bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toward the automated generation of genome-scale metabolic networks in the SEED
Authors: DeJongh Matthew , Formsma Kevin , Boillot Paul , Gould John , Rycenga Matthew , Best Aaron 
Published: April 2007

Abstract

Background
Current methods for the automated generation of genome-scale metabolic networks focus on genome annotation and preliminary biochemical reaction network assembly, but do not adequately address the process of identifying and filling gaps in the reaction network, and verifying that the network is suitable for systems level analysis. Thus, current methods are only sufficient for generating draft-quality networks, and refinement of the reaction network is still largely a manual, labor-intensive process.

Results
We have developed a method for generating genome-scale metabolic networks that produces substantially complete reaction networks, suitable for systems level analysis. Our method partitions the reaction space of central and intermediary metabolism into discrete, interconnected components that can be assembled and verified in isolation from each other, and then integrated and verified at the level of their interconnectivity. We have developed a database of components that are common across organisms, and have created tools for automatically assembling appropriate components for a particular organism based on the metabolic pathways encoded in the organism's genome. This focuses manual efforts on that portion of an organism's metabolism that is not yet represented in the database. We have demonstrated the efficacy of our method by reverse-engineering and automatically regenerating the reaction network from a published genome-scale metabolic model for Staphylococcus aureus. Additionally, we have verified that our method capitalizes on the database of common reaction network components created for S. aureus, by using these components to generate substantially complete reconstructions of the reaction networks from three other published metabolic models (Escherichia coli, Helicobacter pylori, and Lactococcus lactis). We have implemented our tools and database within the SEED, an open-source software environment for comparative genome annotation and analysis.

Conclusion
Our method sets the stage for the automated generation of substantially complete metabolic networks for over 400 complete genome sequences currently in the SEED. With each genome that is processed using our tools, the database of common components grows to cover more of the diversity of metabolic pathways. This increases the likelihood that components of reaction networks for subsequently processed genomes can be retrieved from the database, rather than assembled and verified manually.
Large-scale RNAi screens identify novel genes that interact with the C. elegans retinoblastoma pathway as well as splicing-related components with synMuv B activity
Authors: Ceron Julian , Rual Jean-François , Chandra Abha , Dupuy Denis , Vidal Marc , van den Heuvel Sander 
Published: April 2007

AbstractBackgroundTheretinoblastomatumor suppressor (Rb) acts in a conserved pathway that is deregulated in most human cancers. Inactivation of the single Rb-related gene inCaenorhabditis elegans, lin-35, has only limited effects on viability and fertility, yet causes changes in cell-fate and cell-cycle regulation when combined with inactivation of specific other genes. For instance,lin-35Rb is a synthetic multivulva (synMuv) class B gene, which causes a multivulva phenotype when inactivated simultaneously with a class A or C synMuv gene.ResultsWe used the ORFeome RNAi library to identify genes that interact withC. elegans lin-35Rb and identified 57 genes that showed synthetic or enhanced RNAi phenotypes inlin-35mutants as compared torrf-3anderi-1RNAi hypersensitive mutants. Based on characterizations of a deletion allele, the syntheticlin-35interactorzfp-2was found to suppress RNAi and to cooperate withlin-35Rb in somatic gonad development. Interestingly, ten splicing-related genes were found to function similar tolin-35Rb, as synMuv B genes that prevent inappropriate vulval induction. Partial inactivation of specific spliceosome components revealed further similarities withlin-35Rb functions in cell-cycle control, transgene expression and restricted expression of germline granules.ConclusionWe identified an extensive series of candidatelin-35Rb interacting genes and validatedzfp-2as a novellin-35synthetic lethal gene. In addition, we observed a novel role for a subset of splicing components inlin-35Rb-controlled processes. Our data support novel hypotheses about possibilities for anti-cancer therapies and multilevel regulation of gene expression.
Coordinate regulation of DNA methyltransferase expression during oogenesis
Authors: Lucifero Diana , La Salle Sophie , Bourc'his Déborah , Martel Josée , Bestor Timothy H , Trasler Jacquetta M 
Published: April 2007

Abstract

Background
Normal mammalian development requires the action of DNA methyltransferases (DNMTs) for the establishment and maintenance of DNA methylation within repeat elements and imprinted genes. Here we report the expression dynamics of Dnmt3a and Dnmt3b, as well as a regulator of DNA methylation, Dnmt3L, in isolated female germ cells.

