bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of risperidone in a paediatric population: An observational study
Authors: King B , Zwi K , Nunn K , Longworth J , Dossetor D
Published: September 2003

Objective:  To evaluate the impact of risperidone on functional impairment in a paediatric sample and to document the range of adverse drug reactions.

Methods:  Risperidone treatment in children and adolescents (n = 51) with severe behavioural disturbances was assessed retrospectively to determine clinical response and adverse events. The change in patient functional performance during treatment was assessed using the Royal Alexandra Hospital for Children Measure of Function (MOF) score. Changes in target behaviours (such as severe aggression) were also assessed.

Results:  The average duration of follow up was 9 months. Clinical improvement was demonstrated in 76% of the sample. There was a statistically significant improvement in the mean MOF with risperidone therapy (10.61 with 99% confidence interval 6.6−14.6). Risperidone appeared to be particularly useful in patients with autistic spectrum disorders. Twenty‐five of the 51 patients (49%) experienced side‐effects including sedation (27%), weight gain (20%), anticholinergic (10%) and extrapyramidal (8%) side‐effects.

Conclusions:  This study suggests that risperidone is an effective agent in severely behaviourally disturbed paediatric patients. However, risperidone use is limited by the high frequency of side‐effects. Randomized controlled trial data are required to determine the safety and efficacy of risperidone.
Missed opportunities for a diagnosis of acute otitis media in Aboriginal children
Authors: Gibney KB , Morris PS , Carapetis JR , Skull SA , Leach AJ
Published: September 2003

Objective:  Severe otitis media and its sequelae are common in rural and remote Aboriginal children. Identification of acute otitis media (AOM) is likely to reduce the number of children who go on to develop chronic suppurative otitis media and associated complications. The aim of this study was to compare the diagnoses made by researchers with that documented in the medical records of children admitted to the paediatric isolation ward of the Royal Darwin Hospital, Darwin, Northern Territory.

Methods:  Children aged <8 years admitted to Royal Darwin Hospital were eligible for assessment by pneumatic otoscopy, video‐otoscopy and tympanometry. A diagnosis was made for each child according to the state of their worst ear. Comparisons were made between the researcher diagnoses of ear disease and those documented in the hospital notes by medical staff.

Results:  Thirty‐one children were enrolled during 32 admissions. Most were aged <2 years, Aboriginal, and resided in remote communities. Sixty‐one video‐otoscopic assessments were attempted and sufficiently good images to allow diagnosis were obtained in 105 of 122 ears. Acute otitis media was diagnosed by the research team in 20 of 32 child admissions. Of 29 children who had ear examinations documented by hospital staff, only seven had a diagnosis of AOM recorded. Overall, the research team were almost three times more likely to make this diagnosis (relative risk 2.9, 95% confidence interval 1.6, 5.2). This difference was unlikely to have occurred by chance (P = 0.0002, McNemar's Chi‐squared test).

Conclusions:  In this small study, young Aboriginal children with clear bulging of their tympanic membrane were not diagnosed with AOM by medical staff. Further training in diagnosis, including cleaning of the ear canal, may lead to more accurate assessment and appropriate recommendations for ongoing management.
Hurler's syndrome with cor pulmonale secondary to obstructive sleep apnoea treated by continuous positive airway pressure
Authors: Chan D , Li AM , Yam MC , Li CK , Fok TF
Published: September 2003

Abstract:  A 6‐year‐old boy with Hurler's syndrome presented with right heart failure and pulmonary hypertension secondary to severe obstructive sleep apnoea. Both his sleep apnoea and cor pulmonale were effectively controlled with continuous positive airway pressure therapy.
Gastric pneumatosis in neonates: Revisited
Authors: Travadi JN , Patole SK , Simmer K
Published: September 2003

Abstract:  Pneumatosis intestinalis, found commonly in neonatal necrotising enterocolitis (NEC), can occur in any part of the gastrointestinal tract, from the oesophagus to the rectum. Gastric pneumatosis, defined as air within the wall of the stomach, however, is an extremely rare sign during infancy and is usually secondary to gastric outlet obstruction. The clinical course and outcome of a neonate with gastric pneumatosis associated with NEC is reported along with a brief review of the literature. The findings illustrate that gastric pneumatosis can be the presenting feature of fulminant NEC and may indicate widespread, severe gastrointestinal insult.
Immunization myths and realities: Responding to arguments against immunization
Authors: MacIntyre CR , Leask J
Published: September 2003

Abstract:  As vaccination programs continue to successfully control more and more infectious diseases, and the effects of these diseases become less visible, there has been increased focus on adverse events following immunization. Vaccines have been falsely implicated in the causation of a range of conditions, especially those which affect infants and young children, and whose aetiology is unknown, poorly understood or multifactorial. This paper explores some of the common immunization myths that clinicians may face. It is essential that health professionals have access to accurate information and are able to respond appropriately to parental concerns. This involves good communication; listening, empathy and tailoring advice to the specific concerns of the parent. Finally, health professionals need to provide consistent messages based on solid research evidence.
Geographic variation in phenotypic traits in Phratora spp. and the effects of conditioning on feeding preference
Authors: Peacock L. , Carter P. , Powers S. , Karp A.
Published: September 2003

