bluuebunny/crossref_metadata_2025 huggingface dataset:
A computational/functional genomics approach for the enrichment of the retinal transcriptome and the identification of positional candidate retinopathy genes
Authors: Katsanis Nicholas , Worley Kim C. , Gonzalez Guillermo , Ansley Stephen J. , Lupski James R.
Published: October 2002

Grouping genes by virtue of their sequence similarity, functional association, or spatiotemporal distribution is an important first step in investigating function. Given the recent identification of >30,000 human genes either by analyses of genomic sequence or by derivation/assembly of ESTs, automated means of discerning gene function and association with disease are critical for the efficient processing of this large volume of data. We have designed a series of computational tools to manipulate the EST sequence database (dbEST) to predict EST clusters likely representing genes expressed exclusively or preferentially in a specific tissue. We implemented this tool by extracting 40,000 human retinal ESTs and performing
in silico
subtraction against 1.4 million human ESTs. This process yielded 925 ESTs likely to be specifically or preferentially expressed in the retina. We mapped all retinal-specific/predominant sequences in the human genome and produced a web-based searchable map of the retina transcriptome, onto which we overlaid the positions of all mapped but uncloned retinopathy genes. This resource has provided positional candidates for 42 of 51 uncloned retinopathies and may expedite substantially the identification of disease-associated genes. More importantly, the ability to systematically group ESTs according to their predicted expression profile is likely to be an important resource for studying gene function in a wide range of tissues and physiological systems and to identify positional candidate genes for human disorders whose phenotypic manifestations are restricted to specific tissues/organs/cell types.
Alleles at the
Nicastrin
locus modify presenilin 1- deficiency phenotype
Authors: Rozmahel Richard , Mount Howard T. J. , Chen Fusheng , Nguyen Van , Huang Jean , Erdebil Serap , Liauw Jennifer , Yu Gang , Hasegawa Hiroshe , Gu YongJun , Song You-Qiang , Schmidt Stephen D. , Nixon Ralph A. , Mathews Paul M. , Bergeron Catherine , Fraser Paul , Westaway David , St George-Hyslop Peter
Published: October 2002

Presenilin 1 (PS1), presenilin 2, and nicastrin form high molecular weight complexes that are necessary for the endoproteolysis of several type 1 transmembrane proteins, including amyloid precursor protein (APP) and the Notch receptor, by apparently similar mechanisms. The cleavage of the Notch receptor at the “S3-site” releases a C-terminal cytoplasmic fragment (Notch intracellular domain) that acts as the intracellular transduction molecule for Notch activation. Missense mutations in the presenilins cause familial Alzheimer's disease by augmenting the “γ-secretase” cleavage of APP and overproducing one of the proteolytic derivatives, the Aβ peptide. Null mutations in PS1 inhibit both γ-secretase cleavage of APP and S3-site cleavage of the Notch receptor. Mice lacking PS1 function have defective Notch signaling and die perinatally with severe skeletal and brain deformities. We report here that a genetic modifier on mouse distal chromosome 1, coinciding with the locus containing
Nicastrin
, influences presenilin-mediated Notch S3-site cleavage and the resultant
Notch
phenotype without affecting presenilin-mediated APP γ-site cleavage. Two missense substitutions of residues conserved among vertebrates have been identified in nicastrin. These results indicate that Notch S3-site cleavage and APP γ-site cleavage are distinct presenilin-dependent processes and support a functional interaction between nicastrin and presenilins in vertebrates. The dissociation of Notch S3-site and APP γ-site cleavage activities will facilitate development of γ-secretase inhibitors for treatment of Alzheimer's disease.
Cofactors of serine racemase that physiologically stimulate the synthesis of the
N
-methyl-
d
-aspartate (NMDA) receptor coagonist
d
-serine
Authors: de Miranda Joari , Panizzutti Rogerio , Foltyn Veronika N. , Wolosker Herman
Published: October 2002

High levels of
d
-serine occur in the brain, challenging the notion that
d
-amino acids would not be present or play a role in mammals.
d
-serine levels in the brain are even higher than many
l
-amino acids, such as asparagine, valine, isoleucine, and tryptophan, among others.
d
-serine is synthesized by a serine racemase (SR) enzyme, which directly converts
l
- to
d
-serine. We now report that SR is a bifunctional enzyme, producing both
d
-serine and pyruvate in cultured cells and
in vitro
. Transfection of SR into HEK 293 cells elicits synthesis of
d
-serine and augmented release of pyruvate to culture media. We identified substances present in HEK 293 and astrocyte cell extracts that strongly stimulate
d
-serine production by SR and elicit production of pyruvate. Experiments with recombinant enzyme reveal that Mg
2+
and ATP present in the cell extracts are physiological cofactors and increase 5- to 10-fold the rates of racemization and production of pyruvate. As much as three molecules of pyruvate are synthesized for each molecule of
d
-serine produced by SR. This finding constitutes a previously undescribed mechanism underlying
d
-amino acid synthesis in mammals, different from classical amino acid racemases present in bacteria. Our data link the production of
d
-serine to the energy metabolism, with implications for the metabolic and transmitter crosstalk between glia and neurons.
Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease
Authors: Urbanc B. , Cruz L. , Le R. , Sanders J. , Ashe K. Hsiao , Duff K. , Stanley H. E. , Irizarry M. C. , Hyman B. T.
Published: October 2002

