bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification and proteomic profiling of exosomes in human urine
Authors: Pisitkun Trairak , Shen Rong-Fong , Knepper Mark A.
Published: August 2004

Urine provides an alternative to blood plasma as a potential source of disease biomarkers. One urinary biomarker already exploited in clinical studies is aquaporin-2. However, it remains a mystery how aquaporin-2 (an integral membrane protein) and other apical transporters are delivered to the urine. Here we address the hypothesis that these proteins reach the urine through the secretion of exosomes [membrane vesicles that originate as internal vesicles of multivesicular bodies (MVBs)]. Low-density urinary membrane vesicles from normal human subjects were isolated by differential centrifugation. ImmunoGold electron microscopy using antibodies directed to cytoplasmic or anticytoplasmic epitopes revealed that the vesicles are oriented “cytoplasmic-side inward,” consistent with the unique orientation of exosomes. The vesicles were small (<100 nm), consistent with studies of MVBs and exosomes from other tissues. Proteomic analysis of urinary vesicles through nanospray liquid chromatography-tandem mass spectrometry identified numerous protein components of MVBs and of the endosomal pathway in general. Full liquid chromatography-tandem MS analysis revealed 295 proteins, including multiple protein products of genes already known to be responsible for renal and systemic diseases, including autosomal dominant polycystic kidney disease, Gitelman syndrome, Bartter syndrome, autosomal recessive syndrome of osteopetrosis with renal tubular acidosis, and familial renal hypomagnesemia. The results indicate that exosome isolation may provide an efficient first step in biomarker discovery in urine.
pH-dependent transition between delocalized and trapped valence states of a Cu
A
center and its possible role in proton-coupled electron transfer
Authors: Hwang Hee Jung , Lu Yi
Published: August 2004

A pH-dependent transition between delocalized and trapped mixed valence states of an engineered Cu
A
center in azurin has been investigated by UV-visible absorption and electron paramagnetic resonance spectroscopic techniques. At pH 7.0, the Cu
A
azurin displays a typical delocalized mixed valence dinuclear [Cu(1.5)····Cu(1.5)] spectra with optical absorptions at 485, 530, and 760 nm, and with a seven-line EPR hyperfine. Upon lowering of the pH from 7.0 to 4.0, the absorption at 760 nm shifted to lower energy toward 810 nm, and a four-line EPR hyperfine, typical of a trapped valence, was observed. The pH-dependent transition is reversible because increasing the pH restores all delocalized spectral features. Lowering the pH resulted in not only a trapped valence state, but also a dramatically increased reduction potential of the Cu center (from 160 mV to 340 mV). Mutation of the titratable residues around the metal-binding site ruled out Glu-114 and identified the C-terminal histidine ligand (His-120) as a site of protonation, because the His120Ala mutation abolished the above pH-dependent transition. The corresponding histidine in cytochrome
c
oxidases is along a major electron transfer pathway from Cu
A
center to heme
a
. Because the protonation of this histidine can result in an increased reduction potential that will prevent electron flow from the Cu
A
to heme
a
, the Cu
A
and the histidine may play an important role in regulating proton-coupled electron transfer.
Simultaneous atomic force microscope and fluorescence measurements of protein unfolding using a calibrated evanescent wave
Authors: Sarkar Atom , Robertson Ragan B. , Fernandez Julio M.
Published: August 2004

Fluorescence techniques for monitoring single-molecule dynamics in the vertical dimension currently do not exist. Here we use an atomic force microscope to calibrate the distance-dependent intensity decay of an evanescent wave. The measured evanescent wave transfer function was then used to convert the vertical motions of a fluorescent particle into displacement (SD = <1 nm). We demonstrate the use of the calibrated evanescent wave to resolve the 20.1 ± 0.5-nm step increases in the length of the small protein ubiquitin during forced unfolding. The experiments that we report here make an important contribution to fluorescence microscopy by demonstrating the unambiguous optical tracking of a single molecule with a resolution comparable to that of an atomic force microscope.
Identification of an alternative ligand-binding pocket in the nuclear vitamin D receptor and its functional importance in 1α,25(OH)
2
-vitamin D
3
signaling
Authors: Mizwicki Mathew T. , Keidel Don , Bula Craig M. , Bishop June E. , Zanello Laura P. , Wurtz Jean-Marie , Moras Dino , Norman Anthony W.
Published: August 2004

Structural and molecular studies have shown that the vitamin D receptor (VDR) mediates 1α,25(OH)
2
-vitamin D
3
gene transactivation. Recent evidence indicates that both VDR and the estrogen receptor are localized to plasma membrane caveolae and are required for initiation of nongenomic (NG) responses. Computer docking of the NG-specific 1α,25(OH)
2
-lumisterol to the VDR resulted in identification of an alternative ligand-binding pocket that partially overlaps the genomic pocket described in the experimentally determined x-ray structure. Data obtained from docking five different vitamin D sterols in the genomic and alternative pockets were used to generate a receptor conformational ensemble model, providing an explanation for how VDR and possibly the estrogen receptor can have genomic and NG functionality. The VDR model is compatible with the following: (
i
) NG chloride channel agonism and antagonism; (
ii
) variable ligand-stabilized trypsin digest banding patterns; and (
iii
) differential transcriptional activity, employing different VDR point mutants and 1α,25(OH)
2
-vitamin D
3
analogs.
Feline immunodeficiency virus targets activated CD4
+
T cells by using CD134 as a binding receptor
Authors: de Parseval Aymeric , Chatterji Udayan , Sun Peiqing , Elder John H.
Published: August 2004

