bluuebunny/crossref_metadata_2025 huggingface dataset:
The human disease network
Authors: Goh Kwang-Il , Cusick Michael E. , Valle David , Childs Barton , Vidal Marc , Barabási Albert-László
Published: May 2007

A network of disorders and disease genes linked by known disorder–gene associations offers a platform to explore in a single graph-theoretic framework all known phenotype and disease gene associations, indicating the common genetic origin of many diseases. Genes associated with similar disorders show both higher likelihood of physical interactions between their products and higher expression profiling similarity for their transcripts, supporting the existence of distinct disease-specific functional modules. We find that essential human genes are likely to encode hub proteins and are expressed widely in most tissues. This suggests that disease genes also would play a central role in the human interactome. In contrast, we find that the vast majority of disease genes are nonessential and show no tendency to encode hub proteins, and their expression pattern indicates that they are localized in the functional periphery of the network. A selection-based model explains the observed difference between essential and disease genes and also suggests that diseases caused by somatic mutations should not be peripheral, a prediction we confirm for cancer genes.
Exposing the core promoter is sufficient to activate transcription and alter coactivator requirement at
RNR3
Authors: Zhang Hesheng , Reese Joseph C.
Published: May 2007

Chromatin is a formidable barrier to transcription. Nucleosome density is lowest over the regulatory regions of active genes, and many repressed genes have a tightly positioned nucleosome over their core promoter. However, it has not been shown that nucleosome positioning is sufficient for repression or whether disrupting a core promoter nucleosome specifically can activate gene expression in the absence of activating signals. Here we show that disrupting the nucleosome over the core promoter of
RNR3
is sufficient to drive preinitiation complex assembly and activate transcription in the absence of activating signals. Remodeling of chromatin over the
RNR3
promoter requires the recruitment of the SWI/SNF complex by the general transcription factor TFIID. We found that disrupting the nucleosome over the
RNR3
core promoter relieves its dependence on TFIID and SWI/SNF, indicating a functional link between these two complexes. These results suggest that the specific function of TAF
II
s is to direct the chromatin remodeling step through SWI/SNF recruitment, and not core promoter selectivity. Our results indicate that nucleosome placement plays a dominant role in repression and that the ability of the core promoter to position a nucleosome is a major determinant in TAF
II
dependency of genes
in vivo
.
Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation
Authors: Fritsche Ellen , Schäfer Claudia , Calles Christian , Bernsmann Thorsten , Bernshausen Thorsten , Wurm Melanie , Hübenthal Ulrike , Cline Jason E. , Hajimiragha Hossein , Schroeder Peter , Klotz Lars-Oliver , Rannug Agneta , Fürst Peter , Hanenberg Helmut , Abel Josef , Krutmann Jean
Published: May 2007

UVB radiation-induced signaling in mammalian cells involves two major pathways: one that is initiated through the generation of DNA photoproducts in the nucleus and a second one that occurs independently of DNA damage and is characterized by cell surface receptor activation. The chromophore for the latter one has been unknown. Here, we report that the UVB response involves tryptophan as a chromophore. We show that through the intracellular generation of photoproducts, such as the arylhydrocarbon receptor (AhR) ligand 6-formylindolo[3,2-b]carbazole, signaling events are initiated, which are transferred to the nucleus and the cell membrane via activation of the cytoplasmatic AhR. Specifically, AhR activation by UVB leads to (i) transcriptional induction of cytochrome P450 1A1 and (ii) EGF receptor internalization with activation of the EGF receptor downstream target ERK1/2 and subsequent induction of cyclooxygenase-2. The role of the AhR in the UVB stress response was confirmedin vivoby studies employing AhR KO mice.
In vitroerythropoiesis from bone marrow-derived progenitors provides a physiological assay for toxic and mutagenic compounds
Authors: Shuga J. , Zhang J. , Samson L. D. , Lodish H. F. , Griffith L. G.
Published: May 2007

The goal of this study was to create anin vitrocell culture system that captures essential features of thein vivoerythroid micronucleus (MN) genotoxicity assay, thus enabling increased throughput and controlled studies of the hematopoietic DNA damage response. We show that adult bone marrow (BM) cultures respond to erythropoietin, the principal hormone that stimulates erythropoiesis, with physiological erythropoietic proliferation, differentiation, and enucleation. We then show that thisin vitroerythropoietic system clearly signals exposure to genotoxicants through erythroid MN formation. Furthermore, we determined that DNA repair-deficient (MGMT−/−) BM displayed sensitivity to genotoxic exposurein vivocompared with WT BM and that this phenotypic response was reflected in erythropoietic cultures. These findings suggest that thisin vitroerythroid MN assay is capable of screening for genotoxicity on BM in a physiologically reflective manner. Finally, responses to genotoxicants during erythroid differentiation varied with exposure time, demonstrating that this system can be used to study the effect of DNA damage at specific developmental stages.
A complex thiolate switch regulates the
Bacillus subtilis
organic peroxide sensor OhrR
Authors: Lee Jin-Won , Soonsanga Sumarin , Helmann John D.
Published: May 2007