Results
Our results indicate that these enzymes are coordinately regulated and that their expression peaks during the stage of postnatal oocyte development when maternal methylation imprints are established. We find that Dnmt3a, Dnmt3b, Dnmt3L and Dnmt1o transcript accumulation is related to oocyte diameter. Furthermore, DNMT3L deficient 15 dpp oocytes have aberrantly methylated Snrpn, Peg3 and Igf2r DMRs, but normal IAP and LINE-1 methylation levels, thereby highlighting a male germ cell specific role for DNMT3L in the establishment of DNA methylation at repeat elements. Finally, real-time RT-PCR analysis indicates that the depletion of either DNMT3L or DNMT1o in growing oocytes results in the increased expression of the de novo methyltransferase Dnmt3b, suggesting a potential compensation mechanism by this enzyme for the loss of one of the other DNA methyltransferases.

Conclusion
Together these results provide a better understanding of the developmental regulation of Dnmt3a, Dnmt3b and Dnmt3L at the time of de novo methylation during oogenesis and demonstrate that the involvement of DNMT3L in retrotransposon silencing is restricted to the male germ line. This in turn suggests the existence of other factors in the oocyte that direct DNA methylation to transposons.
Development of the mammalian liver and ventral pancreas is dependent on GATA4
Authors: Watt Alistair J , Zhao Roong , Li Jixuan , Duncan Stephen A 
Published: April 2007

Abstract

Background
In the mouse, the parenchyma of both the liver and ventral pancreas is specified from adjacent domains of the ventral foregut endoderm. GATA4, a zinc finger transcription factor, is strongly expressed in these endodermal domains and molecular analyses have implicated GATA4 in potentiating liver gene expression during the onset of hepatogenesis. We therefore hypothesized that GATA4 has an integral role in controlling the early stages of pancreatic and liver development.

Results
To determine whether GATA4 contributes to development of either the pancreas or liver we characterized the formation of pancreatic and hepatic tissues in embryos derived from Gata4
-/- ES cells by tetraploid embryo complementation. In the absence of GATA4, development of the liver and ventral pancreas was disrupted. At embryonic day (E) 9.5, the liver bud failed to expand although, contrary to expectations, the hepatic endoderm was able to form a pseudo-stratified epithelial liver bud that expressed hepatic genes. Moreover, as we had shown previously, the embryos lacked septum transversum mesenchyme suggesting that liver defects may be cell non-autonomous. Analyses of pancreatic development revealed a complete absence of the ventral but not the dorsal pancreas in Gata4
-/- embryos. Moreover, Gata6
-/- embryos displayed a similar, although less dramatic phenotype, suggesting a critical role for multiple GATA factors at the earliest stages of ventral pancreas development.

Conclusion
This study defines integral roles for GATA factors in controlling early development of the mammalian liver and pancreas.
Rybp, a polycomb complex-associated protein, is required for mouse eye development
Authors: Pirity Melinda K , Wang Wei-Lin , Wolf Louise V , Tamm Ernst R , Schreiber-Agus Nicole , Cvekl Ales 
Published: April 2007

Abstract

Background
Rybp (Ring1 and YY1 binding protein) is a zinc finger protein which interacts with the members of the mammalian polycomb complexes. Previously we have shown that Rybp is critical for early embryogenesis and that haploinsufficiency of Rybp in a subset of embryos causes failure of neural tube closure. Here we investigated the requirement for Rybp in ocular development using four in vivo mouse models which resulted in either the ablation or overexpression of Rybp.

Results
Our results demonstrate that loss of a single Rybp allele in conventional knockout mice often resulted in retinal coloboma, an incomplete closure of the optic fissure, characterized by perturbed localization of Pax6 but not of Pax2. In addition, about one half of Rybp-/- <-> Rybp+/+ chimeric embryos also developed retinal colobomas and malformed lenses. Tissue-specific transgenic overexpression of Rybp in the lens resulted in abnormal fiber cell differentiation and severe lens opacification with increased levels of AP-2α and Sox2, and reduced levels of βA4-crystallin gene expression. Ubiquitous transgenic overexpression of Rybp in the entire eye caused abnormal retinal folds, corneal neovascularization, and lens opacification. Additional changes included defects in anterior eye development.