Despite extensive deposition of putatively neurotoxic amyloid-β (Aβ) protein in the brain, it has not been possible to demonstrate an association of Aβ deposits with neuronal loss in Alzheimer's disease (AD), and neuronal loss is minimal in transgenic mouse models of AD. Using triple immunostaining confocal microscopy and analyzing the images with the cross-correlation density map method from statistical physics, we directly compared Aβ deposition, Aβ morphology, and neuronal architecture. We found dramatic, focal neuronal toxicity associated primarily with thioflavin S-positive fibrillar Aβ deposits in both AD and PSAPP mice. These results, along with computer simulations, suggest that Aβ develops neurotoxic properties
in vivo
when it adopts a fibrillar β-pleated sheet conformation.
Glucose is toxic to glycosome-deficient trypanosomes
Authors: Furuya Tetsuya , Kessler Peter , Jardim Armando , Schnaufer Achim , Crudder Christopher , Parsons Marilyn
Published: October 2002

Trypanosomatids, the etiologic agents of sleeping sickness, leishmaniasis, and Chagas' disease, compartmentalize glycolysis within glycosomes, metabolic organelles related to peroxisomes. Here, we identify a trypanosome homologue of PEX14, one of the components of the peroxisomal protein import docking complex. We have used double-stranded RNA interference to target the PEX14 transcript for degradation. Glycosomal matrix protein import was compromised, and both glycolytic bloodstream stage parasites and mitochondrially respiring procyclic stage parasites were killed. Thus, unlike peroxisomes, glycosomes are essential organelles. Surprisingly, procyclic forms, which can grow in the absence of glucose, were killed byPEX14RNA interference only when simple sugars were present. Thus, interference with glycosome protein import makes glucose toxic to trypanosomes.
A polyketide synthase-peptide synthetase gene cluster from an uncultured bacterial symbiont of
Paederus
beetles
Authors: Piel Jörn
Published: October 2002

Many drug candidates from marine and terrestrial invertebrates are suspected metabolites of uncultured bacterial symbionts. The antitumor polyketides of the pederin family, isolated from beetles and sponges, are an example. Drug development from such sources is commonly hampered by low yields and the difficulty of sustaining invertebrate cultures. To obtain insight into the true producer and find alternative supplies of these rare drug candidates, the putative pederin biosynthesis genes were cloned from total DNA of
Paederus fuscipes
beetles, which use this compound for chemical defense. Sequence analysis of the gene cluster and adjacent regions revealed the presence of ORFs with typical bacterial architecture and homologies. The
ped
cluster, which is present only in beetle specimens with high pederin content, is located on a 54-kb region bordered by transposase pseudogenes and encodes a mixed modular polyketide synthase/nonribosomal peptide synthetase. Notably, none of the modules contains regions with homology to acyltransferase domains, but two copies of isolated monodomain acyltransferase genes were found at the upstream end of the cluster. In line with an involvement in pederin biosynthesis, the upstream cluster region perfectly mirrors pederin structure. The unexpected presence of additional polyketide synthase/nonribosomal peptide synthetase modules reveals surprising insights into the evolutionary relationship between pederin-type pathways in beetles and sponges.
Molecular evidence of HIV-1 transmission in a criminal case
Authors: Metzker Michael L. , Mindell David P. , Liu Xiao-Mei , Ptak Roger G. , Gibbs Richard A. , Hillis David M.
Published: October 2002

A gastroenterologist was convicted of attempted second-degree murder by injecting his former girlfriend with blood or blood-products obtained from an HIV type 1 (HIV-1)-infected patient under his care. Phylogenetic analyses of HIV-1 sequences were admitted and used as evidence in this case, representing the first use of phylogenetic analyses in a criminal court case in the United States. Phylogenetic analyses of HIV-1 reverse transcriptase and
env
DNA sequences isolated from the victim, the patient, and a local population sample of HIV-1-positive individuals showed the victim's HIV-1 sequences to be most closely related to and nested within a lineage comprised of the patient's HIV-1 sequences. This finding of paraphyly for the patient's sequences was consistent with the direction of transmission from the patient to the victim. Analysis of the victim's viral reverse transcriptase sequences revealed genotypes consistent with known mutations that confer resistance to AZT, similar to those genotypes found in the patient.
A priori
establishment of the patient and victim as a suspected transmission pair provided a clear hypothesis for phylogenetic testing. All phylogenetic models and both genes examined strongly supported the close relationship between the HIV-1 sequences of the patient and the victim. Resampling of blood from the suspected transmission pair and independent sequencing by different laboratories provided precaution against laboratory error.
Functional characterization and immunolocalization of the transporter encoded by the life-extending gene
Indy
Authors: Knauf Felix , Rogina Blanka , Jiang Zhirong , Aronson Peter S. , Helfand Stephen L.
Published: October 2002

