45 nonglycosidase α/β barrel proteins with low sequence similarity, PFIT and PFRIT can correctly predict glycosidase function for 84% of the proteins known to function as glycosidases. PFIT and PFRIT incorrectly predict glycosidase function for 25% of the nonglycosidases. The program PSI‐BLAST can also correctly identify 84% of the 19 glycosidases, however, it incorrectly predicts glycosidase function for 50% of the nonglycosidases (twofold greater than PFIT and PFRIT). Overall, we demonstrate that the structure‐based PFIT and PFRIT algorithms are both more selective and sensitive for predicting glycosidase function than the sequence‐based PSI‐BLAST algorithm.
Protein folding by the effects of macromolecular crowding
Authors: Tokuriki Nobuhiko , Kinjo Masataka , Negi Shigeru , Hoshino Masaru , Goto Yuji , Urabe Itaru , Yomo Tetsuya
Published: December 2003

Unfolded states of ribonuclease A were used to investigate the effects of macromolecular crowding on macromolecular compactness and protein folding. The extent of protein folding and compactness were measured by circular dichroism spectroscopy, fluorescence correlation spectroscopy, and NMR spectroscopy in the presence of polyethylene glycol (PEG) or Ficoll as the crowding agent. The unfolded state of RNase A in a 2.4 M urea solution at pH 3.0 became native in conformation and compactness by the addition of 35% PEG 20000 or Ficoll 70. In addition, the effects of macromolecular crowding on inert macromolecule compactness were investigated by fluorescence correlation spectroscopy using Fluorescence‐labeled PEG as a test macromolecule. The size of Fluorescence‐labeled PEG decreased remarkably with an increase in the concentration of PEG 20000 or Ficoll 70. These results show that macromolecules are favored compact conformations in the presence of a high concentration of macromolecules and indicate the importance of a crowded environment for the folding and stabilization of globular proteins. Furthermore, the magnitude of the effects on macromolecular crowding by the different sizes of background molecules was investigated. RNase A and Fluorescence‐labeled PEG did not become compact, and had folded conformation by the addition of PEG 200. The effect of the chemical potential on the compaction of a test molecule in relation to the relative sizes of the test and background molecules is also discussed.
Active‐site alkylation destabilizes human O6‐alkylguanine DNA alkyltransferase
Authors: Rasimas Joseph J. , Dalessio Paula A. , Ropson Ira J. , Pegg Anthony E. , Fried Michael G.
Published: December 2003

O6‐alkylguanine‐DNA alkyltransferase (AGT) repairs pro‐mutagenic O6‐alkylguanine and O4‐alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5–1.2 kcal/mole and the DNA‐binding function by 0.8–1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site
Authors: Adams Julian , Chen Zhi‐Ping , Van Denderen Bryce J.W. , Morton Craig J. , Parker Michael W. , Witters Lee A. , Stapleton David , Kemp Bruce E.
Published: December 2003

AMP‐activated protein kinase (AMPK) is a αβγ heterotrimer that is activated in response to both hormones and intracellular metabolic stress signals. AMPK is regulated by phosphorylation on the α subunit and by AMP allosteric control previously thought to be mediated by both α and γ subunits. Here we present evidence that adjacent γ subunit pairs of CBS repeat sequences (after Cystathionine Beta Synthase) form an AMP binding site related to, but distinct from the classical AMP binding site in phosphorylase, that can also bind ATP. The AMP binding site of the γ1 CBS1/CBS2 pair, modeled on the structures of the CBS sequences present in the inosine monophosphate dehydrogenase crystal structure, contains three arginine residues 70, 152, and 171 and His151. The yeast γ homolog, snf4 contains a His151Gly substitution, and when this is introduced into γ1, AMP allosteric control is substantially lost and explains why the yeast snf1p/snf4p complex is insensitive to AMP. Arg70 in γ1 corresponds to the site of mutation in human γ2 and pig γ3 genes previously identified to cause an unusual cardiac phenotype and glycogen storage disease, respectively. Mutation of any of AMP binding site Arg residues to Gln substantially abolishes AMP allosteric control in expressed AMPK holoenzyme. The Arg/Gln mutations also suppress the previously described inhibitory properties of ATP and render the enzyme constitutively active. We propose that ATP acts as an intrasteric inhibitor by bridging the α and γ subunits and that AMP functions to derepress AMPK activity.
N‐linked glycosylation of dipeptidyl peptidase IV (CD26): Effects on enzyme activity, homodimer formation, and adenosine deaminase binding
Authors: Aertgeerts Kathleen , Ye Sheng , Shi Lihong , Prasad Sridhar G. , Witmer Darbi , Chi Ellen , Sang Bi‐Ching , Wijnands Robert A. , Webb David R. , Swanson Ronald V.
Published: December 2003