Oxidation of protein thiolates is central to numerous redox-regulated processes.
Bacillus subtilis
OhrR is an organic peroxide sensor that represses expression of an inducible peroxiredoxin, OhrA. Here, we present evidence that oxidation of the sole cysteine residue in OhrR leads to a sulfenic acid-containing intermediate that retains DNA-binding activity: further reaction to generate either a mixed disulfide (S-thiolation) or a protein sulfenamide (sulfenyl-amide) derivative is essential for derepression. Protein S-thiolation protects OhrR from overoxidation and provides for a facile regeneration of active OhrR by thiol–disulfide exchange reactions. The sulfenamide can also be reduced by thiol–disulfide exchange reactions, although this process is much slower than for mixed disulfides. Recovery of oxidized OhrR from
B. subtilis
identifies three distinct S-thiolated species, including mixed disulfides with a novel 398-Da thiol, cysteine, and CoASH. Evidence for
in vivo
formation of the sulfenamide derivative is also presented.
Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid
in vivo
Authors: Chen Qi , Espey Michael Graham , Sun Andrew Y. , Lee Je-Hyuk , Krishna Murali C. , Shacter Emily , Choyke Peter L. , Pooput Chaya , Kirk Kenneth L. , Buettner Garry R. , Levine Mark
Published: May 2007

Ascorbate (ascorbic acid, vitamin C), in pharmacologic concentrations easily achieved in humans by i.v. administration, selectively kills some cancer cells but not normal cells. We proposed that pharmacologic ascorbate is a prodrug for preferential steady-state formation of ascorbate radical (Asc
•−
) and H
2
O
2
in the extracellular space compared with blood. Here we test this hypothesis
in vivo
. Rats were administered parenteral (i.v. or i.p.) or oral ascorbate in typical human pharmacologic doses (≈0.25–0.5 mg per gram of body weight). After i.v. injection, ascorbate baseline concentrations of 50–100 μM in blood and extracellular fluid increased to peaks of >8 mM. After i.p. injection, peaks approached 3 mM in both fluids. By gavage, the same doses produced ascorbate concentrations of <150 μM in both fluids. In blood, Asc
•−
concentrations measured by EPR were undetectable with oral administration and always <50 nM with parenteral administration, even when corresponding ascorbate concentrations were >8 mM. After parenteral dosing, Asc
•−
concentrations in extracellular fluid were 4- to 12-fold higher than those in blood, were as high as 250 nM, and were a function of ascorbate concentrations. By using the synthesized probe peroxyxanthone, H
2
O
2
in extracellular fluid was detected only after parenteral administration of ascorbate and when Asc
•−
concentrations in extracellular fluid exceeded 100 nM. The data show that pharmacologic ascorbate is a prodrug for preferential steady-state formation of Asc
•−
and H
2
O
2
in the extracellular space but not blood. These data provide a foundation for pursuing pharmacologic ascorbate as a prooxidant therapeutic agent in cancer and infections.
A highly divergent microsatellite facilitating fast and accurateDRBhaplotyping in humans and rhesus macaques
Authors: Doxiadis Gaby G. M. , de Groot Nanine , Claas Frans H. J. , Doxiadis Ilias I. N. , van Rood Jon J. , Bontrop Ronald E.
Published: May 2007

TheDRBregion of the MHC in primate species is known to display abundant region configuration polymorphism with regard to the number and content of genes present per haplotype. Furthermore, depending on the species studied, the differentDRBgenes themselves may display varying degrees of allelic polymorphism. Because of this combination of diversity (differential gene number) and polymorphism (allelic variation), molecular typing methods for the primateDRBregion are cumbersome. All intactDRBgenes present in humans and rhesus macaques appear to possess, however, a complex and highly divergent microsatellite. Microsatellite analysis of a sizeable panel of outbred rhesus macaques, covering most of the knownMamu-DRBhaplotypes, resulted in the definition of unique genotyping patterns that appear to be specific for a given haplotype. Subsequent examination of a representative panel of human cells illustrated that this approach also facilitates high-resolutionHLA-DRBtyping in an easy, quick, and reproducible fashion. The genetic composition of this complex microsatellite is shown to be in concordance with the phylogenetic relationships of variousHLA-DRBandMamu-DRBexon 2 gene/lineage sequences. Moreover, its length variability segregates with allelic variation of the respective gene. This simple protocol may find application in a variety of research avenues such as transplantation biology, disease association studies, molecular ecology, paternity testing, and forensic medicine.
Irreducible imprecision in atmospheric and oceanic simulations
Authors: McWilliams James C.
Published: May 2007

Atmospheric and oceanic computational simulation models often successfully depict chaotic space–time patterns, flow phenomena, dynamical balances, and equilibrium distributions that mimic nature. This success is accomplished through necessary but nonunique choices for discrete algorithms, parameterizations, and coupled contributing processes that introduce structural instability into the model. Therefore, we should expect a degree of irreducible imprecision in quantitative correspondences with nature, even with plausibly formulated models and careful calibration (tuning) to several empirical measures. Where precision is an issue (e.g., in a climate forecast), only simulation ensembles made across systematically designed model families allow an estimate of the level of relevant irreducible imprecision.
Visual word processing and experiential origins of functional selectivity in human extrastriate cortex
Authors: Baker Chris I. , Liu Jia , Wald Lawrence L. , Kwong Kenneth K. , Benner Thomas , Kanwisher Nancy
Published: May 2007

