bluuebunny/crossref_metadata_2025 huggingface dataset:
Nucleation-dependent conformational conversion of the Y145Stop variant of human prion protein: Structural clues for prion propagation
Authors: Kundu Bishwajit , Maiti Nilesh R. , Jones Eric M. , Surewicz Krystyna A. , Vanik David L. , Surewicz Witold K.
Published: October 2003

One of the most intriguing disease-related mutations in human prion protein (PrP) is the Tyr to Stop codon substitution at position 145. This mutation results in a Gerstmann–Straussler–Scheinker-like disease with extensive PrP amyloid deposits in the brain. Here, we provide evidence for a spontaneous conversion of the recombinant polypeptide corresponding to the Y145Stop variant (huPrP23–144) from a monomeric unordered state to a fibrillar form. This conversion is characterized by a protein concentration-dependent lag phase and has characteristics of a nucleation-dependent polymerization. Atomic force microscopy shows that huPrP23–144 fibrils are characterized by an apparent periodicity along the long axis, with an average period of 20 nm. Fourier-transform infrared spectra indicate that the conversion is associated with formation of β-sheet structure. However, the infrared bands for huPrP23–144 are quite different from those for a synthetic peptide PrP106–126, suggesting conformational non-equivalence of β-structures in the disease-associated Y145Stop variant and a frequently used short model peptide. To identify the region that is critical for the self-seeded assembly of huPrP23–144 amyloid, experiments were performed by using the recombinant polypeptides corresponding to prion protein fragments 23–114, 23–124, 23–134, 23–137, 23–139, and 23–141. Importantly, none of the fragments ending before residue 139 showed a propensity for conformational conversion to amyloid fibrils, indicating that residues within the 138–141 region are essential for this conversion.
Identification of biomarkers for ovarian cancer using strong anion-exchange ProteinChips: Potential use in diagnosis and prognosis
Authors: Kozak Katherine R. , Amneus Malaika W. , Pusey Suzanne M. , Su Feng , Luong Mui N. , Luong Sam A. , Reddy Srinivasa T. , Farias-Eisner Robin
Published: October 2003

One hundred eighty-four serum samples from patients with ovarian cancer (
n
= 109), patients with benign tumors (
n
= 19), and healthy donors (
n
= 56) were analyzed on strong anion-exchange surfaces using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry technology. Univariate and multivariate statistical analyses applied to protein-profiling data obtained from 140 training serum samples identified three biomarker protein panels. The first panel of five candidate protein biomarkers, termed the screening biomarker panel, effectively diagnosed benign and malignant ovarian neoplasia [95.7% sensitivity, 82.6% specificity, 89.2% accuracy, and receiver operating characteristic (ROC) area under the curve of 0.94]. The other two panels, consisting of five and four candidate protein biomarkers each, effectively distinguished between benign and malignant ovarian neoplasia and were therefore referred to as validation biomarker panel I (81.5% sensitivity, 94.9% specificity, 88.2% accuracy, and ROC = 0.94) and validation biomarker panel II (72.8% sensitivity, 94.9% specificity, 83.9% accuracy, and ROC = 0.90). The three ovarian cancer biomarker protein panels correctly diagnosed 41 of the 44 blinded test samples: 21 of 22 malignant ovarian neoplasias [10 of 11 early-stage ovarian cancer (I/II) and 11 of 11 advanced-stage ovarian cancer (III/IV)], 6 of 6 low malignant potential, 5 of the 6 benign tumors, and 9 of 10 normal patient samples. In conclusion, we have discovered three ovarian cancer biomarker protein panels that, when used together, effectively distinguished serum samples from healthy controls and patients with either benign or malignant ovarian neoplasia.
Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-β ligand in transgenic mice
Authors: Bacskai Brian J. , Hickey Gregory A. , Skoch Jesse , Kajdasz Stephen T. , Wang Yanming , Huang Guo-feng , Mathis Chester A. , Klunk William E. , Hyman Bradley T.
Published: October 2003

The lack of a specific biomarker makes preclinical diagnosis of Alzheimer's disease (AD) impossible, and it precludes assessment of therapies aimed at preventing or reversing the course of the disease. The development of a tool that enables direct, quantitative detection of the amyloid-β deposits found in the disease would provide an excellent biomarker. This article demonstrates the real-time biodistribution kinetics of an imaging agent in transgenic mouse models of AD. Using multiphoton microscopy, Pittsburgh compound B (PIB) was imaged with sub-μm resolution in the brains of living transgenic mice during peripheral administration. PIB entered the brain quickly and labeled amyloid deposits within minutes. The nonspecific binding was cleared rapidly, whereas specific labeling was prolonged. WT mice showed rapid brain entry and clearance of PIB without any binding. These results demonstrate that the compound PIB has the properties required for a good amyloid-imaging agent in humans with or at risk for AD.
Functional map and domain structure of MET, the product of the c-
met
protooncogene and receptor for hepatocyte growth factor/scatter factor
Authors: Gherardi Ermanno , Youles Mark E. , Miguel Ricardo N. , Blundell Tom L. , Iamele Luisa , Gough Julian , Bandyopadhyay Abhishek , Hartmann Guido , Butler P. Jonathan G.
Published: October 2003