The type II transmembrane serine protease dipeptidyl peptidase IV (DPPIV), also known as CD26 or adenosine deaminase binding protein, is a major regulator of various physiological processes, including immune, inflammatory, nervous, and endocrine functions. It has been generally accepted that glycosylation of DPPIV and of other transmembrane dipeptidyl peptidases is a prerequisite for enzyme activity and correct protein folding. Crystallographic studies on DPPIV reveal clear N‐linked glycosylation of nine Asn residues in DPPIV. However, the importance of each glycosylation site on physiologically relevant reactions such as dipeptide cleavage, dimer formation, and adenosine deaminase (ADA) binding remains obscure. Individual Asn→Ala point mutants were introduced at the nine glycosylation sites in the extracellular domain of DPPIV (residues 39–766). Crystallographic and biochemical data demonstrate that N‐linked glycosylation of DPPIV does not contribute significantly to its peptidase activity. The kinetic parameters of dipeptidyl peptidase cleavage of wild‐type DPPIV and the N‐glycosylation site mutants were determined by using Ala‐Pro‐AFC and Gly‐Pro‐pNA as substrates and varied by <50%. DPPIV is active as a homodimer. Size‐exclusion chromatographic analysis showed that the glycosylation site mutants do not affect dimerization. ADA binds to the highly glycosylated β‐propeller domain of DPPIV, but the impact of glycosylation on binding had not previously been determined. Our studies indicate that glycosylation of DPPIV is not required for ADA binding. Taken together, these data indicate that in contrast to the generally accepted view, glycosylation of DPPIV is not a prerequisite for catalysis, dimerization, or ADA binding.
Packing, specificity, and mutability at the binding interface between the p160 coactivator and CREB‐binding protein
Authors: Demarest Stephen J. , Deechongkit Songpon , Jane Dyson H. , Evans Ronald M. , Wright Peter E.
Published: December 2003

Among the most common interaction motifs between nuclear proteins is the recognition of one or more amphipathic helices. In an effort to determine principles behind this recognition, we have investigated the interaction between the p160 coactivator protein ACTR and the ACTR‐binding domain of the CREB‐binding protein, CBP. The two proteins use relatively small portions of their primary sequences to form a single synergistically folded domain consisting of six intertwined α‐helices, three from each protein. Neither of the component polypeptides forms a cooperatively folded domain in isolation. However, a considerable amount of residual secondary structure remains in the isolated CBP domain according to CD spectroscopy. Chemical denaturation, differential scanning calorimetry, and ANS binding experiments demonstrate that the isolated CBP domain is not entirely unfolded but forms a helical state with the characteristics of a molten globule. Mutations probing the functional and energetic significance of a buried intermolecular Arg–Asp salt bridge in the interface of the protein complex suggest that these residues are tuned for functional discrimination and not strictly for binding affinity or stability. These results suggest a mechanism for formation of the complex where the unfolded ACTR domain interacts with the partly folded CBP domain in a rapid and specific manner to form the final stable complex.
Refinement of homology‐based protein structures by molecular dynamics simulation techniques
Authors: Fan Hao , Mark Alan E.
Published: December 2003

The use of classical molecular dynamics simulations, performed in explicit water, for the refinement of structural models of proteins generated ab initio or based on homology has been investigated. The study involved a test set of 15 proteins that were previously used by Baker and coworkers to assess the efficiency of the ROSETTA method for ab initio protein structure prediction. For each protein, four models generated using the ROSETTA procedure were simulated for periods of between 5 and 400 nsec in explicit solvent, under identical conditions. In addition, the experimentally determined structure and the experimentally derived structure in which the side chains of all residues had been deleted and then regenerated using the WHATIF program were simulated and used as controls. A significant improvement in the deviation of the model structures from the experimentally determined structures was observed in several cases. In addition, it was found that in certain cases in which the experimental structure deviated rapidly from the initial structure in the simulations, indicating internal strain, the structures were more stable after regenerating the side‐chain positions. Overall, the results indicate that molecular dynamics simulations on a tens to hundreds of nanoseconds time scale are useful for the refinement of homology or ab initio models of small to medium‐size proteins.
Comparison of the 1.85 Å structure of CYP154A1 from Streptomyces coelicolor A3(2) with the closely related CYP154C1 and CYPs from antibiotic biosynthetic pathways
Authors: Podust Larissa M. , Bach Horacio , Kim Youngchang , Lamb David C. , Arase Miharu , Sherman David H. , Kelly Steven L. , Waterman Michael R.
Published: December 2003

