bluuebunny/crossref_metadata_2025 huggingface dataset:
RhlB helicase rather than enolase is the β-subunit of the
Escherichia coli
polynucleotide phosphorylase (PNPase)–exoribonucleolytic complex
Authors: Lin Pei-Hsun , Lin-Chao Sue
Published: November 2005

Escherichia coli
polynucleotide phosphorylase (PNPase), a protein that has both ribonucleolytic and synthetic capabilities, binds, along with the 48-kDa glycolytic enzyme enolase, the 50-kDa DEAD-box protein RhlB helicase and other cellular proteins to the C-terminal “scaffold” region of RNase E to form a complex termed the RNA degradosome. PNPase itself has been reported to exist as a complex (α
3
β
2
) containing trimers of a catalytic subunit (α) and dimers of another subunit (β). The β-subunit has been believed to be enolase; we report here that it is instead the RhlB helicase. Whereas interaction between PNPase-α and enolase was observed in bacteria that synthesize RNase E having a scaffold region, immunoprecipitates from cells expressing PNPase-α, RhlB, and enolase from single-copy chromosomal loci, plus a mutant RNase E protein lacking its C-terminal half, showed direct association of PNPase-α only with RhlB. Using affinity chromatography, we found that PNPase-α and RhlB form a ribonucleolytically active complex corresponding to the mass calculated previously for α
3
β
2
(i.e., 377–380 kDa), whereas no association between PNPase-α and enolase was detected. Chromosomal deletion of the
eno
gene had no effect on the ability of PNPase to degrade either single- or double-stranded RNAs. Collectively, our findings show that direct interaction between PNPase-α and RhlB occurs physiologically in the absence of the RNase E C-terminal region, that enolase association with PNPase-α is a consequence of the interaction of both proteins with RNase E, and that, contrary to current notions, enolase is not the β-subunit of
E. coli
PNPase complex.
Identification of an
Escherichia coli
O157:H7 heme oxygenase with tandem functional repeats
Authors: Suits Michael D. L. , Pal Gour P. , Nakatsu Kanji , Matte Allan , Cygler Miroslaw , Jia Zongchao
Published: November 2005

Heme oxygenases (HOs) catalyze the oxidation of heme to biliverdin, carbon monoxide (CO), and free iron. Iron acquisition is critical for invading microorganisms to enable survival and growth. Here we report the crystal structure of ChuS, which displays a previously uncharacterized fold and is unique compared with other characterized HOs. Despite only 19% sequence identity between the N- and C-terminal halves, these segments of ChuS represent a structural duplication, with a root-mean-square deviation of 2.1 Å between the two repeats. ChuS is capable of using ascorbic acid or cytochrome P450 reductase-NADPH as electron sources for heme oxygenation. CO detection confirmed that ChuS is a HO, and we have identified it in pathogenic
Escherichia coli
O157:H7. Based on sequence analysis, this HO is present in many bacteria, although not in the
E. coli
K-12 strain. The N- and C-terminal halves of ChuS are each a functional HO.
Structure and activity of the axon guidance protein MICAL
Authors: Nadella Mythili , Bianchet Mario A. , Gabelli Sandra B. , Barrila Jennifer , Amzel L. Mario
Published: November 2005

During development, neurons are guided to their targets by short- and long-range attractive and repulsive cues. MICAL, a large multidomain protein, is required for the combined action of semaphorins and plexins in axon guidance. Here, we present the structure of the N-terminal region of MICAL (MICAL
fd
) determined by x-ray diffraction to 2.0 Å resolution. The structure shows that MICAL
fd
is an FAD-containing module structurally similar to aromatic hydroxylases and amine oxidases. In addition, we present biochemical data that show that MICAL
fd
is a flavoenzyme that in the presence of NADPH reduces molecular oxygen to H
2
O
2
(
K
m,NAPDH
= 222 μM;
k
cat
= 77 sec
-1
), a molecule with known signaling properties. We propose that the H
2
O
2
produced by this reaction may be one of the signaling molecules involved in axon guidance by MICAL.
High-resolution structure of the catalytic region of MICAL (molecule interacting with CasL), a multidomain flavoenzyme-signaling molecule
Authors: Siebold Christian , Berrow Nick , Walter Thomas S. , Harlos Karl , Owens Ray J. , Stuart David I. , Terman Jonathan R. , Kolodkin Alex L. , Pasterkamp R. Jeroen , Jones E. Yvonne
Published: November 2005

Semaphorins are extracellular cell guidance cues that govern cytoskeletal dynamics during neuronal and vascular development. MICAL (molecule interacting with CasL) is a multidomain cytosolic protein with a putative flavoprotein monooxygenase (MO) region required for semaphorin-plexin repulsive axon guidance. Here, we report the 1.45-Å resolution crystal structure of the FAD-containing MO domain of mouse MICAL-1 (residues 1-489). The topology most closely resembles that of the NADPH-dependent flavoenzyme
p
-hydroxybenzoate hydroxylase (PHBH). Comparison of structures before and after reaction with NADPH reveals that, as in PHBH, the flavin ring can switch between two discrete positions. In contrast with other MOs, this conformational switch is coupled with the opening of a channel to the active site, suggestive of a protein substrate. In support of this hypothesis, distinctive structural features highlight putative protein-binding sites in suitable proximity to the active site entrance. The unusual juxtaposition of this N-terminal MO (hydroxylase) activity with the characteristics of a multiprotein-binding scaffold exhibited by the C-terminal portion of the MICALs represents a unique combination of functionality to mediate signaling.
Cyclin H binding to the RARα activation function (AF)-2 domain directs phosphorylation of the AF-1 domain by cyclin-dependent kinase 7
Authors: Bour Gaétan , Gaillard Emilie , Bruck Nathalie , Lalevée Sébastien , Plassat Jean-Luc , Busso Didier , Samama Jean-Pierre , Rochette-Egly Cécile
Published: November 2005