Little is known about the large ectodomain of MET, the product of the c-
met
protooncogene and receptor for hepatocyte growth factor/scatter factor (HGF/SF). Here, we establish by deletion mutagenesis that the HGF/SF and heparin-binding sites of MET are contained within a large N-terminal domain spanning the α-chain (amino acids 25–307) and the first 212 amino acids of the β-chain (amino acids 308–519). Neither the cystine-rich domain (amino acids 520–561) nor the C-terminal half of MET (amino acids 562–932) bind HGF/SF or heparin directly. The MET ectodomain, which behaves as a rod-shaped monomer with a large Stokes radius in solution, binds HGF/SF in the absence or presence of heparin, and forms a stable HGF/SF–heparin–MET complex with 1:1:1 stoichiometry. We also show that the ligand-binding domain adopts a β-propeller fold, which is similar to the N-terminal domain of αV integrin, and that the C-terminal half contains four Ig domains (amino acids 563–654, 657–738, 742–836, and 839–924) of the unusual structural E set, which could be modeled on bacterial enzymes. Our studies provide 3D models and a functional map of the MET ectodomain. They have broad implications for structure-function of the MET receptor and the related semaphorin and plexin proteins.
Reprogramming of primordial germ cells begins before migration into the genital ridge, making these cells inadequate donors for reproductive cloning
Authors: Yamazaki Yukiko , Mann Mellissa R. W. , Lee Susan S. , Marh Joel , McCarrey John R. , Yanagimachi Ryuzo , Bartolomei Marisa S.
Published: October 2003

Germ cells undergo epigenetic modifications as they develop, which suggests that they may be ideal donors for nuclear transfer (cloning). In this study, nuclei from confirmed embryonic germ cells were used as donors to determine whether they are competent for cloning and at which stage they are most competent. Embryos cloned from migrating 10.5-days-postcoitum (dpc) primordial germ cells (PGCs) showed normal morphological development to midgestation but died shortly thereafter. In contrast, embryos cloned from later-stage germ cells were developmentally delayed at midgestation. Thus, donor germ cell age inversely correlated with the developmental stage attained by cloned embryos. The methylation status of the
H19
- and
Snrpn
-imprinting control regions in germ cell clones paralleled that of the donors, and revealed that demethylation, or erasure of imprints, was already initiated in PGCs at 10.5 dpc and was complete by 13.5 dpc. Similarly, clones derived from male 15.5-dpc germ cells showed increased methylation correlating with the initiation of
de novo
methylation that resets imprints at this stage, and clones from neonatal germ cells showed nearly complete methylation in the
H19
imprinting control region. These results indicate that the epigenetic state of the donor nucleus is retained in cloned embryos, and that germ cells are therefore inadequate nuclear donors for cloning because they are either erasing or resetting epigenetic patterns.
Establishment of memory for IL-10 expression in developing T helper 2 cells requires repetitive IL-4 costimulation and does not impair proliferation
Authors: Löhning Max , Richter Anne , Stamm Torsten , Hu-Li Jane , Assenmacher Mario , Paul William E. , Radbruch Andreas
Published: October 2003

T helper (Th) lymphocytes can develop memory for the expression of particular cytokines, like IL-4 or IL-10, in that reexpression of those cytokines is independent of the original costimulatory signal IL-4 and depends only on T cell receptor stimulation. Here, we show that in the course of Th2 cell differentiationin vitro, IL-4 memory is established during primary activation of naïve Th cells, whereas the establishment of IL-10 memory requires repetitive stimulation of the Th cell with IL-4 and T cell receptor. Likewise, established IL-10 memory, maintained in the absence of further IL-4 signals, was observed in individual IL-10-producing cells generated fromin vivoantigen-experienced CD62LlowTh cells and isolated by using the newly developed cytometric cytokine secretion assay for IL-10. In naïve Th cells undergoing primary activation, the induction of both IL-4 and IL-10 memory requires DNA synthesis, but reexpression of the cytokine genes can occur throughout cell cycle. Inin vitropolarized Th2 cell populations, Th cells with IL-4 or IL-10 memory do not differ in proliferative behavior. Populations of Th cells isolated from polarized Th2 cultures according to expression of IL-4 or IL-10 also do not differ in proliferative behavior. Their proliferation mainly depends on IL-2. Thus, effector memory Th lymphocytes with memory for IL-4 or IL-10 expression are not intrinsically impaired in their proliferative potential and can play an essential role in reactive immunological memory and its regulation.
Gene expression profiling in Werner syndrome closely resembles that of normal aging
Authors: Kyng Kasper J. , May Alfred , Kølvraa Steen , Bohr Vilhelm A.
Published: October 2003

