bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive chemistry in the Laboratoire de Météorologie Dynamique general circulation model: Description and background tropospheric chemistry evaluation
Authors: Hauglustaine D. A. , Hourdin F. , Jourdain L. , Filiberti M.‐A. , Walters S. , Lamarque J.‐F. , Holland E. A.
Published: February 2004

We provide a description and evaluation of LMDz‐INCA, which couples the Laboratoire de Météorologie Dynamique general circulation model (LMDz) and the Interaction with Chemistry and Aerosols (INCA) model. In this first version of the model a CH4−NOx−CO−O3 chemical scheme representative of the background chemistry of the troposphere is considered. We derive rapid interhemispheric exchange times of 1.13–1.38 years and 0.70–0.82 years, based on surface and pressure‐weighted mixing ratios of inert tracers, respectively. The general patterns of the nitrogen deposition are correctly reproduced by the model. However, scavenging processes remain a major source of uncertainty in current models, with convective precipitation playing a key role in the global distribution of soluble species. The global and annual mean methane (7.9 years) and methylchloroform (4.6 years) chemical lifetimes suggest that OH is too high by about 19–25% in the model. This disagreement with previous estimates is attributed to the missing nonmethane hydrocarbons in this version of the model. The model simulates quite satisfactorily the distribution and seasonal cycle of CO at most stations. At several tropical sites and in the Northern Hemisphere during summer, the OH overestimate leads, however, to a too intense CO chemical destruction. LMDz‐INCA reproduces fairly well the distribution of ozone throughout most of the troposphere. A main disagreement appears in the Northern Hemisphere upper troposphere during summer, due to a too high tropopause in the GCM. When the GCM winds are relaxed toward assimilated meteorology, a much higher variability is obtained for ozone in the upper troposphere, reflecting more frequent stratospheric intrusions. The stratospheric influx of ozone increases from 523 Tg/yr in the base case simulation to 783 Tg/yr in the nudged version.
Error analysis for tropospheric NO2 retrieval from space
Authors: Boersma K. F. , Eskes H. J. , Brinksma E. J.
Published: February 2004

Retrieval uncertainty estimates for vertical tropospheric NO2 columns based on theoretical error source discussions combined with actual Global Ozone Monitoring Experiment (GOME) observations are presented. Contributions to the total retrieval uncertainty are divided into three categories: (1) errors caused by measurement noise and spectral fitting, affecting the slant column density, (2) errors related to the separation of stratospheric and tropospheric NO2 affecting the estimate of the stratospheric slant column, and (3) errors due to uncertainty in model parameters such as clouds, surface albedo, and a priori profile shape, affecting the tropospheric air mass factor. Furthermore, it is shown that a correction for the effective temperature of the trace gas is essential and that a correction for the presence of aerosols needs to be accompanied by aerosol corrections to the cloud retrieval. A discussion of the error components and total retrieval uncertainty is given for March 1997. Tropospheric NO2 columns can be retrieved with a precision of 35–60% over regions with a large contribution of the troposphere to the total column. This error estimate demonstrates the need for highly accurate albedo maps, cloud retrieval schemes, and realistic a priori NO2 profile shapes.
Interplay between antibacterial effectors: A macrophage antimicrobial peptide impairs intracellular
Salmonella
replication
Authors: Rosenberger Carrie M. , Gallo Richard L. , Finlay B. Brett
Published: February 2004

Antimicrobial peptides have established an important role in the defense against extracellular infections, but the expression of cationic peptides within macrophages as an antibacterial effector mechanism against intracellular pathogens has not been demonstrated. Macrophage expression of the murine cathelicidin-related antimicrobial peptide (CRAMP) was increased after infection by the intracellular pathogen
Salmonella typhimurium
, and this increase required reactive oxygen intermediates. By using CRAMP-deficient mice or synthetic CRAMP peptide, we found that CRAMP impaired
Salmonella
cell division
in vivo
and
in vitro
, resulting in long filamentous bacteria. This impaired bacterial cell division also depended on intracellular elastase-like serine protease activity, which can proteolytically activate cathelicidins. Macrophage serine protease activity induced filamentation and enhanced the activity of CRAMP
in vitro
. A peptide-sensitive
Salmonella
mutant showed enhanced survival within macrophages derived from CRAMP-deficient mice, indicating that
Salmonella
can sense and respond to cationic peptides in the intracellular environment. Although cationic peptides have been hypothesized to have activity against pathogens within macrophages, this work provides experimental evidence that the antimicrobial arsenal of macrophages includes cathelicidins. These results show that intracellular reactive oxygen intermediates and proteases regulate macrophage CRAMP expression and activity to impair the replication of an intracellular bacterial pathogen, and they highlight the cooperativity between macrophage antibacterial effectors.
Coexisting proinflammatory and antioxidative endothelial transcription profiles in a disturbed flow region of the adult porcine aorta
Authors: Passerini Anthony G. , Polacek Denise C. , Shi Congzhu , Francesco Nadeene M. , Manduchi Elisabetta , Grant Gregory R. , Pritchard William F. , Powell Steven , Chang Gary Y. , Stoeckert Christian J. , Davies Peter F.
Published: February 2004