The transcriptional activity of nuclear retinoic acid receptors (RARs), which act as RAR/retinoid X receptor (RXR) heterodimers, depends on two activation functions, AF-1 and AF-2, which are targets for phosphorylations and synergize for the activation of retinoic acid target genes. The N-terminal AF-1 domain of RARα is phosphorylated at S77 by the cyclin-dependent kinase (cdk)-activating kinase (CAK) subcomplex (cdk7/cyclin H/MAT1) of the general transcription factor TFIIH. Here, we show that phosphorylation of S77 governing the transcriptional activity of RARα depends on cyclin H binding at a RARα region that encompasses loop 8–9 and the N-terminal tip of helix 9 of the AF-2 domain. We propose a model in which the structural constraints of this region control the architecture of the RAR/RXR/TFIIH complex and therefore the efficiency of RARα phosphorylation by cdk7. To our knowledge, this study provides the first example of a cooperation between the AF-2 and AF-1 domains of RARs through a kinase complex.
Modulation of surgical fibrosis by microbial zwitterionic polysaccharides
Authors: Ruiz-Perez Begonia , Chung Doo R. , Sharpe Arlene H. , Yagita Hideo , Kalka-Moll Wiltrud M. , Sayegh Mohamed H. , Kasper Dennis L. , Tzianabos Arthur O.
Published: November 2005

Bacterial carbohydrates have long been considered T cell-independent antigens that primarily induce humoral immune responses. Recently, it has been demonstrated that bacterial capsules that possess a zwitterionic charge motif can activate CD4
+
T cells after processing and presentation by antigen-presenting cells. Here we show that these zwitterionic polysaccharides can prevent T helper 1-mediated fibrosis by signaling for the release of IL-10 from CD4
+
T cells
in vivo
. IL-10 production by these T cells and their ability to prevent fibrosis is controlled by the inducible costimulator (ICOS)-ICOS ligand pathway. These data demonstrate that the interaction of the zwitterionic polysaccharides with T cells results in modulation of surgical fibrosis
in vivo
and suggest a previously undescribed approach to “harnessing” T cell function to prevent inflammatory tissue disorders in humans.
Androgens regulate the permeability of the blood–testis barrier
Authors: Meng Jing , Holdcraft Robert W. , Shima James E. , Griswold Michael D. , Braun Robert E.
Published: November 2005

Within the mammalian testis, specialized tight junctions between somatic Sertoli cells create basal and apical polarity within the cells, restrict movement of molecules between cells, and separate the seminiferous epithelium into basal and adluminal compartments. These tight junctions form the basis of the blood–testis barrier, a structure whose function and dynamic regulation is poorly understood. In this study, we used microarray gene expression profiling to identify genes with altered transcript levels in a mouse model for conditional androgen insensitivity. We show that testosterone, acting through its receptor expressed in Sertoli cells, regulates the expression ofclaudin 3, which encodes a transient component of newly formed tight junctions. Sertoli cell-specific ablation of androgen receptor results in increased permeability of the blood–testis barrier to biotin, suggesting claudin 3 regulates the movement of small molecules across the Sertoli cell tight junctions. These results suggest that androgen action in Sertoli cells regulates germ cell differentiation, in part by controlling the microenvironment of the seminiferous epithelium. Our studies also indicate that hormonal strategies for male contraception may interfere with the blood–testis barrier.
Sensory suppression during feeding
Authors: Foo H. , Mason Peggy
Published: November 2005

Feeding is essential for survival, whereas withdrawal and escape reactions are fundamentally protective. These critical behaviors can compete for an animal's resources when an acutely painful stimulus affects the animal during feeding. One solution to the feeding-withdrawal conflict is to optimize feeding by suppressing pain. We examined whether rats continue to feed when challenged with a painful stimulus. During feeding, motor withdrawal responses to noxious paw heat either did not occur or were greatly delayed. To investigate the neural basis of sensory suppression accompanying feeding, we recorded from brainstem pain-modulatory neurons involved in the descending control of pain transmission. During feeding, pain-facilitatory ON cells were inhibited and pain-inhibitory OFF cells were excited. When a nonpainful somatosensory stimulus preactivated ON cells and preinhibited OFF cells, rats interrupted eating to react to painful stimuli. Inactivation of the brainstem region containing ON and OFF cells also blocked pain suppression during eating, demonstrating that brainstem pain-modulatory neurons suppress motor reactions to external stimulation during homeostatic behaviors.
X-ray absorption spectroscopy of chloroperoxidase compound I: Insight into the reactive intermediate of P450 chemistry
Authors: Stone Kari L. , Behan Rachel K. , Green Michael T.
Published: November 2005

