bluuebunny/crossref_metadata_2025 huggingface dataset:
Slipped capital femoral epiphysis
Authors: Billing L. , Bogren H. G. , Henrikson B. , Wallin J.
Published: February 2005

This particular ailment has many designations in the literature but none is quite adequate. Here we use the terminology slipped capital femoral epiphysis (SCFE).

The anatomy of the proximal femur in all mammals reflects their growth and function. The main forces acting on the head are perpendicular to the growth plate. The thick tear‐proof perichondrium‐periosteum on the femoral neck is like a stocking attached to the epiphysis and the trochanter region. Growth in length causes a strong tensile stress in the periosteum, pressing the epiphysis against the metaphysis and thus stabilizing the vulnerable growth plate—the periosteum theory. Several factors may diminish the stability of the growth plate.

SCFE begins with fissures, which coalesce to a fracture in the growth plate, invisible on a radiograph. As the slip progresses, an increasing angulation between the epiphysis and the remainder of the femur occurs. Weight and muscular forces displace the epiphysis posteriorly in a flexed hip. A rift in the ventral half of the periosteal stocking occurs at the border to the perichondrium and, after that, a longitudinal rift in the periosteum at the anterior midline of the femoral neck. This rift becomes broader as the epiphysis slips posteriorly, withdrawing the ruptured periosteum.

Displacement of the epiphysis is due to a rotational slip and tilt, made possible by a compression fracture in the posterior part of the metaphysis. Parts of the periosteum function as reins steering the slip direction and counteracting the displacement. SCFE may be regarded as a pseudoarthrosis in the growing cartilage of the plate. The periosteum theory extended to a pseudoarthrosis theory has been supported by findings at surgery and on true lateral radiographs of usual and unusual cases of SCFE presented in this opus.

On a true lateral view, the displacement can be measured as the slipping angle (SA) based on anatomical and geometrical considerations. SA values from 95 normal hips and from 22 contralateral asymptomatic hips from SCFE patients are presented in a histogram and bar graph. Statistically, SCFE is always bilateral, but in about 1/3 of the asymptomatic, contralateral hips, the physis ossifies and closes with SA below 13°, and surgery is not necessary.

It is most important that the position of the femur on the X‐ray table is exactly defined in two dimensions: 1) the angle between the femoral shaft and the tabletop (angle of elevation), 2) the degree of rotation of the femur around its axis. A precisely defined positioning of the femur is a prerequisite for an exact reproducible measurement of the SA on a true lateral view and is also valuable for the evaluation of radiographic “signs”. An aid, the Youth Hip Triangle (YHT), has been designed to facilitate positioning of the femur and measurement of SA. YHT is recommended for routine use in every X‐ray facility. The method is quick, cost effective and makes it possible to diagnose SCFE in the contralateral hip before clinical signs or symptoms have occurred.
A volumetric approach to glandularity estimation in mammography: a feasibility study
Authors: Blot Lilian , Zwiggelaar Reyer
Published: February 2005

In mammography, the reliable estimation of the volume of glandular tissue can lead to improvements in mean glandular dose calculations and mammographic risk assessment. Using thehintmodel, this paper presents a novel approach to the volumetric estimation of glandular tissue. The paper reports investigations into the effects of a range of parameters involved in the model. The results indicate that the robustness for possible clinical use depends on the uncertainty with which the parameters are determined. The paper also discusses the requirements necessary for clinical applications.
MARCH-II Is a Syntaxin-6–binding Protein Involved in Endosomal Trafficking
Authors: Nakamura Nobuhiro , Fukuda Hidekazu , Kato Akira , Hirose Shigehisa
Published: February 2005

Membrane-associated RING-CH (MARCH) is a recently identified member of the mammalian E3 ubiquitin ligase family, some members of which down-regulate the expression of immune recognition molecules. Here, we have identified MARCH-II, which is ubiquitously expressed and localized to endosomal vesicles and the plasma membrane. Immunoprecipitation and in vitro binding studies established that MARCH-II directly associates with syntaxin 6. Overexpression of MARCH-II resulted in redistribution of syntaxin 6 as well as some syntaxin-6–interacting soluble N-ethylmaleimide–sensitive factor attachment protein receptors (SNAREs) into the MARCH-II–positive vesicles. In addition, the retrograde transport of TGN38 and a chimeric version of furin to trans-Golgi network (TGN) was perturbed—without affecting the endocytic degradative and biosynthetic secretory pathways—similar to effects caused by a syntaxin 6 mutant lacking the transmembrane domain. MARCH-II overexpression markedly reduced the cell surface expression of transferrin (Tf) receptor and Tf uptake and interfered with delivery of internalized Tf to perinuclear recycling endosomes. Depletion of MARCH-II by small interfering RNA perturbed the TGN localization of syntaxin 6 and TGN38/46. MARCH-II is thus likely a regulator of trafficking between the TGN and endosomes, which is a novel function for the MARCH family.
Ace2p Controls the Expression of Genes Required for Cell Separation inSchizosaccharomyces pombe
Authors: Alonso-Nuñez Maria Luisa , An Hanbing , Martín-Cuadrado Ana Belén , Mehta Sapna , Petit Claudia , Sipiczki Matthias , del Rey Francisco , Gould Katheleen L. , Vázquez de Aldana Carlos R.
Published: February 2005