Werner syndrome (WS) is a premature aging disorder, displaying defects in DNA replication, recombination, repair, and transcription. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression and that a transcription defect may be crucial to the development of the syndrome. We used cDNA microarrays to characterize the expression of 6,912 genes and ESTs across a panel of 15 primary human fibroblast cell lines derived from young donors, old donors, and WS patients. Of the analyzed genes, 6.3% displayed significant differences in expression when either WS or old donor cells were compared with young donor cells. This result demonstrates that the WS transcription defect is specific to certain genes. Transcription alterations in WS were strikingly similar to those in normal aging: 91% of annotated genes displayed similar expression changes in WS and in normal aging, 3% were unique to WS, and 6% were unique to normal aging. We propose that a defect in the transcription of the genes as identified in this study could produce many of the complex clinical features of WS. The remarkable similarity between WS and normal aging suggests that WS causes the acceleration of a normal aging mechanism. This finding supports the use of WS as an aging model and implies that the transcription alterations common to WS and normal aging represent general events in the aging process.
Repeated neonatal handling with maternal separation permanently alters hippocampal GABA
A
receptors and behavioral stress responses
Authors: Hsu Fu-Chun , Zhang Guo-Jun , Raol Yogendra Sinh H. , Valentino Rita J. , Coulter Douglas A. , Brooks-Kayal Amy R.
Published: October 2003

Increasing evidence suggests that postnatal events, such as handling or maternal separation, can produce long-term changes in brain function. These are often expressed as changes in the profile of endocrine or behavioral responses to stress. Changes in γ-aminobutyric acid type A receptors (GABARs), which mediate the majority of fast synaptic inhibition in adult brain, have been proposed as one potential mediator of these behavioral effects. In the current article, we use a combination of single-cell electrophysiology and antisense mRNA amplification to demonstrate permanent molecular and functional differences in GABARs within hippocampal dentate granule neurons after as few as two episodes of neonatal handling with brief maternal separation. Adult animals that as pups experienced handling with maternal separation maintained a more immature GABAR phenotype and exhibited increased activity in response to swim stress. These findings demonstrate the exquisite sensitivity of the developing GABAergic system to even subtle environmental manipulations and provide an unique molecular mechanism by which postnatal handling with maternal separation may alter stress-related behavior.
Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction
Authors: Oh Hidemasa , Bradfute Steven B. , Gallardo Teresa D. , Nakamura Teruya , Gaussin Vinciane , Mishina Yuji , Pocius Jennifer , Michael Lloyd H. , Behringer Richard R. , Garry Daniel J. , Entman Mark L. , Schneider Michael D.
Published: October 2003

Potential repair by cell grafting or mobilizing endogenous cells holds particular attraction in heart disease, where the meager capacity for cardiomyocyte proliferation likely contributes to the irreversibility of heart failure. Whether cardiac progenitors exist in adult myocardium itself is unanswered, as is the question whether undifferentiated cardiac precursor cells merely fuse with preexisting myocytes. Here we report the existence of adult heart-derived cardiac progenitor cells expressing stem cell antigen-1. Initially, the cells express neither cardiac structural genes nor
Nkx2.5
but differentiate
in vitro
in response to 5′-azacytidine, in part depending on
Bmpr1a
, a receptor for bone morphogenetic proteins. Given intravenously after ischemia/reperfusion, cardiac stem cell antigen 1 cells home to injured myocardium. By using a Cre/Lox donor/recipient pair (α
MHC-Cre
/
R26R
), differentiation was shown to occur roughly equally, with and without fusion to host cells.
Regulation of nitric oxide consumption by hypoxic red blood cells
Authors: Han Tae H. , Qamirani Erion , Nelson Allyson G. , Hyduke Daniel R. , Chaudhuri Gautam , Kuo Lih , Liao James C.
Published: October 2003

The homeostasis of nitric oxide (NO) is attained through a balance between its production and consumption. Shifts in NO bioavailability have been linked to a variety of diseases. Although the regulation of NO production has been well documented, its consumption is largely thought to be unregulated. Here, we have demonstrated that under hypoxic conditions, NO accelerates its own consumption by increasing its entry into RBCs. When RBCs were exposed to NO (1:400 NO/heme ratio) under hypoxic conditions to form HbFe(II)NO, the consumption rate of NO increased significantly. This increase in NO consumption converted the bioactivity of serotonin from a vasodilator to a vasoconstrictor in isolated coronary arterioles. We identified HbFe(II)NO as a potential mediator of accelerated NO consumption. Accelerated NO consumption by HbFe(II)NO-bearing RBCs may contribute to hypoxic pulmonary vasoconstriction and the rebound effect seen on termination of NO inhalation therapy. Furthermore, accelerated NO consumption may exacerbate ischemia-mediated vasospasm and nitrate tolerance. Finally, this phenomenon may be an evolved mechanism to stabilize the vasculature in sepsis.
Juvenile hormone acid methyltransferase: A key regulatory enzyme for insect metamorphosis
Authors: Shinoda Tetsuro , Itoyama Kyo
Published: October 2003