We report the structural characterization of a thiolate-ligated ferryl radical. Using x-ray absorption spectroscopy, we examined chloroperoxidase (CPO) compound I (CPO-I). Our results indicate that CPO-I is an authentic ferryl species with an Fe–O bond of 1.65 Å. Axial-ligand interactions result in a remarkably long 2.48-Å Fe–S bond. Analogous forms of cytochrome P450 and CPO have been shown to possess virtually identical coordination environments. Thus, it seems likely that our findings provide a good structural description of the elusive P450-I.
The transduction of the nitrogen regulation signal inSaccharomyces cerevisiae
Authors: Magasanik Boris
Published: November 2005

In cells ofSaccharomyces cerevisiae, using ammonia as a source of nitrogen, Gln3p is sequestered in the cytoplasm by Ure2p but enters the nucleus when the cells are shifted to a nonpreferred source of nitrogen such as proline. The interpretation of recently published observations provides evidence for the view that Ure2p is the sensor for a drop in the intracellular concentration of glutamine, a signal that results in the polyubiquitination of the vesicle responsible for retaining the Gln3p–Ure2p complex in the cytoplasm. As a consequence of the drop in glutamine concentration, Gln3p is able to enter the nucleus and to activate the transcription of nitrogen-regulated genes.
Genetic diversity and reproductive success in mandrills (
Mandrillus sphinx
)
Authors: Charpentier M. , Setchell J. M. , Prugnolle F. , Knapp L. A. , Wickings E. J. , Peignot P. , Hossaert-McKey M.
Published: November 2005

Recent studies of wild animal populations have shown that estimators of neutral genetic diversity, such as mean heterozygosity, are often correlated with various fitness traits, such as survival, disease susceptibility, or reproductive success. We used two estimators of genetic diversity to explore the relationship between heterozygosity and reproductive success in male and female mandrills (
Mandrillus sphinx
) living in a semifree ranging setting in Gabon. Because social rank is known to influence reproductive success in both sexes, we also examined the correlation between genetic diversity and social rank in females, and acquisition of alpha status in males, as well as length of alpha male tenure. We found that heterozygous individuals showed greater reproductive success, with both females and males producing more offspring. However, heterozygosity influenced reproductive success only in dominant males, not in subordinates. Neither the acquisition of alpha status in males, nor social rank in females, was significantly correlated with heterozygosity, although more heterozygous alpha males showed longer tenure than homozygous ones. We also tested whether the benefits of greater genetic diversity were due mainly to a genome-wide effect of inbreeding depression or to heterosis at one or a few loci. Multilocus effects best explained the correlation between heterozygosity and reproductive success and tenure, indicating the occurrence of inbreeding depression in this mandrill colony.
An index to quantify an individual's scientific research output
Authors: Hirsch J. E.
Published: November 2005

I propose the index
h
, defined as the number of papers with citation number ≥
h
, as a useful index to characterize the scientific output of a researcher.
WNK3 modulates transport of Cl
-
in and out of cells: Implications for control of cell volume and neuronal excitability
Authors: Kahle Kristopher T. , Rinehart Jesse , de los Heros Paola , Louvi Angeliki , Meade Patricia , Vazquez Norma , Hebert Steven C. , Gamba Gerardo , Gimenez Ignacio , Lifton Richard P.
Published: November 2005

The regulation of Cl
-
transport into and out of cells plays a critical role in the maintenance of intracellular volume and the excitability of GABA responsive neurons. The molecular determinants of these seemingly diverse processes are related ion cotransporters: Cl
-
influx is mediated by the Na-K-2Cl cotransporter NKCC1 and Cl
-
efflux via K-Cl cotransporters, KCC1 or KCC2. A Cl
-
/volume-sensitive kinase has been proposed to coordinately regulate these activities via altered phosphorylation of the transporters; phosphorylation activates NKCC1 while inhibiting KCCs, and dephosphorylation has the opposite effects. We show that WNK3, a member of the WNK family of serine-threonine kinases, colocalizes with NKCC1 and KCC1/2 in diverse Cl
-
-transporting epithelia and in neurons expressing ionotropic GABA
A
receptors in the hippocampus, cerebellum, cerebral cortex, and reticular activating system. By expression studies in
Xenopus
oocytes, we show that kinase-active WNK3 increases Cl
-
influx via NKCC1, and that it inhibits Cl
-
exit through KCC1 and KCC2; kinase-inactive WNK3 has the opposite effects. WNK3's effects are imparted via altered phosphorylation and surface expression of its downstream targets and bypass the normal requirement of altered tonicity for activation of these transporters. Together, these data indicate that WNK3 can modulate the level of intracellular Cl
-
via opposing actions on entry and exit pathways. They suggest that WNK3 is part of the Cl
-
/volume-sensing mechanism necessary for the maintenance of cell volume during osmotic stress and the dynamic modulation of GABA neurotransmission.
Control of mammalian glycogen synthase by PAS kinase
Authors: Wilson Wayne A. , Skurat Alexander V. , Probst Brandon , de Paoli-Roach Anna , Roach Peter J. , Rutter Jared
Published: November 2005