In the arterial circulation, regions of disturbed flow (DF), which are characterized by flow separation and transient vortices, are susceptible to atherogenesis, whereas regions of undisturbed laminar flow (UF) appear protected. Coordinated regulation of gene expression by endothelial cells (EC) may result in differing regional phenotypes that either favor or inhibit atherogenesis. Linearly amplified RNA from freshly isolated EC of DF (inner aortic arch) and UF (descending thoracic aorta) regions of normal adult pigs was used to profile differential gene expression reflecting the steady statein vivo. By using human cDNA arrays, ≈2,000 putatively differentially expressed genes were identified through false-discovery-rate statistical methods. A sampling of these genes was validated by quantitative real-time PCR and/or immunostainingen face. Biological pathway analysis revealed that in DF there was up-regulation of several broad-acting inflammatory cytokines and receptors, in addition to elements of the NF-κB system, which is consistent with a proinflammatory phenotype. However, the NF-κB complex was predominantly cytoplasmic (inactive) in both regions, and no significant differences were observed in the expression of key adhesion molecules for inflammatory cells associated with early atherogenesis. Furthermore, there was no histological evidence of inflammation. Protective profiles were observed in DF regions, notably an enhanced antioxidative gene expression. This study provides a public database of regional EC gene expression in a normal animal, implicates hemodynamics as a contributory mechanism to athero-susceptibility, and reveals the coexistence of pro- and antiatherosclerotic transcript profiles in susceptible regions. The introduction of additional risk factors may shift this balance to favor lesion development.
Protein structure prediction for the male-specific region of the human Y chromosome
Authors: Ginalski Krzysztof , Rychlewski Leszek , Baker David , Grishin Nick V.
Published: February 2004

The complete sequence of the male-specific region of the human Y chromosome (MSY) has been determined recently; however, detailed characterization for many of its encoded proteins still remains to be done. We applied state-of-the-art protein structure prediction methods to all 27 distinct MSY-encoded proteins to provide better understanding of their biological functions and their mechanisms of action at the molecular level. The results of such large-scale structure-functional annotation provide a comprehensive view of the MSY proteome, shedding light on MSY-related processes. We found that, in total, at least 60 domains are encoded by 27 distinct MSY genes, of which 42 (70%) were reliably mapped to currently known structures. The most challenging predictions include the unexpected but confident 3D structure assignments for three domains identified here encoded by the
USP9Y
,
UTY
, and
BPY2
genes. The domains with unknown 3D structures that are not predictable with currently available theoretical methods are established as primary targets for crystallographic or NMR studies. The data presented here set up the basis for additional scientific discoveries in human biology of the Y chromosome, which plays a fundamental role in sex determination.
High genetic variability and low local diversity in a population of arbuscular mycorrhizal fungi
Authors: Koch Alexander M. , Kuhn Gerrit , Fontanillas Pierre , Fumagalli Luca , Goudet Jérôme , Sanders Ian R.
Published: February 2004

Arbuscular mycorrhizal fungi (AMF) are ecologically important root symbionts of most terrestrial plants. Ecological studies of AMF have concentrated on differences between species; largely assuming little variability within AMF species. Although AMF are clonal, they have evolved to contain a surprisingly high within-species genetic variability, and genetically different nuclei can coexist within individual spores. These traits could potentially lead to within-population genetic variation, causing differences in physiology and symbiotic function in AMF populations, a consequence that has been largely neglected. We found highly significant genetic and phenotypic variation among isolates of a population of
Glomus intraradices
but relatively low total observed genetic diversity. Because we maintained the isolated population in a constant environment, phenotypic variation can be considered as variation in quantitative genetic traits. In view of the large genetic differences among isolates by randomly sampling two individual spores, <50% of the total observed population genetic diversity is represented. Adding an isolate from a distant population did not increase total observed genetic diversity. Genetic variation exceeded variation in quantitative genetic traits, indicating that selection acted on the population to retain similar traits, which might be because of the multigenomic nature of AMF, where considerable genetic redundancy could buffer the effects of changes in the genetic content of phenotypic traits. These results have direct implications for ecological research and for studying AMF genes, improving commercial AMF inoculum, and understanding evolutionary mechanisms in multigenomic organisms.
Design of artificial cell–cell communication using gene and metabolic networks
Authors: Bulter Thomas , Lee Sun-Gu , Wong Wilson WaiChun , Fung Eileen , Connor Michael R. , Liao James C.
Published: February 2004

Artificial transcriptional networks have been used to achieve novel, nonnative behavior in bacteria. Typically, these artificial circuits are isolated from cellular metabolism and are designed to function without intercellular communication. To attain concerted biological behavior in a population, synchronization through intercellular communication is highly desirable. Here we demonstrate the design and construction of a gene-metabolic circuit that uses a common metabolite to achieve tunable artificial cell–cell communication. This circuit uses a threshold concentration of acetate to induce gene expression by acetate kinase and part of the nitrogen-regulation two-component system. As one application of the cell–cell communication circuit we created an artificial quorum sensor. Engineering of carbon metabolism in
Escherichia coli
made acetate secretion proportional to cell density and independent of oxygen availability. In these cells the circuit induced gene expression in response to a threshold cell density. This threshold can be tuned effectively by controlling ΔpH over the cell membrane, which determines the partition of acetate between medium and cells. Mutagenesis of the enhancer sequence of the glnAp
2
promoter produced variants of the circuit with changed sensitivity demonstrating tunability of the circuit by engineering of its components. The behavior of the circuit shows remarkable predictability based on a mathematical design model.
Activation of integrin β-subunit I-like domains by one-turn C-terminal α-helix deletions
Authors: Yang Wei , Shimaoka Motomu , Chen JianFeng , Springer Timothy A.
Published: February 2004