Juvenile hormone (JH) acid methyltransferase (JHAMT) is an enzyme that converts JH acids or inactive precursors of JHs to active JHs at the final step of JH biosynthesis pathway in insects. By fluorescent mRNA differential display, we have cloned a cDNA encoding JHAMT from the corpora allata (CA) of the silkworm,Bombyx mori(BmJHAMT). TheBmJHAMTcDNA encodes an ORF of 278 aa with a calculated molecular mass of 32,544 Da. The predicted amino acid sequence contains a conservedS-adenosyl-l-methionine (SAM) binding motif found in the family of SAM-dependent methyltransferases. Purified N-terminal 6×His-tagged recombinant BmJHAMT protein expressed inEscherichia colicatalyzed conversion of farnesoic acid and JH acids I, II, and III to their cognate methyl esters in the presence of SAM, confirming that this cDNA encodes a functional JHAMT. Putative orthologs,DmJHAMTandAgJHAMT, were identified from the genome sequence of the fruit flyDrosophila melanogaster, and a malaria vector,Anopheles gambiae, respectively. Northern blot and quantitative RT-PCR analyses revealed that theBmJHAMTgene was expressed specifically in the CA throughout the third and fourth instar. At the beginning of the last (fifth) instar, the expression level ofBmJHAMTdeclined rapidly and became undetectable by day 4 and remained so until pupation. Correlation of theBmJHAMTgene expression and the JH biosynthetic activity in the CA suggests that the transcriptional suppression of theBmJHAMTgene is crucial for the termination of JH biosynthesis in the CA, which is a prerequisite for the initiation of metamorphosis.
Sp8
is crucial for limb outgrowth and neuropore closure
Authors: Bell Sheila M. , Schreiner Claire M. , Waclaw Ronald R. , Campbell Kenneth , Potter S. Steven , Scott William J.
Published: October 2003

In this report we describe the developmental expression and function of Sp8, a member of the Sp family of zinc finger transcription factors, and provide evidence that the
legless
transgene insertional mutant is a hypomorphic allele of the
Sp8
gene.
Sp8
is expressed during embryogenesis in the forming apical ectodermal ridge (AER), restricted regions of the central nervous system, and tail bud. Targeted deletion of the
Sp8
gene gives a striking phenotype, with severe truncation of both forelimbs and hindlimbs, absent tail, as well as defects in anterior and posterior neuropore closure leading to exencephaly and spina bifida. Outgrowth of the limb depends on formation of the AER, a signaling center that forms at the limb bud apex. In
Sp8
mutants, the AER precursor cells are induced and initially express multiple appropriate marker genes, but expression of these genes is not maintained and progression to a mature AER is blocked. These observations indicate that Sp8 functions downstream of Wnt3, Fgf10, and Bmpr1a in the signaling cascade that mediates AER formation.
Y box-binding protein 1 induces resistance to oncogenic transformation by the phosphatidylinositol 3-kinase pathway
Authors: Bader Andreas G. , Felts Katherine A. , Jiang Ning , Chang Hwai Wen , Vogt Peter K.
Published: October 2003

Y box-binding protein 1 (YB-1) is a multifunctional protein that can act as a regulator of transcription and of translation. In chicken embryo fibroblasts transformed by the oncoproteins P3k (phosphatidylinositol 3-kinase) or Akt, YB-1 is transcriptionally down-regulated. Expression of YB-1 from a retroviral vector induces a strong cellular resistance to transformation by P3k or Akt but does not affect sensitivity to transformation by other oncoproteins, such as Src, Jun, or Qin. The YB-1-expressing cells assume a tightly adherent, flat phenotype, with YB-1 localized in the cytoplasm, and show a greatly reduced saturation density. Both cap-dependent and cap-independent translation is inhibited in these cells, but the activity of Akt remains unaffected, suggesting that YB-1 functions downstream of Akt. A YB-1 protein with a loss-of-function mutation in the RNA-binding motif no longer binds to the mRNA cap structure, is localized in the cell nucleus, does not induce the flat cellular phenotype, and fails to interfere with P3k- or Akt-induced oncogenic transformation. This mutant also does not inhibit cap-dependent or cap-independent translation. These results suggest that YB-1 acts like a rapamycin mimic, inhibiting translational events that are required in phosphatidylinositol 3-kinase-driven oncogenic transformation.
Highly specific zinc finger proteins obtained by directed domain shuffling and cell-based selection
Authors: Hurt Jessica A. , Thibodeau Stacey A. , Hirsh Andrew S. , Pabo Carl O. , Joung J. Keith
Published: October 2003

Engineered Cys
2
His
2
zinc finger proteins (ZFPs) can mediate regulation of endogenous gene expression in mammalian cells. Ideally, all zinc fingers in an engineered multifinger protein should be optimized concurrently because cooperative and context-dependent contacts can affect DNA recognition. However, the simultaneous selection of key contacts in even three fingers from fully randomized libraries would require the consideration of >10
24
possible combinations. To address this challenge, we have developed a novel strategy that utilizes directed domain shuffling and rapid cell-based selections. Unlike previously described methods, our strategy is amenable to scale-up and does not sacrifice combinatorial diversity. Using this approach, we have successfully isolated multifinger proteins with improved
in vitro
and
in vivo
function. Our results demonstrate that both DNA binding affinity and specificity are important for cellular function and also provide a general approach for optimizing multidomain proteins.
Targeted Inactivation of the IL-4 Receptor α Chain I4R Motif Promotes Allergic Airway Inflammation
Authors: Blaeser Frank , Bryce Paul J. , Ho Nga , Raman Vidya , Dedeoglu Fatma , Donaldson Debra D. , Geha Raif S. , Oettgen Hans C. , Chatila Talal A.
Published: October 2003