The regulation of glycogen metabolism is critical for the maintenance of glucose and energy homeostasis in mammals. Glycogen synthase, the enzyme responsible for glycogen production, is regulated by multisite phosphorylation in yeast and mammals. We have previously identified PAS kinase as a physiological regulator of glycogen synthase in
Saccharomyces cerevisiae
. We provide evidence here that PAS kinase is an important regulator of mammalian glycogen synthase. Glycogen synthase is efficiently phosphorylated by PAS kinase
in vitro
at Ser-640, a known regulatory phosphosite. Efficient phosphorylation requires a region of PAS kinase outside the catalytic domain. This region appears to mediate a direct interaction between glycogen synthase and PAS kinase, thereby targeting kinase activity to this substrate specifically. This interaction is regulated by the PAS kinase PAS domain, raising the possibility that this interaction (and phosphorylation event) is modulated by the cellular metabolic state. This mode of regulation provides a mechanism for metabolic status to impinge directly on the cellular decision of whether to store or use available energy.
Impaired involution of mammary glands in the absence of milk fat globule EGF factor 8
Authors: Hanayama Rikinari , Nagata Shigekazu
Published: November 2005

During the involution of mammary glands, epithelial cells undergo apoptosis and are cleared for the next cycle of lactation. The clearance of apoptotic epithelial cells is mediated by neighboring epithelial cells and by macrophages that migrate into the mammary glands. Here, we report that milk fat globule EGF factor 8 (MFG-E8), a secreted glycoprotein that binds to apoptotic cells by recognizing phosphatidylserine, was expressed by epithelial cells and macrophages in mammary glands and was involved in engulfment of apoptotic cells. A deficiency ofMFG-E8caused the accumulation of a large number of milk fat globules (MFGs) in the mammary ducts during involution, indicating that the excess MFGs were cleared by an MFG-E8-dependent mechanism. TheMFG-E8-/-mice developed mammary duct ectasia with periductal mastitis, and the redevelopment of the mammary gland for their second litter was impaired. These results demonstrate that MFG-E8-mediated phagocytosis of apoptotic epithelial cells and MFGs is important for efficient involution of mammary glands.
The development of the mucosal immune system pre- and post-weaning: balancing regulatory and effector function
Authors: Bailey M. , Haverson K. , Inman C. , Harris C. , Jones P. , Corfield G. , Miller B. , Stokes C.
Published: November 2005

The mucosal immune system fulfils the primary function of defence against potential pathogens that may enter across vulnerable surface epithelia. However, a secondary function of the intestinal immune system is to discriminate between pathogen-associated and ‘harmless’ antigens, expressing active responses against the former and tolerance to the latter. Control of immune responses appears to be an active process, involving local generation of IgA and of regulatory and/or regulated T lymphocytes. Two important periods of maximum exposure to novel antigens occur in the young animal, immediately after birth and at weaning. In both cases the antigenic composition of the intestinal contents can shift suddenly, as a result of a novel diet and of colonisation by novel strains and species of bacteria. Changes in lifestyles of man, and husbandry of animals, have resulted in weaning becoming much more abrupt than previously in evolution, increasing the number of antigens that must be simultaneously evaluated by neonates. Thus, birth and weaning are likely to represent hazard and critical control points in the development of appropriate responses to pathogens and harmless dietary and commensal antigens. Neonates are born with relatively undeveloped mucosal immune systems. At birth this factor may prevent both expression of active immune responses and development of tolerance. However, colonisation by intestinal flora expands the mucosal immune system in antigen-specific and non-specific ways. At weaning antibody to fed proteins can be detected, indicating active immune responses to fed proteins. It is proposed that under normal conditions the ability of the mucosal immune system to mount active responses to foreign antigens develops simultaneously with the ability to control and regulate such responses. Problems arise when one or other arm of the immune system develops inappropriately, resulting in inappropriate effector responses to harmless food proteins (allergy) or inadequate responses to pathogens (disease susceptibility).
Characterisation of immune responses to food allergens in mice
Authors: Dearman Rebecca J. , Kimber Ian
Published: November 2005

There is considerable interest in the development and evaluation of approaches for the safety assessment of novel foods, and in particular in methods for characterisation of allergenic potential. One strategy that has found favour is a tiered approach in which the potential of novel proteins to induce allergic sensitisation is assessed based on considerations of stability of the protein in a simulated gastric juice and homology with, or structural similarity to, known allergens. Linked to such an approach may be evaluation of serological identity with proteins known to cause allergic disease. With the aim of supplementing such approaches with a more direct measurement of potential allergenic activity, attempts have been made to characterise the quality of immune responses elicited in BALB/c strain mice. Such evaluations comprise measurement of IgG and IgE antibody production and (to a lesser extent) of induced cytokine expression patterns. Investigations to date suggest that in mice proteins provoke variable immune responses, those with the potential to cause allergic sensitisation stimulating IgE (and IgG) antibody production. In contrast, non-allergenic, but nevertheless immunogenic, proteins are associated with IgG antibody responses in the absence of marked IgE production. Consistent with the selective activation of selective type 2 T lymphocyte responses, exposure of mice to allergenic protein is associated with preferential expression of IL-4, -5, -10 and -13. Collectively these data suggest that characterisation of the nature of immune response induced in mice by proteins may provide a useful adjunct or alternative to current strategies for the assessment of allergenic potential.
Selenium in cancer prevention: a review of the evidence and mechanism of action
Authors: Rayman Margaret P.
Published: November 2005