The genus Streptomyces produces two‐thirds of microbially derived antibiotics. Polyketides form the largest and most diverse group of these natural products. Antibiotic diversity of polyketides is generated during their biosynthesis by several means, including postpolyketide modification performed by oxidoreductases, a broad group of enzymes including cytochrome P450 monooxygenases (CYPs). CYPs catalyze site‐specific oxidation of macrolide antibiotic precursors significantly affecting antibiotic activity. Efficient manipulation of Streptomyces CYPs in generating new antibiotics will require identification and/or engineering of monooxygenases with activities toward a diverse array of chemical substrates. To begin to link structure to function of CYPs involved in secondary metabolic pathways of industrially important species, we determined the X‐ray structure of Streptomyces coelicolor A3(2) CYP154A1 at 1.85 Å and analyzed it in the context of the closely related CYP154C1 and more distant CYPs from polyketide synthase (EryF) and nonribosomal peptide synthetase (OxyB) biosynthetic pathways. In contrast to CYP154C1, CYP154A1 reveals an active site inaccessible from the molecular surface, and an absence of catalytic activities observed for CYP154C1. Systematic variations in the amino acid patterns and length of the surface HI loop correlate with degree of rotation of the F and G helices relative to the active site in CYP154A1‐related CYPs, presumably regulating the degree of active site accessibility and its dimensions. Heme in CYP154A1 is in a 180° flipped orientation compared with most other structurally determined CYPs.
Using surface envelopes for discrimination of molecular models
Authors: Dugan Jonathan M. , Altman Russ B.
Published: December 2003

Shape information about macromolecules is increasingly available but is difficult to use in modeling efforts. We demonstrate that shape information alone can often distinguish structural models of biological macromolecules. By using a data structure called a surface envelope (SE) to represent the shape of the molecule, we propose a method that generates a fitness score for the shape of a particular molecular model. This score correlates well with root mean squared deviation (RMSD) of the model to the known test structures and can be used to filter models in decoy sets. The scoring method requires both alignment of the model to the SE in three‐dimensional space and assessment of the degree to which atoms in the model fill the SE. Alignment combines a hybrid algorithm using principal components and a previously published iterated closest point algorithm. We test our method against models generated from random atom perturbation from crystal structures, published decoy sets used in structure prediction, and models created from the trajectories of atoms in molecular modeling runs. We also test our alignment algorithm against experimental electron microscopic data from rice dwarf virus. The alignment performance is reliable, and we show a high correlation between model RMSD and score function. This correlation is stronger for molecular models with greater oblong character (as measured by the ratio of largest to smallest principal component).
The Returns to Education: Macroeconomics
Authors: Sianesi Barbara , Reenen John Van
Published: December 2003

We offer an extensive summary and a critical discussion of the empirical literature on the impact of human capital on macro‐economic performance, with a particular focus on UK policy. We also highlight methodological issues and make recommendations for future research priorities.

Taking the studies as a whole, the evidence that human capital increases productivity is compelling, though still largely divided on whether the stock of education affects the long‐run level or growth rate of GDP. A one‐year increase in average education is found to raise the level of output per capita by between three and six percent according to augmented neo‐classical specifications, while leading to an over one percentage point faster growth according to estimates from the new‐growth theories. Still, over the short‐run planning horizon (four years) the empirical estimates of the change in GDP are of similar orders of magnitude in the two approaches. The impact of increases at different levels of education appear to depend on the level of a country's development, with tertiary education being the most important for growth in OECD countries. Education is found to yield additional indirect benefits to growth. More preliminary evidence seems to indicate that type, quality and efficiency of education matter for growth too.
Caravaggio’s ‘Story of St Matthew’: A Challenge to the Conventions of Painting
Authors: Puttfarken Thomas
Published: December 2003