The major surface glycoprotein of feline immunodeficiency virus (FIV) specifically binds to a 43-kDa glycoprotein expressed on the surface of a subset of T cells in peripheral blood mononuclear cells and IL-2-dependent T cell lines. Binding to this molecule, in conjunction with CXC chemokine receptor (CXCR) 4, is required for productive infection of these cells by primary isolates of FIV. Here, we demonstrate that the 43-kDa molecule is CD134, a receptor for FIV recently identified independently [Shimojima, M.,
et al.
(2004)
Science
303, 1192-1195]. Furthermore, we show that CD134 is specifically up-regulated on CD4
+
T cells that have been activated by treatment with IL-2 and Con A. CD8
+
T cells remained negative for CD134 expression regardless of the activation state. Binding of the FIV major surface glycoprotein on activated CD4
+
T cells was observed through direct interaction with CD134 whereas, on activated CD8
+
T cells, the binding was CD134-independent and mediated by CXCR4 and, to a lesser extent, heparan sulfate proteoglycans. However, this CD134-independent interaction was not sufficient to render CD8
+
T cells permissive to FIV infection, as FIV replicated primarily in activated CD4
+
T cells and not in cells negative for CD134 expression. Altogether, our results substantiate that CD134 acts as a primary binding receptor for FIV and explain the specific targeting and depletion of the CD4
+
T cell population observed during the course of infection independent of the use of CD4 as a binding receptor/coreceptor.
Fitness costs and benefits of novel herbicide tolerance in a noxious weed
Authors: Baucom Regina S. , Mauricio Rodney
Published: August 2004

Glyphosate, the active ingredient in the herbicide RoundUp, has increased dramatically in use over the past decade and constitutes a potent anthropogenic source of selection. In the southeastern United States, weedy morning glories have begun to develop tolerance to glyphosate, representing a unique opportunity to examine the evolutionary genetics of a novel trait. We found genetic variation for tolerance, indicating the potential for the population to respond to selection by glyphosate. However, the following significant evolutionary constraint exists: in the absence of glyphosate, tolerant genotypes produced fewer seeds than susceptible genotypes. The combination of strong positive directional selection in the presence of glyphosate and strong negative directional selection in its absence may indicate that the selective landscape of land use could drive the evolutionary trajectory of glyphosate tolerance. Understanding these evolutionary forces is imperative for devising comprehensive management strategies to help slow the rate of the evolution of tolerance.
A Trim5-cyclophilin A fusion protein found in owl monkey kidney cells can restrict HIV-1
Authors: Nisole Sébastien , Lynch Clare , Stoye Jonathan P. , Yap Melvyn W.
Published: August 2004

Lv1 restriction of HIV-1 in the cells of Old World monkeys is associated with the expression of the Trim5 gene. Uniquely, in owl monkey kidney cells, HIV-1 restriction is dependent on the ability of incoming viral capsid protein to bind cyclophilin A (CypA). Cloning of the owl monkey Trim5 gene now reveals the presence of an inserted CypA pseudogene within intron 7 of the Trim5 gene. This insertion results in the formation of a chimeric Trim5-CypA transcript. Transfer of a cDNA corresponding to this transcript into human cells confers cyclosporin A-sensitive resistance to HIV-1 infection. The restriction factor appears to be a chimeric protein created by retrotransposon-mediated exon shuffling.
NMR structure and peptide hormone binding site of the first extracellular domain of a type B1 G protein-coupled receptor
Authors: Grace Christy R. R. , Perrin Marilyn H. , DiGruccio Michael R. , Miller Charleen L. , Rivier Jean E. , Vale Wylie W. , Riek Roland
Published: August 2004

The corticotropin-releasing factor (CRF) ligand family has diverse effects on the CNS, including the modulation of the stress response. The ligands' effects are mediated by binding to CRF G protein-coupled receptors. We have determined the 3D NMR structure of the N-terminal extracellular domain (ECD
1
) of the mouse CRF receptor 2β, which is the major ligand recognition domain, and identified its ligand binding site by chemical-shift perturbation experiments. The fold is identified as a short consensus repeat (SCR), a common protein interaction module. Mutagenesis reveals the integrity of the hormone-binding site in the full-length receptor. This study proposes that the ECD
1
captures the C-terminal segment of the ligand, whose N terminus then penetrates into the transmembrane region of the receptor to initiate signaling. Key residues of SCR in the ECD
1
are conserved in the G protein-coupled receptor subfamily, suggesting the SCR fold in all of the ECD
1
s of this subfamily.
Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein
Authors: Staprans Silvija I. , Barry Ashley P. , Silvestri Guido , Safrit Jeffrey T. , Kozyr Natalia , Sumpter Beth , Nguyen Hanh , McClure Harold , Montefiori David , Cohen Jeffrey I. , Feinberg Mark B.
Published: August 2004

Given the dual role of CD4 T cells as both immune effectors and targets for HIV infection, the balance of CD4 versus CD8 T cell-mediated responses induced by candidate AIDS vaccines may be critical in determining postvaccination infection outcomes. An attenuated recombinant varicella-zoster virus vaccine expressing the simian immunodeficiency virus (SIV) envelope (Env) elicited nonneutralizing Env-binding antibodies and little if any cytotoxic T lymphocyte responses in rhesus macaques (
Macaca mulatta
). After challenge with SIV, Env vaccinees manifested increased levels of SIV replication, more rapid CD4 depletion, and accelerated progression to AIDS compared with controls. Enhanced SIV replication correlated with increased CD4 T cell proliferation soon after SIV challenge, apparently the result of an anamnestic response to SIV antigens. Thus activation of virus-specific CD4 T cells at the time of exposure to a CD4 T cell-tropic lentivirus, in the absence of an effective CD8 response, may enhance virus replication and disease. These data suggest suggest that candidate AIDS vaccines may not simply be either efficacious or neutral; they may also have the potential to be harmful.
Comparative immunopeptidomics of humans and their pathogens
Authors: Istrail Sorin , Florea Liliana , Halldórsson Bjarni V. , Kohlbacher Oliver , Schwartz Russell S. , Yap Von Bing , Yewdell Jonathan W. , Hoffman Stephen L.
Published: August 2004