How do category-selective regions arise in human extrastriate cortex? Visually presented words provide an ideal test of the role of experience: Although individuals have extensive experience with visual words, our species has only been reading for a few thousand years, a period not thought to be long enough for natural selection to produce a genetically specified mechanism dedicated to visual word recognition
per se
. Using relatively high-resolution functional magnetic resonance imaging (1.4 × 1.4 × 2-mm voxels), we identified a small region of extrastriate cortex in most participants that responds selectively to both visually presented words and consonant strings, compared with line drawings, digit strings, and Chinese characters. Critically, we show that this pattern of selectivity is dependent on experience with specific orthographies: The same region responds more strongly to Hebrew words in Hebrew readers than in nonreaders of Hebrew. These results indicate that extensive experience with a given visual category can produce strong selectivity for that category in discrete cortical regions.
Interaction of TIA-1/TIAR with West Nile and dengue virus products in infected cells interferes with stress granule formation and processing body assembly
Authors: Emara Mohamed M. , Brinton Margo A.
Published: May 2007

The West Nile virus minus-strand 3′ terminal stem loop (SL) RNA was previously shown to bind specifically to cellular stress granule (SG) components, T cell intracellular antigen-1 (TIA-1) and the related protein TIAR.
In vitro
TIAR binding was 10 times more efficient than TIA-1. The 3′(−)SL functions as the promoter for genomic RNA synthesis. Colocalization of TIAR and TIA-1 with the viral replication complex components dsRNA and NS3 was observed in the perinuclear regions of West Nile virus- and dengue virus-infected cells. The kinetics of accumulation of TIAR in the perinuclear region was similar to those of genomic RNA synthesis. In contrast, relocation of TIA-1 to the perinuclear region began only after maximal levels of RNA synthesis had been achieved, except when TIAR was absent. Virus infection did not induce SGs and progressive resistance to SG induction by arsenite developed coincident with TIAR relocation. A progressive decrease in the number of processing bodies was secondarily observed in infected cells. These data suggest that the interaction of TIAR with viral components facilitates flavivirus genome RNA synthesis and inhibits SG formation, which prevents the shutoff of host translation.
Imaging analysis reveals mechanistic differences between first- and second-phase insulin exocytosis
Authors: Ohara-Imaizumi Mica , Fujiwara Tomonori , Nakamichi Yoko , Okamura Tadashi , Akimoto Yoshihiro , Kawai Junko , Matsushima Satsuki , Kawakami Hayato , Watanabe Takashi , Akagawa Kimio , Nagamatsu Shinya
Published: May 2007

The mechanism of glucose-induced biphasic insulin release is unknown. We used total internal reflection fluorescence (TIRF) imaging analysis to reveal the process of first- and second-phase insulin exocytosis in pancreatic β cells. This analysis showed that previously docked insulin granules fused at the site of syntaxin (Synt)1A clusters during the first phase; however, the newcomers fused during the second phase external to the Synt1A clusters. To reveal the function of Synt1A in phasic insulin exocytosis, we generated Synt1A-knockout (Synt1A−/−) mice. Synt1A−/− β cells showed fewer previously docked granules with no fusion during the first phase; second-phase fusion from newcomers was preserved. Rescue experiments restoring Synt1A expression demonstrated restoration of granule docking status and fusion events. Inhibition of other syntaxins, Synt3 and Synt4, did not affect second-phase insulin exocytosis. We conclude that the first phase is Synt1A dependent but the second phase is not. This indicates that the two phases of insulin exocytosis differ spatially and mechanistically.
The budding yeast PP2ACdc55 protein phosphatase prevents the onset of anaphase in response to morphogenetic defects
Authors: Chiroli Elena , Rossio Valentina , Lucchini Giovanna , Piatti Simonetta
Published: May 2007

Faithful chromosome transmission requires establishment of sister chromatid cohesion during S phase, followed by its removal at anaphase onset. Sister chromatids are tethered together by cohesin, which is displaced from chromosomes through cleavage of its Mcd1 subunit by the separase protease. Separase is in turn inhibited, up to this moment, by securin. Budding yeast cells respond to morphogenetic defects by a transient arrest in G2 with high securin levels and unseparated chromatids. We show that neither securin elimination nor forced cohesin cleavage is sufficient for anaphase in these conditions, suggesting that other factors contribute to cohesion maintainance in G2. We find that the protein phosphatase PP2A bound to its regulatory subunit Cdc55 plays a key role in this process, uncovering a new function for PP2ACdc55 in controlling a noncanonical pathway of chromatid cohesion removal.
The acetyltransferase activity of San stabilizes the mitotic cohesin at the centromeres in a shugoshin-independent manner
Authors: Hou Fajian , Chu Chih-Wen , Kong Xiangduo , Yokomori Kyoko , Zou Hui
Published: May 2007

Proper sister chromatid cohesion is critical for maintaining genetic stability. San is a putative acetyltransferase that is important for sister chromatid cohesion in Drosophila melanogaster, but not in budding yeast. We showed that San is critical for sister chromatid cohesion in HeLa cells, suggesting that this mechanism may be conserved in metazoans. Furthermore, although a small fraction of San interacts with the NatA complex, San appears to mediate cohesion independently. San exhibits acetyltransferase activity in vitro, and its activity is required for sister chromatid cohesion in vivo. In the absence of San, Sgo1 localizes correctly throughout the cell cycle. However, cohesin is no longer detected at the mitotic centromeres. Furthermore, San localizes to the cytoplasm in interphase cells; thus, it may not gain access to chromosomes until mitosis. Moreover, in San-depleted cells, further depletion of Plk1 rescues the cohesion along the chromosome arms, but not at the centromeres. Collectively, San may be specifically required for the maintenance of the centromeric cohesion in mitosis.
Myosin-1a powers the sliding of apical membrane along microvillar actin bundles
Authors: McConnell Russell E. , Tyska Matthew J.
Published: May 2007