Caloric restriction extends life span in a variety of species, highlighting the importance of energy balance in aging. A new longevity gene,
Indy
(for
I'm not dead yet
), which doubles the average life span of flies without a loss of fertility or physical activity, was postulated to extend life by affecting intermediary metabolism. We report that functional studies in
Xenopus
oocytes show INDY is a metabolite transporter that mediates the high-affinity, disulfonic stilbene-sensitive flux of dicarboxylates and citrate across the plasma membrane by a mechanism that is not coupled to Na
+
, K
+
, or Cl
−
. Immunocytochemical studies localize INDY to the plasma membrane with most prominent expression in adult fat body, oenocytes, and the basolateral region of midgut cells and show that life-extending mutations in
Indy
reduce INDY expression. We conclude that INDY functions as a novel sodium-independent mechanism for transporting Krebs and citric acid cycle intermediates through the epithelium of the gut and across the plasma membranes of organs involved in intermediary metabolism and storage. The life-extending effect of mutations in
Indy
is likely caused by an alteration in energy balance caused by a decrease in INDY transport function.
Glycosaminoglycans are a potential cause of rheumatoid arthritis
Authors: Wang Julia Y. , Roehrl Michael H.
Published: October 2002

Rheumatoid arthritis (RA) is a chronic, systemic, and inflammatory disease of connective tissue with unknown etiology. We investigated whether aberrant immune responses to glycosaminoglycans (GAGs), a major component of joint cartilage, joint fluid, and other soft connective tissue, causes this disease. Here we show that injection of GAGs such as hyaluronic acid, heparin, and chondroitin sulfates A, B, and C induce arthritis, tendosynovitis, dermatitis, and other pathological conditions in mice. We developed a technique by staining tissue specimens with fluorochrome- or biotin-labeled GAGs to visualize the direct binding between cells and GAGs. We discovered that inflammatory infiltrates from the affected tissue are dominated by a distinct phenotype of GAG-binding cells, a significant portion of which are CD4+T cells. GAG-binding cells seem to be expanded in bone marrow of GAG-immunized mice. Furthermore, we identified GAG-binding cells in inflamed synovial tissue of human patients with RA. Our findings suggest that carbohydrate self-antigenic GAGs provoke autoimmune dysfunctions that involve the expansion of GAG-binding cells which migrate to anatomical sites rich in GAGs. These GAG-binding cells might, in turn, promote the inflammation and pathology seen both in our murine model and in human RA.
The role of ipsilateral premotor cortex in hand movement after stroke
Authors: Johansen-Berg Heidi , Rushworth Matthew F. S. , Bogdanovic Marko D. , Kischka Udo , Wimalaratna Sunil , Matthews Paul M.
Published: October 2002

Movement of an affected hand after stroke is associated with increased activation of ipsilateral motor cortical areas, suggesting that these motor areas in the undamaged hemisphere may adaptively compensate for damaged or disconnected regions. However, this adaptive compensation has not yet been demonstrated directly. Here we used transcranial magnetic stimulation (TMS) to interfere transiently with processing in the ipsilateral primary motor or dorsal premotor cortex (PMd) during finger movements. TMS had a greater effect on patients than controls in a manner that depended on the site, hemisphere, and time of stimulation. In patients with right hemiparesis (but not in healthy controls), TMS applied to PMd early (100 ms) after the cue to move slowed simple reaction-time finger movements by 12% compared with controls. The relative slowing of movements with ipsilateral PMd stimulation in patients correlated with the degree of motor impairment, suggesting that functional recruitment of ipsilateral motor areas was greatest in the more impaired patients. We also used functional magnetic resonance imaging to monitor brain activity in these subjects as they performed the same movements. Slowing of reaction time after premotor cortex TMS in the patients correlated inversely with the relative hemispheric lateralization of functional magnetic resonance imaging activation in PMd. This inverse correlation suggests that the increased activation in ipsilateral cortical motor areas during movements of a paretic hand, shown in this and previous functional imaging studies, represents a functionally relevant, adaptive response to the associated brain injury.
Expression of colony-stimulating factor 1 receptor during prostate development and prostate cancer progression
Authors: Ide Hisamitsu , Seligson David B. , Memarzadeh Sanaz , Xin Li , Horvath Steve , Dubey Purnima , Flick Maryann B. , Kacinski Barry M. , Palotie Aarno , Witte Owen N.
Published: October 2002

Colony-stimulating factor-1 receptor (CSF-1R) is the major regulator of macrophage development and is associated with epithelial cancers of the breast and ovary. Immunohistochemistry analysis of murine prostate development demonstrated epithelial expression of CSF-1R during the protrusion of prostatic buds from the urogenital sinus, during the prepubertal and androgen-driven proliferative expansion and branching of the gland, with a decline in older animals. Models of murine prostate cancer showed CSF-1R expression in areas of carcinoma- and tumor-associated macrophages. Several human prostate cancer cell lines and primary cultures of human prostate epithelial cells had low but detectable levels of CSF-1R. Human prostatectomy samples showed low or undetectable levels of receptor in normal glands or benign prostatic hypertrophy specimens. Staining was strongest in areas of prostatic intraepithelial neoplasia or carcinoma of Gleason histological grade 3 or 4. The activated form of the receptor reactive with antibodies specific for phosphotyrosine modified peptide sequences was observed in samples of metastatic prostate cancer. Immunohistochemistry showed strong expression of CSF-1R by macrophage lineage cells, including villous macrophages and the syncytiotrophoblast layer of placenta, Kupper cells in the liver, and histiocytes infiltrating near prostate cancers. These observations correlate CSF-1R expression with changes in the growth and development of the normal and neoplastic prostate.
Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer
Authors: Yamada Tohru , Goto Masatoshi , Punj Vasu , Zaborina Olga , Chen Mei Ling , Kimbara Kazuhide , Majumdar Dibyen , Cunningham Elizabeth , Das Gupta Tapas K. , Chakrabarty Ananda M.
Published: October 2002