Integrins contain two structurally homologous but distantly related domains: an I-like domain that is present in all β-subunits and an I domain that is present in some α-subunits. Atomic resolution and mutagenesis studies of α I domains demonstrate a C-terminal, axial displacement of the α7-helix that allosterically regulates the shape and affinity of the ligand-binding site. Atomic resolution studies of β I-like domains have thus far demonstrated no similar α7-helix displacement; however, other studies are consistent with the idea that α I and β I-like domains undergo structurally analogous rearrangements. To test the hypothesis that C-terminal, axial displacement of the α7-helix, coupled with β6–α7 loop reshaping, activates β I-like domains, we have mimicked the effect of α7-helix displacement on the β6–α7 loop by shortening the α7-helix by two independent, four-residue deletions of about one turn of α-helix. In the case of integrin αLβ2, each mutant exhibits constitutively high affinity for the physiological ligand intercellular adhesion molecule 1 and full exposure of a β I-like domain activation-dependent antibody epitope. In the case of analogous mutants in integrin α4β7, each mutant shows the activated phenotype of firm adhesion, rather than rolling adhesion, in shear flow. The results show that integrins that contain or lack α I domains share a common pathway of β I-like domain activation, and they suggest that β I-like and α I domain activation involves structurally analogous α7-helix axial displacements.
Probing the antibody-catalyzed water-oxidation pathway at atomic resolution
Authors: Zhu Xueyong , Wentworth Paul , Wentworth Anita D. , Eschenmoser Albert , Lerner Richard A. , Wilson Ian A.
Published: February 2004

Antibodies can catalyze the generation of hydrogen peroxide (H
2
O
2
) from singlet dioxygen (
1
O*
2
) and water via the postulated intermediacy of dihydrogen trioxide (H
2
O
3
) and other trioxygen species. Nine different crystal structures were determined to elucidate the chemical consequences to the antibody molecule itself of exposure to such reactive intermediates and to provide insights into the location on the antibody where these species could be generated. Herein, we report structural evidence for modifications of two specific antibody residues within the interfacial region of the variable and constant domains of different murine antibody antigen-binding fragments (Fabs) by reactive species generated during the antibody-catalyzed water oxidation process. Crystal structure analyses of murine Fabs 4C6 and 13G5 after UV-irradiation revealed complex oxidative modifications to tryptophan L163 and, in 4C6, hydroxylation of the C
γ
of glutamine H6. These discrete modifications of specific residues add further support for the “active site” of the water-oxidation pathway being located within the interfacial region of the constant and variable domains and highlight the general resistance of the antibody molecule to oxidation by reactive oxygen species generated during the water-oxidation process.
Polymorphism in the
Plasmodium falciparum
erythrocyte-binding ligand JESEBL/EBA-181 alters its receptor specificity
Authors: Mayer D. C. Ghislaine , Mu Jian-Bing , Kaneko Osamu , Duan Junhui , Su Xin-zhuan , Miller Louis H.
Published: February 2004

The malaria parasite lives within erythrocytes and depends on the binding of parasite ligands to host cell surface receptors for invasion. The most virulent human malaria parasite,
Plasmodium falciparum
, uses multiple ligands, including EBA-175, BAEBL, and JESEBL of the Duffy-binding-like (DBL) family of erythrocyte-binding proteins, for invasion of human erythrocytes. Region II of these parasite ligands is the erythrocyte-binding domain. Previously, we had shown that polymorphism in region II of BAEBL leads to different erythrocyte-binding specificities. We have now identified and characterized the binding specificity of six JESEBL variants. We sequenced region II of JESEBL from 20
P. falciparum
clones collected from various parts of the world where malaria is endemic. We observed eight JESEBL variants that contained amino acid polymorphisms at five positions among all clones. Seven of the eight variants could be connected by a single base change that led to an amino acid change. We investigated the functional significance of these polymorphisms by transiently expressing region II from six of JESEBL variants on the surface of Chinese hamster ovary cells. We observed four erythrocyte-binding patterns to enzyme-treated erythrocytes. Thus,
P. falciparum
DBL ligands JESEBL and BAEBL can recognize multiple receptors on the erythrocyte surface. In contrast to
Plasmodium vivax
, which has disappeared from West Africa because of the Duffy-negative blood group,
P. falciparum
may have been successful in endemic areas because it has mutated the ligands of the DBL family to create multiple pathways of invasion, thus making selection of refractory erythrocytes unlikely.
Stabilizing selection on genomic divergence in a wild fish population
Authors: Neff Bryan D.
Published: February 2004