Se is an unusual trace element in having its own codon in mRNA that specifies its insertion into selenoproteins as selenocysteine (SeCys), by means of a mechanism requiring a large SeCys-insertion complex. This exacting insertion machinery for selenoprotein production has implications for the Se requirements for cancer prevention. If Se may protect against cancer, an adequate intake of Se is desirable. However, the level of intake in Europe and some parts of the world is not adequate for full expression of protective selenoproteins. The evidence for Se as a cancer preventive agent includes that from geographic, animal, prospective and intervention studies. Newly-published prospective studies on oesophageal, gastric-cardia and lung cancer have reinforced previous evidence, which is particularly strong for prostate cancer. Interventions with Se have shown benefit in reducing the risk of cancer incidence and mortality in all cancers combined, and specifically in liver, prostate, colo-rectal and lung cancers. The effect seems to be strongest in those individuals with the lowest Se status. As the level of Se that appears to be required for optimal effect is higher than that previously understood to be required to maximise the activity of selenoenzymes, the question has been raised as to whether selenoproteins are involved in the anti-cancer process. However, recent evidence showing an association between Se, reduction of DNA damage and oxidative stress together with data showing an effect of selenoprotein genotype on cancer risk implies that selenoproteins are indeed implicated. The likelihood of simultaneous and consecutive effects at different cancer stages still allows an important role for anti-cancer Se metabolites such as methyl selenol formed from γ-glutamyl-selenomethyl-SeCys and selenomethyl-SeCys, components identified in certain plants and Se-enriched yeast that have anti-cancer effects. There is some evidence that Se may affect not only cancer risk but also progression and metastasis. Current primary and secondary prevention trials of Se are underway in the USA, including the Selenium and Vitamin E Cancer Prevention Trial (SELECT) relating to prostate cancer, although a large European trial is still desirable given the likelihood of a stronger effect in populations of lower Se status.
Micronutrients in childhood and the influence of subclinical inflammation
Authors: Thurnham David I. , Mburu Anne S.W. , Mwaniki David L. , Wagt Arjan De
Published: November 2005

In the present paper biomarkers of micronutrient status in childhood and some of the factors influencing them, mainly dietary intake, requirements and inflammation will be examined. On a body-weight basis the micronutrient requirements of children are mostly higher than those of an adult, but most biomarkers of status are not age-related. A major factor that is often overlooked in assessing status is the influence of subclinical inflammation on micronutrient biomarkers. In younger children particularly the immune system is still developing and there is a higher frequency of sickness than in adults. The inflammatory response rapidly influences the concentration in the blood of several important micronutrients such as vitamin A, Fe and Zn, even in the first 24 h, whereas dietary deficiencies can be envisaged as having a more gradual effect on biomarkers of nutritional status. The rapid response to infection may be for protective reasons, i.e. conservation of reserves, or by placing demands on those reserves to mount an effective immune response. However, because there is a high prevalence of disease in many developing countries, an apparently-healthy child may well be at the incubation stage or convalescing when blood is taken for nutritional assessment and the concentration of certain micronutrient biomarkers will not give a true indication of status. Most biomarkers influenced by inflammation are known, but often they are used because they are convenient or cheap and the influence of subclinical inflammation is either ignored or overlooked. The objective of the present paper is to discuss: (1) some of the important micronutrient deficiencies in childhood influenced by inflammation; (2) ways of correcting the interference from inflammation.
Could antioxidant supplementation prevent pre-eclampsia?
Authors: Holmes Valerie A. , McCance David R.
Published: November 2005

Pre-eclampsia is a disorder characterised by pregnancy-induced hypertension and new-onset proteinuria occurring in the second half of pregnancy. Worldwide, approximately 2–3% of all pregnant women develop pre-eclampsia. The condition is a major cause of maternal and fetal morbidity and mortality. Abnormal placentation is an important predisposing factor for pre-eclampsia, while endothelial activation appears to be central to the pathophysiological changes, possibly indicative of a two-stage disorder characterised by reduced placental perfusion and a maternal syndrome. There is increasing evidence that pre-eclampsia is associated with both increased oxidative stress and reduced antioxidant defences, which has led to the hypothesis that oxidative stress may play an important role in the pathogenesis of pre-eclampsia, perhaps acting as the link in a two-stage model of pre-eclampsia. In support of this hypothesis a small, but important, preliminary study has shown a highly significant (P= 0.02) reduction in the incidence of pre-eclampsia in women at risk who were taking a supplement of vitamins C and E from mid-pregnancy. Furthermore, these findings support the hypothesis that oxidative stress is at least partly responsible for the endothelial dysfunction of pre-eclampsia. Several larger multicentre trials are currently underway to evaluate the efficacy, safety and cost benefits of antioxidant supplementation during pregnancy for the prevention of pre-eclampsia in both low- and high-risk women, including women with diabetes. The results of these trials are awaited with interest.
Consistency, Concurrency and Compact Development: Three Faces of Growth Management Implementation in Florida
Authors: Ben-Zadok Efraim
Published: November 2005

This study covers the implementation of Florida Growth Management Act (GMA) from 1985 to 2004. The purpose is to evaluate and compare the implementation of three leading GMA policies: consistency, concurrency and compact development. Consistency mandated co-ordination and compliance among state, regional and local plans. Concurrency dictated the volume and pace of local growth because it required public facilities that support development to be available 'concurrent' with the impact of such development. Compact development aimed to restrain suburban sprawl from spreading towards natural resources and agricultural lands and direct it towards urban areas of mixed land uses and high densities. Each policy dominated the GMA implementation in a defined period. Each changed the implementation course of the Act. The different purposes, critical issues, implementation processes and outcomes of the policies create the 'three faces' evaluation story of the GMA. Shedding light on turmoil and policy change in this multifaceted initiative, the evaluation corrects the image of the Act in literature that is largely preoccupied with the implementation of consistency. The study concludes with implications for Florida and other states that either contemplate or implement similar policies.
Three Challenges for the Compact City as a Sustainable Urban Form: Household Consumption of Energy and Transport in Eight Residential Areas in the Greater Oslo Region
Authors: Holden Erling , Norland Ingrid T.
Published: November 2005