The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)Rα chain and transduces mitogenic signals in response to IL-4. Its physiological functions were analyzed in mice with a germline point mutation that changed the motif's effector tyrosine residue into phenylalanine (Y500F). The Y500F mutation abrogated IRS-2 phosphorylation and impaired IL-4–induced CD4+ T lymphocyte proliferation but left unperturbed Stat6 activation, up-regulation of IL-4-responsive gene products, and Th cell differentiation under Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveness, tissue eosinophilia, and mucus production. These results define an important role for the I4R motif in regulating allergic inflammation.
Prevention of Lipopolysaccharide-induced Microangiopathy by gp49B1
Authors: Zhou Joseph S. , Friend Daniel S. , Feldweg Anna M. , Daheshia Massoud , Li Lin , Austen K. Frank , Katz Howard R.
Published: October 2003

gp49B1 is expressed on mast cells and inhibits immunoglobulin E–dependent activation and inflammation in vivo. We now show that gp49B1 is expressed on neutrophils and prevents neutrophil-dependent vascular injury in response to lipopolysaccharide (LPS). The intradermal (i.d.) injection of LPS into gp49B1-null (gp49B−/−) but not gp49B1-sufficient (gp49B+/+) mice elicited macroscopic hemorrhages by 24 h, which were preceded on microscopic analyses by significantly more intravascular thrombi (consisting of neutrophils, platelets, and fibrin) that occluded venules and by more tissue neutrophils than in gp49B+/+ mice. However, there were no differences in the number of intact (nondegranulating) mast cells or the tissue levels of mediators that promote neutrophil recruitment. Hemorrhage was prevented by depleting neutrophils, blocking β2 integrin–intercellular adhesion molecule 1 interactions, or inhibiting coagulation. These characteristics indicate that gp49B−/− mice are exquisitely sensitive to a local Shwartzman reaction (LSR) after a single i.d. injection of LPS, whereas in the classic LSR, a second exposure is required for increased β2 integrin function, intravascular neutrophil aggregation, formation of occlusive thrombi, and hemorrhage. Moreover, LPS increased gp49B1 expression on neutrophils in vivo. The results suggest that gp49B1 suppresses the LPS-induced increase in intravascular neutrophil adhesion, thereby providing critical innate protection against a pathologic response to a bacterial component.
Sodium and Chloride Concentrations, pH, and Depth of Airway Surface Liquid in Distal Airways
Authors: Song Yuanlin , Thiagarajah Jay , Verkman A.S.
Published: October 2003

The composition and depth of the airway surface liquid (ASL) are key parameters in airway physiology that are thought to be important in the pathophysiology of cystic fibrosis and other diseases of the airways. We reported novel fluorescent indicator and microscopy methods to measure [Na+], [Cl−], pH, and depth of the ASL in large airways (Jayaraman, S., Y. Song, L. Vetrivel, L. Shankar, and A.S. Verkman. 2001. J. Clin. Invest. 107:317–324.). Here we report a stripped-lung preparation to measure ASL composition and depth in small distal airways. Distal ASL was stained with ion- or pH-sensitive fluorescent indicators by infusion into mouse trachea of a perfluorocarbon suspension of the indicator. After stripping the pleura and limited microdissection of the lung parenchyma, airways were exposed for measurement of ASL [Na+], [Cl−], and pH by ratio imaging microscopy, and depth by confocal microscopy. The stripped-lung preparation was validated in stability and tissue viability studies. ASL [Na+] was 122 ± 2 mM, [Cl−] was 123 ± 4 mM and pH was 7.28 ± 0.07, and not dependent on airway size (<100- to >250-μm diameter), ENaC inhibition by amiloride, or CFTR inhibition by the thiazolidinone CFTRinh-172. ASL depth was 8–35 μm depending on airway size, substantially less than that in mouse trachea of ∼55 μm, and not altered significantly by amiloride. These results establish a novel lung preparation and fluorescence approach to study distal airway physiology and provide the first data on the composition and depth of distal ASL.
Constitutive Activation of the Shaker Kv Channel
Authors: Sukhareva Manana , Hackos David H. , Swartz Kenton J.
Published: October 2003

In different types of K+ channels the primary activation gate is thought to reside near the intracellular entrance to the ion conduction pore. In the Shaker Kv channel the gate is closed at negative membrane voltages, but can be opened with membrane depolarization. In a previous study of the S6 activation gate in Shaker (Hackos, D.H., T.H. Chang, and K.J. Swartz. 2002. J. Gen. Physiol. 119:521–532.), we found that mutation of Pro 475 to Asp results in a channel that displays a large macroscopic conductance at negative membrane voltages, with only small increases in conductance with membrane depolarization. In the present study we explore the mechanism underlying this constitutively conducting phenotype using both macroscopic and single-channel recordings, and probes that interact with the voltage sensors or the intracellular entrance to the ion conduction pore. Our results suggest that constitutive conduction results from a dramatic perturbation of the closed-open equilibrium, enabling opening of the activation gate without voltage-sensor activation. This mechanism is discussed in the context of allosteric models for activation of Kv channels and what is known about the structure of this critical region in K+ channels.
Are There A Priori Concepts?
Authors: Austin J. L. , Urmson J. O. , Warnock G. J.
Published: October 2003