Major histocompatibility complex class I molecules present peptides of 8-10 residues to CD8+ T cells. We used 19 predicted proteomes to determine the influence of CD8+ T cell immune surveillance on protein evolution in humans and microbial pathogens by predicting immunopeptidomes, i.e., sets of class I binding peptides present in proteomes. We find that class I peptide binding specificities (i) have had little, if any, influence on the evolution of immunopeptidomes and (ii) do not take advantage of biases in amino acid distribution in proteins other than the concentration of hydrophobic residues in NH2-terminal leader sequences.
Effects of Q/N-rich, polyQ, and non-polyQ amyloids on thede novoformation of the [PSI+] prion in yeast and aggregation of Sup35in vitro
Authors: Derkatch Irina L. , Uptain Susan M. , Outeiro Tiago F. , Krishnan Rajaraman , Lindquist Susan L. , Liebman Susan W.
Published: August 2004

Prions are infectious protein conformations that are generally ordered protein aggregates. In the absence of prions, newly synthesized molecules of these same proteins usually maintain a conventional soluble conformation. However, prions occasionally arise even without a homologous prion template. The conformational switch that results in thede novoappearance of yeast prions with glutamine/aspargine (Q/N)-rich prion domains (e.g., [PSI+]), is promoted by heterologous prions with a similar domain (e.g., [RNQ+], also known as [PIN+]), or by overexpression of proteins with prion-like Q-, N-, or Q/N-rich domains. This finding led to the hypothesis that aggregates of heterologous proteins provide an imperfect template on which the new prion is seeded. Indeed, we show that newly forming Sup35 and preexisting Rnq1 aggregates always colocalize when [PSI+] appearance is facilitated by the [RNQ+] prion, and that Rnq1 fibers enhance thein vitroformation of fibers by the prion domain of Sup35 (NM). The proteins do not however form mixed, interdigitated aggregates. We also demonstrate that aggregating variants of the polyQ-containing domain of huntingtin promote thede novoconversion of Sup35 into [PSI+]; whereas nonaggregating variants of huntingtin and aggregates of non-polyQ amyloidogenic proteins, transthyretin, α-synuclein, and synphilin do not. Furthermore, transthyretin and α-synuclein amyloids do not facilitate NM aggregationin vitro, even though in [PSI+] cells NM and transthyretin aggregates also occasionally colocalize. Our data, especially thein vitroreproduction of the highly specific heterologous seeding effect, provide strong support for the hypothesis of cross-seeding in the spontaneous initiation of prion states.
Fishing down the coast: Historical expansion and collapse of oyster fisheries along continental margins
Authors: Kirby Michael Xavier
Published: August 2004

Estuarine ecosystems have changed dramatically from centuries of fishing, habitat disturbance, sedimentation, and nutrient loading. Degradation of oyster reefs by destructive fishing practices in particular has had a profound effect on estuarine ecology, yet the timing and magnitude of oyster-reef degradation in estuaries is poorly quantified. Here, I evaluate the expansion and collapse of oyster fisheries in 28 estuaries along three continental margins through the analysis of historical proxies derived from fishery records to infer when oyster reefs were degraded. Exploitation for oysters did not occur randomly along continental margins but followed a predictable pattern. Oyster fisheries expanded and collapsed in a linear sequence along eastern North America (
Crassostrea virginica
), western North America (
Ostreola conchaphila
), and eastern Australia (
Saccostrea glomerata
). Fishery collapse began in the estuaries that were nearest to a developing urban center before exploitation began to spread down the coast. As each successive fishery collapsed, oysters from more distant estuaries were fished and transported to restock exploited estuaries near the original urban center. This moving wave of exploitation traveled along each coastline until the most distant estuary had been reached and overfished.
Crystal structure of an oxygen-binding heme domain related to soluble guanylate cyclases
Authors: Pellicena Patricia , Karow David S. , Boon Elizabeth M. , Marletta Michael A. , Kuriyan John
Published: August 2004

Soluble guanylate cyclases are nitric oxide-responsive signaling proteins in which the nitric oxide sensor is a heme-binding domain of unknown structure that we have termed the heme-NO and oxygen binding (H-NOX) domain. H-NOX domains are also found in bacteria, either as isolated domains, or are fused through a membrane-spanning region to methyl-accepting chemotaxis proteins. We have determined the crystal structure of an oxygen-binding H-NOX domain of one such signaling protein from the obligate anaerobe
Thermoanaerobacter tengcongensis
at 1.77-Å resolution, revealing a protein fold unrelated to known structures. Particularly striking is the structure of the protoporphyrin IX group, which is distorted from planarity to an extent not seen before in protein-bound heme groups. Comparison of the structure of the H-NOX domain in two different crystal forms suggests a mechanism whereby alteration in the degree of distortion of the heme group is coupled to changes on the molecular surface of the H-NOX domain and potentially to changes in intermolecular interactions.
Observation of force-detected nuclear magnetic resonance in a homogeneous field
Authors: Madsen L. A. , Leskowitz G. M. , Weitekamp D. P.
Published: August 2004