Microvilli are actin-rich membrane protrusions common to a variety of epithelial cell types. Within microvilli of the enterocyte brush border (BB), myosin-1a (Myo1a) forms an ordered ensemble of bridges that link the plasma membrane to the underlying polarized actin bundle. Despite decades of investigation, the function of this unique actomyosin array has remained unclear. Here, we show that addition of ATP to isolated BBs induces a plus end–directed translation of apical membrane along microvillar actin bundles. Upon reaching microvillar tips, membrane is “shed” into solution in the form of small vesicles. Because this movement demonstrates the polarity, velocity, and nucleotide dependence expected for a Myo1a-driven process, and BBs lacking Myo1a fail to undergo membrane translation, we conclude that Myo1a powers this novel form of motility. Thus, in addition to providing a means for amplifying apical surface area, we propose that microvilli function as actomyosin contractile arrays that power the release of BB membrane vesicles into the intestinal lumen.
RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla
Authors: Rossi Simona W. , Kim Mi-Yeon , Leibbrandt Andreas , Parnell Sonia M. , Jenkinson William E. , Glanville Stephanie H. , McConnell Fiona M. , Scott Hamish S. , Penninger Josef M. , Jenkinson Eric J. , Lane Peter J.L. , Anderson Graham
Published: May 2007

Aire-expressing medullary thymic epithelial cells (mTECs) play a key role in preventing autoimmunity by expressing tissue-restricted antigens to help purge the emerging T cell receptor repertoire of self-reactive specificities. Here we demonstrate a novel role for a CD4+3− inducer cell population, previously linked to development of organized secondary lymphoid structures and maintenance of T cell memory in the functional regulation of Aire-mediated promiscuous gene expression in the thymus. CD4+3− cells are closely associated with mTECs in adult thymus, and in fetal thymus their appearance is temporally linked with the appearance of Aire+ mTECs. We show that RANKL signals from this cell promote the maturation of RANK-expressing CD80−Aire− mTEC progenitors into CD80+Aire+ mTECs, and that transplantation of RANK-deficient thymic stroma into immunodeficient hosts induces autoimmunity. Collectively, our data reveal cellular and molecular mechanisms leading to the generation of Aire+ mTECs and highlight a previously unrecognized role for CD4+3−RANKL+ inducer cells in intrathymic self-tolerance.
New Staging System for Sinonasal Inverted Papilloma in the Endoscopic Era
Authors: Cannady Steven B. , Batra Pete S. , Sautter Nathan B. , Roh Hwan‐Jung , Citardi Martin J.
Published: May 2007

Objectives: Advanced endoscopic techniques have emerged as the preferred treatment modality for sinonasal inverted papilloma (IP); however, a staging system that provides prognostic information has not yet been developed. This study aims to develop a clinically relevant staging system for IP managed with the endoscopic approach as the primary surgical modality.

Design: A systematic review of the English‐language literature (1985–2006) and a single institution's experience.

Methods: From the literature, 445 patients with IP treated by endoscopic resection were identified in 14 reports. Only patients with known IP sites and outcomes were included.

Results: Patients were categorized into three groups on the basis of recurrence rates (RR): group A (IP confined to the nasal cavity, ethmoid sinus, and medial maxillary sinus), 3.0% RR (n = 234); group B (IP with lateral maxillary sinus, sphenoid sinus, or frontal sinus involvement), 19.8% RR (n = 177); and group C (IP with extrasinus extension), 35.3% RR (n = 34). Pearson's chi‐square test showed statistically significant differences for all pair‐wise comparisons between groups (P < .05). Mean follow‐up was 39.8 months.

Conclusions: This new staging system for IP provides information about prognosis (as operationally defined by RR) for IP managed by advanced endoscopic techniques. In contrast, other staging systems for IP reflect surgeon's judgment rather than outcomes data. This new classification for IP provides important objective data for preoperative planning and patient counseling.
Environmental regulation operating at the promoter clearance step of bacterial transcription
Authors: Laishram Rakesh S. , Gowrishankar Jayaraman
Published: May 2007

In vivo transcription of the Escherichia coli argO gene, which encodes an arginine (Arg) exporter, requires the LysR-family regulator protein ArgP (previously called IciA) and is induced in the presence of Arg or its naturally occurring antimetabolite analog canavanine. Lysine (Lys) addition, on the other hand, phenocopies an argP mutation to result in the shutoff of argO expression. We now report that the ArgP dimer by itself is able to bind the argO promoter-operator region to form a binary complex, but that the formation of a ternary complex with RNA polymerase is greatly stimulated only in presence of a coeffector. Both Arg and Lys were proficient as coeffectors for ArgP-mediated recruitment of RNA polymerase to, and open complex formation at, the argO promoter, although only Arg (but not Lys) was competent to activate transcription. The two coeffectors competed for binding to ArgP, and the ternary complex that had been assembled on the argO template in the presence of Lys could be chased into a transcriptionally active state upon Arg addition. Our results support a novel mechanism of argO regulation in which Lys-bound ArgP reversibly restrains RNA polymerase at the promoter, at a step (following open complex formation) that precedes, and is common to, both abortive and productive transcription. This represents, therefore, the first example of an environmental signal regulating the final step of promoter clearance by RNA polymerase in bacterial transcription. We propose that, in E. coli cells, the ternary complex remains assembled and poised at the argO promoter at all times to respond, positively or negatively, to instantaneous changes in the ratio of intracellular Arg to Lys concentrations.
The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development
Authors: Allen Benjamin L. , Tenzen Toyoaki , McMahon Andrew P.
Published: May 2007