The use of live bacteria in the treatment of cancer has a long and interesting history. We report the use of a purified bacterial redox protein, azurin, that enters human cancer (melanoma UISO-Mel-2) cells and induces apoptosis. The induction of apoptosis occurs readily in melanoma cells harboring a functional tumor suppressor protein p53, but much less efficiently in p53-null mutant melanoma (UISO-Mel-6) cells. A redox-negative mutant form of azurin (M44K/M64E) demonstrates much less cytotoxicity to the UISO-Mel-2 cells than the wild-type protein. Azurin has been shown to be internalized in UISO-Mel-2 cells and is localized predominantly in the cytosol and in the nuclear fraction. In the p53-null UISO-Mel-6 cells, azurin is localized only in the cytosol. Thus, intracellular trafficking of azurin to the nucleus is p53-dependent. Azurin forms a complex with p53, thereby stabilizing it and raising its intracellular level in cytosolic, mitochondrial, and nuclear fractions. Corresponding to an increasing level of p53, an inducer of apoptosis, the level of Bax also increases in mitochondria, allowing significant release of mitochondrial cytochrome
c
into the cytosol, thus initiating the onset of apoptosis. The M44K/M64E mutant form of azurin, deficient in cytotoxicity, is also deficient in forming a complex with p53 and is less efficient in stabilizing p53 than wild-type azurin. Azurin has been shown to allow regression of human UISO-Mel-2 tumors xenotransplanted in nude mice and may potentially be used in cancer treatment.
Na pump isoforms in human erythroid progenitor cells and mature erythrocytes
Authors: Hoffman Joseph F. , Wickrema Amittha , Potapova Olga , Milanick Mark , Yingst Douglas R.
Published: October 2002

This study is aimed at identifying the Na pump isoform composition of human erythroid precursor cells and mature human erythrocytes. We used purified and synchronously growing human erythroid progenitor cells cultured for 7–14 days. RNA was extracted from the progenitor cells on different days and analyzed by RT-PCR. The results showed that only the α1, α3, β2, and β3 subunit isoforms and the γ modulator were present. Northern analysis of the erythroid progenitor cells again showed that β2 but not β1 or α2 isoforms were present. The erythroid cells display a unique β subunit expression profile (called β
-profiling
) in that they contain the message for the β2 isoform but not β1, whereas leukocytes and platelets are known to have the message for the β1 but not for the β2 isoform. This finding is taken to indicate that our preparations are essentially purely erythroid and free from white cell contamination. Western analysis of these cultured progenitor cells confirmed the presence of α1, α3, (no α2), β2, β3, and γ together now with clear evidence that β1 protein was also present at all stages. Western analysis of the Na pump from mature human erythrocyte ghosts, purified by ouabain column chromatography, has also shown that α1, α3, β1, β2, β3, and γ are present. Thus, the Na pump isoform composition of human erythroid precursor cells and mature erythrocytes contains the α1 and α3 isoforms of the α subunit, the β1, β2, and β3 isoforms of the β subunit, and the γ modulator.
Tubulin is the endogenous inhibitor of the glyceraldehyde 3-phosphate dehydrogenase isoform that catalyzes membrane fusion: Implications for the coordinated regulation of glycolysis and membrane fusion
Authors: Glaser Paul E. , Han Xianlin , Gross Richard W.
Published: October 2002

Previously we demonstrated that specific chromatographically resolvable isoforms of rabbit brain GAPDH catalyze either glycolytic flux or membrane fusion activity (but not both). Moreover, GAPDH membrane fusion activity was latent until it was separated from an endogenous cytosolic inhibitor by anion-exchange chromatography. Herein we demonstrate that the cytosolic inhibitor is nondialyzable, heat-labile, and trypsin-sensitive, thereby identifying it as a cytosolic protein constituent. Chromatographic purification of the rabbit-brain cytosolic protein inhibitor of GAPDH isoform-catalyzed membrane fusion identified a predominant 55-kDa doublet that contained an internal 15-aa peptide identical to a sequence present in α-tubulin (residues 65–79). The identity of the 55-kDa doublet as tubulin was substantiated through Western blot analysis and inhibition of GAPDH-catalyzed membrane fusion by authentic tubulin. Stopped-flow kinetic analysis demonstrated the high-affinity, rapid, and direct modulation of GAPDH-catalyzed fusion activity by tubulin. Because GTP-activated Rab 2 recruits GAPDH to membranes about to undergo fusion [Tisdale, E. J. (2001)
J. Biol. Chem.
276, 2480–2486] and protein kinase Cι/λ phosphorylates GAPDH modulating its interactions with tubulin [Tisdale, E. J. (2001)
J. Biol. Chem.
277, 3334–3341] , the present study suggests a coordinated mechanism through which membrane trafficking and cellular signaling can be integrated with glycolytic flux.
Auditory system: Peripheral nonlinearity and central additivity, as revealed in the human stapedius-muscle reflex
Authors: Zwislocki Jozef J.
Published: October 2002