The results of a recent survey conducted in eight residential areas in the Greater Oslo Region support the hypothesis that there is a connection between land use characteristics and household consumption of energy and transport. Findings from the survey also lend great support to the compact city as a sustainable urban form. However, three distinct findings indicate that decentralised concentration could lead to even lower energy use in households: while the extent of everyday travel decreases in densely populated areas, the central urban areas represent the highest level of leisure-time travel by plane; the access to a private garden limits the extent of leisure travel; and, the difference in energy use for housing between single-family and multifamily housing is reduced in housing built after 1980, indicating that the established conclusions on the most energy-efficient housing should be questioned.
Do masks terminate the icon?
Authors: Smithson Hannah , Mollon John
Published: November 2005

Iconic memory is operationally defined by part-report experiments (Sperling, 1960). If a mask is presented after the target, the mask is thought to be superposed on the target in the iconic representation, or to displace it from the representation. But could a cue presented after a pattern mask still allow selection within the target array? A target array of letters was followed by a checkerboard mask. We compared two target–mask interstimulus intervals (ISIs; 0 and 100 ms), and six cue delays. At ISI = 0 ms, performance was at chance, for part report and whole report. At ISI = 100 ms, with the shortest cue delay, observers demonstrated a part-report advantage of 25–30%. As cue delay increased the part-report advantage decreased. These results are inconsistent with an iconic memory that is automatically displaced or overwritten by new information. We consider two alternatives: a second-stage store, which represents letters in terms of their high-level features and which the mask cannot penetrate, or a four-dimensional store that preserves separately the representations of the target and its aftercoming mask. We discuss the implications of our results for studies that use backward masking to “terminate the icon”.
Short Article: The interaction of word frequency and word class: A test of the GO model's account of the missing-letter effect
Authors: Roy-Charland Annie , Saint-Aubin Jean
Published: November 2005

When asked to detect target letters while reading a text, participants miss more letters in frequent function words than in less frequent content words. In this phenomenon, known as the missing-letter effect, two factors covary: word frequency and word class. According to the GO model, there should be an interaction between word class and word frequency with more omissions for function than for content words only among high-frequency words. This pattern would be due to the fact that function words could only assume a structure-supporting role if they are identified rapidly, which is only possible for high-frequency words. These predictions were tested by assessing omission rate for frequent and rare function and content words. Results lend support to the GO model with more omissions for frequent than for rare words, and more omissions for the function than for the content word among high-frequency words, but not among low-frequency words. These results were observed both in English (Experiment 1) and in French (Experiment 2).
Evidence‐based Research in Complementary and Alternative Medicine I: History
Authors: Chiappelli Francesco , Prolo Paolo , Cajulis Olivia S.
Published: November 2005

Contemporary Western medicine has witnessed a fragmentation of our conceptualization of the medical endeavor into ‘traditional medicine’ and ‘non‐traditional medicine’. The former is meant to refer to the Western medical tradition, the latter encompasses both ‘complementary’ and ‘alternative’ medical practices. Complementary medicine complements conventional medical treatments, and alternative modes of medical interventions are meant to replace traditional Western medicine. Evidence‐based research must be directed at establishing the best available evidence in complementary and alternative medicine. This paper is the first of a set of four ‘lectures’ that reviews the process of evidence‐based research, and discusses its implications and applications for the early decades of the 21st century. The purpose of this paper is to introduce the series by examining some of the historical and philosophical foundations of this research endeavor.
Does the Precision of News Affect Market Underreaction? Evidence from Returns Following Two Classes of Profit Warnings
Authors: Bulkley George , Herrerias Renata
Published: November 2005

We evaluate whether the market reacts rationally to profit warnings by testing for subsequent abnormal returns. Warnings fall into two classes: those that include a new earnings forecast, and those that offer only the guidance that earnings will be below current expectations. We find significant negative abnormal returns in the first three months following both types of warning. There is also evidence that underreaction is more pronounced when the disclosure is less precise. Abnormal returns are significantly more negative following disclosures that offer only qualitative guidance than when a new earnings forecast is included.
Does Overconfidence Affect Corporate Investment? CEO Overconfidence Measures Revisited
Authors: Malmendier Ulrike , Tate Geoffrey
Published: November 2005

This article presents the growing research area of Behavioural Corporate Finance in the context of one specific example: distortions in corporate investment due to CEO overconfidence. We first review the relevant psychology and experimental evidence on overconfidence. We then summarise the results of Malmendier and Tate (2005a) on the impact of overconfidence on corporate investment. We present supplementary evidence on the relationship between CEOs’ press portrayals and overconfident investment decisions. This alternative approach to measuring overconfidence, developed in Malmendier and Tate (2005b), relies on the perception of outsiders rather than the CEO's own actions. The robustness of the results across such diverse proxies jointly corroborates previous findings and suggests new avenues to measuring executive overconfidence.
Short‐term mortality of bacteraemia in elderly patients with haematological malignancies
Authors: Nørgaard Mette , Larsson Heidi , Pedersen Gitte , Schønheyder Henrik C. , Rothman Kenneth J. , Sørensen Henrik T.
Published: November 2005