We report the experimental realization of BOOMERANG (better observation of magnetization, enhanced resolution, and no gradient), a sensitive and general method of magnetic resonance. The prototype millimeter-scale NMR spectrometer shows signal and noise levels in agreement with the design principles. We present
1
H and
19
F NMR in both solid and liquid samples, including time-domain Fourier transform NMR spectroscopy, multiple-pulse echoes, and heteronuclear
J
spectroscopy. By measuring a
1
H-
19
F
J
coupling, this last experiment accomplishes chemically specific spectroscopy with force-detected NMR. In BOOMERANG, an assembly of permanent magnets provides a homogeneous field throughout the sample, while a harmonically suspended part of the assembly, a detector, is mechanically driven by spin-dependent forces. By placing the sample in a homogeneous field, signal dephasing by diffusion in a field gradient is made negligible, enabling application to liquids, in contrast to other force-detection methods. The design appears readily scalable to μm-scale samples where it should have sensitivity advantages over inductive detection with microcoils and where it holds great promise for application of magnetic resonance in biology, chemistry, physics, and surface science. We briefly discuss extensions of the BOOMERANG method to the μm and nm scales.
The myeloperoxidase product hypochlorous acid oxidizes HDL in the human artery wall and impairs ABCA1-dependent cholesterol transport
Authors: Bergt Constanze , Pennathur Subramaniam , Fu Xiaoyun , Byun Jaeman , O'Brien Kevin , McDonald Thomas O. , Singh Pragya , Anantharamaiah G. M. , Chait Alan , Brunzell John , Geary Randolph L. , Oram John F. , Heinecke Jay W.
Published: August 2004

Although oxidatively damaged lipoproteins are implicated in vascular injury, there is little information regarding the role of high-density lipoprotein (HDL) oxidation in atherogenesis. One potential pathway involves hypochlorous acid (HOCl) produced by myeloperoxidase (MPO), a heme protein secreted by phagocytes. We previously showed that 3-chlorotyrosine is a specific product of HOCl. Therefore, to explore the role of oxidized HDL in the pathogenesis of vascular disease, we used MS to quantify 3-chlorotyrosine in HDL isolated from plasma and atherosclerotic tissue. HDL from human aortic atherosclerotic intima had an 8-fold higher level of 3-chlorotyrosine than plasma HDL. Tandem MS analysis identified MPO as a component of lesion HDL, suggesting that the two interact in the artery wall. Moreover, immunohistochemical studies found that specific epitopes derived from HOCl colocalized with apolipoprotein A-I, the major protein of HDL. These observations strongly support the hypothesis that MPO promotes HDL oxidation in the human artery wall. Levels of 3-chlorotyrosine were elevated in HDL isolated from the blood of humans with established coronary artery disease, suggesting that circulating levels of oxidized HDL represent a unique marker for clinically significant atherosclerosis. HDL or lipid-free apolipoprotein A-I exposed to HOCl was less able to remove cholesterol from cultured cells by a pathway requiring the cell membrane transporter ATP-binding cassette transporter A1. The detection of 3-chlorotyrosine in HDL isolated from vascular lesions raises the possibility that MPO, by virtue of its ability to form HOCl, may promote atherogenesis by counteracting the established antiatherogenic effects of HDL and the ATP-binding cassette transporter A1 pathway.
Structure of heptameric protective antigen bound to an anthrax toxin receptor: A role for receptor in pH-dependent pore formation
Authors: Lacy D. Borden , Wigelsworth Darran J. , Melnyk Roman A. , Harrison Stephen C. , Collier R. John
Published: August 2004

After binding to cellular receptors and proteolytic activation, the protective antigen component of anthrax toxin forms a heptameric prepore. The prepore later undergoes pH-dependent conversion to a pore, mediating translocation of the edema and lethal factors to the cytosol. We describe structures of the prepore (3.6 Å) and a prepore:receptor complex (4.3 Å) that reveal the location of poreforming loops and an unexpected interaction of the receptor with the pore-forming domain. Lower pH is required for prepore-to-pore conversion in the presence of the receptor, indicating that this interaction regulates pH-dependent pore formation. We present an example of a receptor negatively regulating pH-dependent membrane insertion.
Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor
Authors: Kakoki Masao , Takahashi Nobuyuki , Jennette J. Charles , Smithies Oliver
Published: August 2004

Type I human diabetics and streptozotocin-induced diabetic mice with higher genetically determined levels of angiotensin-converting enzyme have an increased risk of developing nephropathy. However, previous experiments in mice and computer simulations indicate that modest increases in angiotensin-converting enzyme have minimal effects on blood pressure and angiotensin II levels, although bradykinin decreases significantly, inferring that bradykinin is critical for protecting the kidney in diabetics. Here, we confirm this inference by demonstrating that Akita diabetic mice lacking the bradykinin B2 receptor develop overt albuminuria, excreting the equivalent of >550 mg/day albumin in humans, which contrasts with the microalbuminuria (equivalent to <150 mg/day) seen in their simply diabetic littermates. The overt albuminuria is accompanied by a marked increase in glomerular mesangial sclerosis. The importance of bradykinin demonstrated here bears strongly on how current drugs reduce diabetic nephropathy and suggests that B2 receptor-specific agonists merit consideration in this context.
A transcriptional coactivator, AtGIF1, is involved in regulating leaf growth and morphology in
Arabidopsis
Authors: Kim Jeong Hoe , Kende Hans
Published: August 2004