Schizosaccharomyces pombe cells divide by medial fission through contraction of an actomyosin ring and deposition of a multilayered division septum that must be cleaved to release the two daughter cells. Here we describe the identification of seven genes (adg1+, adg2+, adg3+, cfh4+, agn1+, eng1+, and mid2+) whose expression is induced by the transcription factor Ace2p. The expression of all of these genes varied during the cell cycle, maximum transcription being observed during septation. At least three of these proteins (Eng1p, Agn1p, and Cfh4p) localize to a ring-like structure that surrounds the septum region during cell separation. Deletion of the previously uncharacterized genes was not lethal to the cells, but produced defects or delays in cell separation to different extents. Electron microscopic observation of mutant cells indicated that the most severe defect is found in eng1Δ agn1Δ cells, lacking the Eng1p endo-β-1,3-glucanase and the Agn1p endo-α-glucanase. The phenotype of this mutant closely resembled that of ace2Δ mutants, forming branched chains of cells. This suggests that these two proteins are the main activities required for cell separation to be completed.
The Pleckstrin Homology Domain Proteins Slm1 and Slm2 Are Required for Actin Cytoskeleton Organization in Yeast and Bind Phosphatidylinositol-4,5-Bisphosphate and TORC2
Authors: Fadri Maria , Daquinag Alexes , Wang Shimei , Xue Tao , Kunz Jeannette
Published: February 2005

Phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2] is a key second messenger that regulates actin and membrane dynamics, as well as other cellular processes. Many of the effects of PtdIns(4,5)P2are mediated by binding to effector proteins that contain a pleckstrin homology (PH) domain. Here, we identify two novel effectors of PtdIns(4,5)P2in the budding yeast Saccharomyces cerevisiae: the PH domain containing protein Slm1 and its homolog Slm2. Slm1 and Slm2 serve redundant roles essential for cell growth and actin cytoskeleton polarization. Slm1 and Slm2 bind PtdIns(4,5)P2through their PH domains. In addition, Slm1 and Slm2 physically interact with Avo2 and Bit61, two components of the TORC2 signaling complex, which mediates Tor2 signaling to the actin cytoskeleton. Together, these interactions coordinately regulate Slm1 targeting to the plasma membrane. Our results thus identify two novel effectors of PtdIns(4,5)P2regulating cell growth and actin organization and suggest that Slm1 and Slm2 integrate inputs from the PtdIns(4,5)P2and TORC2 to modulate polarized actin assembly and growth.
A Rab Requirement Is Not Bypassed inSLY1-20Suppression
Authors: Ballew Nicole , Liu Yiting , Barlowe Charles
Published: February 2005

The Rab GTPase Ypt1p and the large homodimer Uso1p are both required for tethering endoplasmic reticulum-derived vesicles to early Golgi compartments in yeast. Loss-of-function ypt1 and uso1 mutations are suppressed by SLY1-20, a dominant allele that encodes the Sed5p-associated protein, Sly1p. Here, we investigate the mechanism of SLY1-20 suppression. In wild-type strains, Ypt1p can be coimmunoprecipitated with Uso1p; however, in a ypt1Δ/SLY1-20 strain, which lacks this complex, membrane binding of Uso1p was reduced. In spite of Ypt1p depletion, Uso1p-dependent vesicle tethering was not bypassed under the ypt1Δ/SLY1-20 condition. Moreover, tethering and fusion assays with ypt1Δ/SLY1-20 membranes remained sensitive to Rab GDP dissociation inhibitor. These results indicate that an alternative Rab protein satisfies the Ypt1p requirement in Uso1p-dependent tethering when SLY1-20 is expressed. Further genetic and biochemical tests revealed that a related Rab protein, Ypt6, might substitute for Ypt1p in ypt1Δ/SLY1-20 cells. Additional experimentation to address the mechanism of SLY1-20 suppression in a cog2Δ [sec35Δ] strain indicated that the Cog2p subunit of the conserved oligomeric Golgi complex is either functionally redundant or is not directly required for anterograde transport to the Golgi complex.
Highly Cooperative Control of Endocytosis by Clathrin
Authors: Moskowitz Howard S. , Yokoyama Charles T. , Ryan Timothy A.
Published: February 2005

Clathrin assembles into a dynamic two-dimensional lattice on the plasma membrane where it plays a critical role in endocytosis. To probe the regulation of this process, we used siRNA against clathrin, in combination with single cell assays for transferrin uptake as well as total internal reflection microscopy, to examine how endocytic rates and membrane dynamics depend upon cellular clathrin concentration ([Clathrin]). We find that endocytosis is tightly controlled by [Clathrin] over a very narrow dynamic range such that small changes in [Clathrin] can lead to large changes in endocytic rates, indicative of a highly cooperative process (apparent Hill coefficient, n > 6). The number of clathrin assemblies at the cell surface was invariant over a wide range of [Clathrin]; however, both the amount of clathrin in each assembly and the subsequent membrane dynamics were steeply dependent on [Clathrin]. Thus clathrin controls the structural dynamics of membrane internalization via a strongly cooperative process. We used this analysis to show that one important regulator of endocytosis, the actin cytoskeleton, acts noncompetitively as a modulator of clathrin function.
Ase1p Organizes Antiparallel Microtubule Arrays during Interphase and Mitosis in Fission Yeast
Authors: Loïodice Isabelle , Staub Jayme , Setty Thanuja Gangi , Nguyen Nam-Phuong T. , Paoletti Anne , Tran P. T.
Published: February 2005