Bacterial infections are important complications in patients with haematological malignancies. We compared the outcome of bacteraemia among elderly and younger patients with haematological malignancies, and evaluated the impact of comorbidity on this association using population‐based registries from 1992 to 2002. Among 358 patients with an incident haematological malignancy and an episode of bacteraemia, 207 (58%) were older than 60 years and 37 (10%) older than 80 years. The 7‐d mortality was 10% among patients younger than 60 years, 21% among patients aged 60–79 years, and 27% for patients older than 80 years. When compared with patients younger than 60 years, the adjusted mortality rate ratios (MRRs) were 1·9 [95% confidence interval (CI): 0·9–3·8] for patients aged 60–79 years and 1·6 (95% CI: 0·6–4·2) for patients older than 80 years. The 30‐d mortality was 23% among patients younger than 60 years of age, 35% among patients aged 60–79 years, and 54% among patients 80 years or older. Adjusted MRRs were 1·7 (95% CI: 1·1–2·7) and 2·3 (95% CI: 1·2–4·3), respectively. We found that increasing age was associated with increased mortality from bacteraemia in patients with haematological malignancies. An increased burden of comorbidity among the elderly did not explain this association.
Lack of CD27 in myeloma delineates different presentation and outcome
Authors: Moreau Philippe , Robillard Nelly , Jégo Gaétan , Pellat Catherine , Gouill Steven Le , Thoumi Soraya , Avet‐Loiseau Hervé , Harousseau Jean‐Luc , Bataille Régis
Published: November 2005

CD27 expression was evaluated on normal plasma cells (PC), PC from patients with multiple myeloma (MM) at diagnosis or relapse and on human myeloma cell lines (HMCL). CD27 was expressed by normal PC but was lacking in PC from MM patients at diagnosis (36%) and relapse (47%), and in HMCL (92%). The prognostic impact of CD27 expression was evaluated in 42 patients with de novo MM. Overall survival was 92% at 3 years in CD27+ vs. 50% in CD27– MM (P = 0·017). CD27 expression seems to delineate two important subsets of MM with different presenting features and clinical outcomes.
A rapid multifluorescent polymerase chain reaction for genetic counselling in Chinese haemophilia A families
Authors: FANG Y. , WANG X.‐F. , DAI J. , WANG H.‐L.
Published: November 2005

Summary.  Linkage analysis is a widely used strategy for genetic counselling in haemophilia A (HA) families. We attempted to develop more informative markers closely linked to factor VIII (FVIII) gene and establish a rapid multifluorescent polymerase chain reaction (PCR) method with these markers. Five extragenic (DXS15, DXS9901, G6PD, DXS1073 and DXS1108) and one intragenic (F8Civs13) markers were examined in 118 healthy individuals and 12 HA families which had been diagnosed before. Five extragenic markers were within an interval of about 1.5 Mb to FVIII gene and located on each side of the gene. The expected heterozygote rate (HR) of DXS15, DXS9901, G6PD, DXS1073, DXS1108 and F8Civs13 were 74.97%, 79.77%, 56.06%, 59.92%, 39.97% and 47.61%, while the observed HR were 88.24%, 82.35%, 21.57%, 62.75%, 35.29% and 52.94%. When six polymorphic markers were combined together, all the studied females were informative in at least one of these markers and 29.41% of them were detected informative in three markers with the highest frequency. The diagnostic rates of DXS15, DXS9901, G6PD, DXS1073, DXS1108 and F8Civs13 in 12 haemophilia families were 75.00%, 91.67%, 41.67%, 75.00%, 33.33% and 66.67% respectively. All the genetic diagnosis was consistent with the result we analysed before and no recombination was observed. Family 1 was given as an example in this study and was found to be informative in three polymorphic markers DXS15, DXS9901 and DXS1073. The patient's sister was detected the same allele as the proband, but her male fetus did not inherit the affected allele from her, which was consistent with the result of sequencing. It was demonstrated that the multifluorescent PCR method established in this study was convenient and efficient and can be applied to carrier detection and prenatal diagnosis in HA families.
Canadian multi‐institutional survey of immune tolerance therapy (ITT) – experience with the use of recombinant factor VIII for ITT
Authors: BARNES C. , RIVARD G. E. , POON M‐C. , TEITEL J. , PAI M. , KERN M. , BLANCHETTE V. S. , CARCAO M. ,   THE INHIBITOR SUBCOMMITTEE OF THE ASSOCIATION OF HEMOPHILIA CLINIC DIRECTORS OF CANADA
Published: November 2005