Austin discusses the existence, origin, and resemblance of concepts, primarily by discussing the meaning of ‘concept’ and ‘universal’. He argues that, although sometimes it may not be harmful to talk about concepts, we neither understand the meaning of ‘concept’, nor the meaning of ‘acquiring and possessing concepts’, nor a view of concept resemblance as non-sensuous acquaintance or awareness, challenging philosophers who couch their theories in such terms to illuminating them first.
How to Talk
Authors: Austin J. L. , Urmson J. O. , Warnock G. J.
Published: October 2003

Concerned with the question of whether descriptions of identity, i.e. describing X as Y, amount to the same as statements of identity, i.e. stating that X equals Y. Austin characteristically tackles this question by investigating into the nature of a number of relevant speech acts, such as ‘calling’, ‘describing’, and ‘stating’. He concludes negatively that none of the speech acts discussed can be safely used in philosophy in a general way. However, the construction of models of speech situations reveals their underlying complexity: such models are plainly too complicated to accommodate the standard subject-predicate or class-membership models that a straightforward answer to the question raised in this paper would depend on.
The Line and the Cave in Plato's Republic
Authors: Austin J. L. , Urmson J. O. , Warnock G. J.
Published: October 2003

A reconstruction based on previously unpublished notes, of Austin’s views of the Line and Cave allegories in Plato’s Republic. In these drafts, Austin discusses the prominent issues that arise in the context of Plato’s Line allegory, e.g. the questions of division and continuity, and shows how the different stages in the Cave allegory correspond to individual sections of the Line.
Form or contents? On the concept of social economy
Authors: Westlund Hans
Published: October 2003

This paper discusses the concept of social economy. Based on an economic‐historical perspective, reciprocity is seen as the fundamental principle for the social economy. In contrast to the “official” definitions, social economy is not restricted to only certain juridical forms. From the perspective outlined in this paper, social economy and commercial economy emerge not as opposite poles to each other but as parts of a continuous spectrum. Economic activities dominated by social objectives are also performed in other forms than the juridical forms of the social economy. Commercially‐dominated activities contain social elements as well. There are also many examples of social‐economic activities that expand, increase their commercialisation rate and subsequently are transformed to commercial enterprises. Studies on social features of the economy may thus be performed on a very wide field.
Managerial quality, administrative performance and trust in governance revisited
Authors: Vigoda‐Gadot Eran , Yuval Fany
Published: October 2003

Reports on a follow‐up study of the relationship between managerial quality, administrative performance and citizens’ trust in government and in public administration systems. The study was based on a survey of 502 Israeli citizens conducted during 2002 and was compared with a similar study that was conducted during 2001 among 345 Israeli citizens. The research tried to validate and replicate previous findings on the question of causality between performance and trust. As in the 2001 survey the technique of structural equation modeling with LISREL 8.3 was applied to test three competing models that were similar to those tested in the past. The present findings were very consistent with the previous ones found by the authors showing that the second model was the best fit with the data. According to this model managerial quality leads to administrative performance and ultimately to trust in governance. The findings support previous assumptions that administrative performance may be treated as a precondition to trust in governance rather than trust serving as the precondition to performance.
Patients’ satisfaction with nursing care in Jordan
Authors: Alasad Jafar A. , Ahmad Muayyad M.
Published: October 2003

This exploratory study investigated patients’ satisfaction with nursing care at a major teaching hospital in Jordan. A total of 266 in‐patients participated in the study. Patients were recruited from the medical, surgical, and gynecological wards. Pearson correlation, one‐way analysis of variance, and logistic regression analyses were used. The findings showed that patients in surgical wards had lower levels of satisfaction than patients in medical or gynecological wards. Gender, educational level, and having other diseases were significant predictors for patients’ satisfaction with nursing care. Methodological challenges, implications to nursing practice, and recommendations to nursing research are discussed.
Shopper characteristics, product and store choice criteria: a survey in the Greek grocery sector
Authors: Baltas George , Papastathopoulou Paulina
Published: October 2003

Considers the brand and store choice behaviour of grocery shoppers and explores relationships among consumer characteristics, brand choice criteria and store selection criteria. A survey was carried out to collect data on demographic profiles and decision criteria of shoppers in the Greek grocery sector. The data were collected through in‐store, personal interviews and subsequently analysed using descriptive as well as optimal scaling methods. The data reveal asymmetric evaluations of choice criteria and some clear and interesting patterns regarding the two choice processes. In addition, several associations between brand and store preferences are identified and related to specific demographic characteristics of the consumers. The present work is a first attempt at addressing these issues in the grocery Greek market and leaves considerable room for further research.
The five Ss of retail operations: a model and tool for improvement
Authors: Pal John W. , Byrom John W.
Published: October 2003

Reviews the academic and practitioner literature on retail operations and identifies five core elements of retail operations. Proposes a method by which managers can examine ways of improving their operations by the use of a modified cause‐effect technique. Provides worked examples of the technique.
Increasing efficiency in the supply chain for short shelf life goods using RFID tagging
Authors: Kärkkäinen Mikko
Published: October 2003