Previously, we described the
AtGRF
[
Arabidopsis thaliana
growth-regulating factor (GRF)] gene family, which encodes putative transcription factors that play a regulatory role in growth and development of leaves and cotyledons. We demonstrate here that the C-terminal region of GRF proteins has transactivation activity. In search of partner proteins for GRF1, we identified another gene family, GRF-interacting factor (
GIF
), which comprises three members. Sequence and molecular analysis showed that GIF1 is a functional homolog of the human SYT transcription coactivator. We found that the N-terminal region of GIF1 protein was involved in the interaction with GRF1. To understand the biological function of GIF1, we isolated a loss-of-function mutant of
GIF1
and prepared transgenic plants subject to
GIF1
-specific RNA interference. Like
grf
mutants, the
gif1
mutant and transgenic plants developed narrower leaves and petals than did wild-type plants, and combinations of
gif1
and
grf
mutations showed a cooperative effect. The narrow leaf phenotype of
gif1
, as well as that of the
grf
triple mutant, was caused by a reduction in cell numbers along the leaf-width axis. We propose that GRF1 and GIF1 act as transcription activator and coactivator, respectively, and that they are part of a complex involved in regulating the growth and shape of leaves and petals.
Finding fusion genes resulting from chromosome rearrangement by analyzing the expressed sequence databases
Authors: Hahn Yoonsoo , Bera Tapan Kumar , Gehlhaus Kristen , Kirsch Ilan R. , Pastan Ira H. , Lee Byungkook
Published: August 2004

Chromosomal rearrangements resulting in gene fusions are frequently involved in carcinogenesis. Here, we describe a semiautomatic procedure for identifying fusion gene transcripts by using publicly available mRNA and EST databases. With this procedure, we have identified 96 transcript sequences that are derived from 60 known fusion genes. Also, 47 or more additional sequences appear to be derived from 20 or more previously unknown putative fusion genes. We have experimentally verified the presence of a previously unknownIRA1/RGS17fusion in the breast cancer cell line MCF7. The fusion gene encodes the full-length RGS17 protein, a regulator of G protein-coupled signaling, under the control of theIRA1gene promoter. This study demonstrates that databases of ESTs can be used to discover fusion genes resulting from structural rearrangement of chromosomes.
Managing Risk in Cross‐sector R&D Collaborations: Lessons From an International Case Study
Authors: COUCHMAN PAUL K. , FULOP LIZ
Published: August 2004

Cross‐sector collaborations to perform R&D are on the increase, but they do involve various risks for each of the partners. Project risks in such ventures are explored through a case study, a successful collaboration involving an Australian Cooperative Research Centre and Ciba Vision, a division of the Swiss multi‐national Novartis. The analysis examines the project's success factors and its risks. The reputation of researchers, the development of mutual trust among the partners, and the importance of credible commitments made at project initiation are three key factors contributing to the success of commercially focused R&D collaborations.
Success in Failure: The National Centre for Popular Music
Authors: KAM JACQUELINE
Published: August 2004

Management Studies would much rather deal with success than failure. Its treatment of failure is consequently peremptory, defining failure in simple, financial terms. Yet, failure is complex. This paper looks in detail at the case of the National Centre for Popular Music in Sheffield, England. Though the Centre was an unmitigated disaster, individual managers were still able to interpret the part each played as successful. Why was the project outcome so much less than the sum of these individual parts? The dynamics of failure are intriguing. Understanding them would seem to be essential to understanding what brings about success.
Universities and Communities: A Case Study of Change in the Management of a University
Authors: GUNASEKARA CHRYS
Published: August 2004

The role of universities has been evolving over the last 20 years, from a focus on teaching and research towards an enabling, partnership role with industry, government and communities in their proximate geographical spaces. Universities are increasingly linked to place. This paper reports on a case study of a peri‐urban Australian university that has chosen to link its identity with the development of its proximate communities. In doing so, a number of levers of change have been employed, amidst ‘push’ and ‘pull’ factors that have challenged the institutionalisation of change. The strategies employed by university managers have included: industry, government and community participation in university governance; a cooperative education programme; and changes to systems for promotion, performance and recognition. There have been a number of obstacles to change, some of which continue to beset the embedding of a focus on regional and community engagement. Although at a formative stage, this change is already showing promising results. The change levers employed provide some interesting insights for university managers, academic staff and students of organisational change, more generally.
Calcium-dependent regulation of the cell cycle via a novel MAPK–NF-κB pathway in Swiss 3T3 cells
Authors: Sée Violaine , Rajala Nina K.M. , Spiller David G. , White Michael R.H.
Published: August 2004

Nuclear factor kappa B (NF-κB) has been implicated in the regulation of cell proliferation and transformation. We investigated the role of the serum-induced intracellular calcium increase in the NF-κB–dependent cell cycle progression in Swiss 3T3 fibroblasts. Noninvasive photoactivation of a calcium chelator (Diazo-2) was used to specifically disrupt the transient rise in calcium induced by serum stimulation of starved Swiss 3T3 cells. The serum-induced intracellular calcium peak was essential for subsequent NF-κB activation (measured by real-time imaging of the dynamic p65 and IκBα fluorescent fusion proteins), cyclin D1 (CD1) promoter-directed transcription (measured by real-time luminescence imaging of CD1 promoter-directed firefly luciferase activity), and progression to cell division. We further showed that the serum-induced mitogen-activated protein kinase (MAPK) phosphorylation is calcium dependent. Inhibition of the MAPK- but not the PtdIns3K-dependent pathway inhibited NF-κB signaling, and further, CD1 transcription and cell cycle progression. These data suggest that a serum-dependent calcium signal regulates the cell cycle via a MAPK–NF-κB pathway in Swiss 3T3 cells.
Bro1 coordinates deubiquitination in the multivesicular body pathway by recruiting Doa4 to endosomes
Authors: Luhtala Natalie , Odorizzi Greg
Published: August 2004