Human stapedius-muscle contractions in response to 3-kHz, 20-msec tone bursts were determined indirectly by measuring the associated acoustic-impedance changes at the tympanic membrane with an acoustic bridge. The measurement was possible because the bridge practically eliminates the effect of the ear-canal air volume interposed between the tympanic membrane and the tip of the measuring tube. By using burst pairs, temporal additivity of the muscle responses was demonstrated both when the stimulus bursts were presented contralaterally to the measured impedance changes and when the first burst was presented ipsilaterally. The summation time constant was on the order of 200 msec, much longer than the twitch time constant of the muscle fibers. Therefore, the summation had to take place in a nucleus preceding the stapedius muscle. The magnitude of the muscle response obeyed a compressive function paralleling the loudness function up to sound pressure levels of at least 120 dB.
Bidirectional plasticity of excitatory postsynaptic potential (EPSP)-spike coupling in CA1 hippocampal pyramidal neurons
Authors: Daoudal Gaël , Hanada Yasuhiro , Debanne Dominique
Published: October 2002

Integration of synaptic excitation to generate an action potential (excitatory postsynaptic potential-spike coupling or E-S coupling) determines the neuronal output. Bidirectional synaptic plasticity is well established in the hippocampus, but whether active synaptic integration can display potentiation and depression remains unclear. We show here that synaptic depression is associated with an
N
-methyl-
d
-aspartate receptor-dependent and long-lasting depression of E-S coupling. E-S depression is input-specific and is expressed in the presence of γ-aminobutyric acid type A and B receptor antagonists. In single neurons, E-S depression is observed without modification of postsynaptic passive properties. We conclude that a decrease in intrinsic excitability underlies E-S depression and is synergic with glutamatergic long-term depression.
The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate
Authors: Fremeau Robert T. , Burman Jonathon , Qureshi Tayyaba , Tran Cindy H. , Proctor John , Johnson Juliette , Zhang Hui , Sulzer David , Copenhagen David R. , Storm-Mathisen Jon , Reimer Richard J. , Chaudhry Farrukh A. , Edwards Robert H.
Published: October 2002

Quantal release of the principal excitatory neurotransmitter glutamate requires a mechanism for its transport into secretory vesicles. Within the brain, the complementary expression of vesicular glutamate transporters (VGLUTs) 1 and 2 accounts for the release of glutamate by all known excitatory neurons. We now report the identification of VGLUT3 and its expression by many cells generally considered to release a classical transmitter with properties very different from glutamate. Remarkably, subpopulations of inhibitory neurons as well as cholinergic interneurons, monoamine neurons, and glia express VGLUT3. The dendritic expression of VGLUT3 by particular neurons also indicates the potential for retrograde synaptic signaling. The distribution and subcellular location of VGLUT3 thus suggest novel modes of signaling by glutamate.
The signaling domain of the erythropoietin receptor rescues prolactin receptor-mutant mammary epithelium
Authors: Brisken Cathrin , Socolovsky Merav , Lodish Harvey F. , Weinberg Robert
Published: October 2002

The cytokine hormones prolactin and erythropoietin mediate tissue-specific developmental outcomes by activating their cognate receptors, prolactin receptor (PrlR) and erythropoietin receptor (EpoR), respectively. The EpoR is essential for red blood cell formation, whereas a principal function of PrlR is in the development of the mammary gland during pregnancy and lactation [Ormandy, C.,
et al.
(1997)
Genes Dev.
11, 167–178]. The instructive model of differentiation proposes that such distinct, cytokine-dependent developmental outcomes are a result of cytokine receptor-unique signals that bring about induction of lineage-specific genes. This view was challenged by our finding that an exogenously expressed PrlR could rescue EpoR
−/−
erythroid progenitors and mediate their differentiation into red blood cells. Together with similar findings in other hematopoietic lineages, this suggested that cytokine receptors do not play an instructive role in hematopoietic differentiation. Here, we show that these findings are not limited to the hematopoietic system but are of more general relevance to cytokine-dependent differentiation. We demonstrate that the developmental defect of PrlR
−/−
mammary epithelium is rescued by an exogenously expressed chimeric receptor (prl-EpoR) containing the PrlR extracellular domain joined to the EpoR transmembrane and intracellular domains. Like the wild-type PrlR, the prl-EpoR rescued alveologenesis and milk secretion in PrlR
−/−
mammary epithelium. These results suggest that, in cell types as unrelated as erythrocytes and mammary epithelial cells, cytokine receptors employ similar, generic signals that permit the expression of predetermined, tissue-specific differentiation programs.
Efficient production by sperm-mediated gene transfer of human decay accelerating factor (hDAF) transgenic pigs for xenotransplantation
Authors: Lavitrano Marialuisa , Bacci Maria Laura , Forni Monica , Lazzereschi Davide , Di Stefano Carla , Fioretti Daniela , Giancotti Paola , Marfé Gabriella , Pucci Loredana , Renzi Luigina , Wang Hongjun , Stoppacciaro Antonella , Stassi Giorgio , Sargiacomo Massimo , Sinibaldi Paola , Turchi Valeria , Giovannoni Roberto , Della Casa Giacinto , Seren Eraldo , Rossi Giancarlo
Published: October 2002