The leaf beetle genus Phratora (L.) (Coleoptera: Chrysomelidae) includes important pests of cultivated willows and poplars. The feeding preference of P. vulgatissima and P. vitellinae collected from different geographical locations was studied under laboratory conditions. There were geographic differences in the amount consumed of different willow host genotypes by each beetle species. Correlation analysis showed that, regardless of these individual differences between willow genotypes and locations, the ranking of preferred host genotypes was significantly related between locations. There were differences in the preference of host genotypes by P. vulgatissima adults and larvae after being confined to a specific willow genotype for a month, suggesting the possibility of a conditioning effect on food preference. This study also permitted the assessment of possible geographic differentiation in morphological traits. Both beetle species generally showed an increase in body size, width, and percentage fat of dry body weight with a more northerly location. These results are discussed in relation to using varietal mixtures as a pest management strategy.
Reward-dependent plasticity in the primary auditory cortex of adult monkeys trained to discriminate temporally modulated signals
Authors: Beitel Ralph E. , Schreiner Christoph E. , Cheung Steven W. , Wang Xiaoqin , Merzenich Michael M.
Published: September 2003

Adult owl monkeys were trained to detect an increase in the envelope frequency of a sinusoidally modulated 1-kHz tone. Detection was positively correlated with the magnitude of the change in the envelope frequency. Surprisingly, neuronal responses recorded in the primary auditory cortex of trained monkeys were globally suppressed by the modulated tone. However, the contrast in neuronal responsiveness to small increases versus large increases in envelope frequencies was actually enhanced in the trained animals. The results suggest behaviorally contingent inhibitory and excitatory processes that are modulated by the probability that a particular signal predicts a reward.
De novo
synthesis of bacterial glycogen:
Agrobacterium tumefaciens
glycogen synthase is involved in glucan initiation and elongation
Authors: Ugalde Juan E. , Parodi Armando J. , Ugalde Rodolfo A.
Published: September 2003

Evidence is presented indicating that initiation of glycogen synthesis in
Agrobacterium tumefaciens
does not require the presence of α(1,4)-linked glucans. Crude cell extracts incubated with ADP-glucose (Glc) were able to form α(1,4)-linked glucans despite the fact that cells used for extract preparation displayed a genotype that prevented synthesis of Glc-containing sugar nucleotides and thus preformation of α(1,4)-linked glucans and that the defined growth medium used contained glycerol as carbon source.
A. tumefaciens
glycogen synthase (GS) purified to homogeneity from the above-mentioned cells was able to build its own primer by transferring Glc residues from ADP-Glc to an amino acid(s) in the same protein. Primed GS then became the substrate for further GS-catalyzed glucan elongation. It was concluded that, contrary to what happens in mammalian and yeast cells in which two different proteins are required for linear α(1,4)-linked glucan formation (glycogenin for initiation and GS for further elongation), in
A. tumefaciens
and probably in all other bacteria, the same protein is involved in both glycogen initiation and elongation.
Explaining happiness
Authors: Easterlin Richard A.
Published: September 2003

What do social survey data tell us about the determinants of happiness? First, that the psychologists' setpoint model is questionable. Life events in the nonpecuniary domain, such as marriage, divorce, and serious disability, have a lasting effect on happiness, and do not simply deflect the average person temporarily above or below a setpoint given by genetics and personality. Second, mainstream economists' inference that in the pecuniary domain “more is better,” based on revealed preference theory, is problematic. An increase in income, and thus in the goods at one's disposal, does not bring with it a lasting increase in happiness because of the negative effect on utility of hedonic adaptation and social comparison. A better theory of happiness builds on the evidence that adaptation and social comparison affect utility less in the nonpecuniary than pecuniary domains. Because individuals fail to anticipate the extent to which adaptation and social comparison undermine expected utility in the pecuniary domain, they allocate an excessive amount of time to pecuniary goals, and shortchange nonpecuniary ends such as family life and health, reducing their happiness. There is need to devise policies that will yield better-informed individual preferences, and thereby increase individual and societal well-being.
Genetic contributions to generalized arousal of brain and behavior
Authors: Garey J. , Goodwillie A. , Frohlich J. , Morgan M. , Gustafsson J.-A. , Smithies O. , Korach K. S. , Ogawa S. , Pfaff D. W.
Published: September 2003

We have identified a generalized arousal component in the behavior of mice. Analyzed by mathematical/statistical approaches across experiments, investigators, and mouse populations, it accounts for about 1/3 of the variance in arousal-related measures. Knockout of the gene coding for the classical estrogen receptor (ER-α), a ligand-activated transcription factor, greatly reduced arousal responses. In contrast, disrupting the gene for a likely gene duplication product, ER-β, did not have these effects. A combination of mathematical and genetic approaches to arousal in an experimentally tractable mammal opens up analysis of a CNS function of considerable theoretical and practical significance.
Neural image processing by dendritic networks
Authors: Cuntz Hermann , Haag Jürgen , Borst Alexander
Published: September 2003