Summary.  Immune tolerance therapy (ITT) is currently the most effective approach to eradicate inhibitors in patients with haemophilia A. Limited evidence suggests that the use of plasma‐derived factor VIII (pdFVIII) for ITT may be associated with a greater success rate than recombinant factor VIII (rFVIII). Analysis of ITT cases in Canada offered the opportunity to examine the success rate of using rFVIII for ITT, as rFVIII has been used almost exclusively for Canadian haemophilia A patients since 1994. The results of 32 patients from five haemophilia treatment centres were collated. Three patients continue on ITT. Of the 29 patients who completed ITT, 25 (86.2%) used rFVIII exclusively, and four used pdFVIII exclusively or pdFVIII followed by rFVIII. The initial FVIII dosing frequency was once per day in 72.4% of patients at an average dose of 98 U kg−1 (range 50–200). Eight patients (25%) received one or more adjuvant therapies. The median duration of ITT was 1.1 years (mean 1.5 years, range 9 days to 6 years). The overall success rate of the 29 patients who completed ITT was 79.3% (23/29), which is comparable with the results of immune tolerance registries. Our results suggest that the success rate of ITT using rFVIII is not inferior to the results with pdFVIII.
Needles and needleless devices for infusion of anti‐haemophilic factor concentrate: impact on protein structure and function
Authors: PRABHU S. , KAZARIAN T. , HAKOBYAN N. , JABBAR A. , DUNHAM T. , VALENTINO L. A.
Published: November 2005

Summary.  A poor response to the infusion of anti‐haemophilic factor (AHF) concentrates used to control acute bleeding or prevent haemorrhage during surgery may have many causes, including the lack of functional activity of the infused protein concentrate. It is generally recommended to follow the manufacturers’ instructions when administering the factor intravenously. For convenience, infusion sets with 23 gauge butterfly needles are packaged with the major brands of AHF concentrate. In hospitals, blunt connectors for i.v. infusion are becoming more prevalent to reduce the risk of needle stick injuries to both patients and hospital staff. The integrity of AHF infused using such devices has not been examined. We examined the possibility that passage of complex proteins such as AHF through such devices may result in alteration of the protein, rendering it inactive. The results presented here suggest that this is not the case; neither the structure nor the function of AHF protein products was adversely affected by the use of the needleless transfer device (NTD) or the needle types and sizes commonly used in clinical practice. Samples of factor VIII and factor IX AHF concentrate were passed through the B‐D Blunt Plastic Cannula or 23, 27 and 30 gauge needles. No significant changes in electrophoretic mobility or coagulation activity were detected. Samples generally showed slightly increased coagulation activity when compared with the control in which the sample was passed directly out of the syringe with no device attached. These data indicate that the NTD and various needle gauges are acceptable for the infusion of AHF concentrate in a clinical setting. Furthermore, the use of small gauge needles has advantages that may improve adherence to rigorous factor replacement programmes.
Rituximab for congenital haemophiliacs with inhibitors: a Canadian experience
Authors: CARCAO M. , ST LOUIS J. , POON M‐C. , GRUNEBAUM E. , LACROIX S. , STAIN A. M. , BLANCHETTE V. S. , RIVARD G. E. ,   ON BEHALF OF THE INHIBITOR SUBCOMMITTEE OF THE ASSOCIATION OF HEMOPHILIA CLINIC DIRECTORS OF CANADA
Published: November 2005

Summary.  When a high titre inhibitor develops in a patient with haemophilia, attempts are made to eradicate it through immune tolerance induction therapy (ITI) involving the frequent and regular administration of factor, usually for months to years. ITI is successful in only two thirds of patients prompting investigators to explore alternate regimens to use in haemophiliacs failing conventional ITI. Rituximab is an anti‐CD20 monoclonal antibody, which has shown promise in the treatment of B‐cell‐mediated disorders. We developed a protocol for the use of rituximab in haemophilia A (HA) patients failing conventional ITI or in those haemophiliacs where the likelihood of success of conventional ITI is poor. Patients receive 375 mg m−2 of intravenous rituximab weekly for 4 weeks followed by monthly (up to 5 months) until inhibitor disappearance and establishment of normal FVIII pharmacokinetics (recovery and half‐life). Patients are concurrently placed on recombinant FVIII (100 U kg−1 day−1). We have placed five haemophiliacs (four children with severe HA, and one adult with mild HA) on this protocol. In three patients (two with severe HA and one with mild HA) inhibitors disappeared although in neither severe haemophiliac did FVIII pharmacokinetics completely normalize. The fourth patient had a significant drop in inhibitor titres although not a complete disappearance of the inhibitor. All four of these patients ceased bleeding following rituximab. The fifth patient had no response to rituximab. This non‐responding patient was not placed on concurrent FVIII. Our five cases suggest that rituximab may hold promise in the eradication of inhibitors. Prospective randomized studies are required to determine the value of this agent in inhibitor management.
Bacterial Expression and Characterization of a Single‐Chain Variable Fragment Antibody Specific to Several Replicases of Plant (+)RNA Viruses
Authors: Fomitcheva V. W. , Schubert J. , Saalbach I. , Habekuß A. , Kumlehn J. , Conrad U.
Published: November 2005

The use of synthetic antibodies may be an alternative tool for plant protection. RNA‐dependent RNA polymerases (RdRps) play a key role in the process of virus replication. If recombinant antibodies like single‐chain variable fragment antibodies (scFv) are directed against RdRps, they might be used to create virus‐resistant plants. To this end, a recombinant antibody from a phage display library directed against the conserved amino acid domain (glycine‐aspartate‐aspartate, GDD) in the active centre of the RdRp of plant (+)RNA viruses was selected. High expression level in Escherichia coli enabled the purification of scFv which was used to raise polyclonal anti‐scFv antibodies. The scFv was characterized and assessed for specificity to the RdRps of viruses belonging to different families. It reacted with the RdRps of numerous distinct viruses, showing its potential in generating resistance to a large number of (+)RNA viruses containing the GDD motif.