Proper microtubule organization is essential for cellular processes such as organelle positioning during interphase and spindle formation during mitosis. The fission yeast Schizosaccharomyces pombe presents a good model for understanding microtubule organization. We identify fission yeast ase1p, a member of the conserved ASE1/PRC1/MAP65 family of microtubule bundling proteins, which functions in organizing the spindle midzone during mitosis. Using fluorescence live cell imaging, we show that ase1p localizes to sites of microtubule overlaps associated with microtubule organizing centers at both interphase and mitosis. ase1Δ mutants fail to form overlapping antiparallel microtubule bundles, leading to interphase nuclear positioning defects, and premature mitotic spindle collapse. FRAP analysis revealed that interphase ase1p at overlapping microtubule minus ends is highly dynamic. In contrast, mitotic ase1p at microtubule plus ends at the spindle midzone is more stable. We propose that ase1p functions to organize microtubules into overlapping antiparallel bundles both in interphase and mitosis and that ase1p may be differentially regulated through the cell cycle.
Protein aggregation determinants from a simplified model: Cooperative folders resist aggregation
Authors: Clark Louis A.
Published: February 2005

Two‐chain aggregation simulations using minimalist models of proteins G, L, and mutants were used to investigate the fundamentals of protein aggregation. Mutations were selected to break up repeats of hydrophobic beads in the sequence while maintaining native topology and folding ability. Data are collected under conditions in which all chain types have similar folded populations and after equilibrating the separated chains to minimize competition between folding and aggregation. Folding cooperativity stands out as the best single‐chain determinant under these conditions and for these simple models. It can be experimentally measured by the width of the unfolding transition during thermal denaturation and loosely related to population of intermediate‐like states during folding. Additional measures of cooperativity and other properties such as radius of gyration fluctuations and patterning of hydrophobic residues are also examined. Initial contact system states with transition‐state characteristics can be identified and are more expanded than average initial contact states. Two‐chain minimalist model aggregates are considerably less structured than their native states and have minimal domain‐swapping features.
The crystal structure of rabbit phosphoglucose isomerase complexed with D‐sorbitol‐6‐phosphate, an analog of the open chain form of D‐glucose‐6‐phosphate
Authors: Lee Ji Hyun , Jeffery Constance J.
Published: February 2005

Phosphoglucose isomerase (PGI) catalyzes the isomerization of D‐glucose‐6‐phosphate (G6P) and D‐fructose‐6‐phosphate (F6P) in glycolysis and gluconeogenesis. Analysis of previously reported X‐ray crystal structures of PGI without ligand, with the cyclic form of F6P, or with inhibitors that mimic the cis‐enediol intermediate led to proposed mechanisms for the ring opening and isomerization steps in the multistep catalytic mechanism. To help complete our model of the overall mechanism, information is needed about the state of PGI between the ring opening and isomerization steps, in other words, a structure of the enzyme complexed with the open form of a substrate or an analog. Here, we report the crystal structure of rabbit PGI complexed with D‐sorbitol‐6‐phosphate (S6P), an analog of the open chain form of G6P, at 2.0 Å resolution. As was seen in the PGI/F6P structure, a helix containing amino acid residues 512–520 is found in the “out” position, which provides sufficient space in the active site for a substrate in its cyclic form and which is probably the location of that helix just after ring opening (or just before ring closure). However, the S6P ligand is in an extended conformation, as was seen previously with ligands that mimic the cis‐enediol intermediate. The extended conformation enables the ligand to interact with Glu357, which transfers a proton during the isomerization step. The PGI/S6P structure represents the conformation of the enzyme and substrate between the ring opening (or ring closing) step and the isomerization step and helps to complete the model for PGI's catalytic mechanism.
Identification of the ligand binding sites on the molecular surface of proteins
Authors: Kinoshita Kengo , Nakamura Haruki
Published: February 2005

Identification of protein biochemical functions based on their three‐dimensional structures is now required in the post–genome‐sequencing era. Ligand binding is one of the major biochemical functions of proteins, and thus the identification of ligands and their binding sites is the starting point for the function identification. Previously we reported our first trial on structure‐based function prediction, based on the similarity searches of molecular surfaces against the functional site database. Here we describe the extension of our first trial by expanding the search database to whole heteroatom binding sites appearing within the Protein Data Bank (PDB) with the new analysis protocol. In addition, we have determined the similarity threshold line, by using 10 structure pairs with solved free and complex structures. Finally, we extensively applied our method to newly determined hypothetical proteins, including some without annotations, and evaluated the performance of our methods.
Analysis of subsecond protein dynamics by amide hydrogen exchange and mass spectrometry using a quenched‐flow setup
Authors: Rist Wolfgang , Rodriguez Fernanda , Jørgensen Thomas J.D. , Mayer Matthias P.
Published: February 2005