Conclusion
These studies establish Rybp as a novel gene that has been associated with coloboma. Other genes linked to coloboma encode various classes of transcription factors such as BCOR, CBP, Chx10, Pax2, Pax6, Six3, Ski, Vax1 and Vax2. We propose that the multiple functions for Rybp in regulating mouse retinal and lens development are mediated by genetic, epigenetic and physical interactions between these genes and proteins.
Evolutionary proteomics identifies amino acids essential for ligand-binding of the cytokinin receptor CHASE domain
Authors: Heyl Alexander , Wulfetange Klaas , Pils Birgit , Nielsen Nicola , Romanov Georgy A , Schmülling Thomas 
Published: April 2007

Abstract

Background
In plants the hormone cytokinin is perceived by members of a small cytokinin receptor family, which are hybrid sensor histidine kinases. While the immediate downstream signaling pathway is well characterized, the domain of the receptor responsible for ligand binding and which residues are involved in this process has not been determined experimentally.

Results
Using a live cell hormone-binding assay, we show that cytokinin is bound by a receptor domain predicted to be extracellular, the so called CHASE (cyclases, histidine kinase associated sensory extracellular) domain. The CHASE domain occurs not only in plant cytokinin receptors but also in numerous orphan receptors in lower eukaryotes and bacteria. Taking advantage of this fact, we used an evolutionary proteomics approach to identify amino acids important for cytokinin binding by looking for residues conserved in cytokinin receptors, but not in other receptors. By comparing differences in evolutionary rates, we predicted five amino acids within the plant CHASE domains to be crucial for cytokinin binding. Mutagenesis of the predicted sites and subsequent binding assays confirmed the relevance of four of the selected amino acids, showing the biological significance of site-specific evolutionary rate differences.

Conclusion
This work demonstrates the use of a bioinformatic analysis to mine the huge set of genomic data from different taxa in order to generate a testable hypothesis. We verified the hypothesis experimentally and identified four amino acids which are to a different degree required for ligand-binding of a plant hormone receptor.
DNA repair gene XRCC1 polymorphisms and bladder cancer risk
Authors: Sak Sei Chung , Barrett Jennifer H , Paul Alan B , Bishop D Timothy , Kiltie Anne E 
Published: April 2007

AbstractBackgroundCigarette smoking and chemical occupational exposure are the main known risk factors for bladder transitional cell carcinoma (TCC). Oxidative DNA damage induced by carcinogens present in these exposures requires accurate base excision repair (BER). The XRCC1 protein plays a crucial role in BER by acting as a scaffold for other BER enzymes. Variants in the XRCC1 gene might alter protein structure or function or create alternatively spliced proteins which may influence BER efficiency and hence affect individual susceptibility to bladder cancer. Recent epidemiological studies have shown inconsistent associations between these polymorphisms and bladder cancer. To clarify the situation, we conducted a comprehensive analysis of 14 XRCC1 polymorphisms in a case-control study involving more than 1100 subjects.ResultsWe found no evidence of an association between any of the 14 XRCC1 polymorphisms and bladder cancer risk. However, we found carriage of the variant Arg280His allele to be marginally associated with increased bladder cancer risk compared to the wild-type genotype (adjusted odds ratio [95% confidence interval], 1.50 [0.98–2.28], p = 0.06). The association was stronger for current smokers such that individuals carrying the variant 280His allele had a two to three-fold increased risk of bladder cancer compared to those carrying the wildtype genotype (p = 0.09). However, the evidence for gene-environment interaction was not statistically significant (p = 0.45).ConclusionWe provide no evidence of an association between polymorphisms in XRCC1 and bladder cancer risk, although our study had only limited power to detect the association for low frequency variants, such as Arg280His.
Phylogenetic and functional analysis of the Cation Diffusion Facilitator (CDF) family: improved signature and prediction of substrate specificity
Authors: Montanini Barbara , Blaudez Damien , Jeandroz Sylvain , Sanders Dale , Chalot Michel 
Published: April 2007

Abstract

Background
The Cation Diffusion Facilitator (CDF) family is a ubiquitous family of heavy metal transporters. Much interest in this family has focused on implications for human health and bioremediation. In this work a broad phylogenetic study has been undertaken which, considered in the context of the functional characteristics of some fully characterised CDF transporters, has aimed at identifying molecular determinants of substrate selectivity and at suggesting metal specificity for newly identified CDF transporters.