Convolution is one of the most common operations in image processing. Based on experimental findings on motion-sensitive visual interneurons of the fly, we show by realistic compartmental modeling that a dendritic network can implement this operation. In a first step, dendritic electrical coupling between two cells spatially blurs the original motion input. The blurred motion image is then passed onto a third cell via inhibitory dendritic synapses resulting in a sharpening of the signal. This enhancement of motion contrast may be the central element of figure–ground discrimination based on relative motion in the fly.
A causal role for endothelin-1 in the pathogenesis of osteoblastic bone metastases
Authors: Yin Juan Juan , Mohammad Khalid S. , Käkönen Sanna M. , Harris Stephen , Wu-Wong J. Ruth , Wessale Jerry L. , Padley Robert J. , Garrett I. Ross , Chirgwin John M. , Guise Theresa A.
Published: September 2003

Osteoblastic bone metastases are common in prostate and breast cancer patients, but mechanisms by which tumor cells stimulate new bone formation are unclear. We identified three breast cancer cell lines that cause osteoblastic metastases in a mouse model and secrete endothelin-1. Tumor-produced endothelin-1 stimulates new bone formation
in vitro
and osteoblastic metastases
in vivo
via the endothelin A receptor. Treatment with an orally active endothelin A receptor antagonist dramatically decreased bone metastases and tumor burden in mice inoculated with ZR-75-1 cells. Tumor-produced endothelin-1 may have a major role in the establishment of osteoblastic bone metastases, and endothelin A receptor blockade represents effective treatment.
Electroencephalographic signatures of attentional and cognitive default modes in spontaneous brain activity fluctuations at rest
Authors: Laufs H. , Krakow K. , Sterzer P. , Eger E. , Beyerle A. , Salek-Haddadi A. , Kleinschmidt A.
Published: September 2003

We assessed the relation between hemodynamic and electrical indices of brain function by performing simultaneous functional MRI (fMRI) and electroencephalography (EEG) in awake subjects at rest with eyes closed. Spontaneous power fluctuations of electrical rhythms were determined for multiple discrete frequency bands, and associated fMRI signal modulations were mapped on a voxel-by-voxel basis. There was little positive correlation of localized brain activity with alpha power (8–12 Hz), but strong and widespread negative correlation in lateral frontal and parietal cortices that are known to support attentional processes. Power in a 17–23 Hz range of beta activity was positively correlated with activity in retrosplenial, temporo-parietal, and dorsomedial prefrontal cortices. This set of areas has previously been characterized by high but coupled metabolism and blood flow at rest that decrease whenever subjects engage in explicit perception or action. The distributed patterns of fMRI activity that were correlated with power in different EEG bands overlapped strongly with those of functional connectivity, i.e., intrinsic covariations of regional activity at rest. This result indicates that, during resting wakefulness, and hence the absence of a task, these areas constitute separable and dynamic functional networks, and that activity in these networks is associated with distinct EEG signatures. Taken together with studies that have explicitly characterized the response properties of these distributed cortical systems, our findings may suggest that alpha oscillations signal a neural baseline with “inattention” whereas beta rhythms index spontaneous cognitive operations during conscious rest.
Sustained elevation of extracellular dopamine causes motor dysfunction and selective degeneration of striatal GABAergic neurons
Authors: Cyr Michel , Beaulieu Jean-Martin , Laakso Aki , Sotnikova Tatyana D. , Yao Wei-Dong , Bohn Laura M. , Gainetdinov Raul R. , Caron Marc G.
Published: September 2003

Dopamine is believed to contribute to the degeneration of dopamine-containing neurons in the brain. However, whether dopamine affects the survival of other neuronal populations has remained unclear. Here we document that mice with persistently elevated extracellular dopamine, resulting from inactivation of the dopamine transporter gene, sporadically develop severe symptoms of dyskinesia concomitant with apoptotic death of striatal dopamine-responsive γ-aminobutyric acidergic neurons. Chronic inhibition of dopamine synthesis prevents the appearance of motor dysfunction. The neuronal death is associated with overactivation of dopaminergic signaling as evidenced by the robust up-regulation of striatal ΔFosB, cyclin-dependent kinase 5, and p35. Moreover, hyperphosphorylation of the tau protein, a phenomenon associated with the activation of cyclin-dependent kinase 5 in several neurodegenerative disorders, is observed in symptomatic mice. These findings providein vivoevidence that, in addition to its proposed role in the degeneration of dopamine neurons, dopamine can also contribute to the selective death of its target neurons via a previously unappreciated mechanism.
Temporal activation of NF-κB regulates an interferon-independent innate antiviral response against cytoplasmic RNA viruses
Authors: Bose Santanu , Kar Niladri , Maitra Ratan , DiDonato Joseph A. , Banerjee Amiya K.
Published: September 2003

NF-κB is known to exert its antiviral innate immune response via the IFN-β-induced Janus kinase/signal transducers and activators of transcription pathway. However, our current studies have demonstrated that activated NF-κB is capable of directly establishing an antiviral state independent of IFN or secreted soluble factor(s) against two highly pathogenic respiratory RNA viruses. Human parainfluenza virus type 3, a mildly cytopathic virus that induced NF-κB very early during infection was converted to a virulent virus after NF-κB inhibition. In contrast, a highly cytopathic virus, human respiratory syncytial virus that induced NF-κB late during infection, was converted to a mildly cytopathic virus after NF-κB induction before virus replication. This interconversion of cytopathic phenotypes of viruses after NF-κB modulation was further shown to be independent of IFN and soluble secreted factors(s). Moreover, tumor necrosis factor α (TNF-α) and IL-1β elicited an antiviral response, which was NF-κB-dependent. Thus, NF-κB induction directly confers an essential innate antiviral response against human parainfluenza virus type 3 and respiratory syncytial virus, which is independent of IFN-inducible factor(s).
The crystal structure of myelin oligodendrocyte glycoprotein, a key autoantigen in multiple sclerosis
Authors: Clements Craig S. , Reid Hugh H. , Beddoe Travis , Tynan Fleur E. , Perugini Matthew A. , Johns Terrance G. , Bernard Claude C. A. , Rossjohn Jamie
Published: September 2003