Amide hydrogen exchange (HX) in combination with mass spectrometry (MS) is a powerful tool to analyze the folding and dynamics of proteins. In the traditional methodology the exchange time is controlled by manual pipetting, thereby limiting the time resolution to several seconds. Some conformational changes in proteins, however, occur in the subsecond time scale, making it desirable to perform HX at shorter time intervals down to the limit set by the intrinsic chemical exchange rate. We now report the development of the first completely on‐line quenched‐flow setup that allows the performance of HX experiments in the 100‐sec to 30‐sec time scale, on‐line proteolytic digestion using immobilized proteases, rapid desalting, and MS analysis. We show that conformational fluctuations in the range of seconds can be detected and protection factors as small as 10 reproducibly determined. Using this setup we investigated the conformational properties of Escherichia coli heat‐shock transcription factor σ32 free in solution. Our results indicate that the C‐terminal σ4 domain of σ32, which is responsible for the recognition of the −35 region of heat shock promoters, contains more extensive secondary structure than expected when compared with the structure of the homologous σ‐factor σA in complex with the RNA‐polymerase. This setup should be very useful for a more accurate analysis of structural motions in proteins in the subsecond to second time scale relevant to allostery and enzyme function.
Structural features of the focal adhesion kinase–paxillin complex give insight into the dynamics of focal adhesion assembly
Authors: Bertolucci Craig M. , Guibao Cristina D. , Zheng Jie
Published: February 2005

The C‐terminal region of focal adhesion kinase (FAK) consists of a right‐turn, elongated, four‐helix bundle termed the focal adhesion targeting (FAT) domain. The structure of this domain is maintained by hydrophobic interactions, and this domain is also the proposed binding site for the focal adhesion protein paxillin. Paxillin contains five well‐conserved LD motifs, which have been implicated in the binding of many focal adhesion proteins. In this study we determined that LD4 binds specifically to only a single site between the H2 and H3 helices of the FAT domain and that the C‐terminal end of LD4 is oriented toward the H2‐H3 loop. Comparisons of chemical‐shift perturbations in NMR spectra of the FAT domain in complex with the binding region of paxillin and the FAT domain bound to both the LD2 and LD4 motifs allowed us to construct a model of FAK–paxillin binding and suggest a possible mechanism of focal adhesion disassembly.
Polymerization of the SAM domain of MAPKKK Ste11 from the budding yeast: Implications for efficient signaling through the MAPK cascades
Authors: Bhattacharjya Surajit , Xu Ping , Chakrapani Mukundan , Johnston Linda , Ni Feng
Published: February 2005

The sterile α‐motif (SAM) is a protein module ∼70 residues long and mainly involved in the protein–protein interactions of cell signaling and transcriptional repression. The SAM domain of the yeast MAPKKK Ste11 has a well‐folded dimeric structure in solution. Interestingly, the well‐folded dimer of the Ste11 SAM undergoes a time‐dependent self‐assembly upon lowering of the pH, leading to the formation of high molecular weight oligomers. The oligomeric structures rapidly disassemble to the well‐folded dimer upon reversal of the pH to close to neutral conditions. Circular dichroism (CD) and atomic force microscopy (AFM) experiments demonstrate that the oligomeric structure formed at pH 5.0 appears to be highly helical and has architecture akin to proto‐fibrils. Residue‐specific kinetics of pH‐triggered oligomerization obtained from real‐time 15N‐1H HSQC experiments indicate that the dimer‐oligomer transition appears to involve all residues of the well‐folded dimeric structure of the Ste11 SAM. Very interestingly, the interactions of the Ste11 and Ste50 SAM domains also lead to the formation of non‐homogeneous hetero‐complexes with significant populations of high molecular weight aggregates. AFM imaging shows that the Ste11‐Ste50 hetero‐polymeric aggregates assume the shapes of circular nano‐particles with dimensions of 50–60 nano‐meters (nm), in contrast to the proto‐fibrils formed by the Ste11 SAM domain alone. Such intrinsic propensity for dimer to oligomer transition of the Ste50‐binding SAM domain of Ste11 may endow the MAPKKK Ste11 with unique functional properties required for efficient and high fidelity signal transduction in the budding yeast.
An efficient strategy for high‐throughput expression screening of recombinant integral membrane proteins
Authors: Eshaghi Said , Hedrén Marie , Nasser Marina Ignatushchenko Abdel , Hammarberg Tove , Thornell Anders , Nordlund Pär
Published: February 2005

The recombinant expression of integral membrane proteins is considered a major challenge, and together with the crystallization step, the major hurdle toward routine structure determination of membrane proteins. Basic methodologies for high‐throughput (HTP) expression optimization of soluble proteins have recently emerged, providing statistically significant success rates for producing such proteins. Experimental procedures for handling integral membrane proteins are generally more challenging, and there have been no previous comprehensive reports of HTP technology for membrane protein production.