Results
Representative CDF members from all three kingdoms of life (Archaea, Eubacteria, Eukaryotes) were retrieved from genomic databases. Protein sequence alignment has allowed detection of a modified signature that can be used to identify new hypothetical CDF members. Phylogenetic reconstruction has classified the majority of CDF family members into three groups, each containing characterised members that share the same specificity towards the principally-transported metal, i.e. Zn, Fe/Zn or Mn. The metal selectivity of newly identified CDF transporters can be inferred by their position in one of these groups. The function of some conserved amino acids was assessed by site-directed mutagenesis in the poplar Zn2+ transporter PtdMTP1 and compared with similar experiments performed in prokaryotic members. An essential structural role can be assigned to a widely conserved glycine residue, while aspartate and histidine residues, highly conserved in putative transmembrane domains, might be involved in metal transport. The potential role of group-conserved amino acid residues in metal specificity is discussed.

Conclusion
In the present study phylogenetic and functional analyses have allowed the identification of three major substrate-specific CDF groups. The metal selectivity of newly identified CDF transporters can be inferred by their position in one of these groups. The modified signature sequence proposed in this work can be used to identify new hypothetical CDF members.
Bactericidal action of positive and negative ions in air
Authors: Fletcher Louise A , Gaunt Lindsey F , Beggs Clive B , Shepherd Simon J , Sleigh P Andrew , Noakes Catherine J , Kerr Kevin G 
Published: April 2007

Abstract

Background
In recent years there has been renewed interest in the use of air ionisers to control of the spread of airborne infection. One characteristic of air ions which has been widely reported is their apparent biocidal action. However, whilst the body of evidence suggests a biocidal effect in the presence of air ions the physical and biological mechanisms involved remain unclear. In particular, it is not clear which of several possible mechanisms of electrical origin (i.e. the action of the ions, the production of ozone, or the action of the electric field) are responsible for cell death. A study was therefore undertaken to clarify this issue and to determine the physical mechanisms associated with microbial cell death.

Results
In the study seven bacterial species (Staphylococcus aureus, Mycobacterium parafortuitum, Pseudomonas aeruginosa, Acinetobacter baumanii, Burkholderia cenocepacia, Bacillus subtilis and Serratia marcescens) were exposed to both positive and negative ions in the presence of air. In order to distinguish between effects arising from: (i) the action of the air ions; (ii) the action of the electric field, and (iii) the action of ozone, two interventions were made. The first intervention involved placing a thin mica sheet between the ionisation source and the bacteria, directly over the agar plates. This intervention, while leaving the electric field unaltered, prevented the air ions from reaching the microbial samples. In addition, the mica plate prevented ozone produced from reaching the bacteria. The second intervention involved placing an earthed wire mesh directly above the agar plates. This prevented both the electric field and the air ions from impacting on the bacteria, while allowing any ozone present to reach the agar plate. With the exception of Mycobacterium parafortuitum, the principal cause of cell death amongst the bacteria studied was exposure to ozone, with electroporation playing a secondary role. However in the case of Mycobacterium parafortuitum, electroporation resulting from exposure to the electric field appears to have been the principal cause of cell inactivation.

Conclusion
The results of the study suggest that the bactericidal action attributed to negative air ions by previous researchers may have been overestimated.
IFNG +874T/A polymorphism is not associated with American tegumentary leishmaniasis susceptibility but can influence Leishmaniainduced IFN-γ production
Authors: Matos Guilherme Inocêncio , Covas Claudia de J Fernandes , Bittar Rita de Cássia , Gomes-Silva Adriano , Marques Fabiana , Maniero Viviane C , Amato Valdir S , Oliveira-Neto Manoel P , Mattos Marise da Silva , Pirmez Claude , Sampaio Elizabeth P , Moraes Milton O , Da-Cruz Alda Maria 
Published: April 2007