Myelin oligodendrocyte glycoprotein (MOG) is a key CNS-specific autoantigen for primary demyelination in multiple sclerosis. Although the disease-inducing role of MOG has been established, its precise function in the CNS remains obscure. To gain new insights into the physiological and immunopathological role of MOG, we determined the 1.8-Å crystal structure of the MOG extracellular domain (MOGED). MOGEDadopts a classical Ig (Ig variable domain) fold that was observed to form an antiparallel head-to-tail dimer. A dimeric form of native MOG was observed, and MOGEDwas also shown to dimerize in solution, consistent with the view of MOG acting as a homophilic adhesion receptor. The MOG35-55peptide, a major encephalitogenic determinant recognized by both T cells and demyelinating autoantibodies, is partly occluded within the dimer interface. The structure of this key autoantigen suggests a relationship between the dimeric form of MOG within the myelin sheath and a breakdown of immunological tolerance to MOG that is observed in multiple sclerosis.
Biofilm dispersal inXanthomonas campestrisis controlled by cell–cell signaling and is required for full virulence to plants
Authors: Dow J. Maxwell , Crossman Lisa , Findlay Kim , He Yong-Qiang , Feng Jia-Xun , Tang Ji-Liang
Published: September 2003

Therpfgene cluster ofXanthomonas campestrispathovarcampestris(Xcc) is required for the pathogenesis of this bacterium to plants. Severalrpfgenes are involved in the coordinate positive regulation of the production of virulence factors mediated by the small diffusible molecule DSF (for diffusible signal factor). RpfF directs the synthesis of DSF, and a two-component sensory transduction system comprising RpfC and RpfG has been implicated in the perception of the DSF signal and signal transduction. In L medium,rpfF,rpfG, rpfC, andrpfGHCmutants grew as matrix-enclosed aggregates, whereas the wild type grew in a dispersed planktonic fashion. Synthesis of the extracellular polysaccharide xanthan was required for aggregate formation. Addition of DSF triggered dispersion of the aggregates formed by therpfFstrain, but not those ofrpfstrains defective in DSF signal transduction. An extracellular enzyme fromXccwhose synthesis was positively controlled by the DSF/rpfsystem could disperse the aggregates produced by allrpfstrains. The enzyme was identified as the single endo-β-1,4-mannanase encoded by theXccgenome. This enzyme had no detectable activity against soluble xanthan. The endo-β-1,4-mannanase was required for the full virulence ofXccto plants. On the basis of this model system, we propose that one role of the β-mannanase during disease is to promote transitions from an aggregated or biofilm lifestyle to a planktonic lifestyle in response to the DSF signal.
Bacterial pathogens modulate an apoptosis differentiation program in human neutrophils
Authors: Kobayashi Scott D. , Braughton Kevin R. , Whitney Adeline R. , Voyich Jovanka M. , Schwan Tom G. , Musser James M. , DeLeo Frank R.
Published: September 2003

Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against bacterial pathogens. Recent evidence suggests that PMN apoptosis facilitates resolution of inflammation during bacterial infection. Although progress has been made toward understanding apoptosis in neutrophils, very little is known about transcriptional regulation of this process during bacterial infection. To gain insight into the molecular processes that facilitate resolution of infection, we measured global changes in PMN gene expression during phagocytosis of a diverse group of bacterial pathogens. Genes encoding key effectors of apoptosis were up-regulated, and receptors critical to innate immune function were down-regulated during apoptosis induced by phagocytosis of
Burkholderia cepacia
,
Borrelia hermsii
,
Listeria monocytogenes
,
Staphylococcus aureus
, and
Streptococcus pyogenes
. Importantly, we identified genes that comprise a common apoptosis differentiation program in human PMNs after phagocytosis of pathogenic bacteria. Unexpectedly, phagocytosis of
Str. pyogenes
induced changes in neutrophil gene expression not observed with other pathogens tested, including down-regulation of 21 genes involved in responses to IFN. Compared with other bacteria, PMN apoptosis was significantly accelerated by
Str. pyogenes
and was followed by necrosis. Thus, we hypothesize that there are two fundamental outcomes for the interaction of bacterial pathogens with neutrophils: (
i
) phagocytosis of bacteria induces an apoptosis differentiation program in human PMNs that contributes to resolution of bacterial infection, or (
ii
) phagocytosis of microorganisms such as
Str. pyogenes
alters the apoptosis differentiation program in neutrophils, resulting in pathogen survival and disease.
Genetic identification of a respiratory arsenate reductase
Authors: Saltikov Chad W. , Newman Dianne K.
Published: September 2003