Here, we present a generic and integrated parallel HTP strategy for cloning and expression screening of membrane proteins in their detergent solubilized form. Based on this strategy, we provide overall success rates for membrane protein production in Escherichia coli, as well as initial benchmarking statistics of parameters such as expression vectors, strains, and solubilizing detergents. The technologies were applied to 49 E. coli integral membrane proteins with human homologs and revealed that 71% of these proteins could be produced at sufficient levels to allow milligram amounts of protein to be relatively easily purified, which is a significantly higher success rate than anticipated. We attribute the high success rate to the quality and robustness of the methodology used, and to introducing multiple parameters such as different vectors, strains, and detergents. The presented strategy demonstrates the usefulness of HTP technologies for membrane protein production, and the feasibility of large‐scale programs for elucidation of structure and function of bacterial integral membrane proteins.
All three Ca2+‐binding loops of photoproteins bind calcium ions: The crystal structures of calcium‐loaded apo‐aequorin and apo‐obelin
Authors: Deng Lu , Vysotski Eugene S. , Markova Svetlana V. , Liu Zhi‐Jie , Lee John , Rose John , Wang Bi‐Cheng
Published: February 2005

The crystal structures of calcium‐loaded apoaequorin and apo‐obelin have been determined at resolutions 1.7 Å and 2.2 Å, respectively. A calcium ion is observed in each of the three EF‐hand loops that have the canonical calcium‐binding sequence, and each is coordinated in the characteristic pentagonal bipyramidal configuration. The calcium‐loaded apo‐proteins retain the same compact scaffold and overall fold as the unreacted photoproteins containing the bound substrate, 2‐hydroperoxycoelenterazine, and also the same as the Ca2+‐discharged obelin bound with the product, coelenteramide. Nevertheless, there are easily discerned shifts in both helix and loop regions, and the shifts are not the same between the two proteins. It is suggested that these subtle shifts are the basis of the ability of these photoproteins to sense Ca2+ concentration transients and to produce their bioluminescence response on the millisecond timescale. A mechanism of intrastructural transmission of the calcium signal is proposed.
The orientations of cytochrome c in the highly dynamic complex with cytochrome b5 visualized by NMR and docking using HADDOCK
Authors: Volkov Alexander N. , Ferrari Davide , Worrall Jonathan A.R. , Bonvin Alexandre M.J.J. , Ubbink Marcellus
Published: February 2005

The interaction of bovine microsomal ferricytochrome b5 with yeast iso‐1‐ferri and ferrocytochrome c has been investigated using heteronuclear NMR techniques. Chemical‐shift perturbations for 1H and 15N nuclei of both cytochromes, arising from the interactions with the unlabeled partner proteins, were used for mapping the interacting surfaces on both proteins. The similarity of the binding shifts observed for oxidized and reduced cytochrome c indicates that the complex formation is not influenced by the oxidation state of the cytochrome c. Protein–protein docking simulations have been performed for the binary cytochrome b5–cytochrome c and ternary (cytochrome b5)–(cytochrome c)2 complexes using a novel HADDOCK approach. The docking procedure, which makes use of the experimental data to drive the docking, identified a range of orientations assumed by the proteins in the complex. It is demonstrated that cytochrome c uses a confined surface patch for interaction with a much more extensive surface area of cytochrome b5. Taken together, the experimental data suggest the presence of a dynamic ensemble of conformations assumed by the proteins in the complex.
Crystal structure of the pyridoxal‐5′‐phosphate‐dependent serine dehydratase from human liver
Authors: Sun Lei , Bartlam Mark , Liu Yiwei , Pang Hai , Rao Zihe
Published: February 2005

L‐serine dehydratase (SDH), a member of the β‐family of pyridoxal phosphate‐dependent (PLP) enzymes, catalyzes the deamination of L‐serine and L‐threonine to yield pyruvate or 2‐oxobutyrate. The crystal structure of L‐serine dehydratase from human liver (hSDH) has been solved at 2.5 Å‐resolution by molecular replacement. The structure is a homodimer and reveals a fold typical for β‐family PLP‐dependent enzymes. Each monomer serves as an active unit and is subdivided into two distinct domains: a small domain and a PLP‐binding domain that covalently anchors the cofactor. Both domains show the typical open α/β architecture of PLP enzymes. Comparison with the rSDH‐(PLP‐OMS) holo‐enzyme reveals a large structural difference in active sites caused by the artifical O‐methylserine. Furthermore, the activity of hSDH‐PLP was assayed and it proved to show catalytic activity. That suggests that the structure of hSDH‐PLP is the first structure of the active natural holo‐SDH.
β2‐Microglobulin isoforms display an heterogeneous affinity for type I collagen
Authors: Giorgetti Sofia , Rossi Antonio , Mangione Palma , Raimondi Sara , Marini Sara , Stoppini Monica , Corazza Alessandra , Viglino Paolo , Esposito Gennaro , Cetta Giuseppe , Merlini Giampaolo , Bellotti Vittorio
Published: February 2005