A large number ofhDAFtransgenic pigs to be used for xenotransplantation research were generated by using sperm-mediated gene transfer (SMGT). The efficiency of transgenesis obtained with SMGT was much greater than with any other method. In the experiments reported, up to 80% of pigs had the transgene integrated into the genome. Most of the pigs carrying thehDAFgene transcribed it in a stable manner (64%). The great majority of pigs that transcribed the gene expressed the protein (83%). ThehDAFgene was transmitted to progeny. Expression was stable and found incaveolaeas it is in human cells. The expressed gene was functional based onin vitroexperiments performed on peripheral blood mononuclear cells. These results show that our SMGT approach to transgenesis provides an efficient procedure for studies involving large animal models.
Bioactive alkaloids of frog skin: Combinatorial bioprospecting reveals that pumiliotoxins have an arthropod source
Authors: Daly John W. , Kaneko Tetsuo , Wilham Jason , Garraffo H. Martin , Spande Thomas F. , Espinosa Alex , Donnelly Maureen A.
Published: October 2002

Nearly 500 alkaloids have been detected in skin extracts from frogs of the family Dendrobatidae. All seem to have been sequestered unchanged into skin glands from alkaloid-containing arthropods. Ants, beetles, and millipedes seem to be the source of decahydroquinolines, certain izidines, coccinellines, and spiropyrrolizidine oximes. But the dietary source for a major group of frog-skin alkaloids, namely the pumiliotoxins (PTXs), alloPTXs, and homoPTXs, remained a mystery. In hopes of revealing an arthropod source for the PTX group, small arthropods were collected from eight different sites on a Panamanian island, where the dendrobatid frog (
Dendrobates pumilio
) was known to contain high levels of two PTXs. The mixed arthropod collections from several sites, each representing up to 20 arthropod taxa, contained PTX 307A and/or alloPTX 323B. In addition, the mixed arthropod collections from several sites contained a 5,8-disubstituted indolizidine (205A or 235B), representing another class of alkaloids previously unknown from an arthropod. An ant alkaloid, decahydroquinoline 195A, was detected in the mixed arthropod collections from several sites. Thus, “combinatorial bioprospecting” demonstrates that further collection and analysis of individual taxa of leaf-litter arthropods should reveal the taxa from which PTXs, alloPTXs, and 5,8-disubstituted indolizidines are derived.
Estimating physical reflectance spectra from human color-matching experiments
Authors: Romney A. Kimball , Indow Tarow
Published: October 2002

This article presents methods for estimating Munsell reflectance spectra, measured physically with a spectrophotometer, from psychophysically derived color-matching functions. The method is general and may also be used to estimate the reflectance spectra from human cone photoreceptor sensitivities. The color-matching functions and the cone sensitivities were found to contain almost identical information and may be considered to give equivalent estimates. The physical description of the Munsell color structure under D65 illumination was compared to the structure estimated from the human perceptual judgments. The results are virtually indistinguishable.
Electronic detection of DNA by its intrinsic molecular charge
Authors: Fritz Jürgen , Cooper Emily B. , Gaudet Suzanne , Sorger Peter K. , Manalis Scott R.
Published: October 2002

We report the selective and real-time detection of label-free DNA using an electronic readout. Microfabricated silicon field-effect sensors were used to directly monitor the increase in surface charge when DNA hybridizes on the sensor surface. The electrostatic immobilization of probe DNA on a positively charged poly-
l
-lysine layer allows hybridization at low ionic strength where field-effect sensing is most sensitive. Nanomolar DNA concentrations can be detected within minutes, and a single base mismatch within 12-mer oligonucleotides can be distinguished by using a differential detection technique with two sensors in parallel. The sensors were fabricated by standard silicon microtechnology and show promise for future electronic DNA arrays and rapid characterization of nucleic acid samples. This approach demonstrates the most direct and simple translation of genetic information to microelectronics.
JLP: A scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors
Authors: Lee Clement M. , Onésime Djamila , Reddy C. Damodara , Dhanasekaran N. , Reddy E. Premkumar
Published: October 2002

Extracellular signals are transduced into cells through mitogen-activated protein kinases (MAPKs), which are activated by their upstream kinases. Recently, families of scaffolding proteins have been identified to tether specific combinations of these kinases along specific signaling pathways. Here we describe a protein, JLP (c-Jun NH2-terminal kinase-associated leucine zipper protein), which acts as a scaffolding protein to bring together Max and c-Myc along with JNK (c-Jun NH2-terminal kinase) and p38MAPK, as well as their upstream kinases MKK4 (MAPK kinase 4) and MEKK3 (MAPK kinase kinase 3). Thus, JLP defines a family of scaffolding proteins that bring MAPKs and their target transcription factors together for the execution of specific signaling pathways.
Classification and Expression Analysis of Arabidopsis F-Box-Containing Protein Genes
Authors: Kuroda Hirofumi , Takahashi Naoki , Shimada Hiroaki , Seki Motoaki , Shinozaki Kazuo , Matsui Minami
Published: October 2002