It is a convention of European painting that we expect a picture to be a clear visual display of meaning for the benefit of the viewer. Yet this convention is not absolute: artists can deviate from it, even undermine it. Caravaggio’s paintings in the Contarelli Chapel in San Luigi de’ Francesi in Rome have generally been regarded as relatively clear in terms of their overall composition. The questions they have given rise to were concerned instead with the nature of Caravaggio’s realism, his use of light and shade, or his frequent breaches of decorum. However, the traditional ‘readings ’ of the Calling of St Matthew and his depiction of the saint’s Martyrdom are contradicted by two important kinds of evidence: the well‐established significance of both events in Christian hagiography; and a number of details in the paintings which, while not immediately obvious, are nevertheless clear. The traditional readings of the works could only be maintained if one was to argue that (a) Caravaggio had no understanding of the religious significance of the subject matter he had been asked to paint, and (b) he did not care whether the details he chose to include in his compositions had any bearing upon their meaning. It is argued here that the saint himself in the Calling, and the assassin in the Martyrdom, have, in the past, been misidentified. A detailed examination of both works, in the light of the major written sources of the saint’s life (which were easily available both in The Golden Legend and in the Roman Breviary), leads to results which contradict their first, overall effect on the viewer. Why should Caravaggio have adopted such an unusual way of ordering his pictures? The answer is probably twofold: in general, Caravaggio dismissed the orderliness of art, its easy and ostentatious display of subject matter, in favour of a more ‘realistic ’ sense of confusion which needs to be sorted out by the viewer. And more specifically, Caravaggio insisted on the fundamental difference of revelatory divinity: for those to whom it is not revealed it remains obscure and enigmatic, until we work ourselves out of the dark and misleading reality of the first glance to a higher truth.
A Woman’s Place: The Gendering of Genres in Post‐revolutionary French Painting
Authors: Denton Margaret Fields
Published: December 2003

The subject of this essay is the painter Angélique Mongez, who was a student of Jacques‐Louis David. Specifically, this essay examines how Mongez negotiated a place in the all‐male domain of history painting and how her contemporaries, that is the critics, responded to her claims to be a history painter. My discussion centres on the Salon of 1802, when she made her debut with a large historical composition, Astyanax taken from his Mother, but extends to the Salons of 1804 and 1806, when the issue of the woman history painter was debated more fully. Mongez’s challenge of the tradition that considered history painting an endeavour reserved for men was possible because she had access to serious instruction and to the Salons, unencumbered by the restrictive policies of the Royal Academy. For in the post‐revolutionary period one could not exclude women from history painting because any outright proscription was in conflict with democratic principles. The strategy, then, adopted by those who argued against women history painters during this period, was to encourage women artists who restricted themselves to genre painting. At the Salons of 1804 and 1806 the genre painter Henriette Lorimier served as the paradigm of the woman painter and the recommended alternative to Angélique Mongez.
Crisis? What Crisis?
Authors: Padiyar Satish
Published: December 2003

Abigail Soloman‐Godeau. Male Trouble: A Crisis in Representation
Ptolemy’s Chorographia in the New World: Revelations from the Relaciones Geográficas de la Nueva España of 1579–1581
Authors: Moffitt John F.
Published: December 2003

The art‐historical issue raised here concerns some forgotten formal sources for a distinctive cartographic format once commonly informing European map‐making, and the specific proposition examined here in some detail is ‘chorographic’ description. Our immediate point of departure are those maps called pinturas which accompanied the Relaciones Geográficas de la Nueva España (Mexico) of 1579–81. Modern students of the history of cartography recognize that current knowledge of classical map‐making is highly speculative for the lack of any significant surviving examples. Even though the physical products are largely missing, we do know some classical terms for regional to world maps: tabula, forma, figura mundi, orbis pictus, or orbis terrarum descriptio, to which I would like now to add another term, tabulae chorographicae, making reference to a variant cartographic convention for which by far the most complete description is to be found in Ptolemy’s Geography (I, 1). From antique textual references, mainly ekphrasis (descriptions) of lost frescoes with landscape scenes, plus some scanty surviving, specifically cartographic evidence, mostly Roman, precise conclusions can now be drawn about that ancient representational mode – the tabulae chorographicae– which, besides describing the fossilized cartographic technique employed in the Mexican pinturas of c. 1571, likely represents an unrecognized functional precedent for the medieval orbis pictus.
Picasso in Words
Authors: Wood Paul
Published: December 2003

Rosalind Krauss, The Picasso Papers
Hogarthomania and Print Culture
Authors: Hallett Mark
Published: December 2003

David Bindman, Hogarth and His Times: Serious Comedy

Timothy Clayton, The English Print 1688–1802
Limewood, Chiromancy and Narratives of Making. Writing about the materials and processes of sculpture
Authors: Baker Malcolm
Published: December 2003