For more than a decade, it has been recognized that arsenate [H
2
AsO
4
1-
; As(V)] can be used by microorganisms as a terminal electron acceptor in anaerobic respiration. Given the toxicity of arsenic, the mechanistic basis of this process is intriguing, as is its evolutionary origin. Here we show that a two-gene cluster (
arrAB
;
a
rsenate
r
espiratory
r
eduction) in the bacterium
Shewanella
sp. strain ANA-3 specifically confers respiratory As(V) reductase activity. Mutants with in-frame deletions of either
arrA
or
arrB
are incapable of growing on As(V), yet both are able to grow on a wide variety of other electron acceptors as efficiently as the wild-type. Complementation by the wild-type sequence rescues the mutants' ability to respire As(V).
arrA
is predicted to encode a 95.2-kDa protein with sequence motifs similar to the molybdenum containing enzymes of the dimethyl sulfoxide reductase family.
arrB
is predicted to encode a 25.7-kDa iron–sulfur protein.
arrA
and
arrB
comprise an operon that contains a twin arginine translocation (Tat) motif in ArrA (but not in ArrB) as well as a putative anaerobic transcription factor binding site upstream of
arrA
, suggesting that the respiratory As(V) reductase is exported to the periplasm via the Tat pathway and under anaerobic transcriptional control. These genes appear to define a new class of reductases that are specific for respiratory As(V) reduction.
The response regulator Rrp2 is essential for the expression of major membrane lipoproteins in
Borrelia burgdorferi
Authors: Yang Xiaofeng F. , Alani Sophie M. , Norgard Michael V.
Published: September 2003

Borrelia burgdorferi
(
Bb
), the agent of Lyme disease, exists in nature through a complex enzootic life cycle that involves both ticks and mammals. As
Bb
transitions between its two diverse niches, profound adaptive changes occur that are reflected in differential patterns of gene expression, particularly involving lipoprotein genes. Using a mutagenesis approach, we show that Rrp2 (gene BB0763), one of the proteins predicted by the
Bb
genome (
www.tigr.org
) to be a response regulator of a two-component sensory transduction system, is a pivotal regulator governing the expression of major membrane lipoproteins such as OspC, DbpA, and Mlp8, as well as many other mammalian infection-associated immunogens of
Bb.
Sequence analysis additionally suggested that Rrp2 is a bacterial enhancer-binding protein, essential for σ
54
-dependent gene activation. Mutagenesis of a key amino acid residue within a putative activation domain revealed that Rrp2 controlled lipoprotein expression by governing the expression of the alternative σ-factor σ
s
in a σ
54
-dependent manner. We therefore propose a signal transduction pathway involving Rrp2, σ
54
, and σ
s
, which in concert control the expression of key lipoproteins and other infection-associated immunogens in
Bb
.
Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration
Authors: Okigaki M. , Davis C. , Falasca M. , Harroch S. , Felsenfeld D. P. , Sheetz M. P. , Schlessinger J.
Published: September 2003

The biological role of the protein tyrosine kinase, Pyk2, was explored by targeting the Pyk2 gene by homologous recombination. Pyk2–/– mice are viable and fertile, without overt impairment in development or behavior. However, the morphology and behavior of Pyk2–/– macrophages were impaired. Macrophages isolated from mutant mice failed to become polarized, to undergo membrane ruffling, and to migrate in response to chemokine stimulation. Moreover, the contractile activity in the lamellipodia of Pyk2–/– macrophages was impaired, as revealed by measuring the rearward movement toward the nucleus of fibronectin-coated beads on the lamellipodia in opposition to an immobilizing force generated by optical tweezers. Consistently, the infiltration of macrophages into a carageenan-induced inflammatory region was strongly inhibited in Pyk2–/– mice. In addition, chemokine stimulation of inositol (1, 4, 5) triphosphate production and Ca
2
+
release, as well as integrin-induced activation of Rho and phosphatidyl inositol 3 kinase, were compromised in Pyk2–/– macrophages. These experiments reveal a role for Pyk2 in cell signaling in macrophages essential for cell migration and function.
HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+cytolytic T lymphocytes
Authors: Pietra Gabriella , Romagnani Chiara , Mazzarino Paola , Falco Michela , Millo Enrico , Moretta Alessandro , Moretta Lorenzo , Mingari Maria Cristina
Published: September 2003

HLA-E-restricted T cell receptor αβ+CD8+cytolytic T lymphocytes (CTLs) exist as monoclonal expansions in the peripheral blood of some individuals. Here, we show that they recognize, with high avidity, peptides derived from the UL40 protein of different human cytomegalovirus (CMV) strains. Recognition results in the induction of cytotoxicity, IFN-γ production and cell proliferation. Autologous cells pulsed with CMV-derived peptides become susceptible to lysis by HLA-E-restricted CTLs and induce their proliferation. The high avidity for CMV-derived peptides may explain how these cells are generatedin vivoand suggest their possible role in the host defenses against CMV, a virus that evolved various mechanisms to down-regulate classical HLA class I molecules, thus escaping detection by conventional CTLs.
Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice
Authors: Ishida Daisuke , Yang Hailin , Masuda Kyoko , Uesugi Kanami , Kawamoto Hiroshi , Hattori Masakazu , Minato Nagahiro
Published: September 2003