Ubiquitination directs the sorting of cell surface receptors and other integral membrane proteins into the multivesicular body (MVB) pathway. Cargo proteins are subsequently deubiquitinated before their enclosure within MVB vesicles. In Saccharomyces cerevisiae, Bro1 functions at a late step of MVB sorting and is required for cargo protein deubiquitination. We show that the loss of Bro1 function is suppressed by the overexpression of DOA4, which encodes the ubiquitin thiolesterase required for the removal of ubiquitin from MVB cargoes. Overexpression of DOA4 restores cargo protein deubiquitination and sorting via the MVB pathway and reverses the abnormal endosomal morphology typical of bro1 mutant cells, resulting in the restoration of multivesicular endosomes. We further demonstrate that Doa4 interacts with Bro1 on endosomal membranes and that the recruitment of Doa4 to endosomes requires Bro1. Thus, our results point to a key role for Bro1 in coordinating the timing and location of deubiquitination by Doa4 in the MVB pathway.
On orbital partitions and exceptionality of primitive permutation groups
Authors: Guralnick R. , Li Cai , Praeger Cheryl , Saxl J.
Published: August 2004

LetGGandXXbe transitive permutation groups on a setΩ\Omegasuch thatGGis a normal subgroup ofXX. The overgroupXXinduces a natural action on the setOrbl⁡(G,Ω)\operatorname {Orbl}(G,\Omega )of non-trivial orbitals ofGGonΩ\Omega. In the study of Galois groups of exceptional covers of curves, one is led to characterizing the triples(G,X,Ω)(G,X,\Omega )whereXXfixes no elements ofOrbl⁡(G,Ω)\operatorname {Orbl}(G,\Omega ); such triples are calledexceptional. In the study of homogeneous factorizations of complete graphs, one is led to characterizing quadruples(G,X,Ω,P)(G,X,\Omega ,\mathcal {P})whereP\mathcal {P}is a partition ofOrbl⁡(G,Ω)\operatorname {Orbl}(G,\Omega )such thatXXis transitive onP\mathcal {P}; such a quadruple is called aTOD(transitive orbital decomposition). It follows easily that the triple(G,X,Ω)(G,X,\Omega )in a TOD(G,X,Ω,P)(G,X,\Omega ,\mathcal {P})is exceptional; conversely if an exceptional triple(G,X,Ω)(G,X,\Omega )is such thatX/GX/Gis cyclic of prime-power order, then there exists a partitionP\mathcal {P}ofOrbl⁡(G,Ω)\operatorname {Orbl}(G,\Omega )such that(G,X,Ω,P)(G,X,\Omega ,\mathcal {P})is a TOD. This paper characterizes TODs(G,X,Ω,P)(G,X,\Omega ,\mathcal {P})such thatXΩX^\Omegais primitive andX/GX/Gis cyclic of prime-power order. An application is given to the classification of self-complementary vertex-transitive graphs.
Blakers-Massey elements and exotic diffeomorphisms of 𝑆⁶ and 𝑆¹⁴ via geodesics
Authors: Durán C. , Mendoza A. , Rigas A.
Published: August 2004

We use the geometry of the geodesics of a certain left-invariant metric on the Lie group

S
p
(
2
)

Sp(2)

to find explicit related formulas for two topological objects: the Blakers-Massey element (a generator of

π
6

(

S
3

)

\pi _6(S^3)

) and an exotic (i.e. not isotopic to the identity) diffeomorphism of

S
6

S^6

(C. E. Durán, 2001). These formulas depend on two quaternions and their conjugates and we produce their extensions to the octonions through formulas for a generator of

π

14

(

S

7

)

\pi _{14}(S^{7})

and exotic diffeomorphisms of

S

14

S^{14}

, thus giving explicit gluing maps for half of the 15-dimensional exotic spheres expressed as the union of two 15-disks.
The Perron-Frobenius theorem for homogeneous, monotone functions
Authors: Gaubert Stéphane , Gunawardena Jeremy
Published: August 2004

If

A
A

is a nonnegative matrix whose associated directed graph is strongly connected, the Perron-Frobenius theorem asserts that

A
A

has an eigenvector in the positive cone,

(

R

+

)
n

(\mathbb R^{+})^n

. We associate a directed graph to any homogeneous, monotone function,

f
:
(

R

+

)
n

→
(

R

+

)
n

f: (\mathbb R^{+})^n \rightarrow (\mathbb R^{+})^n

, and show that if the graph is strongly connected, then

f
f

has a (nonlinear) eigenvector in

(

R

+

)
n

(\mathbb R^{+})^n

. Several results in the literature emerge as corollaries. Our methods show that the Perron-Frobenius theorem is “really” about the boundedness of invariant subsets in the Hilbert projective metric. They lead to further existence results and open problems.
Spectral properties and dynamics of quantized Henon maps
Authors: Weickert Brendan
Published: August 2004

We study a generalization of the Airy function, and use its properties to investigate the dynamics and spectral properties of the unitary operators on

L
2

(

R

)

L^2(\mathbf {R})

of the form

U
c

:=
F

e

i
(
q
(
x
)
+
c
x
)

U_c:=Fe^{i(q(x)+cx)}

, where

q
q

is a real polynomial of odd degree,

c
c

is a real number, and

F
F

is the Fourier transform. We show that

U
c

U_c

is a quantization of the classical Henon map
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartLayout 1st Row 1st Column f Subscript lamda Baseline colon bold upper R squared 2nd Column a m p semicolon right-arrow bold upper R squared comma left-parenthesis x comma y right-parenthesis 3rd Column a m p semicolon right-arrow from bar left-parenthesis y plus q prime left-parenthesis x right-parenthesis plus c comma negative x right-parenthesis comma EndLayout">

f
λ

:

R

2

a
m
p
;
→

R

2

,
(
x
,
y
)

a
m
p
;
↦
(
y
+

q
′

(
x
)
+
c
,
−
x
)
,

\begin{align*} f_\lambda :\mathbf {R}^2 &\to \mathbf {R}^2 , (x,y) &\mapsto (y+q’(x)+c,-x), \end{align*}

and show that for

c
>
0

c>0

sufficiently large,

U
c

U_c

has purely continuous spectrum. This fact has implications for the dynamics of

U
c

U_c

, which are shown to correspond when the condition is satisfied to the dynamics of its classical counterpart on