Conservation programs use breeding protocols to increase genomic divergence (by mating genetically dissimilar individuals) in an attempt to circumvent population declines resulting from inbreeding depression. However, disruption of either beneficial gene complexes or local genetic adaptations can lead to outbreeding depression, and thus, there should be a reduction in fitness of individuals at either end of the genomic divergence continuum. Although such simultaneous inbreeding and outbreeding depression has been observed in plant populations, it rarely has been demonstrated in animal populations. Here, I use both genetic and phenotypic measures to show that there is stabilizing selection on genomic divergence in a wild population of bluegill sunfish (Lepomis macrochirus). I also show that breeding individuals that exercise mate choice produce offspring that are closer to the optimal level of genomic divergence than random mating alone would predict.
The Shc adaptor protein is critical for VEGF induction by Met/HGF and ErbB2 receptors and for early onset of tumor angiogenesis
Authors: Saucier Caroline , Khoury Hanane , Lai Ka-Man Venus , Peschard Pascal , Dankort David , Naujokas Monica A. , Holash Jocelyn , Yancopoulos George D. , Muller William J. , Pawson Tony , Park Morag
Published: February 2004

The etiology and progression of a variety of human malignancies are linked to the deregulation of receptor tyrosine kinases (RTKs). To define the role of RTK-dependent signals in various oncogenic processes, we have previously engineered RTK oncoproteins that recruit either the Shc or Grb2 adaptor proteins. Although these RTK oncoproteins transform cells with similar efficiencies, fibroblasts expressing the Shc-binding RTK oncoproteins induced tumors with short latency (≈7 days), whereas cells expressing the Grb2-binding RTK oncoproteins induced tumors with delayed latency (≈24 days). The early onset of tumor formation correlated with the ability of cells expressing the Shc-binding RTK oncoproteins to produce vascular endothelial growth factor (VEGF) in culture and an angiogenic response
in vivo
. Consistent with this, treatment with a VEGF inhibitor, VEGF-Trap, blocked the
in vivo
angiogenic and tumorigenic properties of these cells. The importance of Shc recruitment to RTKs for the induction of VEGF was further demonstrated by using mutants of the Neu/ErbB2 RTK, where the Shc, but not Grb2, binding mutant induced VEGF. Moreover, the use of fibroblasts derived from ShcA-deficient mouse embryos, demonstrated that Shc was essential for the induction of VEGF by the Met/hepatocyte growth factor RTK oncoprotein and by serum-derived growth factors. Together, our findings identify Shc as a critical angiogenic switch for VEGF production downstream from the Met and ErbB2 RTKs.
Engineering
Escherichia coli
for efficient conversion of glucose to pyruvate
Authors: Causey T. B. , Shanmugam K. T. , Yomano L. P. , Ingram L. O.
Published: February 2004

Escherichia coli
TC44, a derivative of W3110, was engineered for the production of pyruvate from glucose by combining mutations to minimize ATP yield, cell growth, and CO
2
production (Δ
atpFH
Δ
adhE
Δ
sucA
) with mutations that eliminate acetate production [
poxB
::
FRT
(FLP recognition target) Δ
ackA
] and fermentation products (Δ
focA-pflB
Δ
frdBC
Δ
ldhA
Δ
adhE
). In mineral salts medium containing glucose as the sole carbon source, strain TC44(Δ
focA-pflB
Δ
frdBC
Δ
ldhA
Δ
atpFH
Δ
adhE
Δ
sucA poxB
::
FRT
Δ
ackA
) converted glucose to pyruvate with a yield of 0.75 g of pyruvate per g of glucose (77.9% of theoretical yield; 1.2 g of pyruvate liters
–1
·h
–1
). A maximum of 749 mM pyruvate was produced with excess glucose. Glycolytic flux was >50% faster for TC44 producing pyruvate than for the wild-type W3110 during fully aerobic metabolism. The tolerance of
E. coli
to such drastic changes in metabolic flow and energy production implies considerable elasticity in permitted pool sizes for key metabolic intermediates such as pyruvate and acetyl-CoA. In strain TC44, pyruvate yield, pyruvate titer, and the rate of pyruvate production in mineral salts medium were equivalent or better than previously reported for other biocatalyts (yeast and bacteria) requiring complex vitamin feeding strategies and complex nutrients. TC44 offers the potential to improve the economics of pyruvate production by reducing the costs of materials, product purification, and waste disposal.
Analysis of intergenic transcription in the human IL-4/IL-13 gene cluster
Authors: Rogan David F. , Cousins David J. , Santangelo Samantha , Ioannou Panayiotis A. , Antoniou Michael , Lee Tak H. , Staynov Dontcho Z.
Published: February 2004

During the differentiation of naïve CD4
+
precursors to T helper 1 (Th1) or Th2 effector cells, several epigenetic changes occur in a lineage-specific manner at the
IFN-
γ or
IL-4
/
IL-13
loci. These changes result in alterations in the chromatin structure of these loci and, hence, lineage-restricted expression of the corresponding cytokines. Intergenic transcripts have recently been shown to regulate the expression of genes in the β-globin locus; therefore, we have examined the Th2 cytokine gene cluster during human Th1/Th2 differentiation and in a transgenic mouse line containing the human IL-4/IL-13 genes for intergenic transcripts. We show for the first time that intergenic transcription of this locus is restricted to tissues and lineages in which IL-4 and IL-13 are expressed. We also show that intergenic transcription in the
IL-4
/
IL-13
locus is up-regulated after Th2 differentiation. Furthermore, we demonstrate that the Th2 cytokines and intergenic transcripts are detectable in the thymus. We propose that intergenic transcription is tightly associated with transcriptional competence for the Th2 cytokines and may play a role in their regulation. These results support a progressive differentiation model of T cell lineage commitment.
Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells
Authors: Ovaa Huib , Kessler Benedikt M. , Rolén Ulrika , Galardy Paul J. , Ploegh Hidde L. , Masucci Maria G.
Published: February 2004