Since its publication in 1980 Michael Baxandall’s The Limewood Sculptors of Renaissance Germany has attracted the attention of art‐historians through its re‐thinking of approaches to Northern art, as well as both a case study in the use of descriptive terms about art and as a model for a cultural history of art. This essay deals with a far less widely appreciated feature of the book: its innovatory mode of writing about the materials and processes of sculpture. The first section is concerned with the responses to Limewood Sculptors and argues that the concern with sculptural technique that runs throughout the book deserves more attention. The second section examines various more familiar conventions for writing about sculptural process, ranging from materials‐based descriptive accounts to archivally‐grounded narratives of the commissioning and making of specific works. The third section considers Baxandall’s adoption of Paracelsus’ notion of chiromancy –‘the art of reading the inner character of a person or thing from its external character’– for an understanding of limewood sculpture. This interpretive strategy opens up the possibility of questions of material and process being treated not as a discrete subject but instead being allowed to inform and inflect the discussion of many other issues throughout the book. In particular, an awareness of materials and making is seen as important for our understanding of a sculpture's reception and viewing. In the final section the implications of Baxandall’s writing about sculptural process for other periods and cultures are explored through a discussion of eighteenth‐century sculptural practice and the extent to which materials and process were registered by contemporary viewers. Taking as a case study the ways in which the drawings and models for Roubiliac’s Argyll monument might be interpreted, the essay argues that Baxandall’s writing about sculpture and its making has a methodological resonance far beyond the field of South German Renaissance sculpture.
Michael Baxandall and the Shadows in Plato’s Cave
Authors: Potts Alex
Published: December 2003

Shadows usually lie on the periphery of our visual awareness and yet they constitute visual appearances. Starting from Michael Baxandall’s discussion of this paradox in his recent work on painting and visual cognition in the Enlightenment, this article explores the kinds of shadowing that occur in eighteenth‐century art and also the ambiguous status of shadow effects in contemporary art. It argues that Baxandall’s concerns have significant affinities with those of one of the more important Minimalist artists, Donald Judd. The way Baxandall in his study of shadows seems to abandon the social and cultural historical ambitions of his earlier analysis of Renaissance art, and to adopt a more phenomenological approach, focusing on a viewer's immediate visual engagement with a work, is seen here as symptomatic of a larger shift in the discipline – namely the demise of the systematically historicising imperatives previously more or less taken for granted in serious art historical scholarship.
Two Steps Forward, One Step Back
Authors: Orwicz Michael R.
Published: December 2003

Jane Mayo Roos, Early Impressionism and the French State (1866–1874)

Michel Melot, The Impressionist Print
Ingres Chez Les Fauves
Authors: Benjamin Roger
Published: December 2003

The Bain turc, more than any other Ingres work, escaped the claims of normative art history and spoke to a radical aesthetic community intent on framing a new art. This essay on the reception of Ingres's figure painting reads responses to the Bain turc at the small Ingres retrospective the Society of the Salon d'Automne organized in 1905, and in 1907 when his Grande Odalisque was challenged by the elevation of Manet's Olympia to the Louvre.

Three communities laid claim to Ingres at this time. Scholars like Lapauze and Momméja ratified the Bain turc for the museum community and for its owner, the Prince de Broglie. The Fauvist avant garde had other goals in arranging the retrospective. It is argued that the Bain turc, and the two dozen pencil studies exhibited with it, changed the visual orientation of artists such as Picasso, Matisse and Vallotton.

The third group, standing between the artists and official gate‐keepers, were the critics. Some claimed Ingres for classicism and the French Tradition (albeit one skewed by an octagenarian's sexual longing). Left and Jewish critics close to the Salon rejected the academic authority figure, proclaiming the value of his nudes, line drawing and distorting arabesque. The debate crystallized when Olympia was hung opposite the Grande Baigneuse. Matisse and Apollinaire judged the Manet to be passé, and soon afterwards the pro‐Cubist writers Rivière and Lhote saw in the Grande Baigneuse the model for a revolution in the concept of drawing.
‘For Our Devotion and Pleasure’: The Sexual Objects of Jean, Duc de Berry
Authors: Camille Michael
Published: December 2003

Jean, Duc de Berry (1340–1416), often seen as the first great ‘collector’ in Western art, is also described by some historians as a ‘homosexual’. This article examines the relationship between these two terms and the problematic historical evidence for the latter claim, exploring the duke’s desire for things, images and bodies in less categorical terms. The main argument is that we can best understand Jean’s sexual tastes from the artworks he commissioned and in which we know from contemporary accounts he took great personal delight. Reinterpretations are provided of some well‐known images, such as the January page of the unfinished Trés Riches Heures (1416), where the patron is pictured at the centre of a ‘homosocial’ feast for the eyes. This manuscript, along with the marginal decoration of his Grandes Heures, suggests his enjoyment of beautiful youthful bodies in general and of androgyny in particular. However, this has to be viewed within the very different gender system of the late fourteenth century in which women, youths and children were literally objects of male control. Only in this sense can we begin to understand how the duke’s love of things intersected with his political position and power more generally. Rather than see his collecting in all its polymorphous perversity as a symptom of personal trauma, I want to view it as a socially creative and recuperative act that was part of the performance of a ruthless man of power.