It has been claimed that β2‐microglobulin (β2‐m) interacts with type I and type II collagen, and this property has been linked to the tissue specificity of the β2‐m amyloid deposits that target the osteo‐articular system. The binding parameters of the interaction between collagen and β2‐m were determined by band shift electrophoresis and surface plasma resonance by using bovine collagen of type I and type II and various isoforms of β2‐m. Wild‐type β2‐m binds collagen type I with a Kd of 4.1 × 10−4 M and type II with 2.3 × 10−3 M. By the BIAcore system we monitored the binding properties of the conformers of the slow phase of folding of β2‐m. The folding intermediates during the slow phase of folding do not display any significant difference with respect to the binding properties of the fully folded molecule. The affinity of β2‐m truncated at the third N‐terminal residue does not differ from that reported for the wild‐type protein. Increased affinity for collagen type I is found in the case of N‐terminal truncated species lacking of six residues. The Kd of this species is 3.4 × 10 −5 M at pH 7.4 and its affinity increases to 4.9 × 10−6 M at pH 6.4. Fluctuations of the affinity caused by β2‐m truncation and pH change can cause modifications of protein concentration in the solvent that surrounds the collagen, and could contribute to generate locally a critical protein concentration able to prime the protein aggregation.
Protein folding: Defining a “standard” set of experimental conditions and a preliminary kinetic data set of two‐state proteins
Authors: Maxwell Karen L. , Wildes David , Zarrine‐Afsar Arash , De Los Rios Miguel A. , Brown Andrew G. , Friel Claire T. , Hedberg Linda , Horng Jia‐Cherng , Bona Diane , Miller Erik J. , Vallée‐Bélisle Alexis , Main Ewan R.G. , Bemporad Francesco , Qiu Linlin , Teilum Kaare , Vu Ngoc‐Diep , Edwards Aled M. , Ruczinski Ingo , Poulsen Flemming M. , Kragelund Birthe B. , Michnick Stephen W. , Chiti Fabrizio , Bai Yawen , Hagen Stephen J. , Serrano Luis , Oliveberg Mikael , Raleigh Daniel P. , Wittung‐Stafshede Pernilla , Radford Sheena E. , Jackson Sophie E. , Sosnick Tobin R. , Marqusee Susan , Davidson Alan R. , Plaxco Kevin W.
Published: February 2005

Recent years have seen the publication of both empirical and theoretical relationships predicting the rates with which proteins fold. Our ability to test and refine these relationships has been limited, however, by a variety of difficulties associated with the comparison of folding and unfolding rates, thermodynamics, and structure across diverse sets of proteins. These difficulties include the wide, potentially confounding range of experimental conditions and methods employed to date and the difficulty of obtaining correct and complete sequence and structural details for the characterized constructs. The lack of a single approach to data analysis and error estimation, or even of a common set of units and reporting standards, further hinders comparative studies of folding. In an effort to overcome these problems, we define here a “consensus” set of experimental conditions (25°C at pH 7.0, 50 mM buffer), data analysis methods, and data reporting standards that we hope will provide a benchmark for experimental studies. We take the first step in this initiative by describing the folding kinetics of 30 apparently two‐state proteins or protein domains under the consensus conditions. The goal of our efforts is to set uniform standards for the experimental community and to initiate an accumulating, self‐consistent data set that will aid ongoing efforts to understand the folding process.
Crystal structure of a predicted phosphoribosyltransferase (TT1426) from Thermus thermophilus HB8 at 2.01 Å resolution
Authors: Kukimoto‐Niino Mutsuko , Shibata Rie , Murayama Kazutaka , Hamana Hiroaki , Nishimoto Madoka , Bessho Yoshitaka , Terada Takaho , Shirouzu Mikako , Kuramitsu Seiki , Yokoyama Shigeyuki
Published: February 2005

TT1426, from Thermus thermophilus HB8, is a conserved hypothetical protein with a predicted phosphoribosyltransferase (PRTase) domain, as revealed by a Pfam database search. The 2.01 Å crystal structure of TT1426 has been determined by the multiwavelength anomalous dispersion (MAD) method. TT1426 comprises a core domain consisting of a central five‐stranded β sheet surrounded by four α‐helices, and a subdomain in the C terminus. The core domain structure resembles those of the type I PRTase family proteins, although a significant structural difference exists in an inserted 43‐residue region. The C‐terminal subdomain corresponds to the “hood,” which contains a substrate‐binding site in the type I PRTases. The hood structure of TT1426 differs from those of the other type I PRTases, suggesting the possibility that TT1426 binds an unknown substrate. The structure‐based sequence alignment provides clues about the amino acid residues involved in catalysis and substrate binding.
Solution structure of the PWWP domain of the hepatoma‐derived growth factor family
Authors: Nameki Nobukazu , Tochio Naoya , Koshiba Seizo , Inoue Makoto , Yabuki Takashi , Aoki Masaaki , Seki Eiko , Matsuda Takayoshi , Fujikura Yukiko , Saito Miyuki , Ikari Masaomi , Watanabe Megumi , Terada Takaho , Shirouzu Mikako , Yoshida Mayumi , Hirota Hiroshi , Tanaka Akiko , Hayashizaki Yoshihide , Güntert Peter , Kigawa Takanori , Yokoyama Shigeyuki
Published: February 2005

Among the many PWWP‐containing proteins, the largest group of homologous proteins is related to hepatoma‐derived growth factor (HDGF). Within a well‐conserved region at the extreme N‐terminus, HDGF and five HDGF‐related proteins (HRPs) always have a PWWP domain, which is a module found in many chromatin‐associated proteins. In this study, we determined the solution structure of the PWWP domain of HDGF‐related protein‐3 (HRP‐3) by NMR spectroscopy. The structure consists of a five‐stranded β‐barrel with a PWWP‐specific long loop connecting β2 and β3 (PR‐loop), followed by a helical region including two α‐helices. Its structure was found to have a characteristic solvent‐exposed hydrophobic cavity, which is composed of an abundance of aromatic residues in the β1/β2 loop (β‐β arch) and the β3/β4 loop. A similar ligand binding cavity occurs at the corresponding position in the Tudor, chromo, and MBT domains, which have structural and probable evolutionary relationships with PWWP domains. These findings suggest that the PWWP domains of the HDGF family bind to some component of chromatin via the cavity.
AN ESTIMABLE DYNAMIC GENERAL EQUILIBRIUM MODEL OF WORK, SCHOOLING, AND OCCUPATIONAL CHOICE*
Authors: Lee Donghoon
Published: February 2005