The family of ubiquitin (Ub)-specific proteases (USP) removes Ub from Ub conjugates and regulates a variety of cellular processes. The human genome contains many putative USP-encoding genes, but little is known about USP tissue distribution, pattern of expression, activity, and substrate specificity. We have used a chemistry-based functional proteomics approach to identify active USPs in normal, virus-infected, and tumor-derived human cells. Depending on tissue origin and stage of activation/differentiation, different USP activity profiles were revealed. The activity of specific USPs, including USP5, -7, -9, -13, -15, and -22, was up-regulated by mitogen activation or virus infection in normal T and B lymphocytes. UCH-L1 was highly expressed in tumor cell lines of epithelial and hematopoietic cell origin but was not detected in freshly isolated and mitogen-activated cells. Up-regulation of this USP was a late event in the establishment of Epstein–Barr virus-immortalized lymphoblastoid cell lines and correlated with enhanced proliferation, suggesting a possible role in growth transformation.
Mutation of the zebrafish
choroideremia
gene encoding Rab escort protein 1 devastates hair cells
Authors: Starr Catherine J. , Kappler James A. , Chan Dylan K. , Kollmar Richard , Hudspeth A. J.
Published: February 2004

To identify genes important for hair-cell function, we conducted a mutagenic screen in zebrafish. Larvae from one mutant line,
ru848
, were unresponsive to acoustic stimuli and unable to balance. The mutation results in a 90% reduction in hair-cell number and partial retinal degeneration by 5 days postfertilization. We localized the recessive
ru848
mutation by positional cloning to the zebrafish homolog of the human
Choroideremia
gene, which encodes Rab escort protein 1. This protein is essential for the normal prenylation of Rabs. Mutations in the human gene induce choroideremia, a disease marked by slow-onset degeneration of rod photoreceptors and retinal pigment epithelial cells. The degenerative phenotype resulting from a null mutation in the zebrafish gene indicates that hair cells and retinal cells require Rab escort protein 1 for survival.
Genetic and functional confirmation of the causality of the
DGAT1 K232A
quantitative trait nucleotide in affecting milk yield and composition
Authors: Grisart Bernard , Farnir Frédéric , Karim Latifa , Cambisano Nadine , Kim Jong-Joo , Kvasz Alex , Mni Myriam , Simon Patricia , Frère Jean-Marie , Coppieters Wouter , Georges Michel
Published: February 2004

We recently used a positional cloning approach to identify a nonconservative lysine to alanine substitution (
K232A
) in the bovine
DGAT1
gene that was proposed to be the causative quantitative trait nucleotide underlying a quantitative trait locus (QTL) affecting milk fat composition, previously mapped to the centromeric end of bovine chromosome 14. We herein generate genetic and functional data that confirm the causality of the
DGAT1 K232A
mutation. We have constructed a high-density single-nucleotide polymorphism map of the 3.8-centimorgan
BULGE30–BULGE9
interval containing the QTL and show that the association with milk fat percentage maximizes at the
DGAT1
gene. We provide evidence that the
K
allele has undergone a selective sweep. By using a baculovirus expression system, we have expressed both
DGAT1
alleles in Sf9 cells and show that the
K
allele, causing an increase in milk fat percentage in the live animal, is characterized by a higher
V
max
in producing triglycerides than the
A
allele.
Potentiation of NMDA receptor currents by dopamine D
1
receptors in prefrontal cortex
Authors: Chen Guojun , Greengard Paul , Yan Zhen
Published: February 2004

Interactions between dopamine and
N
-methyl-
d
-aspartate receptors (NMDARs) in prefrontal cortex (PFC) and other brain regions are believed to play an important role in normal mental function and neuropsychiatric disorders. In this study, we examined the regulation of NMDAR currents by the dopamine D
1
receptor in PFC pyramidal neurons. Application of the D
1
receptor agonist SKF81297 caused a prominent increase of the steady-state NMDA-evoked current in acutely isolated PFC pyramidal neurons. The D
1
effect on NMDARs was independent of protein kinase A or protein phosphatase 1, but was abolished by incubation of neurons in Ca
2+
-free medium. Intracellular application of the Ca
2+
chelator, calmodulin, or calmodulin inhibitors largely prevented the D
1
modulation of NMDAR currents. Moreover, inhibiting PKC activity or disrupting PKC association with its anchoring protein also significantly reduced the D
1
effect on NMDAR currents. This upregulation of NMDAR activity by dopamine D
1
receptors and the previous finding on up-regulation of dopamine D
1
receptors by NMDAR activation provide a cellular mechanism for the reciprocal interactions between D
1
and NMDARs. These interactions may play an important role in modulating synaptic plasticity and thus in cognitive and emotional processes.
Identification of a developmentally regulated striatum-enriched zinc-finger gene,
Nolz-1
, in the mammalian brain
Authors: Chang Chiung-Wen , Tsai Chi-Wei , Wang Hsiao-Fang , Tsai Hsiu-Chao , Chen Huei-Ying , Tsai Ting-Fen , Takahashi Hiroshi , Li Hui-Yun , Fann Ming-Ji , Yang Chu-Wen , Hayashizaki Yoshihide , Saito Tetsuichiro , Liu Fu-Chin
Published: February 2004