F-box proteins regulate diverse cellular processes, including cell cycle transition, transcriptional regulation and signal transduction, by playing roles in Skp1p-cullin-F-box protein (SCF) complexes or non-SCF complexes. F-box proteins are encoded by a large gene family. Our database search revealed that at least 568 F-box protein genes are present in the Arabidopsisthaliana (Arabidopsis) genome. Domain search analysis using SMART and Pfam-A databases revealed that 67 of the F-box proteins contained Kelch repeats and 29 contained leucine-rich repeats (LRRs). Interestingly only two F-box proteins contained WD40 repeats that are found in many F-box proteins of other organisms. Kelch repeats, LRRs and WD40 repeats are implicated in protein–protein interactions. This analysis also resulted in the finding of several unique functional domains; however, 448 of the F-box proteins did not contain any known domains. Therefore, these proteins were used to search the Pfam-B database to find novel domains, and three putative ones were found. These domain search analyses led us to classify the Arabidopsis F-box proteins into at least 19 groups based on their domain structures. Macro array analysis showed that several F-box protein genes are expressed in a tissue-specific manner.
Leading in the age of paradox: optimizing behavioral style, job fit and cultural cohesion
Authors: Shelton Charlotte D. , McKenna Mindi K. , Darling John R.
Published: October 2002

Organizations benefit from workforce diversity and also benefit from cultural cohesion. Individuals benefit from job/person fit. However, not only do individuals with diverse behavioral styles often have differing values and interests, they also tend to prefer different types of job assignments and work cultures. Thus, the simultaneous optimization of behavioral style diversity, job/person fit and cultural cohesion would seem to be impossible. This article explores this leadership dilemma and suggests that the skill of quantum thinking can be used to create quantum organizations where seemingly opposite conditions co‐exist. Contemporary organizational development practices such as Future Search, Appreciative Inquiry and Dialogue provide concrete methodologies for embracing paradox and, thus, creating quantum organizations.
Entrepreneurial leadership in high‐tech firms: a field study
Authors: Swiercz Paul Michael , Lydon Sharon R.
Published: October 2002

There are many known reasons why hot start‐ups fail – new technologies, new markets, new distribution channels, inexperienced management teams, etc. – but an unquestionably critical factor is the leadership ability of the entrepreneurial CEO. Conventional wisdom states that professional managers should replace founders because they customarily do not have the necessary leadership skills and experience to further the continued growth of the organization. Recent research, however, has found no evidence that professional managers perform better in high‐growth firms than the original founder. This investigation analyzed the experiences of 27 entrepreneurial CEOs who successfully defied conventional wisdom by leading their organizations from tenuous start‐up to professionally managed enterprise. The research revealed two distinct sets of leadership competencies – labeled self competencies and functional competencies – required of entrepreneurs aspiring to remain at the helm of growth‐driven high‐tech firms.
Managerial intervention in disputes: the role of cognitive biases and heuristics
Authors: Elangovan A.R.
Published: October 2002

Although research on managerial third‐party dispute intervention has made considerable progress during the past two decades, an implicit assumption of rationality has permeated the conceptualizing and modeling of such behaviours. This paper explores the role of cognitive biases and heuristics in managerial intervention, and draws out the implications for outcome selection and third party behaviours.
Shared leadership in the implementation of re‐orientations
Authors: Waldersee Robert , Eagleson Geoff
Published: October 2002

Based on the experience of a hotel corporation, it is argued that the implementation of a re‐orientation is more likely to be successful if its leadership is shared between a task‐oriented and a relations‐oriented leader. The paper builds on the work of Nadler and Tushman who, for re‐orientations, prescribed shared charismatic and instrumental leadership at the top as well as throughout an organization. However, a little bit of charisma can go a long way. In the implementation phase the critical roles to share are those of task and relations, close to where the change is taking place. The implications for research and for management are noted.
Leading from the middle: surviving the squeeze of apparently irreconcilable forces
Authors: Gabel Stewart
Published: October 2002

Leaders and managers often are asked to take positions on various issues that reflect the needs or particular agendas of various individuals or groups with whom they interact directly. Supervisors and subordinates, however, may have differing perspectives on and differing expectations of the leader’s or manager’s decisions or actions. The latter, in turn, commonly feels caught in the “middle” of the conflicting needs or agendas of individuals or groups whose support and approval is needed in order for the leader or manager to function successfully over an extended period of time. This paper describes the phenomenon that the author terms “leading from the middle,” in which he describes the personal and organizational conundrums leaders and managers face when beset by conflicting needs or purposes of others who have realistic or unrealistic expectations of them. An approach towards extricating oneself from this uncomfortable middle position, while also managing successfully from personal and organizational perspectives, is offered.
Women and the New World economy: an island’s experience
Authors: Day‐Hookoomsing Patricia
Published: October 2002

The development of free trade practices in the world market, together with the recent fluctuations on the international money market, is having an increasing impact on the small island economies, such as Mauritius. This paper, written from the practitioner’s point of view, discusses how the restructuring process is affecting female employees. Examples of corrective action being taken in favour of women, such as training programmes in entrepreneurship and leadership, are presented. The difficulties encountered in achieving the training objectives are reviewed and issues needing further attention to optimise the successful involvement of women in the upgrading of the Mauritian workforce are identified.
Moving into management: gender segregation and its effect on managerial attainment
Authors: Brown Kerry , Ridge Stacy
Published: October 2002