R

2

\mathbf {R}^2

.
Change of rings in deformation theory of modules
Authors: Ile Runar
Published: August 2004

Given a

B
B

-module

M
M

and any presentation

B
=
A

/

J

B=A/J

, the obstruction theory of

M
M

as a

B
B

-module is determined by the usual obstruction class

o

A

\mathrm {o}_{\! \scriptscriptstyle {A}}^{\scriptscriptstyle {}}

for deforming

M
M

as an

A
A

-module and a new obstruction class

o

J

\mathrm {o}_{\! \scriptscriptstyle {J}}^{\scriptscriptstyle {}}

 . These two classes give the tool for constructing two obstruction maps which depend on each other and which characterise the hull of the deformation functor. We obtain relations between the obstruction classes by studying a change of rings spectral sequence and by representing certain classes as elements in the Yoneda complex. Calculation of the deformation functor of

M
M

as a

B
B

-module, including the (generalised) Massey products, is thus possible within any

A
A

-free

2
2

-presentation of

M
M

.
A local limit theorem for closed geodesics and homology
Authors: Sharp Richard
Published: August 2004

In this paper, we study the distribution of closed geodesics on a compact negatively curved manifold. We concentrate on geodesics lying in a prescribed homology class and, under certain conditions, obtain a local limit theorem to describe the asymptotic behaviour of the associated counting function as the homology class varies.
Characterizations of regular almost periodicity in compact minimal abelian flows
Authors: Miller Alica , Rosenblatt Joseph
Published: August 2004

Regular almost periodicity in compact minimal abelian flows was characterized for the case of discrete acting group by W. Gottschalk and G. Hedlund and for the case of

0
0

-dimensional phase space by W. Gottschalk a few decades ago. In 1995 J. Egawa gave characterizations for the case when the acting group is

R

\mathbb {R}

. We extend Egawa’s results to the case of an arbitrary abelian acting group and a not necessarily metrizable phase space. We then show how our statements imply previously known characterizations in each of the three special cases and give various other applications (characterization of regularly almost periodic functions on arbitrary abelian topological groups, classification of uniformly regularly almost periodic compact minimal

Z

\mathbb {Z}

- and

R

\mathbb {R}

-flows, conditions equivalent with uniform regular almost periodicity, etc.).
Expansiveness of algebraic actions on connected groups
Authors: Bhattacharya Siddhartha
Published: August 2004

We study endomorphism actions of a discrete semigroup

Γ
\Gamma

on a connected group

G
G

. We give a necessary and sufficient condition for expansiveness of such actions provided

G
G

is either a Lie group or a solenoid.
Global Strichartz estimates for solutions to the wave equation exterior to a convex obstacle
Authors: Metcalfe Jason
Published: August 2004

In this paper, we show that certain local Strichartz estimates for solutions of the wave equation exterior to a convex obstacle can be extended to estimates that are global in both space and time. This extends the work that was done previously by H. Smith and C. Sogge in odd spatial dimensions. In order to prove the global estimates, we explore weighted Strichartz estimates for solutions of the wave equation when the Cauchy data and forcing term are compactly supported.
Geometric aspects of frame representations of abelian groups
Authors: Aldroubi Akram , Larson David , Tang Wai-Shing , Weber Eric
Published: August 2004

We consider frames arising from the action of a unitary representation of a discrete countable abelian group. We show that the range of the analysis operator can be determined by computing which characters appear in the representation. This allows one to compare the ranges of two such frames, which is useful for determining similarity and also for multiplexing schemes. Our results then partially extend to Bessel sequences arising from the action of the group. We apply the results to sampling on bandlimited functions and to wavelet and Weyl-Heisenberg frames. This yields a sufficient condition for two sampling transforms to have orthogonal ranges, and two analysis operators for wavelet and Weyl-Heisenberg frames to have orthogonal ranges. The sufficient condition is easy to compute in terms of the periodization of the Fourier transform of the frame generators.
Complete second order linear differential operator equations in Hilbert space and applications in hydrodynamics
Authors: Kopachevsky N. , Mennicken R. , Pashkova Ju. , Tretter C.
Published: August 2004

We study the Cauchy problem for a complete second order linear differential operator equation in a Hilbert space

H

{\mathcal H}

of the form
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartFraction d squared u Over d t squared EndFraction plus left-parenthesis upper F plus i upper K right-parenthesis StartFraction d u Over d t EndFraction plus upper B u equals f comma u left-parenthesis 0 right-parenthesis equals u Superscript 0 Baseline comma u prime left-parenthesis 0 right-parenthesis equals u Superscript 1 Baseline period">

d
2

u

d

t
2

+
(
F
+

i

K
)

d
u

d
t

+
B
u
=
f
,

u
(
0
)
=

u
0

,

u
′

(
0
)
=

u
1

.

\frac {d^2u}{dt^2}+(F+\textrm {i}K)\frac {du}{dt}+Bu=f,\quad u(0)=u^0, \quad u’(0)=u^1.

\]
Problems of this kind arise, e.g., in hydrodynamics where the coefficients

F
F

,

K
K

, and

B
B

are unbounded selfadjoint operators. It is assumed that

F
F

is the dominating operator in the Cauchy problem above, i.e.,
\[
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="script upper D left-parenthesis upper F right-parenthesis subset-of script upper D left-parenthesis upper B right-parenthesis comma script upper D left-parenthesis upper F right-parenthesis subset-of script upper D left-parenthesis upper K right-parenthesis period">

D

(
F
)
⊂

D

(
B
)
,

D

(
F
)
⊂

D

(
K
)
.