Hedgehog (Hh) signaling is critical for patterning and growth during mammalian embryogenesis. Transcriptional profiling identified Growth-arrest-specific 1 (Gas1) as a general negative target of Shh signaling. Data presented here define Gas1 as a novel positive component of the Shh signaling cascade. Removal of Gas1 results in a Shh dose-dependent loss of cell identities in the ventral neural tube and facial and skeletal defects, also consistent with reduced Shh signaling. In contrast, ectopic Gas1 expression results in Shh-dependent cell-autonomous promotion of ventral cell identities. These properties mirror those of Cdo, an unrelated, cell surface Shh-binding protein. We show that Gas1 and Cdo cooperate to promote Shh signaling during neural tube patterning, craniofacial, and vertebral development. Overall, these data support a new paradigm in Shh signaling whereby positively acting ligand-binding components, which are initially expressed in responding tissues to promote signaling, are then down-regulated by active Hh signaling, thereby modulating responses to ligand input.
Gas1extends the range of Hedgehog action by facilitating its signaling
Authors: Martinelli David C. , Fan Chen-Ming
Published: May 2007

Cellular signaling initiated by Hedgehog binding to Patched1 has profound importance in mammalian embryogenesis, genetic disease, and cancer. Hedgehog acts as a morphogen to specify distinctive cell fates using different concentration thresholds, but our knowledge of how the concentration gradient is interpreted into the activity gradient is incomplete. The membrane protein Growth Arrest-Specific Gene 1 (GAS1) was thought to be a negative regulator of the Hedgehog concentration gradient. Here, we report unexpected genetic evidence thatGas1positively regulates Hedgehog signaling in multiple developmental contexts, an effect particularly noticeable at regions where Hedgehog acts at low concentration. Using a combination of in vitro cell culture and in ovo electroporation assays, we demonstrate that GAS1 acts cooperatively with Patched1 for Hedgehog binding and enhances signaling activity in a cell-autonomous manner. Our data support a model in which GAS1 helps transform the Hedgehog protein gradient into the observed activity gradient. We propose thatGas1is an evolutionarily novel, vertebrate-specific Hedgehog pathway regulator.
Fusarium verticillioides GBB1, a gene encoding heterotrimeric G protein β subunit, is associated with fumonisin B1 biosynthesis and hyphal development but not with fungal virulence
Authors: SAGARAM UMA SHANKAR , SHIM WON‐BO
Published: May 2007

Fusarium verticillioides (Sacc.) Nirenberg (teleomorph Gibberella moniliformis Wineland) is a maize pathogen that causes ear rots and stalk rots. The fungus also produces a group of mycotoxins, fumonisins, on infected ears, which cause considerable health and economic concerns for humans and animals worldwide. To date, our understanding of the molecular mechanisms associated with fungal virulence and fumonisin biosynthesis in F. verticillioides is limited. In this study, GBB1, a gene encoding a putative β subunit of a heterotrimeric G protein, was disrupted and the effects on fumonisin biosynthesis and virulence were evaluated. A GBB1 deletion mutant (Δgbb1) showed no significant differences in radial growth and mycelial mass but produced significantly less fumonisin B1 (FB1) than its wild‐type progenitor. HPLC analysis showed that Δgbb1 produced less than 10 p.p.m. FB1 while the wild‐type produced over 140 p.p.m. when strains were grown on cracked corn kernels. Reduced expression of the key FB1 biosynthetic genes, FUM1 and FUM8, in Δgbb1 provides further evidence that GBB1 is involved in FB1 regulation. Stalk rot virulence, as measured by mean lesion length and by area, was not significantly different in Δgbb1 compared with the wild‐type, suggesting that GBB1 does not regulate virulence in F. verticillioides. Developmentally, hyphae of Δgbb1 do not deviate from the original axis of polarity established upon germ tube emergence in contrast to wild‐type hyphae that meander on and off axis as they grow. Complementation of Δgbb1 with GBB1 restored FB1 production and hyphal growth to wild‐type. The results of this study demonstrate that heterotrimeric G protein β subunit plays an important role in regulation of FB1 biosynthesis and hyphal growth, but not virulence in F. verticillioides.
Tobacco NIMIN2 proteins control PR gene induction through transient repression early in systemic acquired resistance
Authors: ZWICKER SYLVIA , MAST SIMONE , STOS VLATKA , PFITZNER ARTUR J. P. , PFITZNER URSULA M.
Published: May 2007