This article develops and estimates a dynamic general equilibrium overlapping‐generations model of career decisions. The model is fit to data on life cycle employment, schooling, and occupation decisions and on life cycle labor earnings, within and between cohorts observed in the United States between 1968 and 1993. Based on the estimates of the model, the impact of cohort size on skill prices and the general equilibrium effect of a tuition subsidy are assessed.
TRAINING, TURNOVER, AND SEARCH*
Authors: Quercioli Elena
Published: February 2005

This article explores a model of firm‐specific training in a job search environment with labor turnover. The main substantive finding is a positive association between training and wages (when dispersed). The article then precisely characterizes how both wage dispersion and firm profitability depend on the flow value b≥ 0 of workers' unmatched time. It is shown that: (i) for all high values b, no equilibrium exists; (ii) for intermediate values b, multiple equilibria arise, where firms earn zero profits, and choose from a general wage distribution; (iii) for all lower values b, there is a unique equilibrium, with firms earning positive profits, and choosing from an atomless set of wages.
ANARCHY AND AUTARKY: ENDOGENOUS PREDATION AS A BARRIER TO TRADE*
Authors: Anderson James E. , Marcouiller Douglas
Published: February 2005

This article presents a general equilibrium two‐country Ricardian trade model with endogenous transactions costs that arise from individual utility‐maximizing allocation of labor to production and piracy. In the absence of institutions for risk sharing and coordination of defense, autarky obtains over most of the parameter space. When both trade and predation are supported in equilibrium, terms of trade effects can make security immiserizing. In that case, paradoxically, predation creates trade.
HIGH‐TECH AND HIGH CAPABILITY IN A GROWTH MODEL*
Authors: Tong Jian
Published: February 2005

A growth model is developed to substantiate the conventional wisdom that regards high‐tech high‐capability firms as an engine of sustained technological progress. High‐tech industries are characterized by abounding technological opportunities, which promote endogenous high capability firms due to a competitive escalation mechanism. While high‐tech high‐capability firms capitalize on and discharge the existing innovation potentials, they also contribute to recharge (due to knowledge spillovers). They are a source of growth and high wage rate. An inquiry into the reasons why the high‐tech/high‐capability growth mechanism is not widely adoptable across countries points to the role of the underlying corporate governance systems.
INFLATION PERSISTENCE AND FLEXIBLE PRICES*
Authors: Dittmar Robert D. , Gavin William T. , Kydland Finn E.
Published: February 2005

If the central bank follows an interest rate rule, then inflation is likely to be persistent, even when prices are fully flexible. Any shock, whether persistent or not, may lead to inflation persistence. In equilibrium, the dynamics of inflation are determined by the evolution of the spread between the real interest rate and the central bank's target. Inflation persistence can be characterized by a vector autocorrelation function relating inflation and output. This article shows that a flexible‐price, general‐equilibrium business cycle model with money and a central bank using an interest rate target can account for such inflation persistence.
A POSITIVE THEORY OF GEOGRAPHIC MOBILITY AND SOCIAL INSURANCE*
Authors: Hassler John , Rodríguez Mora José V. , Storesletten Kjetil , Zilibotti Fabrizio
Published: February 2005

This article presents a tractable dynamic general equilibrium model explaining cross‐country data on geographical mobility, unemployment, and labor market institutions. Rational forward‐looking agents vote on unemployment insurance (UI). Agents with higher moving costs (larger attachment to their location) prefer more generous UI. Attachment is assumed to increase with the duration of residence. UI mitigates incentives for moving and increases, therefore, the fraction of attached agents and the political support for UI. This self‐reinforcing mechanism can yield two steady‐states: one “European” and one “American.” The former (latter) features high (low) unemployment, low (high) geographical mobility, and high (low) UI.
So How Does the Mind Work?
Authors: Pinker Steven
Published: February 2005

Abstract:  In my book How the Mind Works, I defended the theory that the human mind is a naturally selected system of organs of computation. Jerry Fodor claims that ‘the mind doesn’t work that way’(in a book with that title) because (1) Turing Machines cannot duplicate humans’ ability to perform abduction (inference to the best explanation); (2) though a massively modular system could succeed at abduction, such a system is implausible on other grounds; and (3) evolution adds nothing to our understanding of the mind. In this review I show that these arguments are flawed. First, my claim that the mind is a computational system is different from the claim Fodor attacks (that the mind has the architecture of a Turing Machine); therefore the practical limitations of Turing Machines are irrelevant. Second, Fodor identifies abduction with the cumulative accomplishments of the scientific community over millennia. This is very different from the accomplishments of human common sense, so the supposed gap between human cognition and computational models may be illusory. Third, my claim about biological specialization, as seen in organ systems, is distinct from Fodor's own notion of encapsulated modules, so the limitations of the latter are irrelevant. Fourth, Fodor's arguments dismissing of the relevance of evolution to psychology are unsound.
Adaptationism for Human Cognition: Strong, Spurious or Weak?
Authors: Atran Scott
Published: February 2005