SPA-1 is a principal Rap1 GTPase-activating protein in the hematopoietic progenitors and peripheral T cells, and SPA-1-deficient mice develop a spectrum of myeloproliferative stem cell disorders of late onset. In the present study, we show that SPA-1-deficient mice develop age-dependent T cell unresponsiveness preceding the myeloid disorders, whereas the T cell numbers remained unchanged. Progression of the T cell dysfunction was attributed to the age-dependent increase in CD44
high
T cell population that was unresponsive to T cell receptor stimulation. Younger SPA-1-deficient mice exhibited selectively impaired recall T cell responses against a T-dependent antigen with normal primary antibody response. These results suggested that the unresponsiveness of CD44
high
T cells was antigen-driven
in vivo
. T cells from younger SPA-1
–
/
–
mice showed much greater and more persisted Rap1 activation by anti-CD3 stimulation than control T cells. Furthermore, freshly isolated T cells from SPA-1
–
/
–
mice exhibited progressive accumulation of Rap1GTP as mice aged. T cells from aged SPA-1
–
/
–
mice with high amounts of Rap1GTP showed normal or even enhanced Ras activation with little extracellular signal-regulated kinase activation in response to anti-CD3 stimulation, indicating that excess Rap1GTP induced the uncoupling of Ras-mediated extracellular signal-regulated kinase activation. These results suggested that antigenic activation of naïve T cells in SPA-1
–
/
–
mice was followed by anergic rather than memory state due to the defective down-regulation of Rap1 activation, resulting in the age-dependent progression of overall T cell immunodeficiency.
Engineering asymmetric vesicles
Authors: Pautot Sophie , Frisken Barbara J. , Weitz D. A.
Published: September 2003

Vesicles are bilayers of lipid molecules enclosing a fixed volume of aqueous solution. Ubiquitous in cells, they can be produced
in vitro
to study the physical properties of biological membranes and for use in drug delivery and cosmetics. Biological membranes are, in fact, a fluid mosaic of lipids and other molecules; the richness of their chemical and mechanical properties
in vivo
is often dictated by an asymmetric distribution of these molecules. Techniques for vesicle preparation have been based on the spontaneous assembly of lipid bilayers, precluding the formation of such asymmetric structures. Partial asymmetry has been achieved only with chemical methods greatly restricting the study of the physical and chemical properties of asymmetric vesicles and their use in potential applications for drug delivery. Here we describe the systematic engineering of unilamellar vesicles assembled with two independently prepared monolayers; this process produces asymmetries as high as 95%. We demonstrate the versatility of our method by investigating the stability of the asymmetry. We also use it to engineer hybrid structures comprised of an inner leaflet of diblock copolymer and an independent lipid outer leaflet.
Coarse-grained sequences for protein folding and design
Authors: Brown Scott , Fawzi Nicolas J. , Head-Gordon Teresa
Published: September 2003

We present the results of sequence design on our off-lattice minimalist model in which no specification of native-state tertiary contacts is needed. We start with a sequence that adopts a target topology and build on it through sequence mutation to produce new sequences that comprise distinct members within a target fold class. In this work, we use the α/β ubiquitin fold class and design two new sequences that, when characterized through folding simulations, reproduce the differences in folding mechanism seen experimentally for proteins L and G. The primary implication of this work is that patterning of hydrophobic and hydrophilic residues is the physical origin for the success of relative contact-order descriptions of folding, and that these physics-based potentials provide a predictive connection between free energy landscapes and amino acid sequence (the original protein folding problem). We present results of the sequence mapping from a 20- to the three-letter code for determining a sequence that folds into the WW domain topology to illustrate future extensions to protein design.
Protean agonism at histamine H
3
receptors
in vitro
and
in vivo
Authors: Gbahou Florence , Rouleau Agnès , Morisset Séverine , Parmentier Régis , Crochet Sylvain , Lin Jian-Sheng , Ligneau Xavier , Tardivel-Lacombe Joël , Stark Holger , Schunack Walter , Ganellin C. Robin , Schwartz Jean-Charles , Arrang Jean-Michel
Published: September 2003

G protein-coupled receptors (GPCRs) are allosteric proteins that adopt inactive (R) and active (R
*
) conformations in equilibrium. R
*
is promoted by agonists or occurs spontaneously, leading to constitutive activity of the receptor. Conversely, inverse agonists promote R and decrease constitutive activity. The existence of another pharmacological entity, referred to as “protean” agonists (after Proteus, the Greek god who could change shape), was assumed on theoretical grounds. It was predicted from the existence of constitutive activity that a same ligand of this class could act either as an agonist or an inverse agonist at the same GPCR. Here, we show that proxyfan, a high-affinity histamine H
3
-receptor ligand, acts as a protean agonist at recombinant H
3
receptors expressed in the same Chinese hamster ovary cells. In support of the physiological relevance of the process, we show that proxyfan also behaves as a protean agonist at native H
3
receptors known to display constitutive activity. On neurochemical and behavioral responses in rodents and cats, proxyfan displays a spectrum of activity ranging from full agonism to full inverse agonism. Thus, protean agonism demonstrates the existence of ligand-directed active states LR
*
different from, and competing with, constitutively active states R
*
of GPCRs, and defines a pharmacological entity with important therapeutic implications.
A neural survival factor is a candidate oncogene in breast cancer
Authors: Porter Dale , Weremowicz Stanislawa , Chin Koei , Seth Pankaj , Keshaviah Aparna , Lahti-Domenici Jaana , Bae Young Kyung , Monitto Constance L. , Merlos-Suarez Ana , Chan Jennifer , Hulette Christine M. , Richardson Andrea , Morton Cynthia C. , Marks Jeffrey , Duyao Mabel , Hruban Ralph , Gabrielson Edward , Gelman Rebecca , Polyak Kornelia
Published: September 2003