NPR1 (for Nonexpressor of PR genes; also known as NIM1) is a positive regulator of systemic acquired resistance (SAR) in Arabidopsis, which controls the induction of Pathogenesis‐Related (PR) genes by salicylic acid (SA). NPR1 interacts with members of two protein families, TGA transcription factors and NIMIN (for NIM1‐interacting) proteins. In Arabidopsis, NIMIN1, NIMIN2 and NIMIN3 constitute a small gene family of structurally related, yet distinct members. To unravel the biological significance of NIMIN interaction with NPR1, we searched a tobacco yeast two‐hybrid cDNA library for NPR1‐ and NIMIN2‐binding proteins. One NPR1 cDNA clone and three clones encoding NIMIN proteins were isolated. Although clearly similar to At NPR1, Nt NPR1 does not interact with At NIMIN3. Furthermore, all Nt NIMIN proteins identified are structurally related to At NIMIN2, thus forming a small NIMIN2 subfamily in tobacco. cDNA clones encoding At NIMIN1 or At NIMIN3 homologues were not identified. The function of NIMIN2 proteins was studied by expression of Nt NIMIN2a chimeric genes in tobacco. While constitutive NIMIN2a over‐expression delayed PR‐1 protein induction, suppression of NIMIN2 transcripts enhanced the accumulation of PR‐1 proteins. In both cases, the effects of altered NIMIN2 transcript levels became evident foremost early in SAR. Notably, Nt NIMIN2 gene expression is elevated prior to the induction of the PR‐1a gene. Together, the data suggest that, in tobacco, NIMIN2 proteins control PR‐1 gene expression, and that NIMIN2‐mediated control is exerted through transient PR‐1 repression before SAR has fully developed. Furthermore, although sharing conserved domains and functions, tobacco and Arabidopsis NPR1 and NIMIN proteins are clearly distinct.
Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin
Authors: Forrest Caroline M. , Mackay Gillian M. , Stoy Nicholas , Stone Trevor W. , Darlington L. Gail
Published: May 2007

What is already known about this subject

• There is good evidence that oxidative stress, associated with the generation of free radicals, is a major contributor to joint damage in rheumatoid arthritis.

• It is also well established that melatonin is one of the most powerful, endogenous free radical scavengers, and it is very safe for human use.

• We have therefore examined whether melatonin might be a useful adjunctive compound with which to treat arthritis.

What this study adds

• Once‐nightly administration of melatonin increases concentrations of some inflammatory markers, but patients experience no significant improvement in symptoms and no changes of proinflammatory cytokine concentrations.

• Melatonin is an effective antioxidant, but because it is either not sufficiently effective, or it has some proinflammatory activity, it is not likely to prove beneficial in patients.

Aim

Since melatonin is antioxidant and has some anti‐inflammatory actions, we have tested it as adjunctive treatment in patients with rheumatoid arthritis, to determine whether it can improve patients' symptoms.

Methods

A total of 75 patients were allocated randomly to receive melatonin 10 mg at night in addition to ongoing medication, or a placebo of identical appearance. Monthly blood samples were taken and disease severity assessed over 6 months, plasma being analysed for inflammatory indicators [C‐reactive protein, erythrocyte sedimentation rate (ESR), neopterin], proinflammatory cytokines [interleukin (IL)‐1β, IL‐6, tumour necrosis factor (TNF)‐α], lipid peroxidation products and the kynurenine pathway metabolites of tryptophan.

Results

An increase of ESR (two‐way anova F(1,127) = 5.24, P = 0.024) and neopterin concentrations (F(1,136) = 4.64, P = 0.033) was observed in treated patients compared with controls, reflected also in a significant trend for both to decline in placebo‐treated patients (P = 0.022), but not the melatonin‐treated group. Peroxidation products showed a significant trend to decrease in placebo‐ but not melatonin‐treated patients. These results suggest a proinflammatory action, but there were no significant effects of melatonin treatment on clinical assessments of patient symptoms or the concentrations of three proinflammatory cytokines, IL‐1β, IL‐6 and TNF‐α. Melatonin significantly increased plasma kynurenine concentrations (F(1,124) = 4.24, P = 0.041), again suggesting proinflammatory activity.

Conclusion

A daily dose of 10 mg melatonin shows a slowly developing antioxidant profile in patients with arthritis and increases the concentrations of some inflammatory indicators, but these effects are not associated with any change of proinflammatory cytokine concentrations or clinical symptoms.
Cardiovascular toxicity due to metoprolol poisoning in a patient with coronary artery disease
Authors: Unverir Pinar , Topacoglu Hakan , Bozkurt Selim , Kaynak Firat
Published: May 2007

What is already known about this subject

• Poisoning with β‐blockers can result in cardiovascular and central nervous system effects.

• Although much has been reported about metoprolol poisoning's cardiovascular complications, little attention has been paid to acute myocardial infarction (AMI) accompanied by elevated cardiac markers.

What this study adds

• This case report demonstrates for the first time an association of metoprolol poisoning with acute myocardial infarction in a patient with a previous history of coronary artery disease.

• Metoprolol poisoning can induce acute myocardial reinfarction in patients with prior AMI or known coronary artery disease.

• In other words, metoprolol overdose can trigger myocardial ischaemia and dysrhythmia in patients with coronary artery disease.

Aim

To demonstrate that β‐blocker poisoning results in cardiovascular and central nervous system findings.

Methods

A 56‐year‐old woman was brought to the emergency department, having been admitted to hospital with 1500 mg of metoprolol ingestion 2 h previously. She had undergone percutanerous transluminal coronary angioplasty and stenting because of acute myocardial infarction (AMI). Her ECG revealed ST segment elevation in inferior leads and junctional dysrhythmia. Her clinical symptoms relieved after pacing and hospitalization and she was discharged.

Results

Our patient demonstrated findings of AMI with hypotension and bradycardia that appeared to result from metoprolol poisoning. Although one patient has been reported to have AMI associated with metoprolol poisoning, our patient is unique with her ECG changes and elevated cardiac markers: this is the first time that AMI characterized by elevated cardiac markers associated with metoprolol toxicity has been reported.