Short shelf‐life grocery goods present some of the biggest challenges for supply chain management due to a high number of product variants, strict traceability requirements, short shelf‐life of the products, the need for temperature control in the supply chain, and the large volume of goods handled. A Radio Frequency Identification (RFID) based data capture system can help solve the problems associated with the logistics of short shelf life products. This article discusses the potential of utilising RFID technology for increasing efficiency in the supply chain of short shelf life products. The focus of this article is a RFID trial conducted at Sainsbury’s, which is discussed to study the potential benefits of RFID for short shelf‐life products retailers. Further this article analyses the potential impact of RFID for other supply chain participants. We conclude that when applied with recyclable transport containers, RFID investments can provide quick amortisation of capital whilst offering a range of operational benefits.
The Chinese lodging industry: problems and solutions
Authors: Gu Zheng
Published: October 2003

Based on the operation results of Chinese hotels from 1991‐2000, this paper analyzes problems facing the Chinese lodging industry and proposes solutions. Chinese hotels’ performance, in terms of both revenue and profit, has been deteriorating since the early 1990s. While overcapacity has undoubtedly contributed to the poor performance, declining operation scale and low efficiency on the part of domestically‐owned hotels have aggravated the situation. To improve its operation results, the Chinese lodging industry should grow prudently, tap into the domestic tourist market, close the efficiency gap between domestic‐ownership and foreign‐ownership hotels and pursue economies of scale.
The development of sustainable tourism in the Guianas
Authors: Sinclair Donald , Jayawardena Chandana
Published: October 2003

The Tourism Studies Unit of the University of Guyana coordinated the 2003 World‐wide Hospitality and Tourism Trends (WHATT) Roundtable discussion of the Guianas. The discussion focused mainly on the requirements and challenges for developing sustainable tourism in Guyana and Surinam. The complexities involved in developing a joint approach to the development of sustainable tourism in a twin destination arrangement were discussed. The consensus of the roundtable was that commonalities existing in both the historical experience and tourism product of the Guianas make all the more imperative a sustainable tourism agenda for those territories. That agenda will have special meaning and significance in view of the existence of a territorial dispute involving Guyana and Surinam.
From theory to practice: using new science concepts to create learning organizations
Authors: Shelton Charlotte D. , Darling John R.
Published: October 2003

For the past ten years the management literature has increasingly discussed the concept of learning organizations. Yet, more that a decade later, few organizations have figured out how to create the structures and processes necessary to assure continuous learning. This article purports that this problem can be attributed to the mental models of those leading contemporary organizations. Learning organizations quite simply cannot be created by those who either consciously or unconsciously operate under the traditional, mechanistic organizational paradigm. If leaders are to create authentic learning organizations, they must adapt a new way of viewing reality – a new paradigm or mental model. The authors suggest that the new science theories of chaos, complexity, and quantum mechanics provide the foundation for a new way of thinking about organizations. They demonstrate the relevance of these theories for those who wish to create learning organizations and present a new‐science‐based skill set that enables twenty‐first‐century leaders to move beyond organizational adaptation to proactive change and continuous learning.
Natural Selection Doesn’t Work That Way: Jerry Fodor vs. Evolutionary Psychology on Gradualism and Saltationism
Authors: Ariew André
Published: October 2003

Abstract:  In Chapter Five of The Mind Doesn’t Work That Way, Jerry Fodor argues that since it is likely that human minds evolved quickly as saltations rather than gradually as the product of an accumulation of small mutations, evolutionary psychologists are wrong to think that human minds are adaptations. I argue that Fodor's requirement that adaptationism entails gradualism is wrongheaded. So, while evolutionary psychologists may be wrong to endorse gradualism—and I argue that they are wrong—it does not follow that they are wrong to endorse an adaptationist explanation for how the human mind evolved.
On Fodor's Problem
Authors: Carruthers Peter
Published: October 2003

Abstract: This paper sketches a solution to a problem which has been emphasized by Fodor. This is the problem of how to explain distinctively–human flexible cognition in modular terms. There are three aspects to the proposed account. First, it is suggested that natural language sentences might serve to integrate the outputs of a number of conceptual modules. Second, a creative sentence–generator, or supposer, is postulated. And third, it is argued that a set of principles of inference to the best explanation can be constructed from already–extant aspects of linguistic testimony and discourse interpretation. Most importantly, it is suggested that the resulting architecture should be implementable in ways that are computationally tractable.
Reviews
Authors: Noordhof Paul , Borg Emma
Published: October 2003

Books reviewed in this article:

Michael Tye, Consciousness, Color and Content

J. C. King, Complex Demonstratives: A Quantificational Account
What's in a name? Definitions and conceptualisations of teleworking and homeworking
Authors: Sullivan Cath
Published: October 2003

Interest in paid work performed in the home increasingly focuses on the concept of telework but debate over definitions continues. This paper discusses aspects of this debate and argues that project‐specific definitions are useful and inevitable. The assertion that a single definition should be used by all research in this area is challenged.
Knowledge work in distributed environments: issues and illusions
Authors: Pyöriä Pasi
Published: October 2003

Although Finland is one of the most advanced and competitive economies in the world, with a sophisticated technological infrastructure, only four per cent of Finnish wage earners regard themselves as doing telework, and a further four per cent had tried telework. Empirical evidence of telework is presented in this paper.
Controlling teleworkers: supervision and flexibility revisited
Authors: Dimitrova Dimitrina
Published: October 2003