Abstract: Strong adaptationists explore complex organic design as task‐specific adaptations to ancestral environments. This strategy seems best when there is evidence of homology. Weak adaptationists don’t assume that complex organic (including cognitive and linguistic) functioning necessarily or primarily represents task‐specific adaptation. This approach to cognition resembles physicists’ attempts to deductively explain the most facts with fewest hypotheses. For certain domain‐specific competencies (folkbiology) strong adaptationism is useful but not necessary to research. With group‐level belief systems (religion) strong adaptationism degenerates into spurious notions of social function and cultural selection. In other cases (language, especially universal grammar) weak adaptationism's ‘minimalist’ approach seems productive.
Context‐Sensitive Truth‐Theoretic Accounts of Semantic Competence
Authors: Gross Steven
Published: February 2005

Abstract: According to cognitivist truth‐theoretic accounts of semantic competence, aspects of our linguistic behavior can be explained by ascribing to speakers cognition of truth‐theories. It's generally assumed on this approach that, however much context‐sensitivity speakers’ languages contain, the cognized truth‐theories themselves can be adequately characterized context‐insensitively—that is, without using in the meta‐language expressions whose semantic value can vary across occasions of utterance. In this paper, I explore some of the motivations for and problems and consequences of dropping this assumption.
Recent Defenses of Descriptivism
Authors: Everett Anthony
Published: February 2005

Abstract:  David Sosa, Michael Nelson, and Jason Stanley have recently offered a series of interesting and provocative challenges to Kripke's modal arguments against Descriptivism. In this paper I explore these challenges and some of the issues to which they give rise. I argue that, in the end, all three challenges fail.
Effectiveness of hypermedia annotations for foreign language reading
Authors: Sakar Asim , Ercetin Gulcan
Published: February 2005

Abstract
This study first explores intermediate‐level English learners' preferences for hypermedia annotations while they are engaged in reading a hypermedia text. Second, it examines whether multimedia annotations facilitate reading comprehension in the second language. The participants were 44 adult learners of English as a foreign language studying English for Academic Purposes. Data were collected through a tracking tool, a reading comprehension test, a questionnaire, and interviews. Results indicate that learners preferred visual annotations significantly more than textual and audio annotations. On the other hand, a negative relationship was found between annotation use and reading comprehension. Especially, pronunciations, audiorecordings, and videos were found to affect reading comprehension negatively. However, the qualitative data revealed that the participants had positive attitudes towards annotations and hypermedia reading in general.
An exploration of students' strategy use in inquiry‐based computer‐supported collaborative learning
Authors: Salovaara Hanna
Published: February 2005

Abstract The aim of this study is to investigate students' use of cognitive learning strategies in inquiry‐based computer‐supported collaborative learning (CSCL). A process‐oriented interview framework on cognitive activity, self‐regulation and motivation, and a coding category for analysing cognitive learning strategies and cognitive self‐regulation was developed. The students of an intervention group (n=18) participating in inquiry‐based CSCL and a comparison group (n=8) were interviewed six to eight times during the 3 years of the study. The results derived from the mixed‐method analysis of altogether 161 interviews were compared between the two groups. The results indicate that the students who participated in the inquiry‐based CSCL activities reported deeper‐level cognitive strategies such as monitoring, creating representations and sharing information collaboratively. The students of the comparison group reported more surface‐level strategies such as memorization. However, the findings concerning the utility of CSCL inquiry on cognitive learning strategies were not uniformly positive. It was found that the students of the comparison group reported significantly more strategies under the category of content evaluation. Nevertheless, the results suggest that computer‐supported inquiry‐based learning can enhance the use of cognitive strategies that support learning.
Learning effectiveness in a Web‐based virtual learning environment: a learner control perspective
Authors: Chou Shih‐Wei , Liu Chien‐Hung
Published: February 2005

Web‐based technology has a dramatic impact on learning and teaching. A framework that delineates the relationships between learner control and learning effectiveness is absent. This study aims to fill this void. Our work focuses on the effectiveness of a technology‐mediated virtual learning environment (TVLE) in the context of basic information technology skills training. Grounded in the technology‐mediated learning literature, this study presents a framework that addresses the relationship between the learner control and learning effectiveness, which contains four categories: learning achievement, self‐efficacy, satisfaction, and learning climate. In order to compare the learning effectiveness under traditional classroom and TVLE, we conducted a field experiment. Data were collected from a junior high school of Taiwan. A total of 210 usable responses were analysed. We identified four results from this study. (1) Students in the TVLE environment achieve better learning performance than their counterparts in the traditional environment; (2) Students in the TVLE environment report higher levels of computer self‐efficacy than their counterparts in the traditional environment; (3) Students in the TVLE environment report higher levels of satisfaction than students in the traditional environment; and (4) Students in the TVLE environment report higher levels of learning climate than their counterparts in the traditional environment. The implications of this study are discussed, and further research directions are proposed.