Neural information processed through the striatum of the basal ganglia is crucial for sensorimotor and psychomotor functions. Genes that are highly expressed in the striatum during development may be involved in neural development and plasticity in the striatum. We report in the present study the identification of a previously uncharacterized mammalian member of the
nocA
/
elB
/
tlp-1
family,
Nolz-1
, that is preferentially expressed at high levels in the developing striatum.
Nolz-1
mRNA was expressed as soon as striatal anlage began to form at embryonic day 13 in the rat.
Nolz-1
mRNA was predominantly expressed in the lateral ganglionic eminence (striatal primordium) and was nearly absent in the adjacent structures of the medial ganglionic eminence and the cerebral cortex. Moreover,
Nolz-1
was highly expressed in the subventricular zone of the lateral ganglionic eminence and was colocalized with the early neuronal differentiation markers of TuJ1 and Isl1 and the projection neuron marker of DARPP-32, suggesting that
Nolz-1
was expressed in differentiating progenitors of striatal projection neurons. A time course study showed that
Nolz-1
mRNA was developmentally regulated, as its expression was down-regulated postnatally with low levels remaining in the ventral striatum at adulthood. As the tagged Nolz-1 protein was localized in the nucleus,
Nolz-1
may function as transcriptional regulator. In a model system for neural differentiation,
Nolz-1
mRNA was dramatically induced on neural induction of P19 embryonal carcinoma cells by retinoic acid, suggesting that
Nolz-1
activation may be involved in neural differentiation. Our study suggests that
Nolz-1
is preferentially expressed in differentiating striatal progenitors and may be engaged in the genetic program for controlling striatal development.
Extrapancreatic insulin-producing cells in multiple organs in diabetes
Authors: Kojima Hideto , Fujimiya Mineko , Matsumura Kazuhiro , Nakahara Tamio , Hara Manami , Chan Lawrence
Published: February 2004

Insulin-producing cells normally occur only in the pancreas and thymus. Surprisingly, we found widespread insulin mRNA and protein expression in different diabetic mouse and rat models, including streptozotocin-treated mice and rats,
ob
/
ob
mice, and mice fed high-fat diets. We detected in diabetic mice proinsulin- and insulin-positive cells in the liver, adipose tissue, spleen, bone marrow, and thymus; many cells also produced glucagon, somatostatin, and pancreatic polypeptide. By
in situ
nucleic acid hybridization, diabetic, but not nondiabetic, mouse liver exhibited insulin transcript-positive cells, indicating that insulin was synthesized by these cells. In transgenic mice that express GFP driven by the mouse insulin promoter, streptozotocin-induced diabetes led to the appearance of GFP-positive cells in liver, adipose tissue, and bone marrow; the fluorescent signals showed complete concordance with the presence of immunoreactive proinsulin. Hyperglycemia produced by glucose injections in nondiabetic mice led to the appearance of proinsulin- and insulin-positive cells within 3 days. Bone marrow transplantation experiments showed that most of the extrapancreatic proinsulin-producing cells originated from the bone marrow. Immunoreactive proinsulin- and insulin-positive cells were also detected in the liver, adipose tissue, and bone marrow of diabetic rats, indicating that extrapancreatic, extrathymic insulin production occurs in more than one species. These observations have implications for the regulation of insulin gene expression, modulation of self-tolerance by insulin gene expression, and strategies for the generation of insulin-producing cells for the treatment of diabetes.
The elongation of yeast prion fibers involves separable steps of association and conversion
Authors: Scheibel Thomas , Bloom Jesse , Lindquist Susan L.
Published: February 2004

A self-perpetuating change in the conformation of the translation termination factor Sup35p is the basis for the prion [
PSI
+
], a protein-based genetic element of
Saccharomyces cerevisiae
. In a process closely allied to
in vivo
conversion, the purified soluble, prion-determining region of Sup35p (NM) converts to amyloid fibers by means of nucleated conformational conversion. First, oligomeric species convert to nuclei, and these nuclei then promote polymerization of soluble protein into amyloid fibers. To elucidate the nature of the polymerization step, we created single-cysteine substitution mutants at different positions in NM to provide unique attachment sites for various probes.
In vivo
, the mutants behaved like wild-type protein in both the [
psi
–
] and [
PSI
+
] states.
In vitro
, they assembled with wild-type kinetics and formed fibers with the same morphologies. When labeled with fluorescent probes, two mutants, NM
T158C
and NM
E167C
, exhibited a change in fluorescence coincident with amyloid assembly. These mutants provided a sensitive measure for the kinetics of fiber elongation, and the lag phase in conversion. The cysteine in the mutant NM
K184C
remained exposed after assembly. When labeled with biotin and bound to streptavidin beads, it was used to capture radiolabeled soluble NM in the process of conversion. This process established the existence of a detergent-susceptible intermediate in fiber elongation. Thus, the second stage of nucleated conformational conversion, fiber elongation, itself contains at least two steps: the association of soluble protein with preformed fibers to form an assembly intermediate, followed by conformational conversion into amyloid.
Artemis and p53 cooperate to suppress oncogenic
N-myc
amplification in progenitor B cells
Authors: Rooney Sean , Sekiguchi JoAnn , Whitlow Scott , Eckersdorff Mark , Manis John P. , Lee Charles , Ferguson David O. , Alt Frederick W.
Published: February 2004