Using serial analysis of gene expression (SAGE), we identified a SAGE tag that was present only in invasive breast carcinomas and their lymph node metastases. The transcript corresponding to this SAGE tag, dermcidin (DCD), encodes a secreted protein normally expressed only in the pons of the brain and sweat glands. Array comparative genomic hybridization, fluorescencein situhybridization, and immunohistochemical analyses determined that DCD is overexpressed in ≈10% of invasive breast carcinomas; in some cases its overexpression is coupled with a focal copy number gain of its locus at 12q13.1, and its expression is associated with advanced clinical stage and poor prognosis. Expression of DCD in breast cancer cells promotes cell growth and survival and reduces serum dependency. Putative high- and low-affinity receptors for DCD are present on the cell surface of breast carcinomas and neurons of the brain. Based on these data we hypothesize that DCD may play a role in tumorigenesis by means of enhancing cell growth and survival in a subset of breast carcinomas.
The Role of Migrant Networks in Labor Migration: The Case of China
Authors: Zhao Yaohui
Published: September 2003

Using recent household survey data from rural China, this article investigates determinants of labor migration, paying special attention to the role of migrant networks. Migrant networks are measured by the number of early migrants from the village, comprised of experienced migrants who continue their migratory activities and return migrants. Observations of early migrants are excluded from regression analyses to enable identification. Results show that experienced migrants have a positive and significant effect on subsequent migration, but return migrants do not. This implies that migrant networks are important, and their effects materialize through practical assistance in the process of migration. (JEL J61, O15, Z13)
Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy
Authors: Amano Tetsuya , Yamasaki Satoshi , Yagishita Naoko , Tsuchimochi Kaneyuki , Shin Hiroshi , Kawahara Ko-ichi , Aratani Satoko , Fujita Hidetoshi , Zhang Lei , Ikeda Rie , Fujii Ryoji , Miura Naoki , Komiya Setsuro , Nishioka Kusuki , Maruyama Ikuro , Fukamizu Akiyoshi , Nakajima Toshihiro
Published: September 2003

Rheumatoid arthritis (RA) is one of the most critical articular diseases with synovial hyperplasia followed by impairment of quality of life. However, the mechanism(s) that regulates synovial cell outgrowth is not fully understood. To clarify its mechanism(s), we carried out immunoscreening by using antirheumatoid synovial cell antibody and identified and cloned “Synoviolin/Hrd1”, an E3 ubiquitin ligase. Synoviolin/Hrd1 was highly expressed in the rheumatoid synovium, and mice overexpressing this enzyme developed spontaneous arthropathy. Conversely,synoviolin/hrd1+/-mice were resistant to collagen-induced arthritis by enhanced apoptosis of synovial cells. We conclude that Synoviolin/Hrd1 is a novel causative factor for arthropathy by triggering synovial cell outgrowth through its antiapoptotic effects. Our findings provide a new pathogenetic model of RA and suggest that Synoviolin/Hrd1 could be targeted as a therapeutic strategy for RA.
The delicatessen and speciality food market in the North West
Authors: Vignali‐Ryding Daniella , García Sánchez Judit , Vignali Gianpaolo
Published: September 2003

This case study investigates attitudes towards delicatessen and speciality food for consumers in the North West region. The speciality food sector has experienced above average industry growth over recent years. The UK market for speciality food and drink was £3.3 billion in 2001, according to market analyst Datamonitor, which predicts sales will grow by 5.5 per cent over the next five years. The heart of the category, the traditional speciality counter, shows clear signs of being seriously under threat. Market forces have put speciality food into a paradoxical situation – growing in response to demand while simultaneously losing traditional small outlets. The traditional speciality counter needs to adapt in order to survive
Information literacy: the case or non‐case of Norway?
Authors: Audunson Ragnar , Nordlie Ragnar
Published: September 2003

The term “information literacy” does not have an exact parallel in the Norwegian language, but information policy strategies as well as educational reforms are nevertheless preoccupied with the main elements covered by the term – the ability to find and critically evaluate information within a learning and ICT‐based context. Information literacy consciousness seems to be highest in colleges and universities. Information literacy can be regarded as an essential part of education and learning, of the political goal of promoting social equality and of industrial and economic innovation and competitive ability. In the first planning documents dealing with Norway on the information superhighway, the traditional ideal of equality seemed central. Assignment of responsibility for policies in this field to the ministry of industry and trade may have led to the values of equality being somewhat toned down at the expense of innovation and competitive ability.
Information literacy development in Finland
Authors: Sinikara Kaisa , Järveläinen Leena
Published: September 2003

In Finland there is still much to be done to promote integrated information literacy in higher education. Teamwork between teachers and libraries is well developed in some universities but many are only just beginning to realize what libraries can do for them. Academic libraries have provided user education since the 1950s, but they still have to prove themselves to teaching staff in universities. The Finnish virtual university portal is in the process of integrating library services into their portal, but many negotiations remain before mutual goals are achieved. This article gives an overview of these changes and other information literacy activities in Finnish academic libraries.
Trigger for the occurrence of grain coarsening phenomenon of BS304S31 austenite stainless steel under small plastic strain at high temperature
Authors: Akiyama Masayoshi , Neishi Yutaka , Adachi Yoshitaka , Terada Kenjiro
Published: September 2003