Steady progress has been achieved with implementing legislated public sector equal employment opportunities (EEO) policies and programs to fulfil the aim of increasing the representation of EEO groups in public employment. However, there remain areas of significant gender differences in the public sector labour market. One of the most persistent problems has been segregation by gender and this characteristic employment pattern can be discerned across industry, occupation, firm and type of employment contract. This research compares and contrasts the effect of gender domination on the gender composition of tiers of management and numbers in the Senior Executive Service across a state government public service in Australia. The career progression of males and females in female‐dominated and male‐dominated agencies are examined to determine whether different career outcomes can be discerned under conditions of significantly greater numbers of one gender being employed. Findings indicate that men in female‐dominated agencies have different employment profiles and career patterns to those of women in male‐dominated agencies.
The midlife transition of professional women with children
Authors: Gordon Judith R. , Beatty Joy E. , Whelan‐Berry Karen S.
Published: October 2002

This exploratory study focuses primarily on the nature and components of the midlife transition and secondarily considers its antecedents and consequences for a group of 36 professional women who were married, had children, and had enduring careers. In‐depth interviews with these women provided the data for our analysis. The results suggest that age, family characteristics, and employment characteristics influence the transition. In addition, the women rebalance and develop new perspectives at midlife. Components of the resulting internal and external recalibration are identified. This recalibration resulted in increased satisfaction and overall well‐being.
Managerial sex role stereotyping: a New Zealand perspective
Authors: Sauers Daniel A. , Kennedy Jeffrey C. , O’Sullivan Deirdre
Published: October 2002

The relationship between sex role stereotypes and the characteristics perceived necessary for managerial success was examined among 153 male and 165 female commerce students in New Zealand using the 92‐item Schein Descriptive Index. The results were compared with those from similar studies conducted in the USA, Great Britain, Canada, Germany, Japan, and the People’s Republic of China. Both male and female commerce students in New Zealand perceive successful middle managers as possessing the characteristics, attitudes and temperaments commonly ascribed to men in general and, to a lesser degree, women in general. Discriminant analysis was used to identify the specific attributes used by respondents to distinguish the stereotypes.
The economic determinants of clothing consumption in the UK 1987‐2000
Authors: Jones Richard M. , Hayes Steven G.
Published: October 2002

The fashion market in the UK is extremely unpredictable. However, there are reliable leading indicators which enable the absolute size of the market to be explained with a high degree of accuracy. The paper is a regression model which explains the value of consumer spending on clothing in the UK for the period 1987‐2000. The model uses changes in income and price to explain changes in spending on clothing. The model works in the sense that it explains over 90 per cent of the observed change in spending and the results are consistent with the expectations of economic theory. Estimates of both income and price elasticity of demand are derived from the model. The latter gives some support to the activities of the so‐called discounters while the former supports the argument that the demand for clothing is wants rather than needs driven.
Retail performance measures for seasonal fashion
Authors: Mattila Heikki , King Russell , Ojala Nina
Published: October 2002

Retail success can be defined as achieving high gross margins and customer service levels (i.e. being in‐stock) with as little inventory as possible. Forecast accuracy, process lead‐time, offshore/local sourcing mix and up‐front/replenishment buying mix can have a significant impact on success in connection with sourcing seasonal products with a fashion content. Forecast accuracy depends on the characteristics of the product and supply lead‐time. Lead‐times are traditionally long and buying decisions are often made seven to eight months prior to the start of the selling season. Forecast errors lead to some of the items being liquidated at clearance prices while others stockout and lead to lost sales. As a result retailers often resort to higher mark‐up prices with fashion products. However, typical retail performance measures such as service level, lost sales, product substitute percentage, gross margin, gross margin return on inventory, sell‐through percentage and mark‐down rate mask the source of the problems. In this paper, we discuss these performance measures and propose a new one. Additionally, case study analysis of a group of Finnish department stores is presented.
Forecasting skill needs in the UK clothing industry
Authors: Winterton Jonathan , Winterton Ruth
Published: October 2002

This paper reviews two recent projects dealing with training and skill needs in the British clothing sector undertaken to implement the government’s policies to increase commitment to vocational training and avoid skill shortages: the People Skills Scoreboard and Skills Foresight for the clothing sector. Despite the dramatic contraction of the sector at the end of the 1990s, clothing enterprises in 2001 were still experiencing chronic recruitment difficulties and skill shortages. Moreover, irrespective of skills gaps in the existing workforce and evidence that training is associated with business success, clothing companies remain reluctant to provide adequate training to meet future skills needs, an attitude that is both a cause and consequence of difficulties in retaining skilled labour.
Rural shoppers: who gets their apparel dollars?
Authors: Sullivan Pauline , Savitt Ronald , Zheng Yi , Cui Yanli
Published: October 2002

Traditional competition across apparel store types reflects the dynamics of market positioning in practice. Previous research found that apparel related purchases accounted for over half of the money rural consumers spent out of town. Research on apparel shopping intentions according to store types helps identify to what extent different retail formats compete with each other for customers and enables rural retailers to improve their positioning strategies. Results describe apparel shopping behaviour, in rural population, relative to store type and variables influencing consumers’ shopping intentions. Factors influencing consumers’ shopping choices among different apparel retail formats are identified. Descriptive statistics indicated most apparel shoppers frequented independently owned stores and cross‐shop among retail formats. When store categories were created, data revealed that the retail format category department, discount, and chain stores attracted more customers than the other retail format categories.