The nonhomologous DNA end-joining (NHEJ) pathway contains six known components, including Artemis, a nuclease mutated in a subset of human severe combined immunodeficient patients. Mice doubly deficient for the five previously analyzed NHEJ factors and p53 inevitably develop progenitor B lymphomas harboring der(12)t(12;15) translocations and immunoglobin heavy chain (
IgH
)/
c-myc
coamplification mediated by a breakage-fusion-bridge mechanism. In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice. However, the majority of Artemis/p53-deficient tumors lacked der(12)t(12;15) translocations and
c-myc
amplification and instead coamplified
IgH
and
N-myc
through an intra- or interchromosome 12 breakage-fusion-bridge mechanism. We discuss this finding in the context of potential implications for mechanisms that may target
IgH
locus translocations to particular oncogenes.
Nurturing cognitive competence in preschoolers: A longitudinal study of intergenerational continuity and risk
Authors: Saltaris Christina , Serbin Lisa A. , Stack Dale M. , Karp Jennifer A. , Schwartzman Alex E. , Ledingham Jane E.
Published: February 2004

The current investigation was designed to examine the provision of cognitive stimulation to preschool-aged children from high-risk families. Participants were drawn from the Concordia Longitudinal Risk Project, a prospective, longitudinal investigation of individuals recruited in 1976–77 from lower SES neighbourhoods who were rated by childhood peers on standardised scales of aggression and social withdrawal. Based on a subsample of women followed from childhood to motherhood ( N = 51), we found that childhood behaviour patterns, particularly a history of aggression, negatively predicted cognitive stimulation to preschool-aged offspring, in the context of(1) scaffolding during a structured teaching task, and (2) the quality of the home environment provided for children. In the second part of the study, concurrent analyses focusing on children’s cognitive competence ( N = 80) revealed that parental stimulation predicts the intellectual functioning of preschool-aged offspring within a community-based, high-risk sample. Taken together, the current findings provide evidence for the existence of a pathway of intergenerational transfer of risk operating through cognitive stimulation.
‘‘I learn and I grow big’’: Chinese preschoolers’ purposes for learning
Authors: Li Jin
Published: February 2004

Despite much research on Chinese children’s learning achievement, little research exists on their early development of beliefs about learning. This study examined the perceptions of purposes for and affective and value expression toward learning among 129 Chinese preschoolers aged 3–6 years. To tap culturally valid perspectives, free narratives prompted by story beginnings and responses to probes about books and school scenarios were collected and analysed both qualitatively and quantitatively. We identified four types of benefits from learning that children revealed: (1) Intellectual benefits emphasising acquisition of skill, continuous personal growth, and ‘‘a lot’’ of knowledge; (2) respect/admiration for learning; (3) social benefits for others; and (4) economic benefits. Children also expressed highly positive feelings and value toward learning. These trends increased with age. The findings are discussed in light of Chinese cultural values of learning and their influence on children’s development of beliefs about learning.
Self-perceptions of competence in Brazilian, Canadian, Chinese and Italian children: Relations with social and school adjustment
Authors: Chen Xinyin , Zappulla Carla , Coco Alida Lo , Schneider Barry , Kaspar Violet , De Oliveira Ana Maria , He Yunfeng , Li Dan , Li Boshu , Bergeron Natasha , Tse Hennis Chi-Hang , DeSouza Amanda
Published: February 2004

The purpose of the present study was to examine relations between self-perceptions of competence and social, behavioural, and school adjustment in Brazilian, Canadian, Chinese, and Italian children. Self-perception data were collected through children’s self-reports. Information about social behaviours, peer acceptance, and school achievement was obtained from peer assessments and teacher ratings. Multi-group analyses revealed similar patterns of relations between self-perceptions in scholastic and general self-worth domains and social and school performance in the four samples. However, the relations between self-perceptions of social competence and shyness and academic achievement were different across these samples. Self-perceptions of social competence was negatively associated with shyness in Brazilian, Canadian, and Italian children, but not in the Chinese children, and positively associated with academic achievement in Canadian and Chinese children, but not in Brazilian and Italian children. Similarities and differences in the patterns of relations between self-perceptions and social and school adjustment across cultures indicate that the self system may be a culture-general as well as culture-specific phenomenon.
Early attention and negative emotionality predict later cognitive and behavioural function
Authors: Lawson Katharine R. , Ruff Holly A.
Published: February 2004

Negative emotionality and poor attention may combine or interact as risk factors in development. Negative emotionality is considered a challenge for self-regulation, whereas good attention is a potential means of self-regulation. In the current study, composites of 1- and 2-year maternal ratings of negative emotionality and global ratings of observed attentiveness were predictors for 3.5-year cognitive and behavioural outcome for 75 children. Results of variable-based regression analyses indicated that early negativity and attentiveness predicted IQ and scores on a hyperactivity index; only negativity predicted a global measure of behaviour problems. Results of person-based analyses for groups formed by median splits on negativity and attention suggested that the More Negative/Less Attentive group had significantly poorer outcome than the other three groups combined (those with one or none of the two risk factors). Comparisons of mean differences also suggested a protective effect of greater attentiveness for more negative as opposed to less negative children for all outcomes. The results extend prior work in providing longitudinal data over the first 3 years and including both cognitive and behavioural outcomes.
Parenting behaviours during child problem solving: The roles of child temperament, mother education and personality, and the problem-solving context
Authors: Neitzel Carin , Stright Anne Dopkins
Published: February 2004