Observation by optical microscopy and EBSP have made it clear that the trigger for the grain coarsening phenomenon of austenite stainless steel BS304S31 may be the stacking faults concentrating selectively in a thin layer lying just beneath the grain boundary. When macroscopic plastic strain reached 6 percent, selective concentration of stacking faults was observed. When it reached 20 percent, the distribution of stacking faults became uniform in each grain. After these specimens were heated, concentration of stacking faults disappeared, and grain coarsening occurred at the point with 6 percent strain, but no grain coarsening occurred at the point with 20 percent strain. In order to investigate this concentration of stacking faults, an attempt was made to analyze the deformation in each crystal by using image‐based FEM. The result suggested that there is a possibility that plastic strain concentrates in the vicinity of the grain boundary when the macroscopic plastic strain is small.
The extended Delaunay tessellation
Authors: Calvo Nestor , Idelsohn Sergio R. , Oñate Eugenio
Published: September 2003

The extended Delaunay tessellation (EDT) is presented in this paper as the unique partition of a node set into polyhedral regions defined by nodes lying on the nearby Voronoï spheres. Until recently, all the FEM mesh generators were limited to the generation of tetrahedral or hexahedral elements (or triangular and quadrangular in 2D problems). The reason for this limitation was the lack of any acceptable shape function to be used in other kind of geometrical elements. Nowadays, there are several acceptable shape functions for a very large class of polyhedra. These new shape functions, together with the EDT, gives an optimal combination and a powerful tool to solve a large variety of physical problems by numerical methods. The domain partition into polyhedra presented here does not introduce any new node nor change any node position. This makes this process suitable for Lagrangian problems and meshless methods in which only the connectivity information is used and there is no need for any expensive smoothing process.
New mixed formulations for problems in elasticity
Authors: Djoko J.K. , Reddy B.D.
Published: September 2003

Classical mixed formulations of the boundary‐value problem of linear elasticity are reviewed, and a new three‐field formulation is introduced. The formulation is an extension of the classical Hu‐Washizu approach, and takes the form of a non‐standard mixed problem. Convergence of finite element approximations of both the old and new methods are discussed, with an emphasis on their behaviour in the incompressible limit. Conditions for the stability and uniform convergence of the new method are presented, and it is shown that the Pian‐Sumihara basis, when used in the new formulation, leads to a convergent method.
Molecular simulation and multiscale homogenization analysis for microinhomogeneous clay materials
Authors: Ichikawa Y. , Kawamura K. , Fujii N. , Nattavut Theramast
Published: September 2003

Materials commonly involve microstructure. Clay is a microinhomogeneous material with nanoscale microstructure. Key issues to understand the behavior of such a finely microinhomogeneous material are as follows: the microstructure is characterized in detail, the local distribution of material properties is identified by experiment or simulation, and the microscale characteristics are related to the macroscale behavior by a seamless manner. For characterizing a microstructure of bentonite, we introduce a conforcal laser scanning microscope (CLSM) together with SEM. By CLSM we can specify a 3D configuration under atmospheric condition. Properties of water‐saturated bentonite are mainly controlled by hydrated montmorillonite, which is the major clay mineral of bentonite. Smectite minerals including montmorillonite are extremely fine and poorly crystallized, so it is difficult to determine the properties by experiment. We inquire into the physicochemical properties by a molecular dynamics simulation method. Then, we develop a multiscale homogenization method to extend the microscopic characteristics to the macroscopic behavior. We show numerical examples of a diffusion problem.
E‐business and organisational change
Authors: Jackson Paul , Harris Lisa
Published: September 2003

While much attention has recently been focused on the problems facing Internet start‐ups, the challenge of e‐business affects a much broader constituency of organisations. For established companies, the key challenge is one of change. Such companies must rethink fundamental aspects of company strategy, which may lead to a radical overhaul of existing ways of doing business, with company structure and culture becoming much more customer‐focused. Resistance at all company levels may need to be overcome, with a need to build commitment and consensus around e‐business strategies. However, companies must also deal with a paradox in e‐business change. As the “dot.com” crash showed, there are many strengths in “bricks and mortar” companies. Evolving a new business model based around “e‐enablement” must therefore avoid the “baby and bathwater syndrome”. Only by recognising and rising to these challenges and dilemmas, and devoting sufficient time, resources and expertise to them, will companies make a success of their e‐business ventures.
The telling of violence
Authors: Bryant Melanie , Wolfram Cox Julie
Published: September 2003

This paper explores the retrospective construction of atrocity narratives of organizational change in primary industries of the Latrobe Valley, located in southeast Australia. Within their narratives, participants discuss various forms of workplace violence aimed at employees by management and, in some cases, other employees. In addition, shifting narratives from violence to resignation are explored. As all participants are no longer employed in the organizations described in the narratives, causal associations between workplace violence and resignation choices are of particular interest. In this context, atrocity narratives are presented in a deliberate effort to extend the theorizing of organizational change into domains that are neither attractive nor progressive.