This article revisits the issue of control and autonomy in telework using interviews with professional, managerial and sales teleworkers in a large Canadian telecommunications company. It finds that the changes in control and autonomy are limited to restructuring of the work schedules and the differences across teleworkers are reproduced.
Voter turnout dynamics in post‐Communist Europe
Authors: Kostadinova Tatiana
Published: October 2003

Abstract. Declining levels of turnout recently observed in some East European elections have generated concerns about the performance of the newly emerging democracies. Theories developed to explain turnout in industrialized democracies emphasize the importance of two major groups of factors: institutional and socioeconomic. This article argues that a comprehensive model of voter participation in post‐Communist settings should also include a dynamic component to account for temporal changes generated by the transitional process. I test a model of voter turnout that incorporates explanations of temporal (sequence of elections) and spatial differences (electoral system type, party system characteristics and economic development). Multivariate regression is used to estimate the model, with data from fifteen East European countries over four consecutive elections.
To defect or not to defect? National, institutional and party group pressures on MEPs and their consequences for party group cohesion in the European Parliament
Authors: Faas Thorsten
Published: October 2003

Abstract.This study analyzes party group cohesion and patterns of defections of national party delegations from party group lines in the European Parliament (EP), using a total of 2,582 roll call votes. The study confirms previous findings according to which party groups in the EP show (surprisingly) high levels of cohesion. Nevertheless, it reveals the circumstances under which Members of the EP (MEPs) and their national delegations are more likely to defect, using the candidate selection process, the electoral system and relationships between MEPs and their home parties as explanatory variables. Assuming that MEPs have three different goals (re‐election, office and policy), and want above all to secure re‐election, one can expect that those MEPs whose chances of re‐election are more dependent on national parties than others are more willing to vote against the party group line if a conflict between party group and national party emerges. Empirically, this is confirmed.
Determinants of Timeliness in Product Development
Authors: Cooper Robert G. , Kleinschmidt Elko J.
Published: October 2003

Speed to market is a compelling objective in new product development. Robert Cooper and Elko Kleinschmidt report the results of an extensive study of 103 new product projects in the chemical industry, with a particular emphasis on project timeliness. The key questions addressed in the study are: what are the drivers of an on‐time, fast‐paced project; and to what extent are timeliness and profitability connected? The strongest driver of project timeliness was the use of a cross‐functional, dedicated, accountable team, with a strong leader and top management support. Number two was solid up‐front or predevelopment homework, whereas building in the voice of the customer–a customer‐focused, market‐oriented new product effort–was the third key to on‐time, fast‐paced product development projects. In total, six drivers of project timeliness were uncovered. The authors expand on each timeliness driver, giving details of best practices in the projects and firms studied, as well as their recommendations to managers for driving products to market more quickly. There are some words of caution as well: the link between timeliness and profitability was also investigated, with some sobering and provocative results.
A Conjoint‐based Product Designing Procedure Incorporating Price Competition
Authors: Choi S. Chan , DeSarbo Wayne S.
Published: October 2003

Conjoint analysis has become a major tool in the process of designing and concept testing consumer packaged goods and industrial products. In most applications, however, product concepts are tested against existing sets of competing brands without considering potential competitive reactions. Although many researchers have recognized the need for models to incorporate competitive reactions, few methodological developments have been published thus far. Instead of what‐if analysis, which depends heavily on the managers' intuition about the competitors' reactions, S. Chan Choi and Wayne DeSarbo propose a game theoretic approach that models competing firms' reactions in price. This price reaction model is incorporated in the conjoint simulator for evaluating product concepts against competing brands. They illustrate the methodology using a commercial data set previously collected.
Factors Affecting the Process of Collaborative Product Development: A Study of UK Manufacturers of Information and Communications Technology Products
Authors: Littler Dale , Leverick Fiona , Bruce Margaret
Published: October 2003

Product development is inherently risky, particularly when new technology is involved. Although collaborative product development is promoted as a means for reducing or at least sharing risk, such partnerships present their own challenges. Collaboration can also accentuate many of the risks inherent in product development. For example, any product development project requires effective communication among development team members. In a collaborative effort, this challenge is even greater because the development team spans organizational as well as functional boundaries.

Dale Littler, Fiona Leverick, and Margaret Bruce describe the results of a survey that was conducted to identify the risks and benefits of collaborative product development as well as the key success factors for such relationships. The main reasons cited for collaborating on product development projects include satisfying customer requirements, taking advantage of market opportunities for which the firm lacks necessary skills and technical expertise, and responding to changes in technology. Other reasons for collaboration include reducing the cost and risk of product R&D, improving time to market, and gaining access to new markets.

In addition to the risks associated with product development by a single company, the partners in a collaborative effort face several other challenges. For example, one company might gain inside knowledge of its partner's unique skills and expertise. Despite the cost and time involved in managing the collaboration, such a relationship usually results in less direct control over product development. Of particular concern are the difficulties of coordinating the divergent management styles and budgeting processes of the collaborating firms.

Collaboration requires frequent communication among all involved parties. The likelihood of success is greatly enhanced by the presence of a product or collaboration champion. Other success factors include ensuring that partners contribute as expected, creating the perception of equal benefits among partners, and building trust between partners. Firms that are more experienced with collaboration also cite the importance of flexibility in corporate systems and management style, fit with existing businesses, and the choice of a partner.