{\mathcal D}(F)\subset {\mathcal D}(B),\quad {\mathcal D}(F)\subset {\mathcal D}(K).

\]
We also suppose that

F
F

and

B
B

are bounded from below, but the operator coefficients are not assumed to commute. The main results concern the existence of strong solutions to the stated Cauchy problem and applications of these results to the Cauchy problem associated with small motions of some hydrodynamical systems.
Second order parabolic equations in Banach spaces with dynamic boundary conditions
Authors: Xiao Ti-Jun , Liang Jin
Published: August 2004

In this paper, we exhibit a unified treatment of the mixed initial boundary value problem for second order (in time) parabolic linear differential equations in Banach spaces, whose boundary conditions are of a dynamical nature. Results regarding existence, uniqueness, continuous dependence (on initial data) and regularity of classical and strict solutions are established. Moreover, several examples are given as samples for possible applications.
On peak-interpolation manifolds for 𝐴(Ω) for convex domains in ℂ^{𝕟}
Authors: Bharali Gautam
Published: August 2004

Let

Ω
\Omega

be a bounded, weakly convex domain in

C

n

{\mathbb {C}}^n

,

n
≥
2

n\geq 2

, having real-analytic boundary.

A
(
Ω
)

A(\Omega )

is the algebra of all functions holomorphic in

Ω
\Omega

and continuous up to the boundary. A submanifold

M
⊂
∂
Ω

\boldsymbol {M}\subset \partial \Omega

is said to be complex-tangential if

T
p

(
M
)

T_p(\boldsymbol {M})

lies in the maximal complex subspace of

T
p

(
∂
Ω
)

T_p(\partial \Omega )

for each

p
∈
M

p\in \boldsymbol {M}

. We show that for real-analytic submanifolds

M
⊂
∂
Ω

\boldsymbol {M}\subset \partial \Omega

, if

M
\boldsymbol {M}

is complex-tangential, then every compact subset of

M
\boldsymbol {M}

is a peak-interpolation set for

A
(
Ω
)

A(\Omega )

.
An analogue of continued fractions in number theory for Nevanlinna theory
Authors: Ye Zhuan
Published: August 2004

We show an analogue of continued fractions in approximation to irrational numbers by rationals for Nevanlinna theory. The analogue is a sequence of points in the complex plane which approaches a given finite set of points and at a given rate in the sense of Nevanlinna theory.
Acute Vigabatrin Retinotoxicity in Albino Rats Depends on Light But Not GABA
Authors: Izumi Yukitoshi , Ishikawa Makoto , Benz Ann M. , Izumi Masayo , Zorumski Charles F. , Thio Liu Lin
Published: August 2004

Summary:  Purpose: Vigabatrin (VGB) is an irreversible inhibitor of γ‐aminobutyric acid (GABA) transaminase. Its use as an antiepileptic drug (AED) has been limited because it causes retinal dysfunction, leading to visual field defects (VFDs). We performed this study to identify factors contributing to acute VGB retinotoxicity.

Methods: In ex vivo experiments, Sprague–Dawley rat retinas were isolated and incubated with VGB or GABA in the presence or absence of light. In in vivo experiments, Sprague–Dawley rats were given intraperitoneal injections of VGB and then exposed to light or kept in the dark. The retinas were analyzed histologically by using both light and electron microscopy.

Results: Incubating retinas with 50–500 μM VGB under 20,000 Lux white light for ≤20 h caused a characteristic time‐ and dose‐dependent degeneration limited to the outer retina. Incubating retinas with 500 μM VGB in darkness for 20 h caused no damage. Five hundred micromolar GABA and 50 μM tiagabine were not toxic in the presence or absence of light. Sprague–Dawley rats exposed to an intense white light for 20 h after a 1,000‐mg/kg intraperitoneal injection of VGB showed damage in the outer retina, whereas those kept in the dark did not.

Conclusions: Direct exposure of the retina to VGB causes acute retinotoxicity that depends on light exposure rather than GABA accumulation.
A Novel Nonpharmacologic Treatment for Photosensitive Epilepsy: A Report of Three Patients Tested with Blue Cross‐polarized Glasses
Authors: Kepecs Migdana R. , Boro Alex , Haut Sheryl , Kepecs Gilbert , Moshé Solomon L.
Published: August 2004

Summary: Purpose:Pharmacotherapy for photosensitive epilepsy is not always effective and is associated with well‐recognized toxicities. Nonpharmacologic approaches to the management of photosensitive epilepsy have included the use of sunglasses of various types. Blue lenses have been shown to suppress the photoparoxysmal response more effectively than lenses of other colors with similar overall transmittances. Recently, cross‐polarized glasses have shown promise. The axes of polarization of the two lenses of such glasses are perpendicular to one another. We tested the effect of combining the use of blue and cross‐polarized lenses in three patients with photosensitive epilepsy.

Methods:We recorded the EEG response to photic stimulation, television screens, and computer monitors in three patients with photosensitive epilepsy. If photoparoxysmal responses were provoked in any of these scenarios, testing was repeated with the patient wearing nonpolarized, parallel‐polarized, and blue cross‐polarized sunglasses.

Results:One of our patients had clinical seizures that were inadequately suppressed with moderate doses of valproate (VPA) but completely suppressed with blue cross‐polarized lenses. The second patient's photoparoxysmal response was suppressed by both parallel‐polarized and blue cross‐polarized glasses, whereas the third patient's photoparoxysmal response was not suppressed by either.

Conclusions:These preliminary data suggest that blue cross‐polarized lenses may be useful in the treatment of photosensitive epilepsies and that their efficacy can be predicted in the EEG laboratory.