AbstractBackgroundInterferon-gamma is a key cytokine in the protective responses against intracellular pathogens. A single nucleotide polymorphism (SNP) located in the first intron of the human IFN-γ gene can putatively influence the secretion of cytokine with an impact on infection outcome as demonstrated for tuberculosis and other complex diseases. Our aim was to investigate the putative association of IFNG+874T/A SNP with American tegumentary leishmaniasis (ATL) and also the influence of this SNP in the secretion of IFN-γin vitro.MethodsBrazilian ATL patients (78 cutaneous, CL, and 58 mucosal leishmaniasis, ML) and 609 healthy volunteers were evaluated. The genotype of +874 region in the IFN-γ gene was carried out by Amplification Refractory Mutational System (ARMS-PCR).Leishmania-induced IFN-γ production on peripheral blood mononuclear cell (PBMC) culture supernatants was assessed by ELISA.ResultsThere are no differences between +874T/A SNP frequency in cases and controls or in ML versus CL patients. Cutaneous leishmaniasis cases exhibiting AA genotype produced lower levels of IFN-γ than TA/TT genotypes. In mucosal cases, high and low IFN-γ producers were clearly demonstrated but no differences in the cytokine production was observed among the IFNG +874T or A carriers.ConclusionOur results suggest that +874T/A polymorphism was not associated with either susceptibility or severity to leishmaniasis. Despite this, IFNG +874T/A SNP could be involved in the pathogenesis of leishmaniasis by influencing the amount of cytokine released by CL patients, although it could not prevent disease development. On the other hand, it is possible that in ML cases, other potential polymorphic regulatory genes such as TNF-α and IL-10 are also involved thus interfering with IFN-γ secretion.
Genetic mapping of a new heart rate QTL on chromosome 8 of spontaneously hypertensive rats
Authors: Silva Gustavo JJ , Pereira Alexandre C , Krieger Eduardo M , Krieger José E 
Published: April 2007

Abstract

Background
Tachycardia is commonly observed in hypertensive patients, predominantly mediated by regulatory mechanisms integrated within the autonomic nervous system. The genetic loci and genes associated with increased heart rate in hypertension, however, have not yet been identified.

Methods
An F2 intercross of Spontaneously Hypertensive Rats (SHR) × Brown Norway (BN) linkage analysis of quantitative trait loci mapping was utilized to identify candidate genes associated with an increased heart rate in arterial hypertension.

Results
Basal heart rate in SHR was higher compared to that of normotensive BN rats (365 ± 3 vs. 314 ± 6 bpm, p < 0.05 for SHR and BN, respectively). A total genome scan identified one quantitative trait locus in a 6.78 cM interval on rat chromosome 8 (8q22–q24) that was responsible for elevated heart rate. This interval contained 241 genes, of which 65 are known genes.

Conclusion
Our data suggest that an influential genetic region located on the rat chromosome 8 contributes to the regulation of heart rate. Candidate genes that have previously been associated with tachycardia and/or hypertension were found within this QTL, strengthening our hypothesis that these genes are, potentially, associated with the increase in heart rate in a hypertension rat model.
Analysis of sequence variations in the suppressor of cytokine signaling (SOCS)-3gene in extremely obese children and adolescents
Authors: Hölter Katja , Wermter Anne-Kathrin , Scherag André , Siegfried Wolfgang , Goldschmidt Hanspeter , Hebebrand Johannes , Hinney Anke 
Published: April 2007

Abstract

Background
The suppressor of cytokine signaling (SOCS)-3 is a negative feedback regulator of cytokine signaling and also influences leptin signaling. We investigated association of variations in the coding sequence and promoter region of SOCS3 with extreme obesity in German children and adolescents.

Methods
An initial screen for sequence variations in 181 extremely obese children and adolescents and 188 healthy underweight adults revealed two previously reported single nucleotide polymorphisms (SNPs) in the SOCS3 5' region: -1044 C>A (numbering refers to bases upstream of ATG in exon 2) within a predicted STAT3 binding element and -920 C>A (rs12953258, for numbering, see above).

Results
We did not detect significant differences in allele or genotype frequencies for any of these SNPs between the analysed study groups (all nominal p > 0.2). In addition, we performed a pedigree transmission disequilibrium test (PDT) for the SNP -1044 C>A in families comprising 703 obese children and adolescents, 281 of their obese siblings and both biological parents. The PDT revealed no transmission disequilibrium (nominal p > 0.05).

Conclusion
In conclusion, our data do not suggest evidence for a major role of the respective SNPs in SOCS3 in the pathogenesis of extreme obesity in our study groups.