Conclusions

Emergency physicians should bear in mind that AMI can accompany the presentation of metoprolol overdose in those with coronary artery disease. In other words, metoprolol poisoning can trigger myocardial ischaemia and dysrhythmia in those with coronary artery disease.
Daily ocean monitoring since the 1860s shows record warming of northern European seas
Authors: MACKENZIE BRIAN R. , SCHIEDEK DORIS
Published: May 2007

Ocean temperatures in most parts of the world are increasing and are expected to continue to rise during the 21st century. A major challenge to ecologists and marine resource managers is to understand and predict how these global changes will affect species and ecosystems at local scales where temperature more directly affects biological responses and species interactions. Here, we investigate historical variability in regional sea surface temperature in two large heavily exploited marine ecosystems and compare these variations with expected rates of temperature change for the 21st century. We use four of the world's longest calibrated daily time series to show that trends in surface temperatures in the North and Baltic Seas now exceed those at any time since instrumented measurements began in 1861 and 1880. Temperatures in summer since 1985 have increased at nearly triple the global warming rate, which is expected to occur during the 21st century and summer temperatures have risen two to five times faster than those in other seasons. These warm temperatures and rates of change are due partly to an increase in the frequency of extremely warm years. The recent warming event is exceeding the ability of local species to adapt and is consequently leading to major changes in the structure, function and services of these ecosystems.
A geographic mosaic of passive dispersal: population structure in the endemic Hawaiian amber snail Succinea caduca (Mighels, 1845)
Authors: HOLLAND BRENDEN S. , COWIE ROBERT H.
Published: May 2007

We used 276 cytochrome c oxidase subunit I (COI, 645 bp) and a subset of 84 16S large ribosomal subunit (16S, 451 bp) sequences to evaluate geographic patterns of genetic variation in 24 populations of the endemic Hawaiian land snail Succinea caduca spanning its range on six islands. Haplotype networks, gene tree topologies, pairwise molecular divergence and FST matrices suggest substantial geographic genetic structuring and complex dispersal patterns. Low nucleotide diversity and low pairwise molecular divergence values within populations coupled with higher between population values suggest multiple founder events. High overall haplotype diversity suggests diversification involving rare interpopulation dispersal, fragmentation by historical lava flows and variation in habitat structure. Within‐island rather than between‐island population comparisons accounted for the majority of molecular variance. Although 98% of 153 COI haplotypes were private by population, a Mantel test showed no evidence for isolation by distance. Mismatch distributions and population partitioning patterns suggest that genetic fragmentation has been driven by punctuated, passive dispersal of groups of closely related haplotypes that subsequently expanded and persisted in isolation for long periods (average > 2 million years ago), and that Pleistocene island connections may have been important in enhancing gene flow. Historical availability of mesic coastal habitat, together with effective dispersal may explain the long‐term persistence and unusual multi‐island distribution of this species, contrasting with the single‐island endemism of much of the Hawaiian biota.
Cardiolipin promotes polar localization of osmosensory transporter ProP in Escherichia coli
Authors: Romantsov Tatyana , Helbig Stephan , Culham Doreen E. , Gill Chad , Stalker Leanne , Wood Janet M.
Published: May 2007

The osmolality required to activate osmosensory transporter ProP and the proportion of cardiolipin (CL) among the phospholipids of Escherichia coli rise with growth medium osmolality. Most CL synthesis has been attributed to the cls gene product. Transcription of cls increased with osmolality. The proportion of CL was low and osmolality‐independent in cls– bacteria. It increased more dramatically on the transition to stationary phase in cls– than cls+ bacteria. Thus, Cls is responsible for osmoregulated CL synthesis and other enzymes may contribute to CL accumulation during stationary phase. The proportion of phosphatidylglycerol (PG) was elevated and it increased with medium osmolality in cls– bacteria. A cls defect impaired growth of E. coli on solid and in liquid media at low and, more strongly, at high osmolality. Bacteria cultured at high osmolality without osmoprotectant were shorter and rounder than those cultured at low osmolality or with glycine betaine. Fluorescence microscopy showed that CL and ProP colocalize at the poles and near the septa of dividing E. coli cells. The polar localization of ProP was independent of its expression level but correlated with the proportion and polar localization of CL. Association with CL (and not PG) may be required for polar ProP localization.
Differential signal transduction via TrmB, a sugar sensing transcriptional repressor of Pyrococcus furiosus
Authors: Lee Sung‐Jae , Surma Melanie , Seitz Sabine , Hausner Winfried , Thomm Michael , Boos Winfried
Published: May 2007

TrmB is a transcriptional repressor of the hyperthermophilic archaeon Pyrococcus furiosus serving at least two operons. TrmB represses genes encoding an ABC transporter for trehalose and maltose (the TM system) with trehalose and maltose as inducers. TrmB also represses genes encoding another ABC transporter for maltodextrins (the MD system) with maltotriose and sucrose as inducers. Here we report that glucose which was also bound by TrmB acted as a corepressor (causing stronger repression) for both the TM and the MD system. Binding of glucose by TrmB was increased in the presence of TM promoter DNA. Maltose which acted as inducer for the TM system acted as a corepressor for the MD system intensifying repression. We propose that the differential conformational changes of TrmB in response to binding the different sugars governs the ability of TrmB to interact with the promoter region and represents a simple mechanism for selecting the usage of one carbon source over the other, reminiscent of catabolite repression in bacteria.
Slow graft function after pediatric renal transplantation from volunteer live donors
Authors: Basiri A. , Otukesh H. , Hosseini‐Moghaddam S. M. , Ghazi‐Moghaddam B. , Haidari M. , Sharifian M. , Razzaghi Z.
Published: May 2007