Child temperament, parent openness to experience, conscientiousness, and education, and parent a priori assessments of the task were examined in relation to parenting behaviours during child problem solving. Mothers and their children (73 dyads) were visited the summer before kindergarten. Mothers’ cognitive, emotional, and autonomy support were coded as they provided assistance during four child problem-solving tasks. Mothers with more education provided more metacognitive information. Before education was considered, it appeared that mothers who perceived their children as difficult and who were less open to experiences were less likely to regulate task difficulty, encourage their children’s efforts, and encourage their children’s active role in problem solving. However, more educated mothers regulated task difficulty, encouraged their children’s efforts, and encouraged their children’s active role more when they perceived their children as difficult than when they perceived their children as easy. More educated mothers also were likely to regulate task difficulty and encourage their children’s active role regardless of their openness. Children perceived as difficult were most likely to be rejected and also were particularly likely to be rejected if the mother was highly conscientious. Conscientious mothers were likely to be overly controlling. When mothers perceived the task negatively they were less likely to provide metacognitive information, regulate task difficulty, and encourage the child’s active role; and were more likely to be overcontrolling and rejecting.
Explaining the Success of a Scientific Theory
Authors: Lyons Timothy D.
Published: February 2004

Scientific realists have claimed that the posit that our theories are (approximately) true provides the best or the only explanation for their success. In response, I revive two nonrealist explanations. I show that realists, in discarding them, have either misconstrued the phenomena to be explained or mischaracterized the relationship between these explanations and their own. I contend nonetheless that these nonrealist competitors, as well as their realist counterparts, should be rejected; for none of them succeed in explaining a significant list of successes. I propose a related nonrealist explanation of success that appears to be the most suitable among those considered.
Preservative Realism and Its Discontents: Revisiting Caloric
Authors: Chang Hasok
Published: February 2004

A popular and plausible response against Laudan's “pessimistic induction” has been what I call “preservative realism,” which argues that there have actually been enough elements of scientific knowledge preserved through major theory-change processes, and that those elements can be accepted realistically. This paper argues against preservative realism, in particular through a critical review of Psillos's argument concerning the case of the caloric theory of heat. Contrary to his argument, the historical record of the caloric theory reveals that beliefs about the properties of material caloric, rejected by subsequent theories, were indeed central to the successes of the caloric theory. Therefore caloric remains a favorable case for Laudan. Further, I argue that even confirmed cases of preservation do not warrant an inference to truth.
No Refuge for Realism: Selective Confirmation and the History of Science
Authors: Stanford P. Kyle
Published: February 2004

Realists have responded to challenges from the historical record of successful but ultimately rejected theories with what I call theselective confirmationstrategy: arguing that onlyidleparts of past theories have been rejected, while truly success-generating features have been confirmed by further inquiry. I argue first, that this strategy is unconvincing without someprospectively applicablecriterion of idleness for theoretical posits, and second, that existing efforts to provide one either convict all theoretical posits of idleness (Kitcher) or stand refuted by detailed consideration of the very examples (optical/electromagnetic ether, caloric fluid) to which they appeal (Psillos). I also argue that available avenues for improving on these proposals are unpromising.
Object and Event Concepts: A Cognitive Mechanism of Incommensurability
Authors: Chen Xiang
Published: February 2004

In this paper I examine a cognitive mechanism of incommensurability. Using the frame model of concept representation to capture structural relations within concepts, I reveal an ontological difference between object and event concepts: the former are spatial but the latter temporal. Experiments from cognitive sciences further demonstrate that the mind treats object and event concepts differently. Thus, incommensurability can occur in conceptual change across different ontological categories. I use a historical case to illustrate how the ontological difference between an object and an event concept actually caused incommensurability in the context of nineteenth-century optics. The cognitive and historical analyses indicate that incommensurability can be a local phenomenon and does not necessarily imply incomparability.
Heritability and Indirect Causation
Authors: Sesardic Neven
Published: February 2004

Genetic differences can lead to phenotypic differences either directly or indirectly (via causing differences in external environments, which then affect phenotype). This possibility of genetic effects being mediated by environmental influences is often used by scientists and philosophers to argue that heritability is not a very helpful causal or explanatory notion. In this paper it is shown that these criticisms are based on serious misconceptions about methods of behavior genetics.
Evolvability, Dispositions, and Intrinsicality
Authors: Love Alan C.
Published: February 2004

In this paper I examine a dispositional property that has been receiving increased attention in biology, evolvability. First, I identify three compatible but distinct investigative approaches, distinguish two interpretations of evolvability, and treat the difference between dispositions of individuals versus populations. Second, I explore the relevance of philosophical distinctions about dispositions for evolvability, isolating the assumption that dispositions are intrinsically located. I conclude that some instances of evolvability cannot be understood as purely intrinsic to populations and suggest alternative strategies for resolving this difficulty.