Abstract:  Slow graft function (SGF) may occur during the early post‐transplant period. In this paper, we present our findings regarding SGF after pediatric renal transplantation and its predictive variables. From 1985 to 2004, a total of 300 pediatric renal transplants were performed at our institution. A total of 10 cases with SGF and 50 controls that were operated by the same surgeons were enrolled in this study. The mean age of the recipients and donors was 11.4 (3–15 yr) and 28.05 yr (20–50 yr), respectively. All kidneys were retrieved from living donors. We compared patients with SGF with controls regarding four independent variables: age difference between donors and recipients, serum hemoglobin difference between donors and recipients, mean blood pressure (systolic blood pressure + 2 [diastolic blood pressure]/3) difference between donors and recipients, and weight difference between donors and recipients. The mean age of recipients was 10.5 ± 4.1 in SGF group and 11.6 ± 2.5 in control group (p = 0.4). The differences between donors and recipients regarding weight and mean blood pressure in subjects with SGF were not higher than other patients (42 kg vs. 37.4 kg, p = 0.4; −3 mmHg vs. −4.1 mmHg, p = 0.8). The mean hemoglobin difference between donors and recipients was 6.3 ± 2.1 g/dL in SGF group and 6.7 ± 2.3 g/dL in control group (p = 0.6). The differences between donors and recipients regarding age, weight, mean blood pressure and serum hemoglobin level are not predictive variables for SGF.
Early steroid withdrawal in pediatric renal transplant on newer immunosuppressive drugs
Authors: Delucchi Angela , Valenzuela Marcela , Ferrario Mario , Lillo Ana Maria , Guerrero J. Luis , Rodriguez Eugenio , Cano Francisco , Cavada Gabriel , Godoy Jorge , Rodriguez Jorge , Gonzalez C. Gloria , Buckel Erwin , Contreras Luis
Published: May 2007

Abstract: Steroids have been a cornerstone in renal transplant immunosuppression. New immunosuppressive drugs have led to protocols using early steroid withdrawal or complete avoidance. A prospective protocol in 23 pediatric renal transplant (ages 2–14 yr) who received decreasing steroid doses stopping at day 7 post‐Tx, FK, and MMF were compared with a CsA, AZT, historically matched steroid‐based control group. Basiliximab was used in two doses. Anthropometric, biochemical variables, AR rates, and CMV infection were evaluated and compared using Student’s t‐test and regression analysis. A better growth pattern was seen in steroid withdrawal group. GFR rate and serum glucose were similar in both groups. Total serum cholesterol levels were significantly lower in steroid withdrawal group. The incidence of AR at 12 months was 4.3% in steroid withdrawal group vs. 8.6% in steroid‐based group (p = ns). No difference in CMV infection was observed. Hemoglobin levels were low during the first months in both groups; reached normal values after six months. SBP became higher at 12 months in steroid‐based group. Patient and graft survival was 98% in both groups at one‐yr post‐transplant. Early steroid withdrawal was efficacious, safe, and did not increase risk of rejection, preserving optimal growth, renal function, and reducing cardiovascular risk factors.
Adenovirus‐associated hemorrhagic cystitis in a pediatric renal transplant recipient
Authors: Keswani Mahima , Moudgil Asha
Published: May 2007

Abstract:  Adenovirus infection has been associated with the development of hemorrhagic cystitis in bone marrow transplant recipients. However, limited information exists regarding adenovirus‐associated hemorrhagic cystitis in solid organ transplantation, especially in renal transplant recipients. In most cases, the disease is self‐limited. However, some patients may have a protracted course. Although no particular antiviral agent has been identified as the gold standard of therapy, cidofovir has been found to be effective in a number of bone marrow transplant recipients. In this study, we report a five‐yr‐old boy who presented with adenovirus‐associated hemorrhagic cystitis 68 days after renal transplant and was successfully treated with reduction of immunosuppression and an intermediate dose of intravenous cidofovir.
Gravistimulation leads to asymmetry of both auxin and gibberellin levels in barley pulvini
Authors: Wolbang Carla M. , Davies Noel W. , Taylor Scott A. , Ross John J.
Published: May 2007

The auxin indole‐3‐acetic acid (IAA) is known to promote the biosynthesis of active gibberellins (GAs) in barley (Hordeum vulgare). We therefore investigated the possibility that this interaction might contribute to the gravitropic response of barley leaf sheath pulvini. Barley plants at the inflorescence stage were gravistimulated for varying times, and the pulvini were then separated into upper and lower halves for quantification of IAA and GAs by GC‐MS. Consistent with the Cholodny–Went theory, the lower portion contained more IAA than did the upper portion. This difference was detected as early as 2.5 h after the start of gravistimulation, and bending was also observed at this stage. At later time points tested (6 h and 24 h), but not at 2.5 h or 3 h, the higher auxin content of the lower half was associated with a higher level of GA1, the main bioactive GA in barley. Consistent with that result, the expression of Hv3ox2, which encodes a key enzyme for the conversion of GA20 to GA1, was higher in the lower side than in the upper, after 6 h. It is suggested that in gravistimulated leaf sheath pulvini, auxin accumulates in the lower side, leading to a higher level of GA1, which contributes to the bending response. Further evidence that GAs play a role in the gravitropic response was obtained from GA‐related mutants, including the elongated sln1c mutant, in which GA signalling is constitutive. Pulvinar bending in the sln1c mutant was greater than in the wild‐type. This result indicates that in the lower side of the gravistimulated pulvinus, the relatively high level of bioactive GA facilitates, but does not mediate, the bending response.